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psychiatry directory


“No Feelings for Me, No Feelings for You: A Meta-analysis on Alexithymia and Empathy in Psychopathy”, Burghart & Mier 2022

“No feelings for me, no feelings for you: A meta-analysis on alexithymia and empathy in psychopathy”⁠, Matthias Burghart, Daniela Mier (2022-08):

  • Psychopathy is associated with empathy deficits as well as with alexithymia⁠.
  • The strength of association varies between specific psychopathy factors.
  • Gender moderates the association between psychopathy and alexithymia.

Psychopathy is characterized by extensive emotional impairments. However, the current empirical literature on empathy and alexithymia in psychopathy provides heterogeneous results.

Random-effects models were performed on studies examining the association between psychopathy and the Interpersonal Reactivity Index as well as the Toronto Alexithymia Scale-20. In total, 72 articles providing 716 effect sizes and representing 15,016 participants were included in the analyses. Furthermore, differences among psychopathy factors and the role of potential moderators were assessed.

We found negative relationships between psychopathy and empathy (r = −0.31), empathic concern (r = −0.29), perspective taking (r = −0.22), and personal distress (r = −0.14). In addition, our results yielded positive relationships between psychopathy and alexithymia (r = 0.21), difficulty describing feelings (r = 0.20), difficulty identifying feelings (r = 0.16), and externally-oriented thinking (r = 0.15). The results varied by psychopathy factors, and some were moderated by gender.

These findings suggest that psychopathy is associated with deficits in various empathic processes as well as with an impaired perception of one’s own emotions. Moreover, the results highlight the necessity to investigate these deficits not only across overall constructs, but also across their factors to further improve the understanding of aberrant emotionality in psychopathy.

[Keywords: alexithymia, empathy, meta-analysis⁠, psychopathy]

“How Much Does That Cost? Examining the Economic Costs of Crime in North America Attributable to People With Psychopathic Personality Disorder”, Gatner et al 2022

2022-gatner.pdf: “How much does that cost? Examining the economic costs of crime in North America attributable to people with psychopathic personality disorder”⁠, Dylan T. Gatner, Kevin S. Douglas, Madison F. E. Almond, Stephen D. Hart, P. Randall Kropp (2022-04-25; ⁠, ):

Cost of illness research has established that mental disorders lead to large social burden and massive financial costs. A substantial gap exists for the economic burden of many personality disorders, including psychopathic personality disorder (PPD).

In the current study, we used a top-down prevalence-based cost of illness approach to estimate bounded crime cost estimates of PPD in the United States and Canada. 3 key model parameters (PPD prevalence, relative offending rate of individuals with PPD, and national costs of crime for each country) were informed by existing literature. Sensitivity analyses and Monte Carlo simulations were conducted to provide bounded and central tendency estimates of crime costs, respectively.

The estimated PPD-related costs of crime ranged from $245.50 billion to $1,591.57 billion (simulated means = $512.83 to $964.23 billion) in the United States and $12.14 billion to $53.00 billion (simulated means = $25.33 to $32.10 billion) in Canada. These results suggest that PPD may be associated with a substantial economic burden as a result of crime in North America.

Recommendations are discussed regarding the burden-treatment discrepancy for PPD, as the development of future effective treatment for the disorder may decrease its costly burden on health and justice systems.

[Keywords: psychopathic personality disorder, cost of illness, crime costs, violence, social burden]

“Genomics, Convergent Neuroscience and Progress in Understanding Autism Spectrum Disorder”, Willsey et al 2022

2022-willsey.pdf: “Genomics, convergent neuroscience and progress in understanding autism spectrum disorder”⁠, Helen Rankin Willsey, A. Jeremy Willsey, Belinda Wang, Matthew W. State (2022-04-19; ⁠, ; similar):

More than a hundred genes have been identified that, when disrupted, impart large risk for autism spectrum disorder (ASD). Current knowledge about the encoded proteins—although incomplete—points to a very wide range of developmentally dynamic and diverse biological processes. Moreover, the core symptoms of ASD involve distinctly human characteristics, presenting challenges to interpreting evolutionarily distant model systems. Indeed, despite a decade of striking progress in gene discovery, an actionable understanding of pathobiology remains elusive.

Increasingly, convergent neuroscience approaches have been recognized as an important complement to traditional uses of genetics to illuminate the biology of human disorders. These methods seek to identify intersection among molecular-level, cellular-level and circuit-level functions across multiple risk genes and have highlighted developing excitatory neurons in the human mid-gestational prefrontal cortex as an important pathobiological nexus in ASD. In addition, neurogenesis⁠, chromatin modification and synaptic function have emerged as key potential mediators of genetic vulnerability.

The continued expansion of foundational ‘omics’ data sets, the application of higher-throughput model systems and incorporating developmental trajectories and sex differences into future analyses will refine and extend these results. Ultimately, a systems-level understanding of ASD genetic risk holds promise for clarifying pathobiology and advancing therapeutics.

“The Contributions of Rare Inherited and Polygenic Risk to ASD in Multiplex Families”, Chang et al 2022

“The Contributions of Rare Inherited and Polygenic Risk to ASD in Multiplex Families”⁠, Timothy S. Chang, Matilde Cirnigliaro, Stephanie A. Arteaga, Laura Pérez-Cano, Elizabeth K. Ruzzo, Aaron Gordon et al (2022-04-16; ):

Autism Spectrum Disorder (ASD) has a complex genetic architecture involving contributions from de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation, or its interaction with polygenic risk in ASD.

Here, we performed whole genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having 2 or more affected children with ASD.

Using this study design, we identify 7 novel risk genes supported primarily by rare inherited variation, finding support for a total of 74 genes in our cohort and a total of 152 genes after combining with other studies. Probands demonstrated an increased burden of mutations in 2 or more known risk genes (KARGs)—in 3 families both probands inherited protein-truncating variants in two KARGs. We also find that polygenic risk is over-transmitted from unaffected parents to affected children with rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD polygenic risk over-transmission.

These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.

“Borderline Personality Disorder and the Big Five: Molecular Genetic Analyses Indicate Shared Genetic Architecture With Neuroticism and Openness”, Streit et al 2022

“Borderline Personality Disorder and the Big Five: molecular genetic analyses indicate shared genetic architecture with Neuroticism and Openness”⁠, Fabian Streit, Stephanie H. Witt, Swapnil Awasthi, Jerome C. Foo, Martin Jungkunz, Josef Frank, Lucía Colodro-Conde et al (2022-04-11; ⁠, ):

Both environmental (eg. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/​features in the general population indicate that genetic factors underlying these symptoms/​features are shared in part with the personality traits of the five-factor Model (FFM) of personality—the “Big Five”.

In the present study, the genetic overlap of BPD with the Big Five—Openness to Experience⁠, conscientiousness⁠, Extraversion⁠, Agreeableness⁠, and Neuroticism—was assessed. linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (n = 2,543) and GWAS on the Big Five (n = 76,551–122,886, Neuroticism n = 90,278). polygenic scores (PGS) were calculated to test the association of the genetic disposition for the personality traits with BPD case-control status.

Statistically-significant positive genetic correlations of BPD were found with Neuroticism (rg = 0.34, p = 6.3×10−5) and Openness (rg = 0.24, p = 0.036), but not with the other personality traits (all |rg| < 0.14, all p > 0.30). A cluster and item-level analysis showed positive genetic correlations of BPD with the Neuroticism clusters “Depressed Affect” and “Worry”, and with a broad range of Neuroticism items (n = 348,219–376,352). PGS analyses confirmed the genetic correlations, and found an independent contribution of the personality traits to BPD risk.

The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the “Big Five” are needed to further explore the role of personality traits in the etiology of BPD.

“The LGBTQ+ Gap: Recent Estimates for Young Adults in the United States”, Folch 2022

“The LGBTQ+ Gap: Recent Estimates for Young Adults in the United States”⁠, Marc Folch (2022-04-07; ⁠, ):

This article provides recent estimates of earnings and mental health for sexual and gender minority young adults in the United States.

Using data from a nationally representative sample of bachelor’s degree recipients:

I find a statistically-significant earnings and mental health gap between self-identified LGBTQ+ and comparable heterosexual cisgender graduates. On average, sexual and gender minorities experience 22% lower earnings 10 years after graduation. About half of this gap can be attributed to LGBTQ+ graduates being less likely to complete a high-paying major and work in a high-paying occupation (eg. STEM and business). In addition, LGBTQ+ graduates are more than twice more likely to report having a mental illness.

I then analyze the role of sexual orientation concealment and find a more pronounced earnings and mental health gap for closeted graduates.

[Keywords: LGBTQ+, labor market discrimination, mental health]

“Genetic Variants Associated With Longitudinal Changes in Brain Structure across the Lifespan”, Brouwer et al 2022

2022-brouwer.pdf: “Genetic variants associated with longitudinal changes in brain structure across the lifespan”⁠, Rachel M. Brouwer, Marieke Klein, Katrina L. Grasby, Hugo G. Schnack, Neda Jahanshad, Jalmar Teeuw, Sophia I. Thomopoulos et al (2022-04-05; ⁠, ; similar):

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases.

In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan.

Longitudinal magnetic resonance imaging data from 15,640 individuals [in 40 cohorts] were used to compute rates of change for 15 brain structures.

The most robustly identified genes GPR139⁠, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia⁠, cognitive functioning, insomnia⁠, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes.

Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

“Childhood Trauma and Borderline Personality Disorder Traits: A Discordant Twin Study”, Skaug et al 2022

2022-skaug.pdf: “Childhood trauma and borderline personality disorder traits: A discordant twin study”⁠, Eirunn Skaug, Nikolai O. Czajkowski, Trine Waaktaar, Svenn Torgersen (2022-04-04; ⁠, ; similar):

[cf. Bornavalova et al 2013] This study suggests that exposure to trauma in childhood and/​or adolescence does not lead to later development of borderline personality disorder traits. Rather, the association between trauma and borderline personality disorder traits is better accounted for by shared genetic influences.

A discordant twin design was utilized to examine the potentially causal effects of childhood trauma (CT; i.e., emotional abuse, physical abuse, sexual abuse, and witnessing violence) on borderline personality disorder traits (BPD traits) in early adulthood. The participants were 2,808 twins between 17 and 23 years from the Oslo University Adolescent and Young Adult Twin Project. BPD traits were assessed by the Structured Interview for DSM-IV Personality (SIDP-IV), and CT was assessed using the Childhood Trauma Interview (CTI).

BPD traits (h2 = 0.50) and CT (h2 = 0.33–0.69) were both found to be moderately heritable. Small but statistically-significant associations between CT and BPD traits were found in the total sample. After controlling for shared environmental and genetic factors in the discordant twin pairs, the analyses showed little to no evidence for causal effects of CT on BPD traits.

The results indicated that the associations between CT and BPD traits stem from common genetic influences. These findings are inconsistent with the widely held assumption that CT causes the development of BPD.

[Keywords: borderline personality disorder, childhood trauma, discordant twin design, genetic, adolescents]

“New Insights into the Genetic Etiology of Alzheimer’s Disease and Related Dementias”, Bellenguez et al 2022

“New insights into the genetic etiology of Alzheimer’s disease and related dementias”⁠, Céline Bellenguez, Fahri Küçükali, Iris E. Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C. Naj et al (2022-04-02; ; similar):

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes.

We performed a 2-stage genome-wide association study totaling 111,326 clinically diagnosed/​‘proxy’ AD cases and 677,663 controls.

We found 75 risk loci, of which 42 were new at the time of analysis.

Pathway enrichment analyses confirmed the involvement of amyloid/​tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex.

We also built a new genetic risk score associated with the risk of future AD/​dementia or progression from mild cognitive impairment to AD/​dementia. The improvement in prediction led to a 1.6× to 1.9× increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

“The Relationship of Major Diseases With Childlessness: a Sibling Matched Case-control and Population Register Study in Finland and Sweden”, Liu et al 2022

“The relationship of major diseases with childlessness: a sibling matched case-control and population register study in Finland and Sweden”⁠, Aoxing Liu, Evelina T. Akimova, Xuejie Ding, Sakari Jukarainen, Pekka Vartiainen, Tuomo Kiiskinen, Sara Kuitunen et al (2022-04-02; ⁠, ; similar):

Background: ~20% of men and 15% of women remain childless at the end of their reproductive lifespan, with childlessness increasing over time, yet we lack a comprehensive understanding of the role and relative importance of diseases associated with childlessness, particularly among men.

Methods: We examined all individuals born in Finland (n = 1,035,928) and Sweden (n = 1,509,092) between 1956 and 1968 (men) or 1956 and 1973 (women) and followed them up until the end of 2018. Socio-demographic, health, and reproductive information was obtained from nationwide registers. We assessed the association of 414 diseases across 16 categories with having no children by age 45 (women) and 50 (men) using a matched pair case-control design based on 71,524 pairs of full-sisters and 77,622 full-brothers who were discordant for childlessness as well as a population-based approach.

Findings: Mental-behavioral, congenital anomalies, and endocrine-nutritional-metabolic disorders had the strongest associations with childlessness. Novel associations were discovered with inflammatory (eg. myocarditis) and autoimmune diseases (eg. juvenile idiopathic arthritis). Mental-behavioral disorders had stronger associations amongst men, particularly for schizophrenia and acute alcohol intoxication, while congenital anomalies, obesity-related diseases such as diabetes, and inflammatory diseases had stronger associations amongst women. Associations were dependent on the age at onset of the disease, with the strongest association observed earlier in women (21–25 years old) than men (26–30 years old). For most diseases, the association with childlessness was mediated by singlehood, especially in men. Some diseases, however, remained associated with childlessness among partnered individuals, including some mood and endocrine-nutritional-metabolic disorders. All results can be explored in an interactive online dashboard.

Interpretation: We provide evidence that disease burden across multiple domains is associated with childlessness, identifying modifiable mental-behavioral disorders and novel autoimmune and inflammatory diseases. Evidence can be used for targeted health interventions to counter decreasing fertility, reproductive health, involuntary childlessness, and shrinking populations.

“Clinical Prediction Models in Psychiatry: a Systematic Review of Two Decades of Progress and Challenges”, Meehan et al 2022

“Clinical prediction models in psychiatry: a systematic review of two decades of progress and challenges”⁠, Alan J. Meehan, Stephanie J. Lewis, Seena Fazel, Paolo Fusar-Poli, Ewout W. Steyerberg, Daniel Stahl et al (2022-04-01; ; similar):

Recent years have seen the rapid proliferation of clinical prediction models aiming to support risk stratification and individualized care within psychiatry. Despite growing interest, attempts to synthesize current evidence in the nascent field of precision psychiatry have remained scarce.

This systematic review therefore sought to summarize progress towards clinical implementation of prediction modeling for psychiatric outcomes. We searched MEDLINE⁠, PubMed⁠, Embase⁠, and PsycINFO databases from inception to September 30, 2020, for English-language articles that developed and/​or validated multivariable models to predict (at an individual level) onset, course, or treatment response for non-organic psychiatric disorders (PROSPERO: CRD42020216530). Individual prediction models were evaluated based on 3 key criteria: (1) mitigation of bias and overfitting; (2) generalizability, and (3) clinical utility. The Prediction model Risk Of Bias ASsessment Tool (PROBAST) was used to formally appraise each study’s risk of bias.

228 studies detailing 308 prediction models were ultimately eligible for inclusion. 94.5% of developed prediction models were deemed to be at high risk of bias, largely due to inadequate or inappropriate analytic decisions. Insufficient internal validation efforts (within the development sample) were also observed, while only one-fifth of models underwent external validation in an independent sample. Finally, our search identified just one published model whose potential utility in clinical practice was formally assessed.

Our findings illustrated substantial growth in precision psychiatry with promising progress towards real-world application. Nevertheless, these efforts have been inhibited by a preponderance of bias and overfitting, while the generalizability and clinical utility of many published models has yet to be formally established. Through improved methodological rigor during initial development, robust evaluations of reproducibility via independent validation, and evidence-based implementation frameworks, future research has the potential to generate risk prediction tools capable of enhancing clinical decision-making in psychiatric care.

[ML prediction will work, but like GWASes or deep learning or brain imaging, people will be unhappy how much data it will take.]

“Social Media Use and Its Impact on Adolescent Mental Health: An Umbrella Review of the Evidence”, Valkenburg et al 2022

“Social media use and its impact on adolescent mental health: An umbrella review of the evidence”⁠, Patti M. Valkenburg, Adrian Meier, Ine Beyens (2022-04; ⁠, ; similar):

Literature reviews on how social media use affects adolescent mental health have accumulated at an unprecedented rate of late. Yet, a higher-level integration of the evidence is still lacking.

We fill this gap with an up-to-date umbrella review, a review of reviews published between 2019 and mid-2021. Our search yielded 25 reviews: 7 meta-analyses, 9 systematic, and 9 narrative reviews. Results showed that most reviews interpreted the associations between social media use and mental health as ‘weak’ or ‘inconsistent,’ whereas a few qualified the same associations as ‘substantial’ and ‘deleterious.’

We summarize the gaps identified in the reviews, provide an explanation for their diverging interpretations, and suggest several avenues for future research.

[Keywords: meta-review, social networking sites, SNS, Facebook⁠, Instagram⁠, well-being, depression, depressive symptoms]

Main findings of the reviews: As Table 1 shows, 5 meta-analyses yielded associations of general use of social network sites (SNS use) with higher levels of adolescent ill-being that ranged from very small to moderate (r = 0.05 to r = 0.17)[14, 17, 18, 19, 20], and one did not find such an association (r = 0.02 ns[15]). As for well-being, one meta-analysis found that SNS use was weakly associated with higher levels of well-being (r = +0.05),19 whereas another found that it was weakly related to lower levels of well-being (r = −0.06).17 However, the latter study aggregated well-being outcomes (eg. happiness, life satisfaction) with ill-being outcomes (eg. reversed depression and anxiety scores) in a composite ‘well-being’ score. When this meta-analysis analyzed happiness, life satisfaction, and depression separately, it found that SNS use was associated with both higher levels of well-being and ill-being.17

In all, the available meta-analytic evidence suggests that SNS use is weakly associated with higher levels of ill-being [14, 17, 18, 19, 20] but also with higher levels of well-being[17,19], a result that suggests that ill-being is not simply the flip-side of well-being and vice versa, and that both outcomes should be investigated in their own right [11,39]. Finally, all meta-analyses reported considerable variability in the reported associations. For example, in the meta-analysis by Ivie et al 2020,14 the reported associations of SMU with depressive symptoms ranged from r = −0.10 to r = +0.33.

“Genetics, Leadership Position, and Well-being: An Investigation With a Large-scale GWAS”, Song et al 2022

“Genetics, leadership position, and well-being: An investigation with a large-scale GWAS”⁠, Zhaoli Song, Wen-Dong Li, Xuye Jin, Junbiao Ying, Xin Zhang, Ying Song, Hengtong Li, Qiao Fan (2022-03-14; ⁠, ; similar):

Our study presents the largest whole-genome investigation of leadership phenotypes to date.

We identified genome-wide statistically-significant loci for leadership phenotypes, which are overlapped with top hits for bipolar disorder, schizophrenia⁠, and intelligence.

Our study demonstrated the polygenic nature of leadership, the positive genetic correlations between leadership traits and a broad range of well-being indicators, and the unique association of leadership with well-being after accounting for genetic influences related to other socioeconomic status measures. Our findings offer insights into the biological underpinnings of leadership.

Twin studies document leadership role occupancy (eg. whether one holds formal supervisory or management positions) as a heritable trait. However, previous studies have been underpowered in identifying specific genes associated with this trait, which has limited our understanding of the genetic correlations between leadership and one’s well-being.

We conducted a genome-wide association study (GWAS) on individuals’ leadership phenotypes that were derived from supervisory/​managerial positions and demands among 248,640 individuals of European ancestry from the UK Biobank data…and replicated top variants in 3 independent samples [UKBB followup, Add Health Wave IV, WLS].

Among the 9 genome-wide statistically-significant loci, the identified top regions are pinpointed to previously reported GWAS loci for bipolar disorder (miR-2113/​POUSF2 and LINC01239) and schizophrenia loci (ZSWIM6). We found positive genetic correlations between leadership position and several positive well-being and health indicators, including high levels of subjective well-being, and low levels of anxiety and depression (|rg| > 0.2). Intriguingly, we observed positive genetic correlations between leadership position and some negative well-being indicators, including high levels of bipolar disorder and alcohol intake frequency. We also observed positive genetic correlations between leadership position and shortened longevity, cardiovascular diseases, and body mass index after partialling out the genetic variance attributed to either educational attainment or income. The positive genetic correlation between leadership and bipolar disorder seems potentially more pronounced for those holding senior leadership positions (rg: 0.10 to 0.24), partially due to shared genetic variants with educational attainment.

Our findings provide insights into the polygenic nature of leadership and shared genetic underpinnings between the leadership position and one’s health and well-being.

“The Effect of Smoking on Mental Health: Evidence from a Randomized Trial”, Meckel & Rittenhouse 2022

“The Effect of Smoking on Mental Health: Evidence from a Randomized Trial”⁠, Katherine Meckel, Katherine P. Rittenhouse (2022-03; ):

This paper aims to identify the causal effects of smoking on mental health using data from the Lung Health Study, a randomized trial of smoking cessation treatment with 5 years of follow-up interviews.

In the short-run, distress increases, likely reflecting the effects of nicotine withdrawal. Long-run effects on mental health are small overall, but mask heterogeneity by gender. For women, the cessation program leads to improved mental health, driven by decreases in insomnia and nervousness. Men do not experience these improvements, due in part to a small increase in severe disturbances.

“Multivariate Genomic Architecture of Cortical Thickness and Surface Area at Multiple Levels of Analysis”, Grotzinger et al 2022

“Multivariate Genomic Architecture of Cortical Thickness and Surface Area at Multiple Levels of Analysis”⁠, Andrew David Grotzinger, Travis T. Mallard, Zhaowen Liu, Jakob Seidlitz, Tian Ge, Jordan W. Smoller (2022-02-25; ⁠, ; similar):

Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for cortical thickness (CT) and surface area (SA).

We model this relationship by applying Genomic Structural Equation Modeling (Genomic SEM) to parsimoniously define 5 genomic brain factors for both CT and SA. We reify these factors by demonstrating the generalizability of the model in a semi-independent sample and show that the factors align with biologically and functionally relevant parcellations of the cortex. We apply Stratified Genomic SEM to identify specific categories of genes (eg. neuronal cell types) that are disproportionately associated with pleiotropy across specific subclusters of brain regions, as indexed by the genomic factors. Finally, we examine genetic associations with psychiatric and cognitive correlates, finding that SA is associated with both broad aspects of cognitive function and specific risk pathways for psychiatric disorders.

These analyses provide key insights into the multivariate genomic architecture of two critical features of the cerebral cortex.

“Treatment With Glucagon-like Peptide-1 Receptor Agonists and Incidence of Dementia: Data from Pooled Double-blind Randomized Controlled Trials and Nationwide Disease and Prescription Registers”, Nørgaard et al 2022

“Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers”⁠, Caroline Holm Nørgaard, Sarah Friedrich, Charlotte Thim Hansen, Thomas Gerds, Clive Ballard, Daniel Vega Møller et al (2022-02-23; ; similar):

Introduction: People with type 2 diabetes have increased risk of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer’s disease⁠; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes.

Methods: We assessed exposure to GLP-1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in 2 large data sources with long-term follow-up: pooled data from 3 randomized double-blind placebo-controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry-based cohort (120,054 patients).

Results: Dementia rate was lower both in patients randomized to GLP-1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25–0.86)) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86–0.93 with yearly increased exposure to GLP-1 RAs).

Discussion: Treatment with GLP-1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes.

“Genome-wide Analyses of ADHD Identify 27 Risk Loci, Refine the Genetic Architecture and Implicate Several Cognitive Domains”, Demontis et al 2022

“Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains”⁠, Ditte Demontis, Bragi Walters, Georgios Athanasiadis, Raymond Walters, Karen Therrien, Leila Farajzadeh et al (2022-02-16; ⁠, ; similar):

Attention deficit hyperactivity disorder (ADHD) is a prevalent childhood psychiatric disorder, with a major genetic component. Here we present a GWAS meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide statistically-significant loci, which is more than twice the number previously reported. Fine-mapping risk loci highlighted 76 potential risk genes enriched in genes expressed in brain, particularly the frontal cortex, and in early brain development. Overall, ADHD was associated with several brain specific neuronal sub-types and especially midbrain dopaminergic neurons. In a subsample of 17,896 exome-sequenced individuals, we identified increased load of rare protein-truncating variants in cases for a set of risk genes enriched with likely causal common variants, suggesting implication of SORCS3 in ADHD by both common and rare variants. We found ADHD to be highly polygenic, with around seven thousand variants explaining 90% of the SNP heritability. Bivariate Gaussian mixture modeling estimated that more than 90% of ADHD influencing variants are shared with other psychiatric disorders (autism, schizophrenia and depression) and phenotypes (eg. educational attainment) when both concordant and discordant variants are considered. Additionally, we demonstrated that common variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions including attention.

“Efficacy and Safety of Psilocybin-assisted Treatment for Major Depressive Disorder: Prospective 12-month Follow-up”, Gukasyan et al 2022

“Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up”⁠, Natalie Gukasyan, Alan K. Davis, Frederick S. Barrett, Mary P. Cosimano, Nathan D. Sepeda, Matthew W. Johnson et al (2022-02-15; ; similar):

Background: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes.

Aims: This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received psilocybin.

Methods: This randomized, waiting-list controlled study enrolled 27 patients aged 21–75 with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they received 2 doses of psilocybin with supportive psychotherapy. 24 participants completed both psilocybin sessions and were followed through 12 months following their second dose.

Results: All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were observed at 1-month, 3-month, 6-month, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside the context of the study. Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months, but did not predict improvement in depression.

Conclusions: These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through 12 months following acute intervention in some patients.

[Keywords: insight, long-term effects, major depressive disorder, mystical experience, psilocybin]

“Effect of Offering Care Management or Online Dialectical Behavior Therapy Skills Training vs Usual Care on Self-harm Among Adult Outpatients With Suicidal Ideation: A Randomized Clinical Trial”, Simon et al 2022

2022-simon.pdf: “Effect of Offering Care Management or Online Dialectical Behavior Therapy Skills Training vs Usual Care on Self-harm Among Adult Outpatients With Suicidal Ideation: A Randomized Clinical Trial”⁠, Gregory E. Simon, Susan M. Shortreed, Rebecca C. Rossom, Arne Beck, Gregory N. Clarke, Ursula Whiteside et al (2022-02-15; similar):

Question: Can low-intensity outreach programs, based on effective clinical interventions but delivered primarily online, prevent self-harm or suicidal behavior among outpatients reporting frequent suicidal ideation?

Findings: In this pragmatic randomized clinical trial that included 18,882 outpatients with frequent suicidal ideation, the percentage with nonfatal or fatal self-harm over 18 months was 3.3% among those offered care management, 3.9% among those offered online dialectical behavior therapy skills training, and 3.1% among those receiving usual care, respectively. Compared with usual care, the risk of self-harm was not statistically-significantly different for care management but was statistically-significantly increased for those offered skills training.

Meaning: Compared with usual care, offering care management did not statistically-significantly reduce the risk of self-harm, and offering brief online dialectical behavior therapy skills training increased the risk of self-harm among at-risk adults.

Importance: People at risk of self-harm or suicidal behavior can be accurately identified, but effective prevention will require effective scalable interventions.

Objective: To compare 2 low-intensity outreach programs with usual care for prevention of suicidal behavior among outpatients who report recent frequent suicidal thoughts.

Design, Setting, & Participants: Pragmatic randomized clinical trial including outpatients reporting frequent suicidal thoughts identified using routine Patient Health Questionnaire depression screening at 4 US integrated health systems. A total of 18,882 patients were randomized between March 2015 and September 2018, and ascertainment of outcomes continued through March 2020.

Interventions: Patients were randomized to a care management intervention (n = 2,020) that included systematic outreach and care, a skills training intervention (n = 2,020) that introduced 4 dialectical behavior therapy skills (mindfulness, mindfulness of current emotion, opposite action, and paced breathing), or usual care (n = 2,020). Interventions, lasting up to 12 months, were delivered primarily through electronic health record online messaging and were intended to supplement ongoing mental health care.

Main Outcomes & Measures: The primary outcome was time to first nonfatal or fatal self-harm. Nonfatal self-harm was ascertained from health system records, and fatal self-harm was ascertained from state mortality data. Secondary outcomes included more severe self-harm (leading to death or hospitalization) and a broader definition of self-harm (selected injuries and poisonings not originally coded as self-harm).

Results: A total of 18,644 patients (2,020 [48%] aged 45 years or older; 12,543 [67%] female; 2,020 [50%] from mental health specialty clinics and the remainder from primary care) contributed at least 1 day of follow-up data and were included in analyses. 31% of participants offered care management and 39% offered skills training actively engaged in intervention programs. A total of 540 participants had a self-harm event (including 45 deaths attributed to self-harm and 495 nonfatal self-harm events) over 18 months following randomization: 172 (3.27%) in care management, 206 (3.92%) in skills training, and 162 (3.27%) in usual care. Risk of fatal or nonfatal self-harm over 18 months did not differ statistically-significantly between the care management and usual care groups (hazard ratio [HR], 1.07; 97.5% CI⁠, 0.84–1.37) but was statistically-significantly higher in the skills training group than in usual care (HR, 1.29; 97.5% CI, 1.02–1.64). For severe self-harm, care management vs usual care had an HR of 1.03 (97.5% CI, 0.71–1.51); skills training vs usual care had an HR of 1.34 (97.5% CI, 0.94–1.91). For the broader self-harm definition, care management vs usual care had an HR of 1.10 (97.5% CI, 0.92–1.33); skills training vs usual care had an HR of 1.17 (97.5% CI, 0.97–1.41).

Conclusions & Relevance: Among adult outpatients with frequent suicidal ideation, offering care management did not statistically-significantly reduce risk of self-harm, and offering brief dialectical behavior therapy skills training statistically-significantly increased risk of self-harm, compared with usual care. These findings do not support implementation of the programs tested in this study.

Trial Registration: Identifier: NCT02326883⁠.

“A Comprehensive Map of Genetic Relationships among Diagnostic Categories Based on 48.6 Million Relative Pairs from the Danish Genealogy”, Athanasiadis et al 2022

“A comprehensive map of genetic relationships among diagnostic categories based on 48.6 million relative pairs from the Danish genealogy”⁠, Georgios Athanasiadis, Joeri J. Meijsen, Dorte Helenius, Andrew J. Schork, Andrés Ingason, Wesley K. Thompson et al (2022-02-08; ⁠, ; similar):

The ability to extract multigenerational family relationships from large-scale population cohorts provides a powerful means to understand the heritability of a wide range of diseases and their genetic relationships to each other. By showing how the heritability of broad diagnostic categories changes over time and how said categories are related on the genetic level, our analysis of the Danish genealogy and linked national patient registers illustrates the vast potential of this resource in current biomedical research.

For more than half a century, Denmark has maintained population-wide demographic, health care, and socioeconomic registers that provide detailed information on the interaction between all residents and the extensive national social services system.

We leverage this resource to reconstruct the genealogy of the entire nation based on all individuals legally residing in Denmark since 1968. We cross-reference 6,691,426 individuals with nationwide health care registers to estimate heritability and genetic correlations of 10 broad diagnostic categories involving all major organs and systems.

Heritability estimates for mental disorders were consistently the highest across demographic cohorts (average h2 = 0.406, 95% CI = [0.403, 0.408]), whereas estimates for cancers were the lowest (average h2 = 0.130, 95% CI = [0.125, 0.134]). The average genetic correlation of each of the 10 diagnostic categories with the other 9 was highest for gastrointestinal conditions (average rg = 0.567, 95% CI = [0.566, 0.567]) and lowest for urogenital conditions (average rg = 0.386, 95% CI = [0.385, 0.388]). Mental, pulmonary, gastrointestinal, and neurological conditions had similar genetic correlation profiles.

[Keywords: heritability, genetic correlation, human disease, register data, Denmark, population registry]

Figure 4: Genetic correlations of each of 10 broad diagnostic categories with the remaining 9 by demographic cohort. Only the 4 most data-rich cohorts—Silent Generation, Baby Boomers, Generation X, and Millennials—were considered. Estimates were based on averages from all available relative pairs within a radius of 3 meioses weighted by sampling variance. Blank cells correspond to correlations not statistically-significantly different from zero.

Genetic Correlations: To understand the mutual relationships between the 10 broad diagnostic categories (15), we estimated their genetic correlations (rg) by combining within-category and between-category estimates of the latent correlation into Falconer’s method (16). We considered all family relations within a radius of 3 meioses and restricted the analyses to the 4 most data-rich demographic cohorts mentioned in Genealogy Network Structure (Figure 4 and Dataset S1).

All rg except 2 were positive, and all of them except one were also statistically-significantly different from zero. Overall, rg were highly consistent between consecutive cohorts, thus further boosting confidence in the estimates (SI Appendix, Figure 7). This trend was more marked for certain diagnostic categories such as mental, pulmonary, and neurological than others. In all 10 diagnostic categories, younger cohorts showed lower rg than older generations, whereas the opposite trend was observed for heritability that consistently increased in younger cohorts (Figure 4 and SI Appendix, Dataset S1). The average rg of each of the 10 diagnostic categories with the other 9 categories was highest for gastrointestinal conditions (0.567; SE = 0.0005) and lowest for urogenital conditions (0.386; SE = 0.0008).

“Addiction Chronicity: Are All Addictions the Same?”, Gooding et al 2022

2022-gooding.pdf: “Addiction chronicity: are all addictions the same?”⁠, Nolan B. Gooding, Jennifer N. Williams, Robert J. Williams (2022-02-08; similar):

Background: All addictions have a recurring nature, but their comparative chronicity has never been directly investigated. The purpose of this study is to undertake this investigation.

Method: A secondary analysis was conducted on 2 large scale 5-year Canadian adult cohort studies. A subset of 1,088 individuals were assessed as having either substance use disorder, gambling disorder, excessive behaviors (eg. shopping, sex/​pornography), or 2 or more of these designations (‘multiple addictions’) during the course of these studies. Within each dataset comparisons were made between these 4 groups concerning the number of waves they had their condition; likelihood of having their condition in 2 or more consecutive waves; and likelihood of relapse following remission.

Results: Multiple addictions had statistically-significantly greater chronicity on all measures compared to single addictions. People with an excessive behavior designation had statistically-significantly lower chronicity compared to people with gambling disorder and a tendency toward lower chronicity compared to substance use disorder. Gambling disorder had equivalent chronicity to substance use disorder in one dataset but greater chronicity in the other. However, this latter difference is likely an artifact of the different time frames utilized.

Conclusions: Having multiple addictions represents a more pervasive condition that is persistent for most individuals. Substance use disorder and gambling disorder have intermediate and roughly equivalent levels of chronicity, but considerable individual variability, transient for some, but more chronic for others. In contrast, excessive behaviors such as compulsive shopping are transient for most, and their comparatively lower levels of chronicity questions their designations as ‘addictions’.

[Keywords: addiction, chronicity, longitudinal, cohort, gambling, substance abuse]

…Other excessive behavior tended to be more transient than gambling disorder, with 70.4% of individuals only manifesting the condition in a single time period. This is consistent with the few other studies that have examined the course of these excessive behaviors (King et al 2013; Scharkow et al 2014). The reasons for this lower chronicity are unknown but may be related to the diversity of excessive behaviors assessed (41.0% of the sample reported shopping, 15.3% exercise; 11.1% sex or pornography, 8.3% Internet chat lines; 6.9% video or Internet gaming; 10.4% ‘other’; and 6.9% with 2 or more). It is possible there is less chronicity in certain types that decreased the overall average (this possibility is supported by the fact that gambling disorder is also a type of behavioral addiction and it is more chronic). In any case, the transient nature of these conditions raises a question about their characterization as addictions (Karim & Chaudhri 2012; Rosenberg & Feder 2014). While it is clear that people can become excessively involved in these behaviors, the term ‘addiction’ implies a degree of chronicity somewhat inconsistent with the large majority of people only manifesting the problem in a single time period.

“Genome-wide Association Meta-analysis Identifies 29 New Acne Susceptibility Loci”, Mitchell et al 2022

“Genome-wide association meta-analysis identifies 29 new acne susceptibility loci”⁠, Brittany L. Mitchell, Jake R. Saklatvala, Nick Dand, Fiona A. Hagenbeek, Xin Li, Josine L. Min, Laurent Thomas et al (2022-02-07; ; similar):

Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin. Severely inflamed lesions may leave permanent scars that have been associated with long-term psychosocial consequences.

Here, we perform a GWAS meta-analysis comprising 20,165 individuals with acne from 9 independent European ancestry cohorts.

We identify 29 novel genome-wide statistically-significant loci and replicate 14 of the 17 previously identified risk loci, bringing the total number of reported acne risk loci to 46. Using fine-mapping and eQTL colocalisation approaches, we identify putative causal genes at several acne susceptibility loci that have previously been implicated in Mendelian hair and skin disorders, including pustular psoriasis⁠. We identify shared genetic aetiology between acne, hormone levels, hormone-sensitive cancers and psychiatric traits. Finally, we show that a polygenic risk score calculated from our results explains up to 5.6% of the variance in acne liability in an independent cohort.

Genetic correlations and causal relationships of acne with other traits: Assuming a population prevalence of 30% for acne, the genome-wide statistically-significant acne risk loci explain an estimated 6.01% of the variance in acne liability. However, estimation of heritability explained by all common SNPs⁠, i.e., the SNP-based heritability, indicates that 22.95% (s.e. = 0.02) of the variance in acne liability is explained by common genetic variation across the genome.

We utilised this extensive polygenicity to examine the genetic correlation and potential causal relationship between acne and a series of 935 human diseases and traits, finding 45 traits with statistically-significant genetic correlations (Supplementary Data 7). As has been previously observed, there is evidence of genetic correlation between acne and Crohn’s Disease (rg = 0.19, s.e. = 0.07) (Figure 2a). We also observe evidence of shared genetic architecture with disease traits that are phenotypically associated with acne; this includes breast cancer (rg = 0.16, s.e. = 0.05) and psychiatric disorders such as schizophrenia (rg = 0.18, s.e. = 0.06) and bipolar disorder (rg = 0.12, s.e. = 0.05). There is also evidence of asymmetry in the observed genetic correlation between acne and endogenous testosterone and bilirubin levels, breast cancer, joint pain and headaches (Figure 2b, Supplementary Data 7).

Figure 2: Genetic correlation and latent causal variable analysis between acne and other complex traits. All analyses were conducted using GWAS summary statistic data from 935 complex traits in the CTG-VL platform. (a) Black circles represent point estimates of LD score-based genetic correlations. Error bars indicate 95% confidence intervals. (b) Color bar indicates strength and direction of genetic correlation where red indicates a negative correlation and blue a positive correlation. Red line indicates statistical-significance threshold for multiple testing (FDR < 5%). CI: confidence intervals, GCP: Genetic causal proportion.

“Discovery of Genomic Loci of the Human Cerebral Cortex Using Genetically Informed Brain Atlases”, Makowski et al 2022

2022-makowski.pdf: “Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases”⁠, Carolina Makowski, Dennis van der Meer, Weixiu Dong, Hao Wang, Yan Wu, Jingjing Zou, Cin Liu, Sara B. Rosenthal et al (2022-02-05; ⁠, ; similar):

Genes control cortical surface area: Humans exhibit heritable variation in brain structure and function. To identify how gene variants affect the cerebral cortex⁠, Makowski et al 2022 performed genome-wide association studies in almost 40,000 adults and 9,000 children. They identified more than 400 loci associated with brain surface area and cortical thickness that could be observed through magnetic resonance imaging analyses. Examining biological pathways linking gene variants to phenotypes identified region-specific enrichments of neurodevelopmental functions, some of which were associated with psychiatric disorders. Partitioning genes with heritable variants relative to evolutionary conservation helped to identify a hierarchy of brain development. This analysis identified a human-specific gene-phenotype association related to speech and informs what genes can be studied in various model organisms.

To determine the impact of genetic variants on the brain, we used genetically informed brain atlases in genome-wide association studies of regional cortical surface area and thickness in 39,898 adults and 9,136 children.

We uncovered 440 genome-wide statistically-significant loci in the discovery cohort and 800 from a post hoc combined meta-analysis. Loci in adulthood were largely captured in childhood, showing signatures of negative selection⁠, and were linked to early neurodevelopment and pathways associated with neuropsychiatric risk. Opposing gradations of decreased surface area and increased thickness were associated with common inversion polymorphisms. Inferior frontal regions, encompassing Broca’s area⁠, which is important for speech, were enriched for human-specific genomic elements.

Thus, a mixed genetic landscape of conserved and human-specific features is concordant with brain hierarchy and morphogenetic gradients.

“Reduced Reproductive Success Is Associated With Selective Constraint on Human Genes”, Gardner et al 2022

“Reduced reproductive success is associated with selective constraint on human genes”⁠, Eugene J. Gardner, Matthew D. C. Neville, Kaitlin E. Samocha, Kieron Barclay, Martin Kolk, Mari E. K. Niemi et al (2022-02-03; ⁠, ⁠, ; similar):

Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants1. While genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known2.

Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily due to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is likely mediated by genetically associated cognitive and behavioural traits, which may mean male carriers are less likely to find reproductive partners.

This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. While this genetic association could only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.

“Association between Lithium Levels in Drinking Water and Suicide Rates: Role of Affective Disorders”, Liaugaudaite et al 2022

2022-liaugaudaite.pdf: “Association between lithium levels in drinking water and suicide rates: Role of affective disorders”⁠, Vilma Liaugaudaite, Nijole Raskauskiene, Rima Naginiene, Narseta Mickuviene, Leo Sher (2022-02-01; ; similar):

  • Lithium levels in drinking water are positively associated with the incidence of affective disorders.
  • Higher lithium levels in drinking water are inversely associated with the lower suicide rates in areas with high incidence of affective disorders.
  • Even very low levels of lithium in drinking water may play a role to save lives among people with affective disorders.

Objective: The study aimed to assess the association between lithium levels in drinking water from public supplies and suicide rates in different municipalities of Lithuania in relation with incidence of affective disorders.

Methods: 53 drinking water samples were analysed from the main public drinking water systems of the country’s municipalities. Lithium levels were determined using the ion chromatography method. Information on all registered affective disorders across all age groups and gender within the 5-year period was obtained from the Department of Statistics, and was averaged across the investigation time period. For the statistical analysis, lithium levels were averaged per municipality and plotted against suicide standardized mortality rates per 100,000 populations, within the 5-year period.

Results: We found that lithium levels in drinking water are positively associated with the incidence of affective disorders. Our findings suggest higher incidence rates of affective disorders in the municipalities with a lithium level in drinking water above median compared to those in the municipalities with a lithium level below median and with the same socio-demographic and psychiatric characteristics. Suicide mortality rates are inversely associated with lithium levels in drinking water only in municipalities with higher lithium levels (above median) and with a high rate of affective disorders.

Conclusion: Based on our study results and insights we generate the following hypothesis for the further research, that lithium level in drinking water might have an important protective effect against suicide rates in the population with affective disorders.

[Keywords: lithium, drinking water, affective disorders, suicide]

“Investigation of the Association between Lithium Levels in Drinking Water and Suicide Mortality in Hungary”, Izsak et al 2022

2022-izsak.pdf: “Investigation of the association between lithium levels in drinking water and suicide mortality in Hungary”⁠, Balint Izsak, Anna Hidvegi, Lajos Balint, Tibor Malnasi, Marta Vargha, Tamas Pandics, Zoltan Rihmer, Peter Dome et al (2022-02-01; ; backlinks; similar):

  • Lithium (Li) has been demonstrated to have antisuicidal effects in clinical doses.
  • Some studies have also demonstrated that Li is bioactive in very low doses.
  • We found that tap water Li levels are inversely associated with suicide mortality.

Background: In recent decades, a series of ecological studies from various countries have attempted to reveal whether there is an association between trace amounts of lithium in drinking water and suicide mortality. With some notable exceptions, results have indicated that there is an inverse association between these 2 variables. Since Hungary had extremely high rates of suicide with a persistent spatial pattern, we consider that our country is ideal to investigate this research question.

Methods: We carried out our research on Hungarian data at the level of districts (n = 197). The dependent variable was the age-standardized and gender-standardized mortality ratio for suicide (sSMR). Our main explanatory variable was the tap water lithium level (Li) from public drinking water supply systems using their own water source (n = 1 325). Those data, which give full national coverage, were aggregated to the level of districts. Confounding factors were religiosity, alcohol consumption and income. Various regression models were used for statistical calculations.

Results: Findings from our most appropriate regression model—adjusted for relevant confounding variables and able to handle spatial autocorrelation and heteroscedasticity—suggest a statistically-significant (p < 0.05) and a trend-like (p < 0.10) negative association between Li and sSMR in the total population and among males, respectively. However, such an association was not found between these 2 variables among females.

Conclusion: In line with the majority of findings from other countries, our results indicate that the intake of lithium with drinking water may have a gender-dependent suicide-protective effect.

[Keywords: lithium, drinking water, suicide, prevention, mortality]

“Correlates of “Coddling”: Cognitive Distortions Predict Safetyism-inspired Beliefs, Belief That Words Can Harm, and Trigger Warning Endorsement in College Students”, Celniker et al 2022

2021-celniker.pdf: “Correlates of “Coddling”: Cognitive distortions predict safetyism-inspired beliefs, belief that words can harm, and trigger warning endorsement in college students”⁠, Jared B. Celniker, Megan M. Ringel, Karli Nelson, Peter H. Ditto (2022-02-01; ⁠, ; similar):

  • Cognitive distortions predict safetyism-inspired beliefs in college students.
  • Cognitive distortions predict belief that words can cause serious mental harm.
  • Cognitive distortions predict support for broad use of trigger warnings⁠.
  • Resiliency and analytic thinking negatively predict safetyism-inspired beliefs.
  • Provides first empirical support for some of Lukianoff & Haidt 2018’s claims

In their book, The Coddling of the American Mind⁠, Lukianoff & Haidt 2018 contended that the rise of “safetyism” within American society has inspired beliefs and practices that hinder college students’ socioemotional development. One of their most controversial claims was that college students’ safetyism-inspired beliefs (eg. emotional pain or discomfort is dangerous) are rooted in and supported by cognitive distortions, or negatively biased patterns of thought (eg. emotional reasoning). Citing evocative anecdotes, they argued that such distortions emerge in students’ perceptions of offensive or ideologically-challenging experiences as disproportionately harmful or traumatic. However, no empirical work has substantiated an association between cognitive distortions and safetyism-inspired beliefs or practices.

In a large (n = 786), ethnically and economically diverse sample of college students, we conducted the first examination of the relationship between these variables.

Aligning with Lukianoff and Haidt’s assertions, we found that students’ self-reported prevalence of cognitive distortions positively predicted their endorsement of safetyism-inspired beliefs, the belief that words can harm, and support for the broad use of trigger warnings.

Considering our exploratory results, we argue that greater empirical scrutiny of safetyism-inspired beliefs and practices is warranted before such customs become more widely adopted.

[Keywords: cognitive distortions, college students, trigger warnings, open data]

“Mental Health in People With Minority Sexual Orientations: A Meta-analysis of Population-based Studies”, Wittgens et al 2022

“Mental health in people with minority sexual orientations: A meta-analysis of population-based studies”⁠, Charlotte Wittgens, Mirjam M. Fischer, Pichit Buspavanich, Sabrina Theobald, Katinka Schweizer, Sebastian Trautmann et al (2022-01-28; similar):

Aims: To conduct a meta-analysis of population-based studies to quantify the association between sexual minority status (lesbian women, gay men, and bisexual people) and the risk of common mental disorders (depressive disorders, alcohol use disorders (AUD), anxiety disorders, and suicidality).

Method: PubMed⁠, PsycInfo⁠, Web of Science⁠, the Cochrane Library Database, the Applied Social Sciences Index and Abstracts (ASSIA)/​ ProQuest were searched for relevant studies published between 2000 and May 2020. The PRISMA guidelines were followed for selection processes. 26 studies met the inclusion criteria which included a total of 519,414 heterosexuals, 10,178 lesbian/​gay people and 14,410 bisexual people.

Results: Lesbian/​gay people (ORs between 1.97, 95% [CI = 1.76, 2.19] and 2.89, 95% [CI = 2.41,3.38]) and bisexual people (ORs between 2.70; 95% [CI = 2.21,3.18], and 4.81; 95% [CI = 3.63, 5.99]) had a higher risk for mental disorders than heterosexuals for all investigated diagnostic categories. The risk for depression (OR = 2.70; 95% [CI = 2.21, 3.18]) and suicidality (OR = 4.81; 95% [CI = 3.63, 5.99]) was higher in bisexual compared with lesbian/​gay people. Exploratory meta-regressions revealed no evidence for a decrease in mental health differences between people with minority sexual orientations and heterosexuals in more recent years of data assessment, except for AUD.

Conclusions: These findings clearly suggest disparities in mental health between people with minority sexual orientations and heterosexual people. There is a lack of data regarding a wider spectrum of sexual orientations and mental disorders and studies in non-Western countries.


  • Higher risk for mental disorders in people with minority sexual orientations
  • No indication for decreasing mental health disparities in recent years in exploratory analyses
  • Lack of data regarding wider spectrum of sexual orientations and disorders


  • less than half of the included studies used structured interviews to determine diagnostic status
  • no analysis of the interplay of gender and sexual orientation
  • no analysis of the influence of age, ethnicity, and other socio-demographic variables

…The meta-regression showed that the quality of the included studies comparing lesbian/​gay with heterosexual people was positively associated to mental health differences across all diagnostic categories (b = 0.09; [CI = 0.00, 0.19]) as well as for depression (b = 0.09; [CI = 0.00, 0.17]). Further, the mental health difference between lesbian/​gay people compared with heterosexuals were larger in studies using diagnostic interviews compared with symptom scales for comparisons across all categories pooled together (b = 0.30; [CI = 0.11; 0.51]), as well as for depression (b = 0.33; [CI = 0.17; 0.50]) and alcohol use disorder (b = 0.59 [CI = 0.08; 1.12]), in particular. In other words, the better the study quality and the better the method to determine diagnostic status, the larger the detected mental health disparities for lesbian/​gay people compared with heterosexuals. There was no moderation by the year of data assessment or sexuality measure (ie. identity, history of sexual partners, and behavior) (ps > 0.49).

“Structure-based Discovery of Non-hallucinogenic Psychedelic Analogs”, Cao et al 2022

2022-cao.pdf: “Structure-based discovery of non-hallucinogenic psychedelic analogs”⁠, Dongmei Cao, Jing Yu, Huan Wang, Zhipu Luo, Xinyu Liu, Licong He, Jianzhong Qi, Luyu Fan, Lingjie Tang et al (2022-01-28; ; similar):

Non-hallucinogenic psychedelic analogs: Psychedelic drugs such as lysergic acid diethylamide (LSD) and mushroom-derived psilocybin exert their effects by binding the serotonin 2A receptor (5-HT2AR). These drugs also have antidepressant effects, but the hallucinations they cause complicate their use as therapeutics. Cao et al 2022 present structures of 5-HT2AR bound to psychedelic drugs, the endogenous ligand serotonin⁠, and the non-hallucinogenic drug lisuride⁠. The structures reveal ligand-receptor interactions that cause a bias toward arrestin recruitment. Based on these insights, the authors designed arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucination effects. Arrestin recruitment alone is insufficient for antidepressant effects, but the low G-protein signaling of the arrestin-biased ligands appears to allow antidepressant effects without causing hallucination.

Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use.

Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) & D-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the non-hallucinogenic psychedelic analog lisuride.

Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects.

The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective non-hallucinogenic psychedelic analogs with therapeutic effects.

…Additionally, although 2 recent studies have reported non-hallucinogenic psychedelic analogs with antidepressant-like behavior (15⁠, 16), it remains unclear how to rationally design such compounds…and it is unclear whether the hallucinogenic effects of psychedelics are necessary for therapeutic effects (2⁠, 7⁠, 8⁠, 9⁠, 10).

[Like the research on dissociating ketamine’s psychedelic effects from its anti-depressant effects⁠, work on “trip-free psychedelics” raise the question of how much of the therapeutic benefit comes from the trip and how much from low-level neurological changes. If the latter, and they can be separated, then the weird beliefs & personality changes of heavy-using psychedelicists may be unnecessary: perhaps those simply reflect the enhanced neuroplasticity during the trip while weird experiences happen to extreme disruption of normal cognition like object recognition or concept of self, and are irrelevant to the benefits (rather than themselves producing the benefits as most psychedelicists strongly believe).]

“The Impact of Early Stages of COVID-19 on the Mental Health of Autistic Adults in the United Kingdom: A Longitudinal Mixed-methods Study”, Bundy et al 2022

“The impact of early stages of COVID-19 on the mental health of autistic adults in the United Kingdom: A longitudinal mixed-methods study”⁠, Rebecca Bundy, Will Mandy, Laura Crane, Hannah Belcher, Laura Bourne, Janina Brede, Laura Hull, Jana Brinkert et al (2022-01-27):

During the COVID-19 pandemic⁠, high levels of depression, anxiety and stress have been reported in the general population. However, much less has been reported about the impact of COVID-19 on the mental health of autistic people⁠.

What we did: In the present study, we investigated how the mental health of autistic adults in the United Kingdom changed during the early stages of the COVID-19 pandemic. In total, 133 participants completed an online survey at 2 different time points. Of the 133 participants, 70 completed the survey at the first time point just before the onset of the national lockdown. This allowed us to look at changes in their mental health, from before the lockdown to 10–15 weeks during lockdown. All participants (133) told us about their experiences of the pandemic.

What we found: While many autistic adults told us that their mental health worsened, people’s experience varied. For some autistic adults, aspects of mental health (eg. anxiety, stress) actually improved. Participants also described social changes that had occurred, at home and in the outside world. They described feelings of uncertainty during the pandemic, and discussed how the pandemic had affected some of their previous coping strategies. Participants also told us about their difficulties in accessing healthcare services and food during the early stages of the pandemic.

In our article, we discuss these findings and focus on what needs to change to ensure that autistic people are better supported as the pandemic continues.

We used mixed methods to learn about the nature and drivers of mental health changes among autistic adults in the United Kingdom during the early stages of the COVID-19 pandemic.

In quantitative analyses, we examined the nature and predictors of change in depression, anxiety and stress, prospectively measured in 70 autistic adults at Wave 1 (just before the United Kingdom’s first lockdown) and Wave 2 (10–15 weeks into the United Kingdom’s first lockdown). Retrospective Wave 2 reports of mental health change were also analysed for these 70 participants. For the qualitative analysis, 133 participants (including the 70 from the quantitative analyses) provided reports on their experiences of the pandemic at Wave 2.

In quantitative analyses, retrospective reports indicated that participants’ mental health worsened, but prospective data showed a different picture, with overall anxiety and stress scores reducing between Waves 1 and 2. Nevertheless, the mental health impact of the pandemic on autistic adults was variable, with a sizable minority reporting a substantial decline in mental health.

Qualitative analysis yielded 4 themes that contributed to mental health changes: (1) adjusting to changes to the social world, (2) living with uncertainty, (3) disruptions to self-regulation, and (4) barriers to fulfilling basic needs.

[Keywords: adults, anxiety, autism spectrum disorders, COVID-19, depression, health services, mental health, qualitative research]

“Flashback Phenomena After Administration of LSD and Psilocybin in Controlled Studies With Healthy Participants”, Müller et al 2022

“Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants”⁠, Felix Müller, Elias Kraus, Friederike Holze, Anna Becker, Laura Ley, Yasmin Schmid, Patrick Vizeli, Matthias E. Liechti et al (2022-01-25; ; similar):

Background: LSD and psilocybin are increasingly used in phase I trials and evaluated as therapeutic agents for mental disorders. The phenomenon of reoccurring drug-like experiences after the acute substance effects have worn off was described for both substances and especially attributed to LSD. According to the DSM-V⁠, the persisting and distressing manifestation of these experiences is called hallucinogen-persisting perception disorder (HPPD). Data on both conditions is very limited.

Objective: This study aims to provide descriptive data on reoccurring drug-like experiences after the administration of LSD and psilocybin in controlled studies with healthy participants.

Methods & Materials: Data from 142 healthy subjects enrolled in 6 double-blinded, placebo-controlled, randomized cross-over studies were analyzed. In total, 60 subjects received LSD; 27 subjects received LSD, MDMA⁠, and d-amphetamine⁠; 31 subjects received LSD and psilocybin; and 25 subjects received psilocybin and escitalopram⁠. At the end-of-study visit (mean 39.8 days after last study session, SD 37.2), subjects were asked for any reoccurring drug effects since the initial substance effects had worn off. Those reporting reoccurring perception changes more than 24 h after administration were contacted for follow-up (mean follow-up duration: 31.2 months, SD 28.6).

Results: 13 out of 142 subjects reported reoccurring drug-like experiences (LSD: 7, psilocybin: 2, both: 4). The reported phenomena were predominantly mild and perceived as neutral to pleasant. Flashbacks were mostly of visual nature, lasted for seconds to minutes, and occurred within a week after the last drug administration. 2 subjects reported distressing experiences that subsided spontaneously. One subject reported brief and pleasant visual perception changes which reoccurred for 7 months. None of the subjects reported impairment in their daily lives. None of the cases met DSM-V criteria for HPPD.

Conclusion: Reoccurring drug-like experiences after the administration of LSD and psilocybin are a common phenomenon occurring in up to 9.2% of healthy subjects (7.8% for LSD, 8.3% for psilocybin and 14.3% if both substances are administered). Additionally, our work suggests that flashback phenomena are not a clinically relevant problem in controlled studies with healthy participants.

“Multi-ancestry EQTL Meta-analysis of Human Brain Identifies Candidate Causal Variants for Brain-related Traits”, Zeng et al 2022

2022-zeng.pdf: “Multi-ancestry eQTL meta-analysis of human brain identifies candidate causal variants for brain-related traits”⁠, Biao Zeng, Jaroslav Bendl, Roman Kosoy, John F. Fullard, Gabriel E. Hoffman, Panos Roussos (2022-01-20; ⁠, ; similar):

While large-scale, genome-wide association studies (GWAS) have identified hundreds of loci associated with brain-related traits, identification of the variants, genes and molecular mechanisms underlying these traits remains challenging. Integration of GWAS with expression quantitative trait loci (eQTLs) and identification of shared genetic architecture have been widely adopted to nominate genes and candidate causal variants. However, this approach is limited by sample size, statistical power and linkage disequilibrium⁠.

We developed the multivariate multiple QTL approach and performed a large-scale, multi-ancestry eQTL meta-analysis to increase power and fine-mapping resolution.

Analysis of 3,983 RNA-sequenced samples from 2,119 donors, including 474 non-European individuals, yielded an effective sample size of 3,154. Joint statistical fine-mapping of eQTL and GWAS identified 329 variant-trait pairs for 24 brain-related traits driven by 204 unique candidate causal variants for 189 unique genes.

This integrative analysis identifies candidate causal variants and elucidates potential regulatory mechanisms for genes underlying schizophrenia⁠, bipolar disorder and Alzheimer’s disease⁠.

“Evidence on the Acute and Residual Neurocognitive Effects of Cannabis Use in Adolescents and Adults: a Systematic Meta-review of Meta-analyses”, Dellazizzo et al 2022

2022-dellazizzo.pdf: “Evidence on the acute and residual neurocognitive effects of cannabis use in adolescents and adults: a systematic meta-review of meta-analyses”⁠, Laura Dellazizzo, Stéphane Potvin, Sabrina Giguère, Alexandre Dumais (2022-01-19; ⁠, ; similar):

Background: Cannabis is among the most consumed psychoactive substances world-wide. Considering changing policy trends regarding the substance, it is crucial to understand more clearly its potential acute and residual adverse effects from a public health viewpoint. Cognitive function is one of the targeted areas with conflicting findings. This meta-review measured the magnitude of acute and residual effects of cannabis on cognition in adolescents and adults provided by meta-analyses and evaluated quality of evidence.

Methods: A systematic search was performed in PubMed⁠, PsycINFO⁠, Web of Science and Google Scholar⁠. Meta-analyses were included if they quantitatively examined the performances of users from the general population on cognitive tasks.

Results: The search retrieved 10 eligible meta-analyses (71 effects sizes, n = 43 761) with evidence ranging from low to moderate quality, which were categorized into domains of cognitive functions: executive functions (k = 7), learning and memory (k = 5), attention (k = 4), processing speed (k = 5), perceptual motor function (k = 2) and language (k = 2).

Verbal learning and memory displayed the most robust evidence and were most impaired by acute cannabis intoxication that persisted after intoxication passed. Small-to-moderate acute and residual adverse effects were reported for executive functioning. Cannabis use led to small deficits in inhibitory processes and flexibility, whereas small-to-moderate deficits were reported for working memory and decision-making. Evidence regarding processing speed and attention has shown that cannabis administration induced small-to-moderate adverse effects and residual neurocognitive deficits were observed in heavy cannabis-using youths. Results showed no statistically-significant difference between cannabis users and non-users on language, and small-to-moderate effects for simple motor skills.

Conclusion: Meta-analytical data on the acute effects of cannabis use on neurocognitive function have shown that cannabis intoxication leads to small to moderate deficits in several cognitive domains. These acute impairments accord with documented residual effects, suggesting that the detrimental effects of cannabis persist beyond acute intake.

…Despite the findings provided in this meta-review, several elements need to be discussed when interpreting results. First and foremost, the meta-analyses discussed comprised cross-sectional data with several analyses having relatively small sample sizes, which limits the inference of a causal relationship between cannabis use and cognition as well as the generalizability of results…Although most of the evidence on the cognitive sequelae of cannabis use has been provided by cross-sectional data associated with methodological limitations, a growing number of longitudinal studies, which are useful to address causal inferences, have emerged. This has led to several reviews examining, among others, evidence provided by prospective designed studies[20, 27, 31, 81]. For instance, Bourque et al 27 noted similar findings to those observed in cross-sectional data. Indeed, most studies showed declines in both executive functioning and verbal learning/​memory[82–95], while results were less consistent for processing speed[82, 85, 88, 90, 94–96]. Furthermore, longitudinal data have similarly shed light on the hypotheses that have been put forth to explain the association between cannabis use and cognitive functions (see Bourque et al 27 for an overview). A first hypothesis, that has received mixed evidence, specifies that cannabis use leads to persistent cognitive impairments. These neurotoxic effects last although cannabis users reduce their intake or quit altogether. While some longitudinal studies suggest that cognitive deficits resolve following abstinence[92, 94], other studies have confirmed that cannabis use frequency led to subsequent long-term cognitive decline (ie. executive function) regardless of prolonged cannabis intake, while adjusting for covariates[84, 87, 97]. Following, the premorbid cognitive vulnerability hypothesis proposes that individuals at increased risk of using the substance more regularly already presented cognitive deficits before cannabis use onset. Several studies have shown that specific cognitive impairments (ie. memory and executive functions) seemed to incline individuals to earlier onset of use in addition to more frequent use in comparison to non-using individuals[83–86, 98]. However, such findings were not evident in all studies[82, 87, 97, 99, 100] and some studies more probably support the common antecedent hypothesis[86, 98], which postulates that common factors (eg. externalizing behaviour) may predispose individuals to both cannabis use and cognitive deficits in users. Hence, results from longitudinal co-twin studies have suggested that cannabis use may not necessarily cause neurocognitive decline, but rather that factors related to family background, such as genetic and shared environmental factors, may more clearly explain worse cognitive performances amid cannabis users[86, 98].

“Increased Depressive and Anxiety Symptoms in Non-heterosexual Individuals: Moderation by Childhood Factors Using a Twin Design”, Oginni et al 2022

2022-oginni.pdf: “Increased depressive and anxiety symptoms in non-heterosexual individuals: Moderation by childhood factors using a twin design”⁠, Olakunle Ayokunmi Oginni, Katarina Alanko, Patrick Jern, Frühling Vesta Rijsdijk (2022-01-15; ; similar):

  • The phenotypic associations between sexual orientation and psychosocial distress (high depressive and anxiety symptoms) are not substantially moderated by recalled childhood factors increase (these include childhood gender nonconformity, early-life adversities and poor parent-child relationships).
  • Using the classical twin design, the genetic component of the relationship between sexual orientation and psychological distress increases as childhood gender nonconformity increases.
  • The individual-specific environmental influences on this relationship decrease and then increase as childhood gender nonconformity increases.
  • Genetic risk for psychological distress may manifest more readily among non-heterosexual adults who were gender-nonconforming during childhood; however, non-genetic (individual-specific) protective processes may partly mitigate this risk.

Background: Evidence indicates that minority stress does not sufficiently explain mental health disparities in non-heterosexual compared to heterosexual individuals. We investigated alternative mechanisms whereby childhood factors (childhood gender nonconformity, early-life adversities and parent-child interactions) moderate the relationships between sexual orientation and depressive and anxiety symptoms.

Methods: The sample comprised twin pairs from the Finnish Genetics of Sexuality and Aggression cohort (n = 3,166 individuals, mean age = 37.5 ± 2.93 years). Twin analyses using structural equation modelling was performed in OpenMx⁠. Specifically, we tested whether childhood factors differentially moderated the underlying genetic and environmental influences on the relationships between sexual orientation, and depressive and anxiety symptoms.

Results: The associations between non-heterosexuality, and depressive and anxiety symptoms (r = 0.09, 0.10 respectively) were statistically-significantly influenced by both genetic and environmental factors. The genetic influences explaining the relationships of sexual orientation with depressive and anxiety symptoms were maximal at high levels of childhood gender nonconformity (βA = 0.09 and 0.11 respectively) whereas the individual-specific environmental influences on these relationships were maximal at lower levels of childhood gender nonconformity (βE = −0.10).

Limitations: Childhood factors were assessed retrospectively in a cross-sectional design.

Conclusions: Childhood gender nonconformity is associated with increased genetic and decreased individual-specific environmental influences on mental health among non-heterosexual individuals. Childhood gender nonconformity may, thus, enhance genetic risk and non-genetic protective processes for depressive and anxiety symptoms among non-heterosexual individuals.

[Keywords: sexual orientation, depressive symptoms, anxiety symptoms, childhood stressors, behavior genetics]

“Multivariate Genome-wide Association Meta-analysis of over 1 Million Subjects Identifies Loci Underlying Multiple Substance Use Disorders”, Hatoum et al 2022

“Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders”⁠, Alexander S. Hatoum, Sarah M. C. Colbert, Emma C. Johnson, Spencer B. Huggett, Joseph D. Deak, Gita A. Pathak et al (2022-01-12; ; similar):

Genetic liability to substance use disorders can be parsed into loci conferring general and substance-specific addiction risk. We report a multivariate genome-wide association study that disaggregates general and substance-specific loci for problematic alcohol use, problematic tobacco use, and cannabis and opioid use disorders in a sample of 1,025,550 individuals of European and 92,630 individuals of African descent. Nineteen loci were genome-wide statistically-significant for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries PDE4B was significant (among others), suggesting dopamine regulation as a cross-trait vulnerability. The addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into the genetic architecture of general and substance-specific use disorder risk that may be leveraged as treatment targets.

“Associations of Parental and Perinatal Factors With Subsequent Risk of Stress-related Disorders: a Nationwide Cohort Study With Sibling Comparison”, Li et al 2022

“Associations of parental and perinatal factors with subsequent risk of stress-related disorders: a nationwide cohort study with sibling comparison”⁠, Yuchen Li, Arvid Sjölander, Huan Song, Sven Cnattingius, Fang Fang, Qian Yang, Lorena Fernández de la Cruz et al (2022; ; similar):

Little is known about the contribution of pregnancy-related parental and perinatal factors to the development of stress-related disorders. We aimed to investigate whether parental/​perinatal adversities entail higher risks of stress-related disorders in the offspring, later in life, by accounting for genetic and early environmental factors.

Based on the nationwide Swedish registers, we conducted a population-based cohort study of 3,435,747 singleton births (of which 2,554,235 were full siblings), born 1973–2008 and survived through the age of 5 years. Using both population-based and sibling-based designs, we employed Cox regression to assess the association between parental and perinatal factors with subsequent risk of stress-related disorders. We identified 55,511 individuals diagnosed with stress-related disorders in the population analysis and 37,433 in the sibling analysis.

In the population-based analysis we observed increased risks of stress-related disorders among offspring of maternal/​paternal age <25, single mothers, parity ≥4, mothers with BMI ≥ 25 or maternal smoking in early pregnancy, gestational diabetes, and offspring born moderately preterm (GA 32–36 weeks), or small-for-gestational-age.

These associations were statistically-significantly attenuated toward null in the sibling analysis. Cesarean-section was weakly associated with offspring stress-related disorders in population [hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06–1.12] and sibling analyses (HR 1.10, 95% CI 1.02–1.20).

Our findings suggest that most of the observed associations between parental and perinatal factors and risk of stress-related disorders in the population analysis are driven by shared familial environment or genetics, and underscore the importance of family designs in epidemiological studies on the etiology of psychiatric disorders.

“Shared Brain and Genetic Architectures between Mental Health and Physical Activity”, Zhang et al 2022

“Shared brain and genetic architectures between mental health and physical activity”⁠, Wei Zhang, Sarah E. Paul, Anderson Winkler, Ryan Bogdan, Janine D. Bijsterbosch (2022; ⁠, ; similar):

Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear.

Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (n = 6,389), canonical correlation analysis was applied to estimate associations between the amplitude and connectivity strength of sub-networks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health. We estimated the genetic correlation between mental health and physical activity measures, as well as putative causal relationships by applying linkage disequilibrium score regression, genomic structural equational modeling, and latent causal variable analysis to genome-wide association summary statistics (GWAS n = 91,105–500,199).

Physical activity and mental health were associated with connectivity strength and amplitude of the DMN, SN, and CEN (all r ≥ 0.12, all p < 0.048). These neural correlates exhibited highly similar loading patterns across mental health and physical activity models even when accounting for their shared variance. This suggests a largely shared brain network architecture between mental health and physical activity. Mental health and physical activity were also genetically correlated (|rg| = 0.085–0.121), but we found no evidence for causal relationships between them.

Collectively, our findings provide empirical evidence that mental health and physical activity have shared brain and genetic architectures and suggest potential candidate sub-networks for future studies on brain mechanisms underlying beneficial effects of physical activity on mental health.

“A Systematic Review and Meta-analysis of the Success of Blinding in Antidepressant RCTs”, Scott et al 2022

2022-scott.pdf: “A systematic review and meta-analysis of the success of blinding in antidepressant RCTs”⁠, Amelia J. Scott, Louise Sharpe, Ben Colagiuri (2022-01; ; similar):

  • Successful blinding is an important feature of double-blind randomized controlled trials⁠, and ensures that the safety and efficacy of treatments are accurately appraised.
  • In a range of fields (eg. chronic pain⁠, general medicine), few trials report assessing the success of blinding.
  • We do not know the frequency or success of blinding assessment among antidepressant RCTs within depression.
  • Only 4.7% of RCTs examining antidepressants in depression assess blinding.
  • Overall, blinding is not successful among either patients or investigators.

Successful blinding in double-blind RCTs is crucial for minimizing bias, however studies rarely report information about blinding. Among RCTs for depression, the rates of testing and success of blinding is unknown.

We conducted a systematic review and meta-analysis of the rates of testing, predictors, and success of blinding in RCTs of antidepressants for depression. Following systematic search, further information about blinding assessment was requested from corresponding authors of the included studies. We reported the frequency of blinding assessment across all RCTs, and conducted logistic regression analyses to assess predictors of blinding reporting. Participant and/​or investigator guesses about treatment allocation were used to calculate Bang’s Blinding Index (BI). The BI between RCT arms was compared using meta-analysis.

Across the 295 included trials, only 4.7% of studies assessed blinding. Pharmaceutical company sponsorship predicted blinding assessment; unsponsored trials were more likely to assess blinding. Meta-analysis suggested that blinding was unsuccessful among participants and investigators. Results suggest that blinding is rarely assessed, and often fails, among RCTs of antidepressants.

This is concerning considering controversy around the efficacy of antidepressant medication. Blinding should be routinely assessed and reported in RCTs of antidepressants, and trial outcomes should be considered in light of blinding success or failure.

[Keywords: randomized controlled trials, blinding, depression, antidepressants]

“United States National Institutes of Health Grant Funding for Psychedelic-assisted Therapy Clinical Trials from 2006–2020”, Barnett et al 2022

2022-barnett.pdf: “United States National Institutes of Health grant funding for psychedelic-assisted therapy clinical trials from 2006–2020”⁠, Brian S. Barnett, Sloane E. Parker, Jeremey Weleff (2022; ; similar):

Background: Medicine is currently experiencing a “psychedelic renaissance”, said by many to have commenced in 2006. Since then, clinical trials have consistently demonstrated promising findings for psychedelic-assisted therapies in the treatment of various mental health conditions and addictions. While most of this work has been privately funded, governmental biomedical research funding bodies in countries such as Australia, Canada, Israel, New Zealand, and the United Kingdom have begun supporting it. Given that the United States National Institutes of Health (NIH) is the largest public funder of biomedical research in the world, it is important to understand the degree to which the organization is supporting clinical trials of psychedelic-assisted therapies. We are unaware of existing literature quantifying direct NIH grant support for psychedelic-assisted therapy clinical trials, so we sought to answer this important question by searching all NIH grants awarded since the beginning of the psychedelic renaissance.

Methods: We queried NIH RePORTER, NIH’s grant database, for grants awarded from 2006–2020 mentioning the psychedelics 3,4-Methylenedioxymethamphetamine (MDMA), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ayahuasca⁠, dimethyltryptamine (DMT), ibogaine⁠, lysergic acid (LSD), mescaline⁠, peyote⁠, and psilocybin⁠. We manually reviewed resulting grants to determine whether they directly funded psychedelic-assisted therapy clinical trials.

Results: We identified 0 NIH grants directly funding psychedelic-assisted therapy clinical trials during the study period.

Conclusion: While governmental biomedical research funding bodies in other countries have begun funding clinical trials of psychedelic-assisted therapies during the psychedelic renaissance, NIH has yet to directly fund a single psychedelic-assisted therapy clinical trial. Concerns about risks related to psychedelics, a federal law preventing promotion of legalization of Schedule 1 drugs, and prioritization of grants for other types of studies on psychedelics may explain the dearth of NIH funding for psychedelic-assisted therapy clinical trials.

[Keywords: psychedelics, psychedelic-assisted therapy, hallucinogens, research funding, National Institutes of Health, psilocybin, MDMA, ibogaine, ayahuasca, LSD, dimethyltryptamine]

“Parents Think-incorrectly-that Teaching Their Children That the World Is a Bad Place Is Likely Best for Them”, Clifton & Meindl 2021

2021-clifton.pdf: “Parents think-incorrectly-that teaching their children that the world is a bad place is likely best for them”⁠, Jeremy D. W. Clifton, Peter Meindl (2021-12-27; ⁠, ⁠, ; similar):

[cf. CoZE⁠, risk aversion⁠, just-world hypothesis⁠, Johnson et al 2021⁠/​Roberts & Davidai 2021⁠, thrive /  ​survive] Primal world beliefs (‘primals’) are beliefs about the world’s basic character, such as the world is dangerous.

This article investigates probabilistic assumptions about the value of negative primals (eg. seeing the world as dangerous keeps me safe). We first show such assumptions are common. For example, among 185 parents, 53% preferred dangerous world beliefs for their children. We then searched for evidence consistent with these intuitions in 3 national samples and 3 local samples of undergraduates, immigrants (African and Korean), and professionals (car salespeople, lawyers, and cops), examining correlations between primals and eg.t life outcomes within 48 occupations (total n = 4,535) .

As predicted, regardless of occupation, more negative primals were almost never associated with better outcomes. Instead, they predicted less success, less job and life satisfaction, worse health, dramatically less flourishing, more negative emotion, more depression, and increased suicide attempts.

We discuss why assumptions about the value of negative primals are nevertheless widespread and implications for future research.

[Keywords: Primal world beliefs, success, job satisfaction, health, negative emotions, depression, suicide, life satisfaction, wellbeing]

“Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth”, Birmaher et al 2021

2021-birmaher.pdf: “Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth”⁠, Boris Birmaher, Danella Hafeman, John Merranko, Alyson Zwicker, Benjamin Goldstein, Tina Goldstein, David Axelson et al (2021-12-22; ; similar):

Question: Is bipolar disorder (BD) polygenic risk score (PRS) specifically associated with the familial transmission of BD in youth?

Findings: In this case-control study of 336 parents and 409 offspring, particularly those with mood disorders showed statistically-significantly and specifically higher BD PRS than those without BD. Parental and offspring BD PRS were associated with increased risk for offspring to develop BD, beyond the associations of parental BD diagnosis.

Meaning: Specifically higher BD PRS in BD offspring may add to the clinical validation of BD in youth and increases the risk for BD; however, given the BD PRS’s small association, it cannot be used alone to determine risk to develop BD.

Importance: Establishing genetic contributions to the transmission of bipolar disorder (BD) from parents to offspring may inform the risk of developing this disorder and further serve to validate BD in youth.

Objective: To evaluate the specific association of BD polygenic risk scores (PRSs) on the familial transmission and validity of pediatric BD.

Design, Setting, & Participants: This community-based case-control longitudinal study (Pittsburgh Biological Offspring Study) included parents with BD I/​II and their offspring and parents without BD (healthy or non-BD psychopathology) and their offspring. Participants were recruited between March 2001 and May 2007, and analysis took place from December 2020 to September 2021.

Exposures: PRSs for BD, major depressive disorder⁠, schizophrenia⁠, and attention-deficit hyperactivity disorder⁠.

Main Outcomes & Measures: Participants were prospectively evaluated using standardized interviews blind to parental diagnosis. DNA was extracted from saliva and genotyped. PRSs were constructed based on independent large-scale genome-wide association studies.

Results: A total of 156 parents with BD I/​II and 180 parents without BD (mean [SD] age, 39.6 [7.9] years; 241 female [72%]) as well as 251 offspring of parents with BD and 158 offspring of parents without BD (mean [SD] age, 10.4 [4.7] years; 213 female [52%]) of European ancestry were analyzed. Participants were assessed a mean of 6.7× during a mean (SD) of 13 (3.4) years of follow-up (84% retention).

More offspring of parents with BD developed BD (58 [23.1%] vs 8 [5.1%]; p < 0.001) and depression (126 [50.2%] vs 52 [32.9%]; p < 0.001) compared with offspring of parents without BD. BD PRS was higher in both parents and offspring with BD than parents and offspring without BD (parents: odds ratio⁠, 1.50; 95% CI, 1.19–1.89; p < 0.001; explained 4.8% of the phenotypic variance vs offspring: hazard ratio, 1.34; 95% CI, 1.03–1.7; p = 0.02; explained 5.0% of the phenotypic variance).

BD PRS did not differ across BD subtypes. In a model combining parental and offspring BD PRS, the parental BD PRS association with offspring BD was fully mediated by offspring BD PRS (hazard ratio, 1.40; 95% CI, 1.05–1.86; p = 0.02). Parental BD had a stronger direct association than parental or offspring BD PRS with offspring BD risk (hazard ratio, 5.21; 95% CI, 1.86–14.62; p = 0.002), explaining 30% of the variance. Parental and offspring BD PRS explained 6% of the BD onset variance beyond parental diagnosis [incremental validity]. There were no statistically-significant between-group differences in PRSs for major depressive disorder, schizophrenia, and attention-deficit/​hyperactivity disorder in parents or offspring and they were not statistically-significantly associated with BD onset.

Conclusions & Relevance: The findings of this study add to the extant clinical validation of BD in youth. Parental BD and offspring BD PRS independently associated with the risk of BD in offspring. Although this is promising, the association of BD PRS was relatively small and cannot be used alone to determine BD risk until further developments occur.

“Familial Clustering of Psychiatric Disorders and Low IQ”, Weiser et al 2021

2021-weiser.pdf: “Familial clustering of psychiatric disorders and low IQ”⁠, Mark Weiser, Or Frenkel, Daphna Fenchel, Dorit Tzur, Sven Sandin, Magdalena Janecka, Linda Levi, Michael Davidson et al (2021-12-16; ⁠, ; similar):

Background: Although the ICD and DSM differentiate between different psychiatric disorders, these often share symptoms, risk factors, and treatments. This was a population-based, case-control, sibling study examining familial clustering of all psychiatric disorders and low IQ, using data from the Israel Draft-Board Registry on all Jewish adolescents assessed between 1998 and 2014.

Methods: We identified all cases with autism spectrum disorder (ASD, n = 2128), severe intellectual disability (ID, n = 9572), attention-deficit hyperactive disorder (ADHD) (n = 3272), psychotic (n = 7902), mood (n = 9704), anxiety (n = 10 606), personality (n = 24 816), or substance/​alcohol abuse (n = 791) disorders, and low IQ (⩾2 SDs below the population mean, n = 31 186). Non-CNS control disorders were adolescents with Type-1 diabetes (n = 2427), hernia (n = 29 558) or hematological malignancies (n = 931). Each case was matched with 10 age-matched controls selected at random from the Draft-Board Registry, with replacement, and for each case and matched controls, we ascertained all full siblings. The main outcome measure was the relative recurrence risk (RRR) of the sibling of a case having the same (within-disorder RRR) or a different (across-disorder RRR) disorder.

Results: Within-disorder RRRs were increased for all diagnostic categories, ranging from 11.53 [95% confidence interval (CI): 9.23–14.40] for ASD to 2.93 (95% CI: 2.80–3.07) for personality disorders. The median across-disorder RRR between any pair of psychiatric disorders was 2.16 (95% CI: 1.45–2.43); the median RRR between low IQ and any psychiatric disorder was 1.37 (95% CI: 0.93–1.98). There was no consistent increase in across-disorder RRRs between the non-CNS disorders and psychiatric disorders and/​or low IQ.

Conclusion: These large population-based study findings suggest shared etiologies among most psychiatric disorders, and low IQ.

“More Treatment but No Less Depression: The Treatment-prevalence Paradox”, Ormel et al 2021

“More treatment but no less depression: The treatment-prevalence paradox”⁠, Johan Ormel, Steven D. Hollon, Ronald C. Kessler, Pim Cuijpers, Scott M. Monroe (2021-12-11; ; similar):

  • The puzzling paradox of more treatment but no less depression requires answers.
  • First incidence has probably not increased and offset treatment-driven prevalence drops.
  • The published trial literature substantially overestimates efficacy of treatments⁠.
  • In addition, treatment-quality gaps in routine care reduce effectiveness further.
  • Long-term outcome, under-treatment of recurrence, iatrogenicity need further study.

Treatments for depression have improved, and their availability has markedly increased since the 1980s. Mysteriously the general population prevalence of depression has not decreased. This “treatment-prevalence paradox” (TPP) raises fundamental questions about the diagnosis and treatment of depression.

We propose and evaluate 7 explanations for the TPP. First, 2 explanations assume that improved and more widely available treatments have reduced prevalence, but that the reduction has been offset by an increase in:

  1. misdiagnosing distress as depression, yielding more “false positive” diagnoses; or

  2. an actual increase in depression incidence.

    Second, the remaining 5 explanations assume prevalence has not decreased, but suggest that:

  3. treatments are less efficacious and

  4. less enduring than the literature suggests;

  5. RCT trial efficacy doesn’t generalize to real-world settings;

  6. population-level treatment impact differs for chronic-recurrent versus non-recurrent cases; and

  7. treatments have some iatrogenic consequences.

Any of these 7 explanations could undermine treatment impact on prevalence, thereby helping to explain the TPP.

Our analysis reveals that there is little evidence that incidence or prevalence have increased as a result of error or fact (Explanations 1 and 2), and strong evidence that (a) the published literature overestimates short-term and long-term treatment efficacy, (b) treatments are considerably less effective as deployed in “real world” settings, and (c) treatment impact differs substantially for chronic-recurrent cases relative to non-recurrent cases.

Collectively, these 4 explanations likely account for most of the TPP. Lastly, little research exists on iatrogenic effects of current treatments (Explanation 7), but further exploration is critical.

[Keywords:, depression, treatment, prevalence, more treatment but not less depression, explanations treatment-prevalence paradox]

Possible Explanations for the TPP Evidence and (Preliminary) Conclusions
  1. Have prevalence estimates been spuriously inflated due to increasing societal recognition of depression and associated diagnostic practices?
People have probably become more willing to admit depressive symptoms and to present for treatment, where they may receive false-positive diagnoses of MDD. But since epidemiologic surveys are conducted by well-trained interviewers using structured interviews to generate well-standardized diagnoses, it is unlikely that systematic drift at the population level of ‘caseness’ has occurred. Thus, an increase in “false positives” diagnoses would not mask a treatment-driven drop in “true” epidemiological prevalence.
  1. Have first incidence rates increased and offset a “true” treatment-driven reduction in point-prevalence?
Post-1980 first incidence studies and information on trends in causal risk factors are few, and too inconsistent to provide a conclusive answer. The handful of incidence studies, though, do not hint at any substantial rise in incidence since the 1980’s, and some even suggest a decrease. The evidence is sparse and uncertain, though, and ends around 2010. It seems unlikely that an true increase in depression incidence offsets any treatment-driven prevalence reduction.
  1. Do RCTs overestimate Acute-Phase treatment efficacy? Might biases both within the trials and across the larger literature on medication and psychotherapy inflate these short-term benefits of treatment? | R
RCTs do yield inflated acute-phase efficacy estimates. Adjusted for bias, efficacy drops by a third to half to-modest effect-sizes at best (about 0.30 for medications vs. pill-placebo and psychotherapy vs. care-as-usual). It is unclear how long Acute-Phase treatment benefits persist. Given the biases and large heterogeneity, it is not surprising that there is substantial disagreement about the clinical impact of treatments. It is not that treatments do not work, just that they do not work as well as the published literature suggests, or as is widely believed. Hence, the a more accurate estimate of short-term efficacy is at best modest, which can explain in part the TPP.
  1. Does research on maintenance of treatment gains and long-term efficacy over estimate beneficial effects? Are medication and psychotherapy interventions to prevent relapse-recurrence upwardly biased due to non-eligibility, insufficient response to Acute-Phase treatment, symptom return risk, and a variety of biases that need to be taken into account?
RCTs evaluating treatments aimed to reduce relapse-recurrence risk show substantial efficacy for preventive psychotherapy and for continued medication. However, these “effects” are rife with possible biases (misclassification, unblinding, allegiance effects, and differential mortality) complicating interpretation. In addition, many patients without sufficient response to acute-phase treatment are not eligible for relapse or recurrence prevention trials, and relapse-recurrence rates over 2 years after preventive treatment remain substantial, (though estimates vary greatly). Hence, limited overall long-term efficacy also may help to explain the TPP.
  1. Do RCTs generalize to real-world settings? How large is the gap between RCT-based efficacy and real-world effectiveness?
RCT-based efficacy does not generalize all that well to real-world practice, both for medication and for psychotherapy. Reasons: Large gaps in treatment choice and implementation quality exist in real-world practice; compared to the typical RCT patient, the real-world patient is somewhat less treatable (suicidal ideation; addiction, severe comorbidities). What the gaps, along with naturalistic follow-up studies, tell us is that treatment is not as effective long-term as we would like it to be. This explanation appears to be one of the strongest candidates for understanding the TPP as it also amplifies the contribution of explanations 3 and 4.
  1. Does treatment efficacy vary by different subtypes of depression? Specifically, could differential treatment benefits for chronic-recurrent versus non-recurrent cases dilute the potential beneficial effects of treatments for those most in clinical need? Further, chronic-recurrent cases are often very difficult to treat, or treatment-resistant.
The majority of people who initially become depressed have few if any recurrences, whereas recurrent and chronic cases become or remain depressed for much more time over the course of their lives. The availability of more and better treatments consequently has many more opportunities to benefit the smaller number of chronic-recurrent cases, while treatment effects at the population level for the many more non-recurrent cases most likely will be very limited. The resulting limited effects at the population level for the larger non-recurrent group could dilute more pronounced effects for the chronic-recurrent subgroup, obscuring a positive impact on prevalence for those in greatest need. However, it is unclear to what extent advances in preventive treatments specifically benefit the chronic-recurrent subgroup, or if these treatments are adequately transported into routine care for them (Explanations 3–5). Individually and combined, these subgroup considerations also provide potentially strong explanations for the TPP.
  1. Can treatment sometimes also have counterproductive consequences?
Oppositional perturbation refers to a medication-induced state of built-up perturbation in homeostatic monoamine regulatory mechanisms that “bounces back” when medication is discontinued, and then overshoots the normal balance of monoamine storage and release, increasing the risk for symptom return compared to spontaneous remission. Loss of agency refers to the hypothesis that either medication or psychotherapy could be counterproductive if either or both reduce self-help activity and active coping and thereby interfere with natural recovery mechanisms. Although some indirect evidence exists for each possibility, both mechanisms are largely speculative. The explanatory potential of this concern remains to be demonstrated for understanding the TPP, but is worthy of further investigation.

“Evidence for Excess Familial Clustering of Post Traumatic Stress Disorder in the US Veterans Genealogy Resource”, Cannon-Albright et al 2021

2021-cannonalbright.pdf: “Evidence for excess familial clustering of Post Traumatic Stress Disorder in the US Veterans Genealogy resource”⁠, Lisa A. Cannon-Albright, Jennifer Romesser, Craig C. Teerlink, Alun Thomas, Lawrence J. Meyer (2021-12-11; ; similar):

A genealogy of the United States has been record-linked to National Veteran’s Health Administration (VHA) patient data to allow non-identifiable analysis of familial clustering. This genealogy, including over 70 million individuals linked to over 1 million VHA patients, is the largest such combined resource reported. Analysis of familial clustering among VHA patients diagnosed with post-traumatic stress disorder (PTSD) allowed a test of the hypothesis of an inherited contribution to PTSD.

PTSD is associated strongly with military service and extended familial clustering data have not previously been presented. PTSD-affected VHA patients with genealogy data were identified by presence of an ICD diagnosis code in the VHA medical record in at least 2 different years. The Genealogical Index of Familiality (GIF) method was used to compare the average relatedness of VHA patients diagnosed with PTSD with their expected average relatedness, estimated from randomly selected sets of matched linked VHA patient controls. Relative risks for PTSD were estimated in first-degree, second-degree, and third-degree relatives of PTSD patients who were also VHA patients, using sex and age-matched rates for PTSD estimated from all linked VHA patients. statistically-significant excess pairwise relatedness, and statistically-significantly elevated risk for PTSD in first-degree, second-degree, and third-degree relatives was observed; multiple high-risk extended PTSD pedigrees were identified.

The analysis provides evidence for excess familial clustering of PTSD and identified high-risk PTSD pedigrees. These results support an inherited contribution to PTSD predisposition and identify a powerful resource of high-risk PTSD pedigrees for predisposition gene identification.

[Keywords: genealogy, PTSD, relative risk, high-risk pedigree⁠, US veterans genealogy]

US Veterans Genealogy: Genealogical data for over 70 million individuals gathered from public sources have been linked into an initial genealogy that represents 20–25% of the population of the United States (Cannon-Albright et al 2013, Cannon-Albright et al 2018). The demographic data for 13 million Veterans registered by the Veterans Health Administration (VHA) System was evaluated to record-link to this current US genealogy data using specific software tools included in GenMergeDB⁠, which has been used to create, and link records to, multiple genealogical resources for decades (Cannon-Albright et al 2018). ~1 million of the VHA patients were linked to an unique individual in the genealogy. After this initial record linking, no individual identifying data was used; informed consent was waived. A total of 284,382 of these linked VHA patients have extensive genealogy data, including at least 6 of their 14 immediate ancestors (both parents, and all 4 grandparents); many have much more genealogy data. This study analyzed these 284,382 VHA patients and their over 3 million ancestors, providing sufficient numbers of both close and distant relatives for appropriate genetic analysis. Access to over 300 million coded diagnoses or medical procedures linked to the 1 million VHA patients with linked genealogy (who remained unidentified) was approved by the Institutional Review Board and an oversight committee for the VHA resource.

The US Veterans Genealogy Resource currently includes VHA patients born in every state of the US. Among the ~1 million VHA patients with any linked genealogy data, 67,926 (6.5%) were female. We observed a similar percentage of among those 284,382 Veterans who link to an individual with at least 6 ancestors in the US Veterans Genealogy (4.5%). There are patients with genealogy identified in all 23 VHA Veterans Integrated Service Networks in 2017 (VISNs or local VHA health care providers) across the U.S. ~81% of the linked VHA patients have VISN data, and among those, the largest numbers of linked VHA patients were in VISN 8 (Florida, Puerto Rico, US Virgin Islands; n = 71,238), VISN 23 (Illinois, Iowa, Minnesota, Nebraska, North and South Dakota; n = 64,763), and VISN 16 (Arkansas, Louisiana, Mississippi, Oklahoma, Texas; n = 59,142). The birth years for VHA patients linked to genealogy data ranged from the 1890s to the 1990s. There was a large peak of births for the 972,306 linked males for the birth years 1921–1930 (24% of all linked males born in this range) and a peak for the 67,926 linked females for birth years 1951–1960 (20% of all linked females born in this range).

“Genome-wide Association Study and Multi-trait Analysis of Opioid Use Disorder Identifies Novel Associations in 639,709 Individuals of European and African Ancestry.”, Deak et al 2021

“Genome-wide association study and multi-trait analysis of opioid use disorder identifies novel associations in 639,709 individuals of European and African ancestry.”⁠, Joseph D. Deak, Hang Zhou, Marco Galimberti, Daniel F. Levey, Frank Wendt, Sandra Sanchez-Roige, Alexander S. Hatoum et al (2021-12-05; ; similar):

Background: Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci.
Methods: We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program (MVP), Psychiatric Genomics Consortium (PGC), iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total n = 639,709 (Ncases = 20,858) across ancestries. OUD cases were defined as having lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD).
Results: The EUR meta-analysis identified three genome-wide statistically-significant (GWS; p≤5× 10−8) lead SNPs, one at FURIN (rs11372849; p = 9.54× 10−10) and two OPRM1 variants (rs1799971, p = 4.92× 10−09 ; rs79704991, p = 1.37× 10−08; r2 = 0.02). Rs1799971 (p = 4.91× 10−08) and another OPRM1 variant (rs9478500; p = 1.95× 10−8; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14× 10−47) and AUD (rg = 0.77; p = 6.36× 10−78). The OUD-MTAG resulted in 18 GWS loci, all of which map to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes.
Conclusion: We identified multiple OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

“Trace Elements in Drinking Water and the Incidence of Attention-deficit Hyperactivity Disorder”, Thygesen et al 2021

2021-thygesen.pdf: “Trace elements in drinking water and the incidence of attention-deficit hyperactivity disorder”⁠, Malene Thygesen, Jörg Schullehner, Birgitte Hansen, Torben Sigsgaard, Denitza D. Voutchkova, Søren Munch Kristiansen et al (2021-12-01; ; similar):

Background: Trace elements have been suggested to have neurotoxic effects and increase the risk of neurodevelopmental disorders, but studies of a potential role of trace elements in relation to Attention-Deficit/​Hyperactivity Disorder (ADHD) are very limited. The objective of this study was to conduct an exploratory analysis investigating the associations between 17 geogenic trace elements (Ba⁠, Co⁠, Eu⁠, I⁠, Li⁠, Mo⁠, Rb⁠, Re⁠, Rh⁠, Sb⁠, Sc⁠, Se⁠, Si⁠, Sr⁠, Ti⁠, U and Y) found in Danish drinking water and the risk of developing ADHD.

Methods: In this cohort study, 284,309 individuals, born 1994–2007, were followed for incidence of ADHD from the age of 5 until the end of study, December 31, 2016. We conducted survival analyses, using Poisson regression to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CI) in 3 different confounder adjustment scenarios.

Results: In a model including adjustments for age, sex, calendar year, parental socio-economic status, neighborhood level socio-economic status and parental psychiatric illness, we found that 6 of the 17 trace elements (Sr, Rb, Rh, Ti, Sb and Re) were associated with an increased risk of ADHD, whereas 2 (Ba and I) were inversely associated with ADHD. However, when including region as a covariate in the model, most trace elements were no longer associated with ADHD or the association changed direction. 4 trace elements (I, Li, Rb, and Y) remained statistically-significantly associated with ADHD but in an inverse direction and for 3 of these (I, Li and Y), we found statistically-significant interactions with region in their association with ADHD.

Conclusion: The trace elements under investigation, at levels found in Danish drinking water, do not seem to contribute to the development of ADHD and our findings highlight the importance of examining consistency of associations across geographic areas.

[Keywords: trace elements, drinking water, neurodevelopment, ADHD]

“Deletion of Loss-of-Function-Intolerant Genes and Risk of 5 Psychiatric Disorders”, Wainberg et al 2021

2021-wainberg.pdf: “Deletion of Loss-of-Function-Intolerant Genes and Risk of 5 Psychiatric Disorders”⁠, Michael Wainberg, Daniele Merico, Guillaume Huguet, Mehdi Zarrei, Sebastien Jacquemont, Stephen W. Scherer et al (2021-12-01; ; similar):

Copy number variants (CNVs) are key etiological contributors to neuropsychiatric disorders. Most psychiatric CNV studies have focused on several dozen loci, collectively comprising less than 2% of the genome, where CNVs spontaneously recur sufficiently often to have individually detectable psychiatric associations. We hypothesized that knowledge of gene function could guide the search for nonrecurrent CNVs across the remaining 98%. Specifically, probability of loss-of-function intolerance (pLI) and loss-of-function observed/​expected upper bound fraction (LOEUF), 2 gene-level metrics of variation constraint against protein-truncating variants⁠, have been reported to be uniquely associated with the cognitive consequences of CNVs. Here, we show that pLI and LOEUF are similarly associated with the psychiatric consequences of both recurrent and nonrecurrent gene deletions.

Methods: We studied 431 146 self-reported White UK Biobank participants (234 544 females) with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes from linked inpatient, primary care, or death records, excluding participants with neurodevelopmental disorders (ICD-10 codes F70-F89) or who failed CNV quality control (eMethods in the Supplement). The North West Centre for Research Ethics Committee granted ethical approval to UK Biobank⁠, and informed consent was obtained from participants. We stratified genes into 8 categories based on Genome Aggregation Database’s pLI scores (low [0-<0.5], medium [0.5-<0.9], high [0.9-<0.99], or extreme [0.99–1]) and recurrence type (recurrent for genes overlapping any of 32 previously defined recurrent neuropsychiatric deletion CNV loci [eTable in the Supplement] and nonrecurrent otherwise). For each category, we used Firth logistic regression to test whether carriers of CNVs deleting any gene in the category had higher rates of anxiety disorders (F40/​F41), bipolar disorder (F31), major depressive disorder (MDD) (F32/​F33), obsessive-compulsive disorder (OCD) (F42), and schizophrenia (F20).

To guard against incorrectly associating the consequences of one CNV category to another, we excluded participants with recurrent deletions when computing associations for nonrecurrent deletions. We also excluded participants with higher-pLI deletions when computing associations for lower-pLI deletions of the same recurrence type. To reduce false-positives, we analyzed CNV calls from 2 different computational pipelines and required them to agree that a gene was fully deleted. As a sensitivity analysis, we replaced pLI with LOEUF, using thresholds capturing similar numbers of genes (low: ≥0.5; medium: 0.4-<0.5; high: 0.3-<0.4; extreme: 0-<0.3).

Results: Nonrecurrent CNVs deleting extreme-pLI genes were found in 787 participants (0.2%). A total of 571 unique extreme-pLI genes were deleted by nonrecurrent CNVs in 1 or more participants (Table 1), including key neurotransmitter receptors, ion channels, and neurodevelopmental genes.

pLI and LOEUF scores were associated with psychopathogenicity (Figure 1). The 787 participants with nonrecurrent extreme-pLI gene deletions exhibited statistically-significantly higher rates of anxiety (odds ratio [OR], 1.45 [95% CI, 1.11–1.88]), bipolar disorder (OR, 2.78 [95% CI, 1.24–6.23]), MDD (OR, 1.44 [95% CI, 1.14–1.81]), OCD (OR, 6.75 [95% CI, 1.25–36.31]), and schizophrenia (OR, 3.79 [95% CI, 1.45–9.94]). Conversely, the 54 413 participants (12.6%) with nonrecurrent low-pLI gene deletions displayed no greater rates of any disorder: anxiety (OR, 0.99 [95% CI, 0.96–1.03]), bipolar disorder (OR, 0.99 [95% CI, 0.87–1.13]), MDD (OR, 1.00 [95% CI, 0.97–1.03]), OCD (OR, 0.95 [95% CI, 0.76–1.19]), or schizophrenia (OR, 0.96 [95% CI, 0.82–1.13]).

pLI and LOEUF were also associated with CNV psychopathogenicity. Participants with recurrent CNVs deleting extreme-pLI genes had substantially higher rates of anxiety (OR, 1.78 [95% CI, 1.27–2.51]), bipolar disorder (OR, 6.46 [95% CI, 1.49–28.02]), MDD (OR, 2.15 [95% CI, 1.60–2.88]), OCD (OR, 12.07 [95% CI, 1.45–100.77]), and schizophrenia (OR, 8.39 [95% CI, 2.89–24.37]). Conversely, participants with recurrent deletions of low-pLI genes had only modestly increased risk of anxiety (OR, 1.34 [95% CI, 1.06–1.70]) and MDD (OR, 1.25 [95% CI, 1.01–1.54]) and did not have statistically-significantly altered risk of bipolar disorder (OR, 1.39 [95% CI, 0.56–3.50]), OCD (OR, 0.36 [95% CI, 0.09–1.42]), or schizophrenia (OR, 1.41 [95% CI, 0.39–5.13]).

Discussion: While recurrent CNVs are well-known contributors to psychopathology, the current study showed that nonrecurrent CNVs are associated with psychiatric disease risk. Gene-level metrics of mutational constraint were associated with psychopathogenic CNVs, both recurrent and nonrecurrent. The 0.2% of participants with nonrecurrent deletions of extreme-pLI genes had statistically-significantly higher rates of all 5 psychiatric disorders surveyed, whereas participants with nonrecurrent deletions of only low-pLI genes (the vast majority) had no detectable increase in psychiatric disease risk. Limitations of this study include microarray-based CNV calling, incomplete phenotype ascertainment, and ignoring partial gene deletions, as well as the inability to generalize these findings to other racial and ethnic groups.

These results suggest that interpreting CNVs using mutational constraint metrics, such as pLI, may augment population-based psychiatric genomic screening programs. Our approach may ultimately help identify opportunities for early diagnosis and intervention, including personalized therapies targeting specific nonrecurrent CNVs.

“What Doesn’t Kill Her, Will Make Her Depressed”, Li & Sunder 2021

2021-li.pdf: “What doesn’t kill her, will make her depressed”⁠, Yanan Li, Naveen Sunder (2021-12-01; ⁠, ; similar):

  • We estimate the long run impact of the 1959–61 Chinese famine on mental health.
  • Overall, the famine had null effects for cohorts born during the famine.
  • However, women experience large and statistically-significant negative effects, while men have insignificant effects.
  • The results are plausibly driven by selection of the fittest and the Fetal origins hypothesis⁠.

In this paper we study the long run effects of the 1959–61 Chinese Famine on mental health outcomes. We focus on cohorts that were born during the famine and examine their mental health as adults, when they are roughly 55 years of age.

We find that early-life exposure to this famine leads to a large statistically-significant negative impact on women’s mental health, while there is limited effect on men. This gender differential effect is observed because male fetuses experience a stronger natural selection as compared to female fetuses, which implies that in the longer run, surviving females may exhibit larger detrimental effects of early-life famine exposure.

Thus, the observed effects are a composite of 2 well-established factors, the survival of the fittest and the Fetal Origins hypothesis.

[Keywords: famine, difference-in-differences⁠, mental health, fertility, China]

“Social Distancing and Influenza Mortality in 1918 Did Not Increase Suicide Rates in the United States”, Gaddy 2021

“Social distancing and influenza mortality in 1918 did not increase suicide rates in the United States”⁠, Hampton Gray Gaddy (2021-12; similar):

  • 1918–19 ‘lockdowns’ in US cities did not correlate with elevated suicide rates.
  • US cities with higher Spanish influenza mortality also did not have higher suicide rates.
  • Both of these findings contradict previous, weaker analyses.
  • Limited evidence suggests that social distancing may have decreased suicide rates.

Recent research has suggested that the social distancing mandates introduced in the United States during the main waves of the 1918–20 influenza pandemic caused an increase in suicide rates. However, that finding relies on poor-quality, temporally mismatched data and has signs of omitted variable bias. Similarly, a long-standing finding that American suicide rates in 1918–20 were also boosted by the influenza mortality of the time has gone unquestioned in the literature, despite the original research admitting its risk of ecological fallacy.

Using higher-powered mortality data, I cast doubt on both findings by analyzing the experiences of the pandemic in 43 of the largest American cities of the time. In line with some populations’ experiences of COVID-19, I report tentative evidence that social distancing mandates during the 1918–20 pandemic may have been associated with decreased suicide rates.

Larger, cross-national investigations of the effects of historical pandemics and social distancing mandates on mental health and suicide are needed.

[Keywords: 1918 influenza pandemic, United States, suicide, social distancing, mental health, social epidemiology]

“Studies of Autistic Traits in the General Population Are Not Studies of Autism”, Sasson & Bottema-Beutel 2021

2021-sasson.pdf: “Studies of autistic traits in the general population are not studies of autism”⁠, Noah J. Sasson, Kristen Bottema-Beutel (2021-11-26; similar):

Studies of autistic traits in the general population are becoming increasingly prevalent. In this letter to the editor, we caution researchers against framing and interpreting studies of autistic traits in the general population as extending to autism and implore them to be clear about when their study sample does and does not include autistic participants.

[Keywords: autism quotient⁠, autism traits, autistic traits, broad autism phenotype]

A recent study in this journal, “Anthropomorphic Tendencies in Autism” (Clutterbuck et al in press), included no autistic people as participants. Rather, the authors surveyed an online sample from the general population using the Autism Spectrum Quotient (AQ10), a 10-item self-report measure of autistic traits that may not be psychometrically sound in the general population (Taylor et al 2020). The nature of the sample was not clear from the title or the abstract, which states the study “re-examined the relationship between autism and anthropomorphism in a large sample of adults.” Clarity about participants is important, because studies about autistic traits and studies about autism are not the same…

“Dimensional Characterizations of Gender Diversity Are Associated With Higher Polygenic Propensity for Cognitive Performance in a Neurodiverse Sample”, Thomas et al 2021

“Dimensional characterizations of gender diversity are associated with higher polygenic propensity for cognitive performance in a neurodiverse sample”⁠, Taylor R. Thomas, Ashton J. Tener, Ji Seung Yang, John F. Strang, Jacob J. Michaelson (2021-11-24; ; similar):

Both sex and gender are characteristics that play a key role in risk and resilience in health and well-being. Current research lacks the ability to quantitatively describe gender and gender diversity, and is limited to endorsement of categorical gender identities, which are contextually and culturally dependent. A more objective, dimensional approach to characterizing gender diversity will enable researchers to advance the health of gender-diverse people by better understanding how genetic factors interact to determine health outcomes. To address this research gap, we leveraged the Gender Self-Report (GSR), a questionnaire that captures multiple dimensions of gender diversity. We then performed polygenic score associations with brain-related traits like cognitive performance, personality, and neuropsychiatric conditions. The GSR was completed by n = 818 independent adults with or without autism in the SPARK cohort, and GSR factor analysis identified two factors: Binary (divergence from gender presumed by designated sex to the opposite) and Nonbinary (divergence from male and female gender norms) Gender Diversity (BGD and NGD, respectively). We performed polygenic associations (controlling for age, sex, and autism diagnostic status) in a subset of n = 452 individuals and found higher polygenic propensity for cognitive performance was associated with greater BGD (B = 0.017, p = 0.049) and NGD (B = 0.036, p = 0.002), and higher polygenic propensity for educational attainment was also associated with greater NGD (B = 0.030, p = 0.015). We did not observe any statistically-significant associations with personality or neuropsychiatric polygenic scores in this sample. Overall, our results suggest cognitive processes and gender diversity share overlapping genetic factors, indicating the biological utility of the GSR while also underscoring the importance of quantitatively measuring gender diversity in health research contexts.

“Adults Who Microdose Psychedelics Report Health Related Motivations and Lower Levels of Anxiety and Depression Compared to Non-microdosers”, Rootman et al 2021

“Adults who microdose psychedelics report health related motivations and lower levels of anxiety and depression compared to non-microdosers”⁠, Joseph M. Rootman, Pamela Kryskow, Kalin Harvey, Paul Stamets, Eesmyal Santos-Brault, Kim P. C. Kuypers et al (2021-11-18; ⁠, ; backlinks; similar):

The use of psychedelic substances at sub-sensorium microdoses⁠, has gained popular academic interest for reported positive effects on wellness and cognition.

The present study describes microdosing practices, motivations and mental health among a sample of self-selected microdosers (n = 4,050) and non-microdosers (n = 4,653) via a mobile application.

Psilocybin was the most commonly used microdose substances in our sample (85%) and we identified diverse microdose practices with regard to dosage, frequency, and the practice of stacking which involves combining psilocybin with non-psychedelic substances such as Lion’s Mane mushrooms⁠, chocolate⁠, and niacin⁠. Microdosers were generally similar to non-microdosing controls with regard to demographics, but were more likely to report a history of mental health concerns. Among individuals reporting mental health concerns, microdosers exhibited lower levels of depression, anxiety, and stress across gender. Health and wellness-related motives were the most prominent motives across microdosers in general, and were more prominent among females and among individuals who reported mental health concerns.

Our results indicate health and wellness motives and perceived mental health benefits among microdosers, and highlight the need for further research into the mental health consequences of microdosing including studies with rigorous longitudinal designs.

[Keywords: addiction, ADHD⁠, anxiety, Autism spectrum disorders, Bipolar disorder, Depression, human behaviour, Obsessive Compulsive Disorder, Post-Traumatic Stress Disorder, psychiatric disorders, psychology, psychosis, Schizophrenia]

Design and participants: We collected cross-sectional data between November 2019 and July 2020 from self-selected respondents recruited via media related to psychedelic use such as podcasts and online psychedelic research conference presentations. Participants were directed to the website⁠. The website directed participants to install the Quantified Citizen (QC) application32 to their Apple mobile device. The QC application was only available on Apple iOS devices at the time of study; as such, participants were limited to iPhone users. The application hosted the study and participants completed questionnaires and assessments entirely within the application. To encourage participation, users were explicitly not asked to submit any personally identifiable information and use of the application was designed to be completely anonymous. All participants endorsed being 18 years of age or older and capable of responding to an English survey. Nonetheless, given the anonymous nature of the study design, these inclusion criteria could not be verified beyond participant self-report. All participants provided informed consent prior to study initiation. Data are drawn from the baseline and supplementary questionnaires from a longitudinal study of microdosing and mental health and consisted of a maximal total of 123 questions, organized hierarchically such that many items were contingent on prior responses.

“The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum”, Mahjani et al 2021

“The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum”⁠, Behrang Mahjani, Lambertus Klei, Manuel Mattheisen, Matthew W. Halvorsen, Abraham Reichenberg, Kathryn Roeder et al (2021-11-18; ; similar):

Objective: Obsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of genetic variation across the allele frequency spectrum to this heritability remains uncertain. The authors used 2 new homogeneous cohorts to estimate the heritability of OCD from inherited genetic variation and contrasted the results with those of previous studies.

Methods: The sample consisted of 2,090 Swedish-born individuals diagnosed with OCD and 4,567 control subjects, all genotyped for common genetic variants, specifically >400,000 single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, the authors estimated the heritability of OCD, both overall and partitioned according to MAF bins.

Results: Narrow-sense heritability of OCD was estimated at 29% (SE = 4%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 10% of heritability, and estimated heritability per MAF bin roughly followed expectations based on a simple model for SNP-based heritability.

Conclusions: These results indicate that common inherited risk variation (MAF ≥0.01) accounts for most of the heritable variation in OCD. SNPs with low MAF contribute meaningfully to the heritability of OCD, and the results are consistent with prediction under the “infinitesimal model” (also referred to as the “polygenic model”), where risk is influenced by a large number of loci across the genome and across MAF bins.

…The heritability of OCD, historically estimated by analysis of twin and family studies and within the context of the ACE model (A, additive genetic, also known as narrow-sense heritability; C, shared environment; and E, nonshared environment), is reported to be in the range of 35%–50% (1, 4, 8–14)…It is useful to compare the heritability results from family-based and SNP-based approaches. Family-based studies, being more direct, typically yield estimates of heritability with lower standard errors, whereas the inaccuracy of estimating distant relationships from genetic data tends to produce fuzzier estimates. Family-based estimates also tend to yield higher estimates of heritability because the familial covariance reflects both rare and common genetic variation, whereas SNP-based estimates mostly arise from covariance due to common genetic variants. Looking at the results summarized above, one might conclude that this is also operating for OCD, that is, that family-based studies are producing higher heritability estimates than SNP-based studies.

However, in an influential study of data from the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) by Davis et al5 (1,061 case subjects, 4,236 control subjects, 373,846 SNPs), there was no evidence for heritability from SNPs with minor allele frequency (MAF) < 0.05, and over 60% of total heritability mapped to the most common variants (MAF >0.3). In addition, in a meta-analysis of data from the International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Study (OCGAS) (16), ~60% of heritability was accounted for by SNPs with MAF >0.4 in both the OCGAS sample alone and in the combined sample. If this observation were true, it could have profound implications for which evolutionary forces shaped this unusual mapping of risk alleles to their population frequency distribution. For example, balancing selection⁠, where multiple alleles are maintained in the gene pool of a population at frequencies larger than expected from genetic drift alone, may play a role in OCD.

“Autism-related Dietary Preferences Mediate Autism-gut Microbiome Associations”, Yap et al 2021

2021-yap.pdf: “Autism-related dietary preferences mediate autism-gut microbiome associations”⁠, Chloe X. Yap, Anjali K. Henders, Gail A. Alvares, David L. A. Wood, Lutz Krause, Gene W. Tyson, Restuadi Restuadi et al (2021-11-11; ⁠, ; backlinks; similar):

  • Limited autism-microbiome associations from stool metagenomics of n = 247 children
  • Romboutsia timonensis was the only taxa associated with autism diagnosis
  • Autistic traits such as restricted interests are associated with less-diverse diet
  • Less-diverse diet, in turn, is associated with lower microbiome alpha-diversity

There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way.

We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project.

We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency⁠. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency.

Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.

[Keywords: autism spectrum disorder, autism, gut microbiome, restricted and repetitive behaviors and interests, diet, metagenomics, stool consistency, brain-gut-microbiome axis]

“A Nation-Wide Swedish Cohort Study on Early Maternal Age at First Childbirth and Risk for Offspring Deaths, Accidents, and Suicide Attempts”, Sujan et al 2021

2021-sujan.pdf: “A Nation-Wide Swedish Cohort Study on Early Maternal Age at First Childbirth and Risk for Offspring Deaths, Accidents, and Suicide Attempts”⁠, Ayesha C. Sujan, Lauren M. O’Reilly, Martin E. Rickert, Henrik Larsson, Paul Lichtenstein, A. Sara Oberg et al (2021-11-11; ; similar):

In a sample of over one million Swedish first-born offspring, we examined associations between early maternal age at first childbirth (MAFC; i.e., < 20 and 20–24 vs 25–29 years) and offspring non-accidental deaths, accidental deaths, deaths by suicide, non-fatal accidents, and suicide attempts.

We included year of birth and several maternal and paternal characteristics as covariates and conducted maternal cousin comparisons to adjust for unmeasured confounding.

Early MAFC (eg. teenage childbearing) was associated with all outcomes, with the most pronounced risk elevation for accidental deaths [Hazard Ratio (HR) < 20 2.50, 95% confidence interval (CI) 2.23, 2.80], suicides (HR < 20 2.08, 95% CI 1.79, 2.41), and suicide attempts (HR < 20 2.85, 95% CI 2.71, 3.00). Adjusting for covariates and comparing cousins greatly attenuated associations (eg. accidental deaths HR < 20 1.61, 95% CI 1.22, 2.11; suicides HR < 20 1.01, 95% CI 0.69, 1.47; and suicide attempts HR < 20 1.35, 95% CI 1.19, 1.52). A similar pattern emerged for non-accidental deaths and non-fatal accidents.

Therefore, results indicated maternal background factors may be largely responsible for observed associations.

[Keywords: maternal age at childbearing, teenage childbearing, offspring outcomes, deaths, suicides, accidents]

“Largest Psilocybin Trial Finds the Psychedelic Is Effective in Treating Serious Depression”, Goldhill 2021

“Largest psilocybin trial finds the psychedelic is effective in treating serious depression”⁠, Olivia Goldhill (2021-11-09; ; similar):

Eagerly awaited results of the largest-ever study of psilocybin were announced Tuesday, with Compass Pathways revealing the psychedelic drug was highly efficacious as a therapy for treatment-resistant depression⁠. Still, the company’s stock price dropped 16.4% by the close of trading, perhaps because of safety concerns among investors.

The Phase 2b study is the largest randomized, controlled, double-blind trial of psilocybin, the psychedelic compound in magic mushrooms. The company said it found that patients who were given the highest dose, 25 milligrams, had a statistically-significant decrease in depressive symptoms compared to those given 1 milligram, which is such a low dose it functions as a placebo.

Overall, 29.1% of patients in the highest-dose group were in remission 3 weeks after treatment, compared to 7.6% of those in the control group, and more than a quarter of the patients in the 25-milligram arm were still in remission 3 months after treatment. Those who received the highest dose also experienced an average reduction on a measure of clinical depression (the Montgomery-Asberg Depression Rating Scale) that was 6.6 points greater than those who took 1 milligram. Other patients were given a 10-milligram dose, but there was not a statistically-significant impact for those patients compared with the 1-milligram arm.

“Psilocybin Therapy Increases Cognitive and Neural Flexibility in Patients With Major Depressive Disorder”, Doss et al 2021

“Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder”⁠, Manoj K. Doss, Michal Považan, Monica D. Rosenberg, Nathan D. Sepeda, Alan K. Davis, Patrick H. Finan et al (2021-11-08; ; similar):

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin.

In an open-label study of 24 patients with major depressive disorder⁠, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (eg. the anterior cingulate cortex⁠, or ACC).

Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility.

These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.

“Sex Significantly Impacts the Function of Major Depression-linked Variants in Vivo”, Mulvey et al 2021

“Sex significantly impacts the function of major depression-linked variants in vivo”⁠, Bernard Mulvey, Din Selmanovic, Joseph D. Dougherty (2021-11-04; ; similar):

Genome-wide association studies have discovered blocks of common variants—likely transcriptional-regulatory—associated with major depressive disorder (MDD), though the functional subset and their biological impacts remain unknown. Likewise, why depression occurs in females more frequently than males is unclear. We therefore tested the hypothesis that risk-associated functional variants interact with sex and produce greater impact in female brains. We developed methods to directly measure regulatory variant activity and sex interactions using massively parallel reporter assays (MPRAs) in the mouse brain in vivo, in a cell type-specific manner. We measured activity of >1,000 variants from >30 MDD loci, identifying extensive sex-by-allele effects in mature hippocampal neurons and suggesting sex-differentiated impacts of genetic risk may underlie sex bias in disease. Unbiased informatics approaches indicated that functional MDD variants recurrently disrupt sex hormone receptor binding sequences. We confirmed this with MPRAs in neonatal brains, comparing brains undergoing the masculinizing hormone surge to hormonally-quiescent juveniles. Our study provides novel insights into the influence of age, biological sex, and cell type on regulatory-variant function, and provides a framework for in vivo parallel assays to functionally define interactions between organismal variables like sex and regulatory variation.

Like This Meta-analysis: Screen Media and Mental Health”, Ferguson et al 2021

2021-ferguson.pdf: Like this meta-analysis: Screen media and mental health”⁠, Christopher J. Ferguson, Linda K. Kaye, Dawn Branley-Bell, Patrick Markey, James D. Ivory, Dana Klisanin et al (2021-11; ; similar):

The question of whether screen time⁠, particularly time spent with social media and smartphones, influences mental health outcomes remains a topic of considerable debate among policy makers, the public, and scholars. Some scholars have argued passionately that screen media may be contributing to an increase in poor psychosocial functioning and risk of suicide, particularly among teens. Other scholars contend that the evidence is not yet sufficient to support such a dramatic conclusion.

The current meta-analysis included 37 effect sizes from 33 separate studies. To consider the most recent research, all studies analyzed were published between 2015 and 2019. Across studies, evidence suggests that screen media plays little role in mental health concerns. In particular, there was no evidence that screen media contribute to suicidal ideation or other mental health outcomes. This result was also true when investigating smartphones or social media specifically.

Overall, as has been the case for previous media such as video games, concerns about screen time and mental health are not based in reliable data.

[Keywords: social media, suicide, smartphones, adolescence, depression]

…Main results for the meta-analysis are presented in Table 1: As can be seen from these results, the effect sizes for relationships between screen time as well as specific screen media such as smartphones and social media were very small and in no case passed the r = 0.10 threshold for interpretation as hypothesis supportive. statistically-significant heterogeneity existed in all data sets, although this was particularly true for correlational studies and those which examined general screen time, as opposed to longitudinal studies or those examining specific screen media. Longitudinal studies did not provide any more evidence for effects than correlational studies, suggesting there is little evidence for a cumulative effect…Effect sizes were slightly smaller in more recent years. It should be noted that the statistical sensitivity to detect these moderator effects was relatively low due to the small number of studies.

“Reality Shifting: Psychological Features of an Emergent Online Daydreaming Culture”, Somer et al 2021

“Reality shifting: psychological features of an emergent online daydreaming culture”⁠, Eli Somer, Etzel Cardeña, Ramiro Figueiredo Catelan, Nirit Soffer-Dudek (2021-10-30; ; similar):

Reality shifting (RS) is a trendy mental activity that emerged abruptly following the flare-up of the COVID-19 pandemic in 2020 and seems to be practiced mainly by members of the post-millennial generation⁠. RS, described as the experience of being able to transcend one’s physical confines and visit alternate, mostly fictional, universes, is discussed by many on Internet platforms. One RS forum boasts over 40,000 members and RS clips on some social media platforms have been viewed over 1.7 billion times…The pertinent hashtag #realityshifting on TikTok has accumulated over 706 million views (TikTok, #realityshifting, n.d.-a) while #shiftingrealities has accrued over 1.8 billion views (TikTok #shiftingrealities, n.d.-b). The term has also received mainstream media coverage, as exemplified by a recent story in the Washington Post (Andrews 2021)⁠. Here is how a member described her practice online:

Shifting is a very strange experience. It’s like an extremely vivid dream, yet it’s more real than any dream I’ve ever had. Before I plan on shifting, I write myself a script in the notes app on my phone, in which I plan exactly what happens in the desired reality. This makes it easier to visualize exactly what I want to happen—so I might script that I want to go to Hogwarts and for Draco to be my boyfriend, or that he will flirt with me.

The experience of shifting is reportedly facilitated by specific induction methods involving relaxation, concentration of attention, and autosuggestion. Some practitioners report a strong sense of presence in their desired realities, reified by some who believe in the concrete reality of the alternate world they shift to. One of the most popular alternate universes involves environments adopted from the Harry Potter book and film series.

…We describe the phenomenology of RS as reported online and then compare it to related phenomena such as hypnosis⁠, tulpamancy⁠, dissociation⁠, immersive and maladaptive daydreaming⁠, and lucid dreaming⁠. We propose a theoretical model of interactive factors giving rise to RS, and conclude that it is an important, uninvestigated emerging phenomenon and propose future research directions.

Respawning: Respawning is a radical manifestation of the escapist psychological role RS can play. Some RS practitioners are motivated to permanently sever their ties with the current reality (CR) and live in an alternate desired reality (DR) of choice, opting to leave their “clones” (ie. someone who will continue interacting in the CR) behind and leaving the CR forever (eg. Madame Lovi 2003).

“Global Urbanicity Is Associated With Brain and Behaviour in Young People”, Xu et al 2021

2021-xu.pdf: “Global urbanicity is associated with brain and behaviour in young people”⁠, Jiayuan Xu, Xiaoxuan Liu, Qiaojun Li, Ran Goldblatt, Wen Qin, Feng Liu, Congying Chu, Qiang Luo, Alex Ing et al (2021-10-28; ⁠, ; similar):

Urbanicity is a growing environmental challenge for mental health.

Here, we investigate correlations of urbanicity with brain structure and function, neuropsychology and mental illness symptoms in young people from China and Europe (total n = 3,867). We developed a remote-sensing satellite measure (UrbanSat) to quantify population density at any point on Earth.

UrbanSat estimates of urbanicity were correlated with brain volume, cortical surface area and brain network connectivity in the medial prefrontal cortex and cerebellum. UrbanSat was also associated with perspective-taking and depression symptoms, and this was mediated by neural variables. Urbanicity effects were greatest when urban exposure occurred in childhood for the cerebellum, and from childhood to adolescence for the prefrontal cortex.

As UrbanSat can be generalized to different geographies, it may enable assessments of correlations of urbanicity with mental illness and resilience globally.

“Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated With Proxy Alzheimer’s Disease”, Wightman et al 2021

“Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s Disease”⁠, Douglas P. Wightman, Jeanne E. Savage, Christiaan A. de Leeuw, Iris E. Jansen, Danielle Posthuma (2021-10-18; ⁠, ; similar):

We generated a proxy Alzheimer’s disease phenotype for 148,508 individuals in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer’s disease. We identified four genes statistically-significantly associated with the proxy phenotype, three of which have been previously associated with clinically diagnosed Alzheimer’s disease (SORL1, TREM2, and TOMM40). We identified one gene (HEXA) which has not been previously associated with Alzheimer’s disease but is known to contribute to neurodegenerative disease. Here we show that proxy Alzheimer’s disease can capture some of the rare variant association signal for Alzheimer’s disease and can be used to highlight genes and variants of interest. The proxy phenotype allows for the utilisation of large genetic databases without clinically diagnosed Alzheimer’s disease patients to uncover variants and genes that contribute to Alzheimer’s disease.

“Genetic Map of Regional Sulcal Morphology in the Human Brain”, Sun et al 2021

“Genetic map of regional sulcal morphology in the human brain”⁠, Benjamin B. Sun, Stephanie J. Loomis, Fabrizio Pizzagalli, Natalia Shatokhina, Jodie N. Painter, Christopher N. Foley et al (2021-10-15; ; similar):

The human brain is a complex organ underlying many cognitive and physiological processes, affected by a wide range of diseases. Genetic associations with macroscopic brain structure are emerging, providing insights into genetic sources of brain variability and risk for functional impairments and disease. However, specific associations with measures of local brain folding, associated with both brain development and decline, remain under-explored. Here we carried out detailed large-scale genome-wide associations of regional brain cortical sulcal measures derived from magnetic resonance imaging data of 40,169 individuals in the UK Biobank. Combining both genotyping and whole-exome sequencing data (~12 million variants), we discovered 388 regional brain folding associations across 77 genetic loci at p < 5× 10−8, which replicated at p < 0.05. We found genes in associated loci to be independently enriched for expression in the cerebral cortex, neuronal development processes and differential regulation in early brain development. We integrated coding associations and brain eQTLs to refine genes for various loci and demonstrated shared signal in the pleiotropic KCNK2 locus with a cortex-specific KCNK2 eQTL. Genetic correlations with neuropsychiatric conditions highlighted emerging patterns across distinct sulcal parameters and related phenotypes. We provide an interactive 3D visualization of our summary associations, making complex association patterns easier to interpret, and emphasising the added resolution of regional brain analyses compared to global brain measures. Our results offer new insights into the genetic architecture underpinning brain folding and provide a resource to the wider scientific community for studies of pathways driving brain folding and their role in health and disease.

“Investigating Perceived Heritability of Mental Health Disorders and Attitudes toward Genetic Testing in the United States, United Kingdom, and Australia”, Morosoli et al 2021

2021-morosoli.pdf: “Investigating perceived heritability of mental health disorders and attitudes toward genetic testing in the United States, United Kingdom, and Australia”⁠, José Juan Morosoli, Lucía Colodro-Conde, Fiona Kate Barlow, Sarah E. Medland (2021-09-25; ; similar):

Our beliefs about the heritability of psychiatric traits may influence how we respond to the use of genetic information in this area. In the present study, we aim to inform future education campaigns as well as genetic counseling interventions by exploring common fears and misunderstandings associated with learning about genetic predispositions for mental health disorders.

We surveyed 3,646 genetic research participants from Australia [QIMR], and 960 members of the public from the United Kingdom, and the United States [Prolific Academic survey platform], and evaluated attitudes toward psychiatric genetic testing. Participants were asked hypothetical questions about their interest in psychiatric genetic testing, perceived usefulness of psychiatric genetic testing, and beliefs about malleability of behavior, among others. We also asked them to estimate the heritability of alcohol dependence, schizophrenia, and major depression.

We found a high interest in psychiatric genetic testing. In most cases, more than a third of the participants showed serious concerns related to learning about personal genetic predisposition, such as not wanting to have children if they knew they had a high genetic predisposition, or not wanting to choose a partner with a high genetic predisposition for a mental health problem. Finally, we found a statistically-significant association between most participants’ attitudes and their lay estimates of heritability, which highlights the complexity of educating the public about genetics.

[Keywords: attitudes, genetic literacy, genetic testing, public understanding of genetics]

“A Biomarker-based Study of Prenatal Smoking Exposure and Autism in a Finnish National Birth Cohort”, Cheslack-Postava et al 2021

2021-cheslackpostava.pdf: “A biomarker-based study of prenatal smoking exposure and autism in a Finnish national birth cohort”⁠, Keely Cheslack-Postava, Andre Sourander, Susanna Hinkka-Yli-Salomäki, Ian W. McKeague, Heljä-Marja Surcel et al (2021-09-10; ; similar):

This study explored whether prenatal exposure to tobacco smoke in mothers is related to the diagnosis of autism in their children, by measuring the levels of cotinine⁠, a biomarker for tobacco exposure, in stored serum samples drawn from mothers during pregnancy.

The levels of cotinine in the mothers of children diagnosed with autism were similar to those in the mothers of control children of similar age and gender distribution.

Maternal exposure to tobacco smoke during pregnancy is a common and persistent exposure linked to adverse neurodevelopmental outcomes in the offspring. However, previous studies provide mixed evidence regarding the relationship between prenatal smoking and offspring autism.

This study used cotinine level, a biomarker for nicotine⁠, to investigate the relationship between prenatal smoking and autism. The authors conducted a population-based case-control study nested in a national cohort of all births in Finland from 1987 to 2005. Cases diagnosed with childhood autism (ICD-10 /  ​9 code F84.0/​299.0) through 2007 were identified using data from linked national registers. Each case was matched with a control on date of birth (±30 days), sex, and place of birth (n = 962 pairs). Maternal serum cotinine levels were prospectively measured in first-trimester to early second-trimester serum samples archived in a national biobank using a quantitative immunoassay. Data were analyzed using conditional logistic regression⁠.

Prenatal maternal levels of serum cotinine were not associated with the odds of autism, whether cotinine was classified continuously, by deciles, or using previously defined categories corresponding to probable maternal smoking status. After adjusting for maternal age, paternal age, previous births, and any history of parental psychiatric disorder, the odds ratio for categorical high versus low cotinine, using a 3-level exposure variable, was 0.98 (95% CI = 0.76, 1.26; p = 0.88).

In conclusion, this national birth cohort-based study does not provide evidence for an association between maternal cotinine, a biomarker of maternal smoking, and risk of autism.

[Keywords: autism, autistic disorder, cotinine, prenatal exposure delayed effects, smoking]

“Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors”, Mullins et al 2021

“Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors”⁠, Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy et al (2021-09-08; ; similar):

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders⁠.

Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.

Results: 2 loci reached genome-wide statistical-significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program⁠. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlations with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status⁠, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with non-psychiatric traits remained largely unchanged.

Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

[Keywords: genetic correlation, genome-wide association study, pleiotropy, polygenicity, suicide, suicide attempt]

“Neurodevelopmental Disorders and Subsequent Risk of Violent Victimization: Exploring Sex Differences and Mechanisms”, Ghirardi et al 2021

2021-ghirardi.pdf: “Neurodevelopmental disorders and subsequent risk of violent victimization: exploring sex differences and mechanisms”⁠, Laura Ghirardi, Ralf Kuja-Halkola, Erik Pettersson, Amir Sariaslan, Louise Arseneault, Seena Fazel, Brian M. D’Onofrio et al (2021-09-01; similar):

Background: Neurodevelopmental disorders (NDs) are associated with experiences of victimization, but mechanisms remain unclear. We explored sex differences and the role of familial factors and externalizing problems in the association between several NDs and violent victimization in adolescence and young adulthood.

Methods: Individuals born in Sweden 1985–1997, residing in Sweden at their 15th birthday, were followed until date of violent victimization causing a hospital visit or death, death due to other causes, emigration, or December 31, 2013, whichever came first. The exposures were diagnoses of attention-deficit/​hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID) and other NDs. We used three different Cox regression models: a crude model, a model adjusted for familial confounding using sibling-comparisons, and a model additionally adjusted for externalizing problems.

Results: Among 1 344 944 individuals followed, on average, for 5 years, 74 487 were diagnosed with NDs and 37 765 had a hospital visit or died due to violence. ADHD was associated with an increased risk of violent victimization in males [hazard ratio (HR) 2.56; 95% confidence interval (CI) 2.43–2.70)] and females (HR 5.39; 95% CI 4.97–5.85). ASD and ID were associated with an increased risk of violent victimization in females only. After adjusting for familial factors and externalizing problems, only ADHD was associated with violent victimization among males (HR 1.27; 95% CI 1.06–1.51) and females (HR 1.69; 95% CI 1.21–2.36).

Conclusions: Females with NDs and males with ADHD are at greater risk of being victim of severe violence during adolescence and young adulthood. Relevant mechanisms include shared familial liability and externalizing problems. ADHD may be independently associated with violent victimization.

“Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis”, Strom et al 2021

“Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis”⁠, Nora I. Strom, Jakob Grove, Sandra M. Meier, Marie Bækvad-Hansen, Judith Becker Nissen, Thomas Damm Als et al (2021-08-31; ; similar):

Among patients with obsessive-compulsive disorder (OCD), 65–85% manifest another psychiatric disorder concomitantly or at some other time point during their life. OCD is highly heritable, as are many of its comorbidities. A possible genetic heterogeneity of OCD in relation to its comorbid conditions, however, has not yet been exhaustively explored.

We used a framework of different approaches to study the genetic relationship of OCD with 3 commonly observed comorbidities, namely major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD).

First, using publicly available summary statistics from large-scale genome-wide association studies, we compared genetic correlation patterns for OCD, MDD, ADHD, and ASD with 861 somatic and mental health phenotypes. Secondly, we examined how polygenic risk scores (PRS) of 8 traits that showed heterogeneous correlation patterns with OCD, MDD, ADHD, and ASD partitioned across comorbid subgroups in OCD using independent unpublished data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). The comorbid subgroups comprised of patients with only OCD (n = 366), OCD and MDD (n = 1,052), OCD and ADHD (n = 443), OCD and ASD (n = 388), and OCD with more than 1 comorbidity (n = 429).

We found that PRS of all traits but BMI were statistically-significantly associated with OCD across all subgroups (Neuroticism: p = 1.19 × 10−32, bipolar disorder: p = 7.51 × 10−8, anorexia nervosa: p = 3.52 × 10−20, age at first birth: p = 9.38 × 10−5, educational attainment: p = 1.56 × 10−4, OCD: p = 1.87 × 10−6, insomnia: p = 2.61 × 10−5, BMI: p = 0.15). For age at first birth, educational attainment, and insomnia PRS estimates statistically-significantly differed across comorbid subgroups (p = 2.29 × 10−4, p = 1.63 × 10−4, and p = 0.045, respectively). Especially for anorexia nervosa, age at first birth, educational attainment, insomnia, and neuroticism the correlation patterns that emerged from genetic correlation analysis of OCD, MDD, ADHD, and ASD were mirrored in the PRS associations with the respective comorbid OCD groups.

Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across OCD comorbid subgroups.

“Familial Confounding Affected the Associations between Maternal Smoking during Pregnancy and Offspring Speech and Language, Scholastic and Coordination Disorders”, Arrhenius et al 2021

“Familial confounding affected the associations between maternal smoking during pregnancy and offspring speech and language, scholastic and coordination disorders”⁠, Bianca Arrhenius, Amir Sariaslan, Auli Suominen, Andre Sourander, David Gyllenberg (2021-08-07; ⁠, ; similar):

  • Finnish national register data were used to examine any associations between prenatal smoking and children diagnosed with selected developmental disorders by the end of 2012.
  • We found a modest association between prenatal smoking and speech and language, scholastic and coordination disorders when cases were compared with unrelated population controls.
  • However, there was no association between those factors when we compared differentially exposed siblings.

Aim: This study examined the associations between prenatal smoking and speech and language, scholastic, coordination and mixed developmental disorders in offspring, using sibling and population controls.

Methods: National Finnish registers were used to identify all 690 654 singletons born between 1996 and 2007 and any cases diagnosed with speech and language, scholastic, coordination and mixed developmental disorders by the end of 2012. Cases were compared to population controls, biological full-siblings and maternal half-siblings born during the same period. Conditional logistic regression was used to assess any associations between smoking during pregnancy and the selected developmental disorders.

Results: Prenatal smoking was higher in the mothers of the 27 297 cases (21.7%) than the 99 876 population controls (14.5%). The adjusted odds ratio for smoking throughout pregnancy, and any diagnosis of speech and language, scholastic, coordination or mixed developmental disorders, was 1.29 (95% confidence interval 1.24–1.34). However, when we compared a subsample of 15 406 cases and their 20 657 siblings, the association was no longer statistically-significant (odds ratio 1.09, 95% confidence interval 0.98–1.21).

Conclusion: The sibling comparisons suggested that the associations between prenatal smoking and speech and language, scholastic, coordination and mixed developmental disorders were confounded by familial factors shared by differentially exposed siblings.

“Mental Healthcare Utilization of Transgender Youth Before and After Affirming Treatment”, Hisle-Gorman et al 2021

2021-hislegorman.pdf: “Mental Healthcare Utilization of Transgender Youth Before and After Affirming Treatment”⁠, Elizabeth Hisle-Gorman, Natasha A. Schvey, Terry A. Adirim, Anna K. Rayne, Apryl Susi, Timothy A. Roberts et al (2021-08-01; similar):

Objective: Transgender and gender-diverse (TGD) adolescents experience increased mental health risk compared to cisgender peers. Limited research suggests improved outcomes following gender-affirmation. This study examined mental healthcare and psychotropic medication utilization among TGD youth compared to their siblings without gender-related diagnoses and explored utilization patterns following gender-affirming care.

Method: This retrospective cohort study used military healthcare data from 2010–2018 to identify mental healthcare diagnoses and visits, and psychotropic medication prescriptions among TGD youth who received care for gender dysphoria before age 18, and their siblings. Logistic and Poisson regression analyses compared mental health diagnosis, visits, and psychotropic prescriptions of TGD youth to their siblings, and compared healthcare utilization pre-initiation and post-initiation of gender-affirming pharmaceuticals among TGD adolescents.

Results: 3,754 TGD adolescents and 6,603 cisgender siblings were included.

TGD adolescents were more likely to have a mental health diagnosis (OR 5.45, 95% CI [4.77–6.24]), use more mental healthcare services (IRR 2.22; 95% CI [2.00–2.46]), and be prescribed more psychotropic medications (IRR = 2.57; 95% CI [2.36–2.80]) compared to siblings. The most pronounced increases in mental healthcare were for adjustment, anxiety, mood, personality, psychotic disorders, and suicidal ideation/​attempted suicide. The most pronounced increased in psychotropic medication were in SNRIs, sleep medications, anti-psychotics and lithium.

Among 963 TGD youth (Mage: 18.2) using gender-affirming pharmaceuticals, mental healthcare did not statistically-significantly change (IRR = 1.09, 95% CI [0.95–1.25]) and psychotropic medications increased (IRR = 1.67, 95% CI [1.46–1.91]) following gender-affirming pharmaceutical initiation; older age was associated with decreased care and prescriptions.

Conclusion: Results support clinical mental health screening recommendations for TGD youth. Further research is needed to elucidate the longer-term impact of medical affirmation on mental health, including family and social factors associated with the persistence and discontinuation of mental healthcare needs among TGD youth.

[Keywords: transgender, gender-diverse, mental health, adolescent, youth]

“The Nature of Hereditary Influences on Insanity from Research on Asylum Records in Western Europe in the Mid-19th Century”, Kendler 2021

2021-kendler.pdf: “The nature of hereditary influences on insanity from research on asylum records in Western Europe in the mid-19th century”⁠, Kenneth S. Kendler (2021-07-06; ; similar):

This article explores the nature of psychiatric genetics research conducted in asylums in Western Europe in the mid-19th century through an examination of 4 studies published 1841 to 1864 from Great Britain, France, and Germany.

They all utilize asylum records to determine if patients had a hereditary predisposition (HP) to mental illness. A diverse range of topics were investigated, with most attention on whether men or women are more likely to transmit, or are more sensitive to the receipt of, an HP. When statistically-significant sex effects were seen, they consistently found women to be more likely to transmit and/​or more sensitive to the receipt of an HP. Other questions explored included:

  1. the relationship between an HP and recurrence rates;
  2. the degree of homogeneity versus heterogeneity of transmission of specific mental illnesses in families;
  3. the level of HP among different forms of mental illness; and
  4. differences in the proportion of psychiatric patients with an HP as a function of their religion.

While the method of assessment of familial/​genetic risk was relatively crude, even at this early stage in the history of psychiatric genetics, investigators were asking thoughtful questions about the nature and clinical impact of that risk.

“The Potential Role of Glial Cells in Driving the Prion-like Transcellular Propagation of Tau in Tauopathies”, Amro et al 2021

“The potential role of glial cells in driving the prion-like transcellular propagation of tau in tauopathies”⁠, Zein Amro, Andrea J.Yool, Lyndsey E. Collins-Praino (2021-07; ; similar):

  • Evidence suggests that tau can be secreted extracellularly and propagate in a prion-like manner.
  • Astrocyte and microglia activation can precede neurotoxicity in tauopathy⁠.
  • Astrocytes and microglia can internalise tau.
  • Astrocytes and microglia can secrete tau, feeding into the prion-like hypothesis of tau spread.
  • Better understanding of glia cell contribution to tau propagation may be beneficial for therapeutic intervention.

Dementia is one of the leading causes of death worldwide, with tauopathies, a class of diseases defined by pathology associated with the microtubule-enriched protein, tau, as the major contributor. Although tauopathies, such as Alzheimer’s disease and Frontotemporal dementia⁠, are common amongst the ageing population, current effective treatment options are scarce, primarily due to the incomplete understanding of disease pathogenesis. The mechanisms via which aggregated forms of tau are able to propagate from one anatomical area to another to cause disease spread and progression is yet unknown.

The prion-like hypothesis of tau propagation proposes that tau can propagate along neighbouring anatomical areas in a similar manner to prion proteins in prion diseases, such as Creutzfeldt-Jacob disease⁠. This hypothesis has been supported by a plethora of studies that note the ability of tau to be actively secreted by neurons, propagated and internalised by neighbouring neuronal cells, causing disease spread. Surfacing research suggests a role of reactive astrocytes and microglia in early pre-clinical stages of tauopathy through their inflammatory actions. Furthermore, both glial types are able to internalise and secrete tau from the extracellular space, suggesting a potential role in tau propagation; although understanding the physiological mechanisms by which this can occur remains poorly understood.

This review will discuss the current literature around the prion-like propagation of tau, with particular emphasis on glial-mediated neuroinflammation and the contribution it may play in this propagation process.

[Keywords: Alzheimer’s disease, prion-like hypothesis, astrocytes, microglia, neuroinflammation]

“Exome Sequencing in Obsessive-compulsive Disorder Reveals a Burden of Rare Damaging Coding Variants”, Halvorsen et al 2021

2021-halvorsen.pdf: “Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants”⁠, Mathew Halvorsen, Jack Samuels, Ying Wang, Benjamin D. Greenberg, Abby J. Fyer, James T. McCracken, Daniel A. Geller et al (2021-06-28; ; similar):

Obsessive-compulsive disorder (OCD) affects 1–2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk.

In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants.

In case-control analyses (n = 1,263/​11,580), the most statistically-significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4–22.5, p = 2.3 × 10−6). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, p = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, p = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, p = 7.33 × 10−3).

These data support a contribution of rare coding variants to OCD genetic risk.

“Personalized Machine Learning of Depressed Mood Using Wearables”, Shah et al 2021

“Personalized machine learning of depressed mood using wearables”⁠, Rutvik V. Shah, Gillian Grennan, Mariam Zafar-Khan, Fahad Alim, Sujit Dey, Dhakshin Ramanathan, Jyoti Mishra et al (2021-06-09; ⁠, ; similar):

Depression is a multifaceted illness with large interindividual variability in clinical response to treatment. In the era of digital medicine and precision therapeutics, new personalized treatment approaches are warranted for depression.

Here, we use a combination of longitudinal ecological momentary assessments of depression, neurocognitive sampling synchronized with electroencephalography⁠, and lifestyle data from wearables to generate individualized predictions of depressed mood over a 1-month time period. This study, thus, develops a systematic pipeline for N-of-1 personalized modeling of depression using multiple modalities of data. In the models, we integrate 7 types of supervised machine learning (ML) approaches for each individual, including ensemble learning and regression-based methods. All models were verified using 4× nested cross-validation⁠.

The best-fit as benchmarked by the lowest mean absolute percentage error, was obtained by a different type of ML model for each individual, demonstrating that there is no one-size-fits-all strategy. The voting regressor, which is a composite strategy across ML models [which simply averages the model predictions], was best performing on-average across subjects. However, the individually selected best-fit models still showed statistically-significantly less error than the voting regressor performance across subjects. For each individual’s best-fit personalized model, we further extracted top-feature predictors using Shapley statistics. Shapley values revealed distinct feature determinants of depression over time for each person ranging from co-morbid anxiety⁠, to physical exercise, diet, momentary stress and breathing performance, sleep times, and neurocognition.

In future, these personalized features can serve as targets for a personalized ML-guided, multimodal treatment strategy for depression.

“Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder”, Daghlas et al 2021

2021-daghlas.pdf: “Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder”⁠, Iyas Daghlas, Jacqueline M. Lane, Richa Saxena, Céline Vetter (2021-05-26; ; backlinks; similar):

  • Question: Does a tendency toward sleeping and waking earlier have a potential causal role in reducing the risk of major depressive disorder?
  • Findings: This 2-sample Mendelian randomization analysis of data from nearly 840 000 adults of European ancestry found an association between earlier sleep timing patterns and lower risk of major depressive disorder.
  • Meaning: These data suggest that sleep timing patterns are a risk factor for major depressive disorder, and they should be examined further in randomized clinical trials of sleep interventions.
  • Importance: Morning diurnal preference is associated with reduced risk of major depressive disorder (MDD); however, causality in this association is uncertain.
  • Objective: To examine the association of genetically proxied morning diurnal preference with depression risk using Mendelian randomization.

Design, Setting, and Participants: This 2-sample Mendelian randomization study used summary-level genetic associations with diurnal preference and MDD. Up to 340 genetic loci associated with diurnal preference in a meta-analysis of the UK Biobank and 23andMe cohorts were considered as genetic proxies for diurnal preference. The effect size of these variants was scaled using genetic associations with accelerometer-based measurement of sleep midpoint. Genetic associations with MDD were obtained from a meta-analysis of genome-wide association studies data from the Psychiatric Genomics Consortium and UK Biobank. The inverse-variance weighted method was used to estimate the association of genetically proxied morning diurnal preference, corresponding to a 1-hour earlier sleep midpoint, with MDD risk.

Exposures: Morning diurnal preference scaled to a 1-hour earlier, objectively measured sleep midpoint.

Main Outcomes and Measures: Risk of MDD, including self-reported and clinically diagnosed cases, as ascertained in meta-analyses of genome-wide association studies.

Results: A total of 697 828 individuals (all of European ancestry) were in the UK Biobank and 23andMe cohorts; 85 502 in the UK Biobank had measurements of the sleep midpoint. A further 170 756 individuals with MDD and 329 443 control participants (all of European ancestry) were in the Psychiatric Genomics Consortium and UK Biobank data. Genetically proxied earlier diurnal preference was associated with a 23% lower risk of depression (odds ratio [OR] per 1-hour earlier sleep midpoint, 0.77 [95% CI, 0.63–0.94]; p = 0.01). This association was similar when restricting analysis to individuals with MDD as stringently defined by the Psychiatric Genomics Consortium (OR, 0.73 [95% CI, 0.54–1.00]; p = 0.05) but not statistically-significant when defined by hospital-based billing codes in the UK Biobank (OR, 0.64 [95% CI, 0.39–1.06]; p = 0.08). Sensitivity analyses examining potential bias due to pleiotropy or reverse causality showed similar findings (eg. intercept [SE], 0.00 [0.001]; p = 0.66 by Egger intercept test).

Conclusions and Relevance: The results of this Mendelian randomization study support a protective association of earlier diurnal preference with risk of MDD and provide estimates contextualized to an objective sleep timing measure. Further investigation in the form of randomized clinical trials may be warranted. [See also how sleep deprivation can temporarily relieve depression (Boland et al 2017)]

“Defining and Measuring Meditation-Related Adverse Effects in Mindfulness-Based Programs”, Britton et al 2021

2021-britton.pdf: “Defining and Measuring Meditation-Related Adverse Effects in Mindfulness-Based Programs”⁠, Willoughby B. Britton, Jared R. Lindahl, David J. Cooper, Nicholas K. Canby, Roman Palitsky (2021-05-18; similar):

Research on the adverse effects of mindfulness-based programs (MBPs) has been sparse and hindered by methodological imprecision. The 44-item Meditation Experiences Interview (MedEx-I) was used by an independent assessor to measure meditation-related side effects (MRSEs) following three variants of an 8-week program of mindfulness-based cognitive therapy (n = 96). Each item was queried for occurrence, causal link to mindfulness meditation practice, duration, valence, and impact on functioning. Eighty-three percent of the MBP sample reported at least one MRSE. Meditation-related adverse effects with negative valences or negative impacts on functioning occurred in 58% and 37% of the sample, respectively. Lasting bad effects occurred in 6% to 14% of the sample and were associated with signs of dysregulated arousal (hyperarousal and dissociation). Meditation practice in MBPs is associated with transient distress and negative impacts at similar rates to other psychological treatments.

“Parental Income and Mental Disorders in Children and Adolescents: Prospective Register-based Study”, Kinge et al 2021

“Parental income and mental disorders in children and adolescents: prospective register-based study”⁠, Jonas Minet Kinge, Simon Øverland, Martin Flatø, Joseph Dieleman, Ole Røgeberg, Maria Christine Magnus et al (2021-05-11; ⁠, ; backlinks; similar):

  • Mental disorders in children decreased continuously with increasing parental income for all mental disorders, except eating disorders.
  • The parental-income gradient was largest for attention-deficit hyperactivity disorder, followed by anxiety and depression.
  • Our study suggests that associations between lower parental income and children’s mental disorders were partly, but not fully, attributed to other socio-demographic factors, parents’ own mental disorders and genetic factors.

Background: Children with low-income parents have a higher risk of mental disorders, although it is unclear whether other parental characteristics or genetic confounding explain these associations and whether it is true for all mental disorders.

Methods: In this registry-based study of all children in Norway (n = 1 354 393) aged 5–17 years from 2008 to 2016, we examined whether parental income was associated with childhood diagnoses of mental disorders identified through national registries from primary healthcare, hospitalizations and specialist outpatient services.

Results: There were substantial differences in mental disorders by parental income, except for eating disorders in girls. In the bottom 1% of parental income, 16.9% [95% confidence interval (CI): 15.6, 18.3] of boys had a mental disorder compared with 4.1% (95% CI: 3.3, 4.8) in the top 1%. Among girls, there were 14.2% (95% CI: 12.9, 15.5) in the lowest, compared with 3.2% (95% CI: 2.5, 3.9) in the highest parental-income percentile. Differences were mainly attributable to attention-deficit hyperactivity disorder in boys and anxiety and depression in girls. There were more mental disorders in children whose parents had mental disorders or low education, or lived in separate households. Still, parental income remained associated with children’s mental disorders after accounting for parents’ mental disorders and other factors, and associations were also present among adopted children.

Conclusions: Mental disorders were 3× to 4× more prevalent in children with parents in the lowest compared with the highest income percentiles. Parents’ own mental disorders, other socio-demographic factors and genetic confounding did not fully explain these associations.

[Keywords: mental disorders, income, inequality, childhood, adolescence, adolescent, child, income, mental disorders, parent, psychiatric, disorders of infancy/​childhood/​adolescence] [Discussion]

“MDMA-assisted Therapy for Severe PTSD: a Randomized, Double-blind, Placebo-controlled Phase 3 Study”, Mitchell et al 2021

“MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study”⁠, Jennifer M. Mitchell, Michael Bogenschutz, Alia Lilienstein, Charlotte Harrison, Sarah Kleiman, Kelly Parker-Guilbert et al (2021-05-10; ; similar):

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective.

We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with 3 preparatory and 9 integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study.

MDMA was found to induce statistically-significant and robust attenuation in CAPS-5 score compared with placebo (p < 0.0001, d = 0.91) and to statistically-significantly decrease the SDS total score (p = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities.

We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

“There Is No Evidence That Associations Between Adolescents’ Digital Technology Engagement and Mental Health Problems Have Increased”, Vuorre et al 2021

“There Is No Evidence That Associations Between Adolescents’ Digital Technology Engagement and Mental Health Problems Have Increased”⁠, Matti Vuorre, Amy Orben, Andrew K. Przybylski (2021-05-03; ; similar):

Digital technology is ubiquitous in modern adolescence, and researchers are concerned that it has negative impacts on mental health that, furthermore, increase over time.

To investigate whether technology is becoming more harmful, we examined changes in associations between technology engagement and mental health in 3 nationally representative samples.

Results: were mixed across types of technology and mental health outcomes: Technology engagement had become less strongly associated with depression in the past decade, but social-media use had become more strongly associated with emotional problems. We detected no changes in 5 other associations or differential associations by sex.

There is therefore little evidence for increases in the associations between adolescents’ technology engagement and mental health. Information about new digital media has been collected for a relatively short time; drawing firm conclusions about changes in their associations with mental health may be premature. We urge transparent and credible collaborations between scientists and technology companies.

[Keywords: mental health, depression, social media, adolescents, open materials]

“No Evidence of Creative Benefit Accompanying Dyslexia: A Meta-Analysis”, Erbeli et al 2021

2021-erbeli.pdf: “No Evidence of Creative Benefit Accompanying Dyslexia: A Meta-Analysis”⁠, Florina Erbeli, Peng Peng, Marianne Rice (2021-04-24; similar):

Research on the question of creative benefit accompanying dyslexia has produced conflicting findings. In this meta-analysis, we determined summary effects of mean and variance differences in creativity between groups with and without dyslexia. Twenty studies were included (n = 770 individuals with dyslexia, n = 1,671 controls). A random-effects robust variance estimation (RVE) analysis indicated no mean (g = −0.02, p = 0.84) or variance differences (g = −0.0004, p = 0.99) in creativity between groups. The mean summary effect was moderated by age, gender, and creativity domain. Compared with adolescents, adults with dyslexia showed an advantage over nondyslexic adults in creativity. In addition, a higher proportion of males in the dyslexia group was associated with poorer performance compared with the controls. Finally, the dyslexia group showed a significant performance disadvantage in verbal versus figural creativity. Regarding variance differences, they varied across age and creativity domains. Compared with adults, adolescents showed smaller variability in the dyslexia group. If the creativity task measured verbal versus figural or combined creativity, then the dyslexia group exhibited smaller variability. Altogether, our results suggest that individuals with dyslexia as a group are no more creative or show greater variability in creativity than peers without dyslexia.

“Trial of Psilocybin versus Escitalopram for Depression”, Carhart-Harris et al 2021

2021-carhartharris.pdf: “Trial of Psilocybin versus Escitalopram for Depression”⁠, Robin Carhart-Harris, Bruna Giribaldi, Rosalind Watts, Michelle Baker-Jones, Ashleigh Murphy-Beiner, Roberta Murphy et al (2021-04-15; ; backlinks; similar):

Background: psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.

Methods: In a phase 2, double-blind, randomized controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram⁠, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive 2 separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or 2 separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.

Results: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group.

The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (p = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54).

Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons⁠. The incidence of adverse events was similar in the trial groups.

Conclusions: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a statistically-significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants.

(Funded by the Alexander Mosley Charitable Trust and Imperial College London’s Centre for Psychedelic Research; number, NCT03429075⁠.)

“Parental Characteristics and Offspring Mental Health and Related Outcomes: a Systematic Review of Genetically Informative Literature”, Jami et al 2021

“Parental characteristics and offspring mental health and related outcomes: a systematic review of genetically informative literature”⁠, Eshim S. Jami, Anke R. Hammerschlag, Meike Bartels, Christel M. Middeldorp (2021-04-01; ⁠, ; similar):

Various parental characteristics, including psychiatric disorders and parenting behaviours, are associated with offspring mental health and related outcomes in observational studies. The application of genetically informative designs is crucial to disentangle the role of genetic and environmental factors (as well as gene-environment correlation) underlying these observations, as parents provide not only the rearing environment but also transmit 50% of their genes to their offspring.

This article first provides an overview of behavioural genetics, matched-pair, and molecular genetics designs that can be applied to investigate parent-offspring associations, whilst modelling or accounting for genetic effects. We then present a systematic literature review of genetically informative studies investigating associations between parental characteristics and offspring mental health and related outcomes, published since 2014.

The reviewed studies provide reliable evidence of genetic transmission of depression, criminal behaviour, educational attainment, and substance use. These results highlight that studies that do not use genetically informative designs are likely to misinterpret the mechanisms underlying these parent-offspring associations. After accounting for genetic effects, several parental characteristics, including parental psychiatric traits and parenting behaviours, were associated with offspring internalizing problems, externalizing problems, educational attainment, substance use, and personality through environmental pathways.

Overall, genetically informative designs to study intergenerational transmission prove valuable for the understanding of individual differences in offspring mental health and related outcomes, and mechanisms of transmission within families.

“The Acute Antisuicidal Effects of Single-dose Intravenous Ketamine and Intranasal Esketamine in Individuals With Major Depression and Bipolar Disorders: A Systematic Review and Meta-analysis”, Xiong et al 2021

2021-xiong.pdf: “The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis”⁠, Jiaqi Xiong, Orly Lipsitz, David Chen-Li, Joshua D. Rosenblat, Nelson B. Rodrigues, Isabelle Carvalho et al (2021-02-01; ; similar):

  • Single-dose intravenous ketamine/​intranasal esketamine has rapid and robust acute effects in reducing suicidal ideation (SI).
  • Future high-quality research on the anti-SI efficacy of alternative administration routes and formulations of ketamine is needed.
  • Dosage, routes of administration, and formulations are factors to be considered for optimizing SI treatment using ketamine.

The efficacy of ketamine in reducing suicidal ideation (SI) has been previously reported. We aimed to evaluate acute anti-SI effects of single-dose ketamine in different formulations/​routes of administration by pooling results from randomized controlled trials (RCTs). A systematic search was conducted on Cochrane, Embase⁠, MEDLINE⁠, and PubMed from inception to July 1st, 2020. Studies were selected based on pre-determined eligibility criteria. Effect sizes of different formulations/​routes at various time points were computed using random-effects models. With data from nine eligible RCTs (n = 197), the pooled effect size for anti-SI effects at the 24-h time point was 1.035 (n = 6, CI: 0.793 to 1.277, p < 0.001) for intravenous (IV) racemic ketamine and 1.309 (n = 1, CI: 0.857 to 1.761, p < 0.001) for intranasal (IN) esketamine. An additional five RCTs were available for qualitative analysis. RCTs were identified for oral/​sublingual ketamine for depression, however, none of these trials reported anti-SI effects preventing quantitative analysis for these routes of delivery. No RCTs for intramuscular (IM) ketamine were identified. The findings suggest that single-dose IV ketamine/​IN esketamine is associated with robust reductions in suicidal thoughts at 2-h, 4-h, and 24-h post-intervention. In addition, future studies on IM/​oral/​sublingual ketamine and comparative studies are warranted to evaluate the anti-SI efficacy of distinct formulations and routes of administration.

[Keywords: glutamate, NMDA, suicidal ideation (SI), mood disorders]

“Predicting Mental Health From Followed Accounts on Twitter”, Costello et al 2021

“Predicting Mental Health From Followed Accounts on Twitter”⁠, Cory Costello, Sanjay Srivastava, Reza Rejaie, Maureen Zalewski (2021-01-25; ; backlinks; similar):

The past decade has seen rapid growth in research linking stable psychological characteristics (ie. traits) to digital records of online behavior in Online Social Networks (OSNs) like Facebook and Twitter, which has implications for basic and applied behavioral sciences. Findings indicate that a broad range of psychological characteristics can be predicted from various behavioral residue online, including language used in posts on Facebook (Park et al 2015) and Twitter (Reece et al 2017), and which pages a person ‘likes’ on Facebook (eg. Kosinski, Stillwell, & Graepel, 2013). The present study examined the extent to which the accounts an user follows on Twitter can be used to predict individual differences in self-reported anxiety, depression, post-traumatic stress, and anger. Followed accounts on Twitter offer distinct theoretical and practical advantages for researchers; they are potentially less subject to overt impression management and may better capture passive users. Using an approach designed to minimize overfitting and provide unbiased estimates of predictive accuracy, our results indicate that each of the four constructs can be predicted with modest accuracy (out-of-sample r’s of ~0.2). Exploratory analyses revealed that anger, but not the other constructs, was distinctly reflected in followed accounts, and there was some indication of bias in predictions for women (vs. men) but not for racial/​ethnic minorities (vs. majorities). We discuss our results in light of theories linking psychological traits to behavior online, applications seeking to infer psychological characteristics from records of online behavior, and ethical issues such as algorithmic bias and users’ privacy.

…As planned in the initial pre-registered protocol, we evaluated both selected and non-selected models in the holdout data. For our central research question, estimating how well mental health can be predicted by followed accounts, we found that the selected models achieved moderate, nontrivial accuracy for all four outcomes. For depression, the correlation between predicted and observed score was r = 0.24, for anxiety it was r = 0.20, for post-traumatic stress it was r = 0.19, and for anger it was r = 0.23. Figure 6 shows these estimates.

To aid in interpretation, Figure 6 also shows two relevant estimates from prior work to serve as comparative benchmarks: the predictive accuracies for well-being and neuroticism from Kosinski and colleagues’ (2013) paper predicting psychological constructs from Facebook like-ties. As seen in Figure 6, the present estimates are between these two prior estimates, suggesting that twitter friends predict mental health about as well as Facebook likes predict related constructs.

Figure 6: Out-of-Sample Accuracy for Selected Models

The correlations from both the selected and non-selected models are shown in Figure 7. This allows us to evaluate how effective the model-selection process was in picking the best-performing model. The selected model out-performed the eleven non-selected models for anger and post-traumatic stress, was second best for depression, and fourth best for anxiety. When one or more non-selected models outperformed the selected ones, it was by a relatively small margin, but the lowest-performing non-selected models were substantially worse than the selected ones.

The correlations from both the selected and non-selected models are shown in Figure 7. This allows us to evaluate how effective the model-selection process was in picking the best-performing model. The selected model out-performed the eleven non-selected models for anger and post-traumatic stress, was second best for depression, and fourth best for anxiety. When one or more non-selected models outperformed the selected ones, it was by a relatively small margin, but the lowest-performing non-selected models were substantially worse than the selected ones.

Figure 7: Out-of-sample Accuracy for Selected and Non-Selected Models

“State-dependent Responses to Intracranial Brain Stimulation in a Patient With Depression”, Scangos 2021

2021-scangos.pdf: “State-dependent responses to intracranial brain stimulation in a patient with depression”⁠, Katherine W. Scangos (2021-01-18; ; backlinks; similar):

Deep brain stimulation is a promising treatment for severe depression, but lack of efficacy in randomized trials raises questions regarding anatomical targeting. We implanted multi-site intracranial electrodes in a severely depressed patient and systematically assessed the acute response to focal electrical neuromodulation. We found an elaborate repertoire of distinctive emotional responses that were rapid in onset, reproducible, and context and state dependent. Results provide proof of concept for personalized, circuit-specific medicine in psychiatry.

[See also: Grover et al 2021⁠; media: Nature⁠, NYT⁠.]

“High-frequency Neuromodulation Improves Obsessive-compulsive Behavior”, Grover et al 2021

2021-grover.pdf: “High-frequency neuromodulation improves obsessive-compulsive behavior”⁠, Shrey Grover, John A. Nguyen, Vighnesh Viswanathan, Robert M. G. Reinhart (2021-01-18; ; backlinks; similar):

Nearly one billion people worldwide suffer from obsessive-compulsive behaviors, yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning, which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing.

We target the orbitofrontal cortex with alternating current⁠, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward-guided but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms.

The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest an unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.

[See also: Scangos et al 2021⁠; media: Nature⁠, NYT⁠.]

“Genome Scans of Dog Behavior Implicate a Gene Network Underlying Psychopathology in Mammals, including Humans”, Zapata et al 2021

“Genome scans of dog behavior implicate a gene network underlying psychopathology in mammals, including humans”⁠, Isain Zapata, Erin E. Hecht, James A. Serpell, Carlos E. Alvarez (2021; ; similar):

Genetic studies show a general factor associated with all human psychopathology and strongly correlated with personality and intelligence, but its basis is unknown. We performed genome scans of 17 normal and problem behaviors in three multi-breed dog cohorts. 21 of 90 mapped loci were supported for the same, or a related, trait in a second cohort. Several of those loci were also associated with brain structure differences across breeds; and six of the respective top-candidate genes are also associated with human brain structure and function. More broadly, the geneset of canine behavioral scans is supported by enrichment for genes mapped for human behavior, personality, cognition, psychopathology and brain structure. The biology implicated includes, neurogenesis, axon guidance, angiogenesis, brain structure, alternative splicing, disease association, Hox-family transcription factors, and subiculum expression. Because body size and behavior are correlated in dogs, we isolated the effect of body size in the dog mapping and in the comparative human UK Biobank analyses. Our dog findings are consistent with pleiotropy of diverse brain traits with energy metabolism and growth, and suggest behavioral variations often affect neurogenesis. There is support for such pleiotropy in humans and well-powered genetic studies of human psychiatric traits consistently implicate neurogenesis. We propose a genetic network which underlies neuron birth and development throughout life is associated with evolutionary adaptation of behavior and the general psychopathology factor. This understanding has implications for genetic and environmental contributions to psychiatric disease. We discuss how canine translational models can further accelerate the study of psychopathology.

Author summary

We genetically mapped diverse normal and problem behaviors in dogs. The well-established approach we used is ideally suited for finding variation that is common across dog breeds and for pin-pointing the most likely gene candidates. Our analysis of the genes implicated at 90 genome regions shows they are enriched for (8) genes mapped for diverse brain functions and pathologies in humans; (2) genes involved in brain development throughout life; and (3) footprints of evolution in dogs, humans and other animals. We propose that is consistent with evolutionary conservation of the general genetic factor of mental health in humans, which is correlated with personality and intelligence. The implications are that this super-network of genes is preferentially targeted by evolutionary adaptation for behavior and that its dysregulation increases risk of mental health disorders.

“Intelligence and General Psychopathology in the Vietnam Experience Study: A Closer Look”, Kirkegaard & Nyborg 2021

2021-kirkegaard.pdf: “Intelligence and General Psychopathology in the Vietnam Experience Study: A Closer Look”⁠, Emil O. W. Kirkegaard, Helmuth Nyborg (2021; ⁠, ; backlinks; similar):

Prior research has indicated that one can summarize the variation in psychopathology measures in a single dimension, labeled P by analogy with the g factor of intelligence. Research shows that this P factor has a weak to moderate negative relationship to intelligence.

We used data from the Vietnam Experience Study to reexamine the relations between psychopathology assessed with the MMPI (Minnesota Multiphasic Personality Inventory) and intelligence (total n = 4,462: 3,654 whites, 525 blacks, 200 Hispanics, and 83 others).

We show that the scoring of the P factor affects the strength of the relationship with intelligence. Specifically, item response theory-based scores correlate more strongly with intelligence than sum-scoring or scale-based scores: r’s = −0.35, −0.31, and −0.25, respectively.

We furthermore show that the factor loadings from these analyses show moderately strong Jensen patterns such that items and scales with stronger loadings on the P factor also correlate more negatively with intelligence (r = −0.51 for 566 items= −0.60 for 14 scales).

Finally, we show that training an elastic net model on the item data allows one to predict intelligence with extremely high precision, r = 0.84. We examined whether these predicted values worked as intended with regards to cross-racial predictive validity, and relations to other variables. We mostly find that they work as intended, but seem slightly less valid for blacks and Hispanics (r’s = 0.85, 0.83, and 0.81, for whites, Hispanics, and blacks, respectively).

[Keywords: Vietnam Experience Study, MMPI, general psychopathology factor, intelligence, cognitive ability, machine learning, elastic net, LASSO⁠, random forest⁠, crud factor]

…To further examine predictive accuracy, we trained a lasso model to see if a relatively sparse model could be obtained. The validity of the lasso model, however, was essentially identical to the elastic net one, and the optimal lasso fit was not very sparse (363 out of 556 items used)…It is seen that about 90 items are needed to reach a correlation accuracy of 0.80, whereas only 3 items are needed to reach 0.50. This may be surprising, but some items have absolute correlations to g of around 0.40, so it is unsurprising that combining 3 of them yields a model accuracy at 0.50.

…Finally, we fit a random forest model. This performed slightly worse than the elastic net (r = 0.78). The failure of the random forest model to do better than the elastic net indicates that nonlinear and interaction effects are not important in a given dataset for the purpose of prediction. In other words, the additive assumption is supported for this dataset and outcome variable

“The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study”, Giannakopoulou et al 2021

“The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study”⁠, Olga Giannakopoulou, Kuang Lin, Xiangrui Meng, Mei-Hsin Su, Po-Hsiu Kuo, Roseann E. Peterson, Swapnil Awasthi et al (2021; ; similar):

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations.

Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression.

Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021.

Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts.

Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires.

Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, p = 4.43×10–8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, p = 6.48×10–9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, p = 0.53 for rs4656484 and β = -0.005, SE = 0.004, p = 0.28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent.

Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

“A Non-hallucinogenic Psychedelic Analogue With Therapeutic Potential”, Cameron et al 2021

“A non-hallucinogenic psychedelic analogue with therapeutic potential”⁠, Lindsay P. Cameron, Robert J. Tombari, Ju Lu, Alexander J. Pell, Zefan Q. Hurley, Yann Ehinger, Maxemiliano V. Vargas et al (2021; ; backlinks; similar):

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias.

Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog—a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step.

In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol-seeking and heroin-seeking behaviour, and produce antidepressant-like effects.

This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

“In Memoriam: Scott O. Lilienfeld (1960–2020)”, Lynn et al 2021

2021-lynn.pdf: “In Memoriam: Scott O. Lilienfeld (1960–2020)”⁠, Steven Jay Lynn, Robert D. Latzman, Sherryl H. Goodman, Patricia A. Brennan, Sally Satel (2021; ; similar):

Memorializes Scott O. Lilienfeld (1960–2020), one of the most influential figures in contemporary clinical psychology⁠.

His contributions were prodigious and spanned psychopathy and personality disorders, psychiatric classification and diagnosis, dissociation, memory and trauma, neuroscience, and cultural sensitivity. He authored, coauthored, and co-edited more than 500 articles and book chapters and 20 books, including the Encyclopedia of Clinical Psychology. His intellectual reach extended to writing introductory psychology and graduate textbooks, to op-eds and coverage in major news outlets, TV appearances, radio programs, podcasts, and lectures across the world. He made his mark in editorial roles including as editor-in-chief of Clinical Psychological Science, and as past editor and founder of the Scientific Review of Mental Health Practice.

“The Psychology of Asymmetric Zero-sum Beliefs”, Roberts & Davidai 2021

2021-roberts.pdf: “The psychology of asymmetric zero-sum beliefs”⁠, Russell Roberts, Shai Davidai (2021; ⁠, ⁠, ; backlinks; similar):

[see also “Win-win denial: The psychological underpinnings of zero-sum thinking”, Johnson et al 2021] Zero-sum beliefs reflect the perception that one party’s gains are necessarily offset by another party’s losses.

Although zero-sum relationships are, from a strictly theoretical perspective, symmetrical, we find evidence for asymmetrical zero-sum beliefs: The belief that others gain at one’s own expense, but not vice versa. Across various contexts (international relations, interpersonal negotiations, political partisanship, organizational hierarchies) and research designs (within/​between-participant), we find that people are more prone to believe that others’ success comes at their own expense than they are to believe that their own success comes at others’ expense. Moreover, we find that people exhibit asymmetric zero-sum beliefs only when thinking about how their own party relates to other parties but not when thinking about how other parties relate to each other. Finally, we find that this effect is moderated by how threatened people feel by others’ success and that reassuring people about their party’s strengths eliminates asymmetric zero-sum beliefs.

We discuss the theoretical contributions of our findings to research on interpersonal and intergroup zero-sum beliefs and their implications for understanding when and why people view life as zero-sum.

[Keywords: zero-sum beliefs, intergroup relations, interpersonal relations, conflict, perceived threat]

…In 7 studies (including 2 preregistered experiments), we examine the psychology of asymmetric zero-sum beliefs. Studies 1 and 2 examine whether people believe that other countries (Study 1) and people (Study 2) gain at their expense, but not vice versa. Study 3 examines whether asymmetric zero-sum beliefs are unique to contexts that directly involve one’s own party, but not to contexts that involve other parties’ relations to one another. We show that people exhibit asymmetric zero-sum beliefs when considering how their own country’s outcomes relate to another country’s outcomes (ie. U.S.-China relations), but not when thinking about 2 separate countries (ie. Germany-China relations). Study 4 replicates and extends this effect in the domain of political parties and examines the role of threat in asymmetric zero-sum beliefs. We examine whether the degree to which political partisans feel threatened by an opposing party predicts how much they see that party as gaining at their own party’s expense. Finally, Studies 5, 6A, and 6B examine the causal role of threat on asymmetric zero-sum beliefs in both interpersonal and intergroup contexts by manipulating how threatened people feel by an opposing party. We find that people exhibit asymmetric zero-sum beliefs when feeling threatened by others’ success, but not when feeling reassured about their own success.

“Exploratory Study of Cat Adoption in Families of Children With Autism: Impact on Children's Social Skills and Anxiety”, Carlisle et al 2020

2021-carlisle.pdf: “Exploratory study of cat adoption in families of children with autism: Impact on children's social skills and anxiety”⁠, Gretchen K. Carlisle, Rebecca A. Johnson, Ze Wang, Jessica Bibbo, Nancy Cheak-Zamora, Leslie A. Lyons et al (2020-12-06; ):


  • First randomized controlled trial of cat adoption in families of children with ASD.
  • Adoption of temperament screened shelter cat may benefit children with ASD.
  • Positive exploratory findings indicate need for study with larger sample.

Purpose: The diagnosis of Autism Spectrum Disorder (ASD) occurs in one in 54 children and companion animals (CA) are common in families of children with ASD. Despite evidence of CA ownership benefits for children with ASD, little is known about cats. The purpose was to explore the impact of shelter cat adoption by families of children with ASD.

Design and methods: This was the first randomized controlled trial of adoption of a temperament screened cat by families of children with ASD. Families assigned to the treatment group adopted a cat and were followed for 18 weeks. Families assigned to the control group were followed for 18 weeks without intervention, then converted to treatment, by adopting a cat and were followed another 18 weeks. Adopted cats were screened using the Feline Temperament Profile to identify a calm temperament. Surveys measured children’s social skills and anxiety and parent/​child cat bonding.

Results: Our study (n = 11) found cat adoption was associated with greater Empathy and less Separation Anxiety for children with ASD, along with fewer problem behaviors including Externalizing, Bullying and Hyperactivity/​Inattention. Parents and children reported strong bonds to the cats.

Conclusion: This exploratory study found introduction of a cat into the home may have a positive impact on children with ASD and their parents. Based on this initial finding, future studies with larger sample sizes are recommended.

Practice implications: If parents of children with ASD are considering cat adoption, health care providers might consider recommending adoption of a cat screened for calm temperament.

[Keywords: children with autism spectrum disorder, companion animals, cats, social skills, pets]

“Integrating the Study of Personality and Psychopathology in the Context of Gene-environment Correlations across Development”, Perlstein & Waller 2020

2020-perlstein.pdf: “Integrating the study of personality and psychopathology in the context of gene-environment correlations across development”⁠, Samantha Perlstein, Rebecca Waller (2020-11-29; ⁠, ; similar):

Objective: A key principle of individual differences research is that biological and environmental factors jointly influence personality and psychopathology. Genes and environments interact to influence the emergence and stability of both normal and abnormal behavior (ie. genetic predisposition, X, is exacerbated or buffered under environmental conditions, Y, or vice versa), including by shaping the neural circuits underpinning behavior. The interplay of genes and environments is also reflected in various ways in which they are correlated (ie. rGE). That is, the same genetic factors that give rise to personality or psychopathology also shape that person’s environment.

Methods: In this review, we outline passive, evocative, and active rGE processes and review the findings of studies that have addressed rGE in relation to understanding individual differences in personality and psychopathology across development.

Results: Throughout, we evaluate the question of whether it is possible, not only to differentiate the person from their problems, but also to differentiate the person from their problems and their environment.

Conclusions: We provide recommendations for future research to model rGE and better inform our ability to study personality and psychopathology, while separating the influence of the environment.

“Common Variants Contribute to Intrinsic Human Brain Functional Networks”, Zhao et al 2020

“Common variants contribute to intrinsic human brain functional networks”⁠, Bingxin Zhao, Tengfei Li, Stephen M. Smith, Di Xiong, Xifeng Wang, Yue Yang, Tianyou Luo, Ziliang Zhu et al (2020-09-17; ⁠, ⁠, ; similar):

The human brain remains active in the absence of explicit tasks and forms networks of correlated activity. Resting-state functional magnetic resonance imaging (rsfMRI) measures brain activity at rest, which has been linked with both cognitive and clinical outcomes. The genetic variants influencing human brain function are largely unknown.

Here we utilized rsfMRI from 44,190 individuals of multiple ancestries (37,339 in the UK Biobank) to discover and validate the common genetic variants influencing intrinsic brain activity.

We identified hundreds of novel genetic loci associated with intrinsic functional signatures (p < 2.8 × 10−11), including associations to the central executive, default mode, and salience networks involved in the triple network model of psychopathology. A number of intrinsic brain activity associated loci colocalized with brain disorder GWAS (eg. Alzheimer’s disease, Parkinson’s disease, schizophrenia) and cognition, such as 19q13.32, 17q21.31, and 2p16.1. Particularly, we detected a colocalization between one (rs429358) of the two variants in the APOE ε4 locus and function of the default mode, central executive, attention, and visual networks. Genetic correlation analysis demonstrated shared genetic influences between brain function and brain structure in the same regions. We also detected statistically-significant genetic correlations with 26 other complex traits, such as ADHD, major depressive disorder, schizophrenia, intelligence, education, sleep, subjective well-being⁠, and neuroticism.

Common variants associated with intrinsic brain activity were enriched within regulatory element in brain tissues.

“Closed Loop Enhancement and Neural Decoding of Human Cognitive Control”, Basu et al 2020

“Closed loop enhancement and neural decoding of human cognitive control”⁠, Ishita Basu, Ali Yousefi, Britni Crocker, Rina Zelmann, Angelique C. Paulk, Noam Peled, Kristen K. Ellard et al (2020-09-16; ; similar):

Cognitive control is the ability to withhold a default, prepotent response in favor of a more adaptive choice. Control deficits are common across mental disorders, including depression, anxiety, and addiction. Thus, a method for improving cognitive control could be broadly useful in disorders with few effective treatments.

Here, we demonstrate closed-loop enhancement of one aspect of cognitive control by direct brain stimulation in humans. We stimulated internal capsule/​striatum in participants undergoing intracranial epilepsy monitoring as they performed a cognitive control/​conflict task. Stimulation enhanced performance, with the strongest effects from dorsal capsule/​striatum stimulation.

We then developed a framework to detect control lapses and stimulate in response. This closed-loop approach produced larger behavioral changes than open-loop stimulation, with a slight improvement in performance change per unit of energy delivered. Finally, we decoded task performance directly from activity on a small number of electrodes, using features compatible with existing closed-loop brain implants.

Our findings are proof of concept for a new approach to treating severe mental disorders, based on directly remediating underlying cognitive deficits.

“Association between Naturally Occurring Lithium in Drinking Water and Suicide Rates: Systematic Review and Meta-analysis of Ecological Studies”, Memon et al 2020

2020-memon.pdf: “Association between naturally occurring lithium in drinking water and suicide rates: systematic review and meta-analysis of ecological studies”⁠, Anjum Memon, Imogen Rogers, Sophie M. D. D. Fitzsimmons, Ben Carter, Rebecca Strawbridge, Diego Hidalgo-Mazzei et al (2020-07-27; ⁠, ; backlinks; similar):

Background: The prevalence of mental health conditions and national suicide rates are increasing in many countries. Lithium is widely and effectively used in pharmacological doses for the treatment and prevention of manic/​depressive episodes, stabilising mood and reducing the risk of suicide. Since the 1990s, several ecological studies have tested the hypothesis that trace doses of naturally occurring lithium in drinking water may have a protective effect against suicide in the general population.

Aims: To synthesise the global evidence on the association between lithium levels in drinking water and suicide mortality rates.

Method: The MEDLINE⁠, Embase⁠, Web of Science and PsycINFO databases were searched to identify eligible ecological studies published between 1 January 1946 and 10 September 2018. Standardised regression coefficients for total (ie. both genders combined), male and female suicide mortality rates were extracted and pooled using random-effects meta-analysis. The study was registered with PROSPERO (CRD42016041375).

Results: The literature search identified 415 articles; of these, 15 ecological studies were included in the synthesis. The random-effects meta-analysis showed a consistent protective (or inverse) association between lithium levels/​concentration in publicly available drinking water and total (pooled β = −0.27, 95% CI −0.47 to −0.08; p = 0.006, I2 = 83.3%), male (pooled β = −0.26, 95% CI −0.56 to 0.03; p = 0.08, I2 = 91.9%) and female (pooled β = −0.13, 95% CI −0.24 to −0.02; p = 0.03, I2 = 28.5%) suicide mortality rates. A similar protective association was observed in the six studies included in the narrative synthesis, and subgroup meta-analyses based on the higher/​lower suicide mortality rates and lithium levels/​concentration.

Conclusions: This synthesis of ecological studies, which are subject to the ecological fallacy/​bias, supports the hypothesis that there is a protective (or inverse) association between lithium intakes from public drinking water and suicide mortality at the population level. Naturally occurring lithium in drinking water may have the potential to reduce the risk of suicide and may possibly help in mood stabilisation, particularly in populations with relatively high suicide rates and geographical areas with a greater range of lithium concentration in the drinking water. All the available evidence suggests that randomised community trials of lithium supplementation of the water supply might be a means of testing the hypothesis, particularly in communities (or settings) with demonstrated high prevalence of mental health conditions, violent criminal behaviour, chronic substance misuse and risk of suicide.

“Specific Antisocial and Borderline Personality Disorder Criteria and General Substance Use: A Twin Study”, Rosenström et al 2020

2020-rosenstrom.pdf: “Specific Antisocial and Borderline Personality Disorder Criteria and General Substance Use: A Twin Study”⁠, Tom Rosenström, Fartein Ask Torvik, Eivind Ystrom, Steven H. Aggen, Nathan A. Gillespie, Robert F. Krueger et al (2020-06-25; ⁠, ; similar):

Antisocial (ASPD) and borderline (BPD) personality disorders (PDs) are associated with increased risk for substance use. They are “specific” risk factors among PDs in that they withstand adjusting for the other PDs, whereas the reverse does not hold. Specificity is a classic sign of causation. This empirical work addresses 3 further problems that can undermine causal inferences in personality and substance-use research: hierarchical nature of etiologic factors in psychiatry, imperfectly operationalized PD criteria, and possible genetic or environmental confounding, as seen in lack of “etiologic continuity.” We used exploratory structural equation bifactor modeling and biometric models to mitigate these problems. The participants were Norwegian adult twins of ages 19–36 years (n = 2,801). Criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM–5), PDs were assessed using a structured interview. General substance-use risk was indicated by World Health Organization Composite International Diagnostic Interviewed alcohol use disorder and illicit drug use, and by self-reported regular smoking. A general risk factor for all criteria of both ASPD and BPD was the strongest individual correlate of general substance use and showed etiologic continuity, though just 3 specific PD criteria could predict substance use to the same extent. The findings indicate that a broad latent factor for both ASPD and BPD may be a specific and a genetically and environmentally unconfounded risk factor for substance use. Substance-use treatment research might benefit from attending to transdiagnostic models of ASPD, BPD, and related behavioral disinhibition.

“Dimensions over Categories: a Meta-analysis of Taxometric Research”, Haslam et al 2020

2020-haslam.pdf: “Dimensions over categories: a meta-analysis of taxometric research”⁠, Nick Haslam, Melanie J. McGrath, Wolfgang Viechtbauer, Peter Kuppens (2020-06-04; ; similar):

Taxometric procedures have been used extensively to investigate whether individual differences in personality and psychopathology are latently dimensional or categorical (‘taxonic’). We report the first meta-analysis of taxometric research, examining 317 findings drawn from 183 articles that employed an index of the comparative fit of observed data to dimensional and taxonic data simulations. Findings supporting dimensional models outnumbered those supporting taxonic models five to one. There were systematic differences among 17 construct domains in support for the two models, but psychopathology was no more likely to generate taxonic findings than normal variation (ie. individual differences in personality, response styles, gender, and sexuality). No content domain showed aggregate support for the taxonic model. Six variables—alcohol use disorder, intermittent explosive disorder, problem gambling, autism, suicide risk, and pedophilia—emerged as the most plausible taxon candidates based on a preponderance of independently replicated findings. We also compared the 317 meta-analyzed findings to 185 additional taxometric findings from 96 articles that did not employ the comparative fit index. Studies that used the index were 4.88× more likely to generate dimensional findings than those that did not after controlling for construct domain, implying that many taxonic findings obtained before the popularization of simulation-based techniques are spurious. The meta-analytic findings support the conclusion that the great majority of psychological differences between people are latently continuous, and that psychopathology is no exception.

“Psychedelic Psychiatry’s Brave New World”, Nutt et al 2020

“Psychedelic Psychiatry’s Brave New World”⁠, David Nutt, David Erritzoe, Robin Carhart-Harris (2020-04-02; ; backlinks; similar):

After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results.

Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin⁠, show promise for addressing a range of serious disorders, including depression and addiction.

“Psychometric Concerns With the 10-item Autism-Spectrum Quotient (AQ10) As a Measure of Trait Autism in the General Population”, Taylor et al 2020

“Psychometric concerns with the 10-item Autism-Spectrum Quotient (AQ10) as a measure of trait autism in the general population”⁠, Emily C. Taylor, Lucy A. Livingston, Rachel A. Clutterbuck, Punit Shah (2020-03-05):

The 10-item Autism-Spectrum Quotient (AQ10) is a self-report questionnaire used in clinical and research settings as a diagnostic screening tool for autism in adults. The AQ10 is also increasingly being used to quantify trait autism along an unitary dimension and correlated against performance on other psychological/​medical tasks. However, its psychometric properties have yet to be examined when used in this way.

By analysing AQ10 data from a large non-clinical sample of adults (n = 6,595), we found that the AQ10 does not have an unifactorial factor structure, and instead appears to have several factors. The AQ10 also had poor internal reliability.

Taken together, whilst the AQ10 has important clinical utility in screening for diagnosable autism, it may not be a psychometrically robust measure when administered in non-clinical samples from the general population. Therefore, we caution against its use as a measure of trait autism in future research.

[Keywords: autism, psychometrics, reliability, screening, questionnaire]

“Nothing Ventured, Nothing Gained: Parasite Infection Is Associated With Entrepreneurial Initiation, Engagement, and Performance”, Lerner et al 2020

2020-lerner.pdf: “Nothing Ventured, Nothing Gained: Parasite Infection is Associated with Entrepreneurial Initiation, Engagement, and Performance”⁠, Daniel A. Lerner, Lars Alkærsig, Markus A. Fitza, Carina Lomberg, Stefanie K. Johnson (2020-01-27; ; similar):

There is growing evidence that human biology and behavior are influenced by infectious microorganisms. One such microorganism is the protozoan Toxoplasma gondii (TG). Using longitudinal data covering the female population of Denmark, we extend research on the relationship between TG infection and entrepreneurial activity and outcomes. Results indicate that TG infection is associated with a subsequent increase in the probability of becoming an entrepreneur, and is linked to other outcomes including venture performance. With parasite behavioral manipulation antithetical to rational judgment, we join a growing conversation on biology and alternative drivers of business venturing.

“Long-term Follow-up of Psilocybin-assisted Psychotherapy for Psychiatric and Existential Distress in Patients With Life-threatening Cancer”, Agin-Liebes et al 2020

2020-aginliebes.pdf: “Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer”⁠, Gabrielle I. Agin-Liebes, Tara Malone, Matthew M. Yalch, Sarah E. Mennenga, K. Linnae Ponté, Jeffrey Guss et al (2020-01-09; ; similar):

Background: A recently published randomized controlled trial compared single-dose psilocybin with single-dose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric distress. Results suggested that psilocybin-assisted psychotherapy facilitated improvements in psychiatric and existential distress, quality of life, and spiritual well-being up to seven weeks prior to the crossover. At the 6.5-month follow-up, after the crossover, 60–80% of participants continued to meet criteria for clinically-significant antidepressant or anxiolytic responses.

Methods: The present study is a long-term within-subjects follow-up analysis of self-reported symptomatology involving a subset of participants that completed the parent trial. All 16 participants who were still alive were contacted, and 15 participants agreed to participate at an average of 3.2 and 4.5 years following psilocybin administration.

Results: Reductions in anxiety, depression, hopelessness, demoralization, and death anxiety were sustained at the first and second follow-ups. Within-group effect sizes were large. At the second (4.5 year) follow-up ~60–80% of participants met criteria for clinically-significant antidepressant or anxiolytic responses. Participants overwhelmingly (71–100%) attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually important experiences of their lives.

Conclusion: These findings suggest that psilocybin-assisted psychotherapy holds promise in promoting long-term relief from cancer-related psychiatric distress. Limited conclusions, however, can be drawn regarding the efficacy of this therapy due to the crossover design of the parent study. Nonetheless, the present study adds to the emerging literature base suggesting that psilocybin-facilitated therapy may enhance the psychological, emotional, and spiritual well-being of patients with life-threatening cancer.

“Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome”, Pereira et al 2019

2019-pereira.pdf: “Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome”⁠, Joana da Cruz Pereira, Kieran Rea, Yvonne M. Nolan, Olivia F. O’Leary, Timothy G. Dinan, John F. Cryan et al (2019-09-30; ⁠, ; similar):

Depression remains one of the most prevalent psychiatric disorders, with many patients not responding adequately to available treatments. Chronic or early-life stress is one of the key risk factors for depression. In addition, a growing body of data implicates chronic inflammation as a major player in depression pathogenesis. More recently, the gut microbiota has emerged as an important regulator of brain and behavior and also has been linked to depression. However, how this holy trinity of risk factors interact to maintain physiological homeostasis in the brain and body is not fully understood. In this review, we integrate the available data from animal and human studies on these three factors in the etiology and progression of depression. We also focus on the processes by which this microbiota-immune-stress matrix may influence centrally mediated events and on possible therapeutic interventions to correct imbalances in this triune.

“Large-scale GWAS Reveals Insights into the Genetic Architecture of Same-sex Sexual Behavior”, Ganna et al 2019

“Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior”⁠, Andrea Ganna, Karin J. H. Verweij, Michel G. Nivard, Robert Maier, Robbee Wedow, Alexander S. Busch, Abdel Abdellaoui et al (2019-08-29; ⁠, ⁠, ⁠, ; similar):

Twin studies and other analyses of inheritance of sexual orientation in humans has indicated that same-sex sexual behavior has a genetic component. Previous searches for the specific genes involved have been underpowered and thus unable to detect genetic signals. Ganna et al 2019 perform a genome-wide association study on 493,001 participants from the United States, the United Kingdom, and Sweden to study genes associated with sexual orientation (see the Perspective by Mills). They find multiple loci implicated in same-sex sexual behavior indicating that, like other behavioral traits, nonheterosexual behavior is polygenic.

Introduction: Across human societies and in both sexes, some 2 to 10% of individuals report engaging in sex with same-sex partners, either exclusively or in addition to sex with opposite-sex partners. Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for the specific genes involved have been underpowered to detect effect sizes realistic for complex traits.

Rationale: For the first time, new large-scale datasets afford sufficient statistical power to identify genetic variants associated with same-sex sexual behavior (ever versus never had a same-sex partner), estimate the proportion of variation in the trait accounted for by all variants in aggregate, estimate the genetic correlation of same-sex sexual behavior with other traits, and probe the biology and complexity of the trait. To these ends, we performed genome-wide association discovery analyses on 477,522 individuals from the United Kingdom and United States, replication analyses in 15,142 individuals from the United States and Sweden, and follow-up analyses using different aspects of sexual preference.

Results: In the discovery samples (UK Biobank and 23andMe), 5 autosomal loci were statistically-significantly associated with same-sex sexual behavior. Follow-up of these loci suggested links to biological pathways that involve sex hormone regulation and olfaction. 3 of the loci were statistically-significant in a meta-analysis of smaller, independent replication samples. Although only a few loci passed the stringent statistical corrections for genome-wide multiple testing and were replicated in other samples, our analyses show that many loci underlie same-sex sexual behavior in both sexes. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in male and female same-sex sexual behavior, and the genetic influences were positively but imperfectly correlated between the sexes [genetic correlation coefficient (rg)= 0.63; 95% confidence intervals, 0.48 to 0.78]. These aggregate genetic influences partly overlapped with those on a variety of other traits, including externalizing behaviors such as smoking, cannabis use, risk-taking, and the personality trait “openness to experience.” Additional analyses suggested that sexual behavior, attraction, identity, and fantasies are influenced by a similar set of genetic variants (rg > 0.83); however, the genetic effects that differentiate heterosexual from same-sex sexual behavior are not the same as those that differ among nonheterosexuals with lower versus higher proportions of same-sex partners, which suggests that there is no single continuum from opposite-sex to same-sex preference.

Conclusion: Same-sex sexual behavior is influenced by not one or a few genes but many. Overlap with genetic influences on other traits provides insights into the underlying biology of same-sex sexual behavior, and analysis of different aspects of sexual preference underscore its complexity and call into question the validity of bipolar continuum measures such as the Kinsey scale. Nevertheless, many uncertainties remain to be explored, including how sociocultural influences on sexual preference might interact with genetic influences. To help communicate our study to the broader public, we organized workshops in which representatives of the public, activists, and researchers discussed the rationale, results, and implications of our study.

Disaster Artist—Insanity Is No Shortcut to Inspiration”, Lakeman 2019

Disaster Artist—Insanity is No Shortcut to Inspiration”⁠, Matt Lakeman (2019-04-29; ; similar):

I read Disaster Artist on a whim when the movie came out. I’ve since gone through the audiobook 3.5 times and can confidently say it’s one of my favorite books of all time. I expected just to hear funny anecdotes about the making of a famously awful movie and the man behind it⁠, but I found so much more depth. In my eyes, Disaster Artist is an examination of insanity (which I am defining as “the inability to perceive reality to the degree of low or non-functionality in regular life”). The book is a pushback against a subtle cultural norm that sees crazy people as having some sort of gift or potential or insight that everyone else doesn’t.

This message hit me especially hard because I had my first real experience with a crazy person only a few months before I read Disaster Artist…We fired our employee. We offered a small severance, about ¼ of his monthly salary, just to smooth things over. The employee demanded a full month’s salary, which he said he needed to provide for his wife and child. Then he (an ex-marine) threatened to personally kill me if we didn’t pay him.

That 30 minute phone call was terrifying. I wasn’t actually scared of being murdered, and we never gave in to his demands, but it wasn’t until that call that I understood what it meant to be crazy. It unnerved me in a sort of staring into the abyss way. This man was truly detached from reality. He either didn’t know or could not understand the facts before him. When presented with reality, he would lash out in pain and anguish and fury at phantom targets. I would make calm, reasonable arguments about how he had violated his work contract, hurt our business, hurt our clients, and lied to us, and he would respond with nonsensical excuses, random tangents, blaming his personal life, and never ever coming close to acknowledging his own culpability.

I came away from the conversation with a mixture of pity, revulsion, and dread. I don’t know if this guy was bipolar, drug-addled, schizophrenic, or what, but I was 100% sure that this man lived in a nightmare. Everything was confusing and nonsensical to him. The world was dark, malevolent, and couldn’t stop hurting him even as he tried his best. I had an image of him sitting alone in his tiny apartment listening to that one student’s song over-and-over again on repeat while his mind blurred between random scientific and historical topics until he could no longer fight the urge to pick up the phone and call me or someone like me who took enough pity on him to politely listen for a few minutes until we made excuses and left him back alone in silence.

I see Tommy Wiseau, the creator of The Room and the subject of Disaster Artist, in the same category as my ex-employee. The form of their insanity is somewhat different, but both men live tortured, miserable lives, and constantly lash out at bystanders because of it. However, unlike my ex-employee, Wiseau is beloved by the masses precisely for his insanity. This is a dangerous, inaccurate, unfair reality, and in my opinion, is precisely what the Disaster Artist book argues against.

“Strange-face Illusions during Eye-to-eye Gazing in Dyads: Specific Effects on Derealization, Depersonalization and Dissociative Identity”, Caputo 2019

2019-caputo.pdf: “Strange-face illusions during eye-to-eye gazing in dyads: specific effects on derealization, depersonalization and dissociative identity”⁠, Giovanni B. Caputo (2019-04-02; ; similar):

Experimentally induced strange-face illusions can be perceived when 2 individuals look at each other in the eyes under low illumination for about 10 minutes. This task of subject-other eye-to-eye gazing produces the following perceptions by the subject: (1) mild to huge deformations and color/​shape changes of face and facial features; (2) lifeless, unmoving faces and immaterial presences akin to out-of-body experiences⁠; (3) pseudo-hallucinations, enlightened ‘idealized’ faces and personalities—rather than the other’s actual face. Dissociative phenomena seem to be involved, whereas the effects of non-pathological dissociation on strange-face illusions have not yet been directly investigated.

In the present study, dissociative perceptions and strange-face illusions were measured through self-report questionnaires on a large sample (n = 90) of healthy young individuals.

Results: of correlation and factor analyses suggest that strange-face illusions can involve, respectively: (1) strange-face illusions correlated to derealization; (2) strange-face illusions correlated to depersonalization; and (3) strange-face illusions of identity, which are supposedly correlated to identity dissociation. The findings support the separation between detachment and compartmentalization in dissociative processes. Effects of gender show that strange-face illusions are more frequent in men with respect to women if dyads are composed of individuals of different-gender. Furthermore, drawings of strange-faces, which were perceived by portrait artists in place the others’ faces, allowed a direct illustration of examples of dissociative identities.

Findings: are discussed in relation to the 3-level model of self-referential processing.

[Keywords: bodily self, consciousness, eye contact, identity, intersubjectivity, mirror-gazing⁠, OBE, projection, tonic immobility⁠, 2-person synchronization]

“Bifactor and Hierarchical Models: Specification, Inference, and Interpretation”, Markon 2019

2019-markon.pdf: “Bifactor and Hierarchical Models: Specification, Inference, and Interpretation”⁠, Kristian E. Markon (2019-01-16; ⁠, ⁠, ; backlinks; similar):

Bifactor and other hierarchical models [in factor analysis] have become central to representing and explaining observations in psychopathology, health, and other areas of clinical science, as well as in the behavioral sciences more broadly. This prominence comes after a relatively rapid period of rediscovery, however, and certain features remain poorly understood.

Here, hierarchical models are compared and contrasted with other models of superordinate structure, with a focus on implications for model comparisons and interpretation. Issues pertaining to the specification and estimation of bifactor and other hierarchical models are reviewed in exploratory as well as confirmatory modeling scenarios⁠, as are emerging findings about model fit and selection⁠.

Bifactor and other hierarchical models provide a powerful mechanism for parsing shared and unique components of variance, but care is required in specifying and making inferences about them.

[Keywords: hierarchical model, higher order, bifactor, model equivalence, model complexity]

Figure 1: Hierarchical and related models. (a) Spearman’s (1904a, 1904b) 2-factor model, a precursor to hierarchical and bifactor models. The 2-factor model includes a general factor (G) as well as systematic specific factors (S) and random error factors (e). As originally formulated, Spearman’s 2-factor model cannot be estimated, but it established the idea of a superordinate general factor plus subordinate specific factors that account for systematic residual influences not accounted for by the general factor. (b) The hierarchical or bifactor model, which includes superordinate general factors (G) as well as subordinate specific factors (S); error factors are not shown. Bifactor models are a subtype of hierarchical model with one superordinate factor and multiple subordinate factors. The 2-factor model and hierarchical model are examples of top-down models, in that subordinate factors instantiate residual effects that are unexplained by the superordinate factor.

…Bifactor models are now ubiquitous in the structural modeling of psychopathology. They have been central to general factor models of psychopathology (eg. Caspi et al 2014⁠, Laceulle et al 2015⁠, Lahey et al 2012⁠, Stochl et al 2015) and have become a prominent focus in modeling a range of phenomena as diverse as internalizing psychopathology (Naragon-Gainey et al 2016), externalizing psychopathology (Krueger et al 2007), psychosis (Shevlin et al 2017), somatic-related psychopathology (Witthöft et al 2016), cognitive functioning (Frisby & Beaujean 2015), and constructs central to prominent therapeutic paradigms (Aguado et al 2015). They have also become central to modeling method effects, such as informant (Bauer et al 2013), keying (Gu et al 2017⁠, Tomas & Oliver 1999), and other effects (DeMars 2006), and they have been used to explicate fundamental elements of measurement theory (Eid et al 2017).

Although bifactor and other hierarchical models are now commonplace, this was not always so. Their current ubiquity follows a long period of relative neglect (Reise 2012), having been derived in the early 20th century (Holzinger & Harman 1938⁠, Holzinger & Swineford 1937) before being somewhat overlooked for a number of decades and then being rediscovered more recently. Bifactor models were mistakenly dismissed as equivalent to and redundant with other superordinate structural models (eg. Adcock 1964, Humphreys 1981, Wherry 1959, Reise 2012, Yung et al 1999); as differences between bifactor models and other types of superordinate structural models became more recognized (Yung et al 1999), interest in bifactor models reemerged.

Summary Points:

  1. Bifactor and other hierarchical models represent superordinate structure in terms of orthogonal general and specific factors representing distinct, non-nested components of shared variance among indicators. This contrasts with higher-order models, which represent superordinate structure in terms of specific factors that are nested in general factors, and correlated-factors models, which represent superordinate structure in terms of correlations among subordinate factors.
  2. Higher-order models can be approached as a constrained form of hierarchical models, in which direct relationships between superordinate factors and observed variables in the hierarchical model are constrained to equal the products of superordinate-subordinate paths and subordinate-observed variable paths.
  3. Multiple exploratory factor analytic approaches to the delineation of hierarchical structure are available, including rank-deficient transformations, analytic rotations, and targeted rotations. Among other things, these transformations and rotations differ in the number of factors being rotated, the nature of those factors, and how superordinate factor structures are approximated.
  4. Misspecification or under-specification of confirmatory bifactor and hierarchical models can occur for multiple reasons. Problems with model identification may occur (1) with specific patterns of homogeneity in estimated or observed covariances, (2) if factors are allowed to correlate in inadmissible ways, or (3) if covariate paths imply inadmissible correlations. Signs of model misspecification may be evident in anomalous estimates, such as loading estimates near boundaries, or estimates that are suggestive of other types of models.
  5. Common model fit statistics can overstate the fit of bifactor models due to the tendency of bifactor and other hierarchical models to overfit to data in general, regardless of plausibility or population structure. Hierarchical models are similar to exploratory factor models in their expansiveness of fit, and, in general, they are more expansive in fit than other confirmatory models.

Future Issues:

  1. Research is needed to determine how to best account for the flexibility of hierarchical models when comparing models and evaluating model fit, given that the relative flexibility of hierarchical models can only partly be accounted for by the number of parameters. Approaches based on minimum description length and related paradigms, such as Bayesian inference with reference priors⁠, are promising in this regard.
  2. More research is needed to clarify the properties of hierarchical structures when they are embedded in longitudinal models and models with covariates. As with challenges of multicollinearity in regression, parsing unique general and specific factor components of explanatory paths may be inferentially challenging in the presence of strongly related predictors, covariates, and outcomes.
  3. More can be learned about the specification and identification of hierarchical models and the relationships between hierarchical models and other types of models, such as exploratory factor models. Similarities in overfitting patterns between exploratory and hierarchical models, approaches to hierarchical structure through bifactor rotations, and patterns of anomalous estimates that are sometimes obtained with hierarchical models, point to important relationships between exploratory and hierarchical models. Further explication of model specification principles with hierarchical models would also help clarify the appropriate structures to consider when evaluating models.

“Autistic Traits, Resting-state Connectivity and Absolute Pitch in Professional Musicians: Shared and Distinct Neural Features”, Wenhart et al 2018

“Autistic traits, resting-state connectivity and absolute pitch in professional musicians: shared and distinct neural features”⁠, T. Wenhart, R. A. I. Bethlehem, S. Baron-Cohen, E. Altenmüller (2018-10-30; ⁠, ):

Background: Recent studies indicate increased autistic traits in musicians with absolute pitch and a higher incidence of absolute pitch in people with autism. Theoretical accounts connect both of these with shared neural principles of local hyper-connectivity and global hypo-connectivity, enhanced perceptual functioning and a detail-focused cognitive style. This is the first study to investigate absolute pitch proficiency, autistic traits and brain correlates in the same study.

Sample and Methods: Graph theoretical analysis was conducted on resting state (eyes closed and eyes open) EEG connectivity (wPLI, weighted Phase Lag Index) matrices obtained from 31 absolute pitch (AP) and 33 relative pitch (RP) professional musicians. Small Worldness, Global Clustering Coefficient and Average Path length were related to autistic traits, passive (tone identification) and active (pitch adjustment) absolute pitch proficiency and onset of musical training using Welch-two-sample-tests, correlations and general linear models.

Results: Analyses revealed increased Path length (delta 2–4 Hz), reduced Clustering (beta 13–18 Hz), reduced Small-Worldness (gamma 30–60 Hz) and increased autistic traits for AP compared to RP. Only Clustering values (beta 13–18 Hz) were predicted by both AP proficiency and autistic traits. Post-hoc single connection permutation tests among raw wPLI matrices in the beta band (13–18 Hz) revealed widely reduced interhemispheric connectivity between bilateral auditory related electrode positions along with higher connectivity between F7-F8 and F8-P9 for AP. Pitch naming ability and Pitch adjustment ability were predicted by Path length, Clustering, autistic traits and onset of musical training (for pitch adjustment) explaining 44% respectively 38% of variance.

Conclusion: Results show both shared and distinct neural features between AP and autistic traits. Differences in the beta range were associated with higher autistic traits in the same population. In general, AP musicians exhibit a widely underconnected brain with reduced functional integration and reduced small-world-property during resting state. This might be partly related to autism-specific brain connectivity, while differences in Path length and Small-Worldness reflect other ability-specific influences. This is further evidence for different pathways in the acquisition and development of absolute pitch, likely influenced by both genetic and environmental factors and their interaction.

“The Cumulative Effect of Reporting and Citation Biases on the Apparent Efficacy of Treatments: the Case of Depression”, Vries et al 2018

2018-devries.pdf: “The cumulative effect of reporting and citation biases on the apparent efficacy of treatments: the case of depression”⁠, Y. A. de Vries, A. M. Roest, P. de Jonge, P. Cuijpers, M. R. Munafò, J. A. Bastiaansen (2018-08-18; ; backlinks; similar):

Evidence-based medicine is the cornerstone of clinical practice, but it is dependent on the quality of evidence upon which it is based. Unfortunately, up to half of all randomized controlled trials (RCTs) have never been published, and trials with statistically-significant findings are more likely to be published than those without (Dwan et al 2013). Importantly, negative trials face additional hurdles beyond study publication bias that can result in the disappearance of non-significant results (Boutron et al 2010; Dwan et al 2013; Duyx et al 2017). Here, we analyze the cumulative impact of biases on apparent efficacy, and discuss possible remedies, using the evidence base for two effective treatments for depression: antidepressants and psychotherapy.

Figure 1: The cumulative impact of reporting and citation biases on the evidence base for antidepressants. (a) displays the initial, complete cohort of trials, while (b) through (e) show the cumulative effect of biases. Each circle indicates a trial, while the color indicates the results or the presence of spin. Circles connected by a grey line indicate trials that were published together in a pooled publication. In (e), the size of the circle indicates the (relative) number of citations received by that category of studies.

“Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study”, Martin-Brevet et al 2018

“Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study”⁠, Sandra Martin-Brevet, Borja Rodríguez-Herreros, Jared A. Nielsen, Clara Moreau, Claudia Modenato, Anne M. Maillard et al (2018-08-15; ⁠, ; similar):

Background: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder⁠, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.

Methods: Using voxel-based and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at 7 sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.

Results: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen’s d > 1), the superior and middle temporal gyri (deletion < control; Cohen’s d < −1), and the caudate and hippocampus (control > duplication; −0.5 > Cohen’s d > −1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.

Conclusions: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. effect-sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.

[Keywords: 16p11.2, autism spectrum disorder, copy number variant, genetics, imaging, neurodevelopmental disorders]

“Genome-wide Statistically-significant Regions in 43 Utah High-risk Families Implicate Multiple Genes Involved in Risk for Completed Suicide”, Coon et al 2018

“Genome-wide statistically-significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide”⁠, Hilary Coon, Todd M. Darlington, Emily DiBlasi, W. Brandon Callor, Elliott Ferris, Alison Fraser, Zhe Yu et al (2018-08-13; ; similar):

Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests genetic factors play a significant role in completed suicide.

We linked a resource of >4,500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over 8 million individuals. This linking has resulted in the identification of high-risk extended families (7–9 generations) with significant familial risk of completed suicide.

Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07 to 1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk.

While PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory.

However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

“Analysis of Shared Heritability in Common Disorders of the Brain”, Consortium 2018

“Analysis of shared heritability in common disorders of the brain”⁠, The Brainstorm Consortium (2018-06-22; ⁠, ; similar):

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified statistically-significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

“Snake Venom Use As a Substitute for Opioids: A Case Report and Review of Literature”, Mehra et al 2018

“Snake Venom Use as a Substitute for Opioids: A Case Report and Review of Literature”⁠, Aseem Mehra, Debashish Basu, Sandeep Grover (2018-05; similar):

The mind-altering agents such as tobacco, cannabis, and opium have been widely used since the evolution of human being. These substances have been widely used for recreational purposes. However, derivatives from reptiles such as snakes, reptiles, and scorpions can also be used for recreational purposes and as a substitute for other substances. Their use is rare and related literature is very scanty.

In this report, we present a case of snake venom abuse and review the existing literature.

“Psilocybin With Psychological Support for Treatment-resistant Depression: Six-month Follow-up”, Carhart-Harris et al 2018

“Psilocybin with psychological support for treatment-resistant depression: six-month follow-up”⁠, R L. Carhart-Harris, M. Bolstridge, C. M J. Day, J. Rucker, R. Watts, D. E Erritzoe, M. Kaelen, B. Giribaldi et al (2018; ; backlinks; similar):

Rationale: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.

Objectives: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.

Methods: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.

Results: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.

Conclusions: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained statistically-significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

“Film Review: The Haunting (1963)”, Dean 2017

“Film Review: The Haunting (1963)”⁠, Remy Dean (2017-10-31; ⁠, ; backlinks; similar):

Gidding hints that the house itself is doing the haunting [in The Haunting], implying that the architectural environment is responsible for reflecting back the fears of those within, teasing out their vulnerabilities, feeding upon them, and making them manifest. The house becomes a monster, a maleficent presence that resents its human tenants. If the house can be read as a metaphor for the body, as is often the case in Gothic mansions and castles, then the occupants become its consciousness, the archetypes inhabiting its ego and id. Then the house inevitably suffers from a mental schism, a multiple personality disorder. The characters become those internal voices of nagging doubt and paranoia for the house… and it eventually suffers a mental breakdown.

Despite filming in England, the setting remained as New England. Ettington Park in Stratford-upon-Avon was the spooky mansion that Robert Wise chose for Hill House’s exteriors, reputedly selected from a list he sourced from the British Psychical Research Society of buildings considered to be genuinely haunted. This is the first ‘character’ to appear in the film, emerging out of darkness and looking very eerie indeed, due to the inventive use of infra-red film stock.

It’s been argued that the house is the true star of the film, and I have to admit it turns in a memorable ‘performance’. This, though, has more to do with marvellous production design by Elliot Scott and the huge labyrinthine sets built at Borehamwood⁠. Corridors were made to converge or open out, creating a subtly expressionistic feel and rooms were constructed slightly askew, sometimes with walls that angled inward. Scott went on to design Labyrinth (1986) and the first two Indiana Jones sequels.

The Haunting is regularly included in Top 10 lists of the scariest films ever made. But the special effects are limited to only a few ingenious mechanical effects, as the terror is mostly the result of brilliant sound-design, clever use of shadows, and inventive camerawork.

Wise chose to shoot the film in Panavision’s wide format and every shot makes full use of it, with beautiful compositions and plenty of visual interest across every inch of the screen. The otherworldly atmosphere and ominous tracking shots, enhanced by special lenses, work in tandem with the subtly distorted sets.

Wise had some problems sourcing the wide-angle lenses he needed, mainly because they didn’t exist at that time. He wanted the interior to look deep, dark, and foreboding, seeming to move as if we were within a living thing. The available lenses just weren’t cutting it for him. He badgered Bob Gottschalk, president of Panavision⁠, until he let slip that wider-lenses were in development at their optics labs. Gottschalk explained that they were early prototypes and the lenses caused unacceptable distortions. This was exactly what Wise wanted! After signing a disclaimer to waive any legal repercussions, he became the first director to use such wide angles, imbuing Hill House with its unique and disquieting visual personality.

The unique look of the film goes a long way to creating the brooding atmosphere, but the sound design was the real breakthrough. The slightest creak of floorboard or sigh of draught makes audiences hold their breath to better listen, and then cacophonous groans and thuds really get the heart racing.

…Of course, our emotional involvement hinges on the performances of the actors. It seems that the personal circumstances and attitudes of the actors already reflected the characters they were to play. Harris admits that she was suffering from a bout of depression during filming, and this inadvertently helped her play the central role of the sensitive Eleanor, who feels isolated and shunned by her colleagues, and so becomes victim to the seductively malign atmosphere of the house. Her performance is both fragile and disturbingly unhinged in turns. The voice-over she provides, to share her character’s paranoia, might have looked corny on paper to those American studio executives, but Harris delivers it so perfectly that it draws the sympathies of the audience. We feel for her, even as she seems to succumb to madness and becomes the willing victim.

The Haunting stands alongside Night of the Demon (1957) and The Innocents (1961) as a defining classic in the cinema of the supernatural. It has never been surpassed and its ‘presence’ is palpable in most intelligent psychological horror films to this day. If special effects had been used more extensively, then it surely would have dated, but keeping the focus on mood and the psychological aspects of the narrative has ensured it remains as effective as ever.

It’s the best Halloween film I could recommend.

“Serotonin and Brain Function: a Tale of Two Receptors”, Carhart-Harris & Nutt 2017

2017-carharttharris.pdf: “Serotonin and brain function: a tale of two receptors”⁠, R. L. Carhart-Harris, D. J. Nutt (2017-08-31; ; backlinks; similar):

Previous attempts to identify an unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors.

We propose that passive coping (ie. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (ie. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/​or relationship to it via 5-HT2AR-mediated plasticity may also be important—and increasingly so as the level of adversity reaches a critical point.

We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

“Meta-Analysis of the Antidepressant Effects of Acute Sleep Deprivation”, Boland et al 2017

2017-boland.pdf: “Meta-Analysis of the Antidepressant Effects of Acute Sleep Deprivation”⁠, Elaine M. Boland, Hengyi Rao, David F. Dinges, Rachel V. Smith, Namni Goel, John A. Detre, Mathias Basner et al (2017-01-01; ⁠, ; backlinks)

“The Psychosis Continuum: Testing a Bifactor Model of Psychosis in a General Population Sample”, Shevlin et al 2017

“The Psychosis Continuum: Testing a Bifactor Model of Psychosis in a General Population Sample”⁠, Mark Shevlin, Eoin McElroy, Richard P. Bentall, Ulrich Reininghaus, Jamie Murphy (2017; backlinks; similar):

Although the factor structure of psychosis continues to be debated by taxonomists, recent studies have supported a bifactor model consisting of a general psychosis factor and 5 uncorrelated symptom-specific factors. While this model has received support in clinical samples, it has not been tested at the general population level. Analysis was conducted on Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (n = 34 653). Twenty-two psychotic symptoms were used as observed indicators of psychosis. These items were chosen based on their conceptual similarity to the items used in a similar study based on clinical samples. Confirmatory factor analysis and confirmatory bifactor modeling were used to test a variety of competing models. The best fitting model consisted of a general psychosis factor that was uncorrelated with 5 specific factors: positive, negative, disorganization, mania, and depression. These findings suggest that the bifactor model can be extended to general population samples, supporting the continuity between clinical and subclinical psychotic experiences. Theoretical and practical implications are discussed.

“Clarifying the Latent Structure and Correlates of Somatic Symptom Distress: A Bifactor Model Approach”, Witthöft et al 2017

2016-witthoft.pdf: “Clarifying the Latent Structure and Correlates of Somatic Symptom Distress: A Bifactor Model Approach”⁠, Michael Witthöft, Susanne Fischer, Fabian Jasper, Fred Rist (2017; backlinks; similar):

Distressing somatic symptoms are ubiquitous both in mental disorders and medical diseases. From a psychometric perspective, the structure of somatic symptom distress is unclear, and little is known about the strengths of associations to related constructs, such as health anxiety and somatosensory amplification.

To clarify the structure of somatic symptom distress and to explore associations to health anxiety, somatosensory amplification, and functional somatic syndromes, data sets of 2 samples of college students from Germany (n = 1,520) and Switzerland (n = 3,053) were investigated with confirmatory factor analysis with robust estimation.

A bifactor model (with 1 general and 4 orthogonal specific symptom factors—gastrointestinal, fatigue, cardio-pulmonary, and pain symptoms) revealed the best model fit. Medium-sized associations were found among latent factors of general somatic symptom distress, health anxiety, and depression. First evidence for the construct validity of the latent variables within the proposed bifactor structure was gained by observing (1) strong associations between the general somatic symptom distress factor and somatosensory amplification and (2) statistically-significant associations between both the general somatic symptom factor as well as the symptom-specific factors with functional somatic syndromes.

The results offer a theoretically and psychometrically plausible model for the structure of somatic symptom distress and suggest a distinction between cognitive-affective and sensory aspects of symptom perception. The findings are compatible with current cognitive psychological and neuropsychological approaches to symptom perception and imply that somatic symptom distress is a multidimensional phenomenon that is both strongly linked to but also clearly separable from related constructs.

[Keywords: somatic symptom disorder, medically unexplained symptoms (MUS), somatoform disorders, functional somatic syndromes, bifactor model]

“Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics”, Holland et al 2016

“Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics”⁠, Dominic Holland, Yunpeng Wang, Wesley K. Thompson, Andrew Schork, Chi-Hua Chen, Min-Tzu Lo, Aree Witoelar et al (2016-02-16; ; similar):

genome-wide association studies (GWAS) result in millions of summary statistics (“z-scores”) for single-nucleotide polymorphism (SNP) associations with phenotypes. These rich datasets afford deep insights into the nature and extent of genetic contributions to complex phenotypes such as psychiatric disorders, which are understood to have substantial genetic components that arise from very large numbers of SNPs. The complexity of the datasets, however, poses a large challenge to maximizing their utility. This is reflected in a need for better understanding the landscape of z-scores, as such knowledge would enhance causal SNP and gene discovery, help elucidate mechanistic pathways, and inform future study design.

Here we present a parsimonious methodology for modeling effect-sizes and replication probabilities, relying only on summary statistics from GWAS sub-studies, and a scheme allowing for direct empirical validation. We show that modeling z-scores as a mixture of Gaussians is conceptually appropriate, in particular taking into account ubiquitous non-null effects that are likely in the datasets due to weak linkage disequilibrium with causal SNPs. The 4-parameter model allows for estimating the degree of polygenicity of the phenotype and predicting the proportion of chip heritability explainable by genome-wide statistically-significant SNPs in future studies with larger sample sizes. We apply the model to recent GWAS of schizophrenia (n = 82,315) and putamen volume (n = 12,596), with ~9.3 million SNP z-scores in both cases.

We show that, over a broad range of z-scores and sample sizes, the model accurately predicts expectation estimates of true effect sizes and replication probabilities in multistage GWAS designs. We assess the degree to which effect sizes are over-estimated when based on linear-regression association coefficients. We estimate the polygenicity of schizophrenia to be 0.037 and the putamen to be 0.001, while the respective sample sizes required to approach fully explaining the chip heritability are 106 and 105. The model can be extended to incorporate prior knowledge such as pleiotropy and SNP annotation.

The current findings suggest that the model is applicable to a broad array of complex phenotypes and will enhance understanding of their genetic architectures.

“Rapid and Sustained Symptom Reduction following Psilocybin Treatment for Anxiety and Depression in Patients With Life-threatening Cancer: a Randomized Controlled Trial”, Ross et al 2016

“Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial”⁠, Stephen Ross, Anthony Bossis, Jeffrey Guss, Gabrielle Agin-Liebes, Tara Malone, Barry Cohen, Sarah E. Mennenga et al (2016; ; backlinks; similar):

Background: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.

Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/​kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.

Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (~60–80% of participants continued with clinically-significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.

Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.

Trial Registration: Identifier: NCT00957359.

“A Comparison and Integration of Structural Models of Depression and Anxiety in a Clinical Sample: Support for and Validation of the Tri-level Model”, Naragon-Gainey et al 2016

“A comparison and integration of structural models of depression and anxiety in a clinical sample: Support for and validation of the tri-level model”⁠, Kristin Naragon-Gainey, Jason M. Prenoveau, Timothy A. Brown, Richard E. Zinbarg (2016; backlinks; similar):

Prominent structural models of depression and anxiety arise from 2 traditions: (a) the tripartite/​integrative hierarchical model based on symptom dimensions, and (b) the fear/​anxious-misery model based on diagnostic comorbidity data. The tri-level model of depression and anxiety was developed to synthesize these structural models, postulating that narrow (disorder-specific), intermediate (fear and anxious-misery), and broad (general distress) structural factors are needed to most fully account for covariation among these symptoms. Although this model has received preliminary support (Prenoveau et al 2010), the current study compares it with the above established models and seeks to validate the best-fitting structure. We evaluated the tri-level model and alternative structural models in a large clinical sample (n = 1,000) using bifactor analysis. In exploratory and confirmatory subsamples, the tri-level model provided a good fit to the data and each of the 3 levels (narrow, intermediate, and broad) accounted for substantial variance; this model provided a superior fit relative to more parsimonious competing structural models. Furthermore, impairment was independently associated with all 3 levels of the tri-level model, comorbidity was most closely linked to the broad tri-level dimensions, and the factors generally showed the expected convergent/​discriminant associations with diagnoses. Results suggested several revisions to prior research: (a) worry may be best modeled at the broadest structural level, rather than as an indicator of anxious-misery or fear; (b) social interaction anxiety may belong with anxious-misery, rather than fear; and (c) obsessive-compulsive disorder is generally associated with fear disorders, but hoarding is associated with both fear and anxious-misery.

“The Enduring Effects of Psychodynamic Treatments vis-à-vis Alternative Treatments: A Multilevel Longitudinal Meta-analysis”, III et al 2015

2015-kivlighan.pdf: “The enduring effects of psychodynamic treatments vis-à-vis alternative treatments: A multilevel longitudinal meta-analysis”⁠, D. Martin Kivlighan III, Simon B. Goldberg, Maleeha Abbas, Brian T. Pace, Noah E. Yulish, Joel G. Thomas et al (2015-08-01; similar):

  • Examined the enduring impact of dynamic treatments versus non-dynamic treatments.
  • Calculated 4 ESs; targeted, non-targeted, personality, and combined measures.
  • Treatments were not statistically-significantly different at post-treatment for all 4 ESs.
  • Post-treatment slopes for all 4 ESs were non-significant.
  • Dynamic and non-dynamic treatments were equivalent at post-treatment and beyond.

Although evidence suggests that the benefits of psychodynamic treatments are sustained over time, presently it is unclear whether these sustained benefits are superior to non-psychodynamic treatments. Additionally, the extant literature comparing the sustained benefits of psychodynamic treatments compared to alternative treatments is limited with methodological shortcomings.

The purpose of the current study was to conduct a rigorous test of the growth of the benefits of psychodynamic treatments relative to alternative treatments across distinct domains of change (ie. all outcome measures, targeted outcome measures, non-targeted outcome measures, and personality outcome measures). To do so, the study employed strict inclusion criteria to identify randomized clinical trials that directly compared at least one bona fide psychodynamic treatment and one bona fide non-psychodynamic treatment. Hierarchical linear modeling (Raudenbush et al 2011) was used to longitudinally model the impact of psychodynamic treatments compared to non-psychodynamic treatments at post-treatment and to compare the growth (ie. slope) of effects beyond treatment completion.

Findings: from the present meta-analysis indicated that psychodynamic treatments and non-psychodynamic treatments were equally efficacious at post-treatment and at follow-up for combined outcomes (k = 20), targeted outcomes (k = 19), non-targeted outcomes (k = 17), and personality outcomes (k = 6).

Clinical implications, directions for future research, and limitations are discussed.

[Keywords: psychodynamic, meta-analysis, follow up, efficacy, comparative trials]

“Beauty in Mind: The Effects of Physical Attractiveness on Psychological Well-Being and Distress”, Gupta et al 2015

2015-gupta.pdf: “Beauty in Mind: The Effects of Physical Attractiveness on Psychological Well-Being and Distress”⁠, Nabanita Datta Gupta, Nancy L. Etcoff, Mads M. Jaeger (2015-06-14; ; similar):

Attractive people enjoy many social and economic advantages. Most studies find effects of attractiveness on happiness or life satisfaction, but based on traditional cross-sectional approaches.

We use a large longitudinal survey consisting of a sample of male and female high school graduates from Wisconsin [Wisconsin Longitudinal Study] followed from their late teens to their mid-1960s. The panel construction of the data and the fact that interviews of the siblings of the respondents are available allow us to analyze the effects of physical appearance on psychological well-being (human flourishing) and ill-being (distress and depression) conditioning on unobserved individual heterogeneity via random effects.

We find a statistically-significant positive relationship between measures of physical attractiveness (greater facial attractiveness at high school, and lower BMI and greater height in middle age) and a measure of psychological well-being, and a statistically-significant negative relationship between measures of physical attractiveness and distress/​depression. These effects are slightly smaller when we adjust for demographics and mental ability but, with the exception of height, remain statistically-significant.

Our results suggest that attractiveness impacts psychological well-being and depression directly as well as through its effects on other life outcomes.

[Keywords: physical attractiveness, psychological well-being, distress, longitudinal survey, random effects, sibling differences]

“The Structure of Psychopathology in Adolescence: Replication of a General Psychopathology Factor in the TRAILS Study”, Laceulle et al 2015

2015-laceulle.pdf: “The Structure of Psychopathology in Adolescence: Replication of a General Psychopathology Factor in the TRAILS Study”⁠, Odilia M. Laceulle, Wilma A. M. Vollebergh, Johan Ormel (2015-02-23; backlinks; similar):

This study aimed to replicate a study by Caspi and colleagues, which proposed that the structure of psychopathology is characterized by a general psychopathology factor, in addition to smaller internalizing and externalizing factors.

Our study expanded the approach of the original by using continuous adolescent data and testing additional models, including both self-reported and parent-reported data, to bolster the robustness of the findings.

Our findings indicate that the structure of psychopathology is best characterized by a model including a general factor, in addition to smaller internalizing and externalizing factors.

These results emphasize the importance of this model for understanding the structure of psychopathology. Given the increasing emphasis on the importance of, and need for, replication, the overall evidence of a general factor seems rather robust.

“Common Psychiatric Disorders Share the Same Genetic Origin: a Multivariate Sibling Study of the Swedish Population”, Pettersson et al 2015

2015-pettersson.pdf: “Common psychiatric disorders share the same genetic origin: a multivariate sibling study of the Swedish population”⁠, E Pettersson, H. Larsson, P. Lichtenstein (2015-01-01; ⁠, )

“Bifactor Analysis and Construct Validity of the Five Facet Mindfulness Questionnaire (FFMQ) in Non-clinical Spanish Samples”, Aguado et al 2015

“Bifactor analysis and construct validity of the five facet mindfulness questionnaire (FFMQ) in non-clinical Spanish samples”⁠, Jaume Aguado, Juan V. Luciano, Ausias Cebolla, Antoni Serrano-Blanco, Joaquim Soler, Javier García-Campayo et al (2015; ; backlinks; similar):

The objective of the present study was to examine the dimensionality, reliability, and construct validity of the Five Facet Mindfulness Questionnaire (FFMQ) in three Spanish samples using structural equation modeling (SEM). Pooling the FFMQ data from 3 Spanish samples (n = 1191), we estimated the fit of two competing models (correlated five-factor vs. bifactor) via confirmatory factor analysis. The factorial invariance of the best fitting model across meditative practice was also addressed. The pattern of relationships between the FFMQ latent dimensions and anxiety, depression, and distress was analyzed using SEM. FFMQ reliability was examined by computing the omega and omega hierarchical coefficients. The bifactor model, which accounted for the covariance among FFMQ items with regard to one general factor (mindfulness) and five orthogonal factors (observing, describing, acting with awareness, non-judgment, and non-reactivity), fit the FFMQ structure better than the correlated five-factor model. The relationships between the latent variables and their manifest indicators were not invariant across the meditative experience. Observing items had significant loadings on the general mindfulness factor, but only in the meditator sub-sample. The SEM analysis revealed significant links between mindfulness and symptoms of depression and stress. When the general factor was partialled out, the acting with awareness facet did not show adequate reliability. The FFMQ shows a robust bifactor structure among Spanish individuals. Nevertheless, the Observing subscale does not seem to be adequate for assessing mindfulness in individuals without meditative experience.

“Low-dose Paroxetine Exposure Causes Lifetime Declines in Male Mouse Body Weight, Reproduction and Competitive Ability As Measured by the Novel Organismal Performance Assay”, Ruff et al 2015

2015-gaukler.pdf: “Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay”⁠, James S. Ruff, Tessa Galland, Kirstie A. Kandaris, Tristan K. Underwood, Nicole M. Liu, Elizabeth L. Young et al (2015; ⁠, ⁠, ; backlinks; similar):

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy.

We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete amongst each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship.

Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points. In cages, paroxetine-exposed breeders took 2.3× longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study were undetected in preclinical trials with dose 2.5-8× higher than human therapeutic doses.

These data indicate that OPAs detect phenotypic adversity and provide unique information that could useful towards safety testing during pharmaceutical development.

[Keywords: intraspecific competition, pharmacodynamics, reproductive success, semi-natural enclosures, SSRI, toxicity assessment.]

“Illustrations of Madness: James Tilly Matthews and the Air Loom”, Jay 2014

“Illustrations of Madness: James Tilly Matthews and the Air Loom”⁠, Mike Jay (2014-11-12; ; similar):

Mike Jay recounts the tragic story of James Tilly Matthews, a former peace activist of the Napoleonic Wars who was confined to London’s notorious Bedlam asylum in 1797 for believing that his mind was under the control of the “Air Loom”—a terrifying machine whose mesmeric rays and mysterious gases were brainwashing politicians and plunging Europe into revolution, terror, and war.

…Over the ten years they had spent together in Bedlam, Matthews revealed his secret world to Haslam in exhaustive detail. Around the corner from Bedlam, in a dank basement cellar by London Wall, a gang of villains were controlling and tormenting him with a machine called an “Air Loom”. Matthews had even drawn a technical diagram of the device, which Haslam included in his book with a sarcastic commentary that invited the reader to laugh at its absurdity: a literal “illustration of madness”. But Matthews’ drawing has a more unnerving effect than Haslam allows. Levers, barrels, batteries, brass retorts and cylinders are rendered with the cool conviction of an engineer’s blueprint. It is the first ever published work of art by an asylum inmate, but it would hardly have looked out of place in the scientific journals or enyclopaedias of its day.

The Air Loom worked, as its name suggests, by weaving “airs”, or gases, into a “warp of magnetic fluid” which was then directed at its victim. Matthews’ explanation of its powers combined the cutting-edge technologies of pneumatic chemistry and the electric battery with the controversial science of animal magnetism, or mesmerism. The finer detail becomes increasingly strange. It was fuelled by combinations of “fetid effluvia”, including “spermatic-animal-seminal rays”, “putrid human breath”, and “gaz from the anus of the horse”, and its magnetic warp assailed Matthews’ brain in a catalogue of forms known as “event-workings”. These included “brain-saying” and “dream-working”, by which thoughts were forced into his brain against his will, and a terrifying array of physical tortures from “knee nailing”, “vital tearing” and “fibre ripping” to “apoplexy-working with the nutmeg grater” and the dreaded “lobster-cracking”, where the air around his chest was constricted until he was unable to breathe. To facilitate their control over him, the gang had implanted a magnet into his brain. He was tormented constantly by hallucinations, physical agonies, fits of laughter or being forced to parrot whatever words they chose to feed into his head. No wonder some people thought he was mad.

The machine’s operators were a gang of undercover Jacobin terrorists, who Matthews described with haunting precision. Their leader, Bill the King, was a coarse-faced and ruthless puppetmaster who “has never been known to smile”; his second-in-command, Jack the Schoolmaster, took careful notes on the Air Loom’s operations, pushing his wig back with his forefinger as he wrote. The operator was a sinister, pockmarked lady known only as the “Glove Woman”. The public face of the gang was a sharp-featured woman named Augusta, superficially charming but “exceedingly spiteful and malignant” when crossed, who roamed London’s west end as an undercover agent.

The operation directed at Matthews was only part of a larger story. There were more Air Looms and their gangs concealed across London, and their unseen influence extended all the way up to the Prime Minister, William Pitt, whose mind was firmly under their control. Their agents lurked in streets, theatres and coffee-houses, where they tricked the unsuspecting into inhaling magnetic fluids. If the gang were recognised in public, they would grasp magnetised batons that clouded the perception of anyone in the vicinity. The object of their intrigues was to poison the minds of politicians on both sides of the Channel, and thereby keep Britain and revolutionary France locked into their ruinous war.

“Mood, Anxiety and Psychotic Phenomena Measure a Common Psychopathological Factor”, Stochl et al 2014

2015-stochl.pdf: “Mood, anxiety and psychotic phenomena measure a common psychopathological factor”⁠, J. Stochl, G. M. Khandaker, G. Lewis, J. Perez, I. M. Goodyer, S. Zammit, S. Sullivan, T. J. Croudace et al (2014-09-14; backlinks; similar):

Background: Psychotic phenomena are common in the general population but are excluded from diagnostic criteria for mild to moderate depression and anxiety despite their co-occurrence and shared risk factors. We used item response theory modelling to examine whether the co-occurrence of depressive, anxiety and psychotic phenomena is best explained by: (1) a single underlying factor; (2) two separate, uncorrelated factors; (3) two separate yet linked factors; or (4) two separate domains along with an underlying ‘common mental distress’ (CMD) factor. We defined where, along any latent continuum, the psychopathological items contributed most information.

Method: We performed a secondary analysis of cross-sectional, item-level information from measures of depression, anxiety and psychotic experiences in 6617 participants aged 13 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and 977 participants aged 18 years from the ROOTS schools-based sample. We replicated results from one sample in the other and validated the latent factors against an earlier parental measure of mental state.

Results: In both cohorts depression, anxiety and psychotic items were best represented as a bi-factor model with a single, unitary CMD factor on which psychotic items conveyed information about the more severe end (model 4); residual variation remained for psychotic items. The CMD factor was statistically-significantly associated with the prior parental measure.

Conclusions: Psychotic phenomena co-occur with depression and anxiety in teenagers and may be a marker of severity in a single, unitary dimension of CMD. Psychotic phenomena should be routinely included in epidemiological assessments of psychiatric morbidity, otherwise the most severe symptomatology remains unmeasured.

“The P Factor: One General Psychopathology Factor in the Structure of Psychiatric Disorders?”, Caspi et al 2014

“The p Factor: One General Psychopathology Factor in the Structure of Psychiatric Disorders?”⁠, Avshalom Caspi, Renate M. Houts, Daniel W. Belsky, Sidra J. Goldman-Mellor, HonaLee Harrington, Salomon Israel et al (2014; backlinks; similar):

Mental disorders traditionally have been viewed as distinct, episodic, and categorical conditions. This view has been challenged by evidence that many disorders are sequentially comorbid, recurrent/​chronic, and exist on a continuum. Using the Dunedin Multidisciplinary Health and Development Study, we examined the structure of psychopathology, taking into account dimensionality, persistence, co-occurrence, and sequential comorbidity of mental disorders across 20 years, from adolescence to midlife. Psychiatric disorders were initially explained by three higher-order factors (Internalizing, Externalizing, and Thought Disorder) but explained even better with one General Psychopathology dimension. We have called this dimension the p factor because it conceptually parallels a familiar dimension in psychological science: the g factor of general intelligence. Higher p scores are associated with more life impairment, greater familiality, worse developmental histories, and more compromised early-life brain function. The p factor explains why it is challenging to find causes, consequences, biomarkers, and treatments with specificity to individual mental disorders. Transdiagnostic approaches may improve research.

“The 1% of the Population Accountable for 63% of All Violent Crime Convictions”, Falk et al 2014

“The 1% of the population accountable for 63% of all violent crime convictions”⁠, Orjan Falk, Märta Wallinius, Sebastian Lundström, Thomas Frisell, Henrik Anckarsäter, Nóra Kerekes (2014; ⁠, ⁠, ; similar):

Purpose: Population-based studies on violent crime and background factors may provide an understanding of the relationships between susceptibility factors and crime. We aimed to determine the distribution of violent crime convictions in the Swedish population 1973–2004 and to identify criminal, academic, parental, and psychiatric risk factors for persistence in violent crime.

Method: The nationwide multi-generation register was used with many other linked nationwide registers to select participants. All individuals born in 1958–1980 (2,393,765 individuals) were included. Persistent violent offenders (those with a lifetime history of three or more violent crime convictions) were compared with individuals having one or two such convictions, and to matched non-offenders. Independent variables were gender, age of first conviction for a violent crime, nonviolent crime convictions, and diagnoses for major mental disorders, personality disorders, and substance use disorders.

Results: A total of 93,642 individuals (3.9%) had at least one violent conviction. The distribution of convictions was highly skewed; 24,342 persistent violent offenders (1.0% of the total population) accounted for 63.2% of all convictions. Persistence in violence was associated with male sex (OR 2.5), personality disorder (OR 2.3), violent crime conviction before age 19 (OR 2.0), drug-related offenses (OR 1.9), nonviolent criminality (OR 1.9), substance use disorder (OR 1.9), and major mental disorder (OR 1.3).

Conclusions: The majority of violent crimes are perpetrated by a small number of persistent violent offenders, typically males, characterized by early onset of violent criminality, substance abuse, personality disorders, and nonviolent criminality.

“Development of a Short Sleeper Phenotype After Third Ventriculostomy in a Patient With Ependymal Cysts”, Seystahl et al 2014

“Development of a short sleeper phenotype after third ventriculostomy in a patient with ependymal cysts”⁠, Katharina Seystahl, Helen Könnecke, Oguzkan Sürücü, Christian R. Baumann, Rositsa Poryazova (2014; ):

A naturally short sleeper phenotype with a sleep need of less than 6 hours without negative impact on health or performance is rare. We present a case of an acquired short sleeper phenotype after third ventriculostomy. A 59-year-old patient suffering from chronic hydrocephalus reported an average of 7–8 h of nocturnal sleep. After surgical intervention, the patient noted a strikingly reduced sleep need of 4–5 h without consequent fatigue or excessive daytime sleepiness, but with good daytime performance and well-balanced mood. Short sleep per 24 hours was confirmed by actigraphy. Postoperative imaging revealed decreased pressure around the anterior third ventricle. The temporal link between development of a short sleeper phenotype and third ventriculostomy is striking. This might suggest that individual short sleep need is not only determined by genetics but can be also be induced by external factors.

“The Devil’s Bait: Symptoms, Signs, and the Riddle of Morgellons”, Jamison 2013

“The Devil’s Bait: Symptoms, signs, and the riddle of Morgellons”⁠, Leslie Jamison (2013-09-01; ; similar):

For Paul, it started with a fishing trip. For Lenny, it was an addict whose knuckles were covered in sores. Dawn found pimples clustered around her swimming goggles. Kendra noticed ingrown hairs. Patricia was attacked by sand flies on a Gulf Coast beach. Sometimes the sickness starts as blisters, or lesions, or itching, or simply a terrible fog settling over the mind, over the world.

For me, Morgellons disease started as a novelty: people said they had a strange ailment, and no one—or hardly anyone—believed them. But there were a lot of them, reportedly 12,000, and their numbers were growing. Their illness manifested in many ways, including fatigue, pain, and formication (a sensation of insects crawling over the skin). But the defining symptom was always the same: fibers emerging from their bodies. Not just fibers but fuzz, specks, and crystals. They didn’t know what this stuff was, or where it came from, or why it was there, but they knew—and this was what mattered, the important word—that it was real.

…Browne’s “harsh hairs” were the early ancestors of today’s fibers. Photos online show them in red, white, and blue—like the flag—and also black and translucent. These fibers are the kind of thing you describe in relation to other kinds of things: jellyfish or wires, animal fur or taffy candy or a fuzzball off your grandma’s sweater. Some are called goldenheads, because they have a golden-colored bulb. Others simply look sinister, technological, tangled.

Patients started bringing these threads and flecks and fuzz to their doctors, storing them in Tupperware or matchboxes, and dermatologists actually developed a term for this phenomenon. They called it “the matchbox sign”, an indication that patients had become so determined to prove their disease that they might be willing to produce fake evidence.

…This isn’t an essay about whether Morgellons disease is real. That’s probably obvious by now. It’s an essay about what kinds of reality are considered prerequisites for compassion. It’s about this strange sympathetic limbo: Is it wrong to speak of empathy when you trust the fact of suffering but not the source?

“Tests of a Direct Effect of Childhood Abuse on Adult Borderline Personality Disorder Traits: a Longitudinal Discordant Twin Design”, Bornovalova et al 2013

“Tests of a direct effect of childhood abuse on adult borderline personality disorder traits: a longitudinal discordant twin design”⁠, Marina A. Bornovalova, Brooke M. Huibregtse, Brian M. Hicks, Margaret Keyes, Matt McGue, William Iacono et al (2013; ⁠, ; backlinks; similar):

We used a longitudinal twin design to examine the causal association between sexual, emotional, and physical abuse in childhood (before age 18) and borderline personality disorder (BPD) traits at age 24 using a discordant twin design and biometric modeling. Additionally, we examined the mediating and moderating effects of symptoms of childhood externalizing and internalizing disorders on the link between childhood abuse and BPD traits. Although childhood abuse, BPD traits, and internalizing and externalizing symptoms were all correlated, the discordant twin analyses and biometric modeling showed little to no evidence that was consistent with a causal effect of childhood abuse on BPD traits. Instead, our results indicate that the association between childhood abuse and BPD traits stems from common genetic influences that, in some cases, also overlap with internalizing and externalizing disorders. These findings are inconsistent with the widely held assumption that childhood abuse causes BPD, and they suggest that BPD traits in adulthood are better accounted for by heritable vulnerabilities to internalizing and externalizing disorders.

“Is There a General Factor of Prevalent Psychopathology during Adulthood?”, Lahey et al 2012

“Is there a general factor of prevalent psychopathology during adulthood?”⁠, Benjamin B. Lahey, Brooks Applegate, Jahn K. Hakes, David H. Zald, Ahmad R. Hariri, Paul J. Rathouz (2012; backlinks; similar):

The patterns of comorbidity among prevalent mental disorders in adults lead them to load on “externalizing”, “distress”, and “fears” factors. These factors are themselves robustly correlated, but little attention has been paid to this fact. As a first step in studying the implications of these interfactor correlations, we conducted confirmatory factor analyses on diagnoses of 11 prevalent Diagnostic and Statistical Manual of Mental Disorders (4th ed.) mental disorders in a nationally representative sample. A model specifying correlated externalizing, distress, and fears factors fit well, but an alternative model was tested in which a “general” bifactor was added to capture what these disorders share in common. There was a modest but significant improvement in fit for the bifactor model relative to the 3-factor oblique model, with all disorders loading strongly on the bifactor. Tests of external validity revealed that the fears, distress, and externalizing factors were differentially associated with measures of functioning and potential risk factors. Nonetheless, the general bifactor accounted for significant independent variance in future psychopathology, functioning, and other criteria over and above the fears, distress, and externalizing factors. These findings support the hypothesis that these prevalent forms of psychopathology have both important common and unique features. Future studies should determine whether this is because they share elements of their etiology and neurobiological mechanisms. If so, the existence of common features across diverse forms of prevalent psychopathology could have important implications for understanding the nature, etiology, and outcomes of psychopathology.

“The Activity-Based Anorexia Mouse Model”, Klenotich & Dulawa 2012

2012-klenotich.pdf: “The Activity-Based Anorexia Mouse Model”⁠, Stephanie J. Klenotich, Stephanie C. Dulawa (2012; ⁠, ; similar):

Animals housed with running wheels and subjected to daily food restriction show paradoxical reductions in food intake and increases in running wheel activity.

This phenomenon, known as activity-based anorexia (ABA), leads to marked reductions in body weight that can ultimately lead to death. Recently, ABA has been proposed as a model of anorexia nervosa (AN). AN affects about 8 per 100,000 females and has the highest mortality rate among all psychiatric illnesses. Given the reductions in quality of life, high mortality rate, and the lack of pharmacological treatments for AN, a better understanding of the mechanisms underlying AN-like behavior is greatly needed.

This chapter provides basic guidelines for conducting ABA experiments using mice. The ABA mouse model provides an important tool for investigating the neurobiological underpinnings of AN-like behavior and identifying novel treatments.

[Keywords: activity-based anorexia, hyperactivity, anorexia nervosa, animal model, mice, food restriction]

“Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review”, Hart et al 2011

“Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review”⁠, Carl L. Hart, Caroline B. Marvin, Rae Silver, Edward E. Smith (2011-11-16; ; backlinks; similar):

The prevailing view is that recreational methamphetamine use causes a broad range of severe cognitive deficits, despite the fact that concerns have been raised about interpretations drawn from the published literature. This article addresses an important gap in our knowledge by providing a critical review of findings from recent research investigating the impact of recreational methamphetamine use on human cognition. Included in the discussion are findings from studies that have assessed the acute and long-term effects of methamphetamine on several domains of cognition, including visuospatial perception, attention, inhibition, working memory, long-term memory, and learning. In addition, relevant neuroimaging data are reviewed in an effort to better understand neural mechanisms underlying methamphetamine-related effects on cognitive functioning.

In general, the data on acute effects show that methamphetamine improves cognitive performance in selected domains, that is, visuospatial perception, attention, and inhibition. Regarding long-term effects on cognitive performance and brain-imaging measures, statistically-significant differences between methamphetamine users and control participants have been observed on a minority of measures. More importantly, however, the clinical-significance of these findings may be limited because cognitive functioning overwhelmingly falls within the normal range when compared against normative data. In spite of these observations, there seems to be a propensity to interpret any cognitive and/​or brain difference(s) as a clinically-significant abnormality. The implications of this situation are multiple, with consequences for scientific research, substance-abuse treatment, and public policy.

“A Viral Infection of the Mind? The Curious Case of Encephalitis Lethargica”, Foley 2011

“A viral infection of the mind? The curious case of encephalitis lethargica”⁠, Paul Foley (2011-10-12; ⁠, ; similar):

But the illness provoked a flood of publications throughout the 1920s and 1930s, as its kaleidoscopic combination of neurologic and psychiatric phenomena provided insights into brain function that had previously been the subject of speculation. These insights have had an enduring impact upon both neurology and psychiatry.

…The psychiatric facets of this phase were no less important. A peculiar lack of internal drive separating the patient from their world was typical. Despite normal intelligence, these patients could not summon the will power to execute their wishes. More insightful sufferers described how neither their perceptions nor their own thoughts were associated with the required emotional content that permitted exercise of their will. Patients could appreciate that a pianist played with great technical skill, for instance, but no longer sensed the beauty of the music…The only consolation was that this same apathy often meant the sufferers were not overly depressed by their illness or by the prospect of a life in an institution (remembering that these young patients might live for another half century or more).

…The second phase was marked by a general loss of concentration and interest in life, giving a vague sensation that the patient was not the person they had once been. But this period, which resembled chronic fatigue syndrome, was the calm before the storm. Unbeknownst to the victim, localized neurodegeneration proceeded apace through the first phase, and after an interval—lasting between a few days and 30 years—post-encephalitic parkinsonism (PEP) emerged. Unmistakable and irreversible, PEP consigned the young sufferers (mostly between 15 and 35 years of age) to decades of disability. For those who had not yet passed adolescence, the second period was marked by pathologic changes of character that approached the psychopathic.

Younger children, between 5 and 10 years old, might merely irritate with their clinginess; their impaired concentration; their incessant restlessness and need for noise; and their lack of consideration for others—not unlike current attention deficit disorders. But as they grew in strength, their incorrigible impulsiveness escalated in violence and they posed a danger to themselves and others. Errant behaviours included cruelty to anyone who crossed them; destructiveness; lying; and self-mutilation including, in one example, removal of eyes. When they reached adolescence, these patients manifested inappropriate and excessive sexuality, including sexual assault without regard for age or gender. Bizarrely, these children were driven by impulsiveness, not self-interest. Thefts, for example, were not undertaken for personal benefit and stolen goods were often immediately forgotten, or given away. Patients often expressed genuine remorse for their actions, explaining they recognized their wrongdoing but had been compelled to act as they did.

Some children improved after adolescence, but in many the only brake on their bad behavior was the parkinsonism that developed as they entered adulthood. Those not confined to hospital with parkinsonism often proceeded to a life of habitual criminality—mostly theft in men, prostitution in women, but also ranging up to rape and murder.

This phenomenon encouraged many countries to re-examine laws regarding legal responsibility in those whose actions were curtailed neither by encouragement nor prison, but who nonetheless maintained a sense of what was socially appropriate.

“A Randomized Trial on the Efficacy of Methylphenidate and Modafinil for Improving Cognitive Functioning and Symptoms in Patients With a Primary Brain Tumor”, Gehring et al 2011

2011-gehring.pdf: “A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor”⁠, K. Gehring, S. Y. Patwardhan, R. Collins, M. D. Groves, C. J. Etzel, C. A. Meyers, J. S. Wefel (2011-10-02; ):

Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients.

An open-label, randomized, pilot trial examined both the general and differential efficacy of 4 weeks of methylphenidate (MPH) and modafinil (MOD) in 24 brain tumor patients. Participants completed cognitive tests and self-report measures of fatigue, sleep disturbance, mood and quality of life at baseline and after 4 weeks.

Following stimulant treatment, there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention. Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy. Inconsistent, differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD. There was also evidence of a general beneficial effect on patient-reported measures of fatigue, mood, and quality of life, with no statistically-significant differences between treatment arms in these measures over time.

The results from this small pilot study should be interpreted with caution, but appear to warrant additional research, in larger study samples, targeting fatigue, processing speed and executive function, and exploring different doses of stimulants. Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment.

[Keywords: cognitive deficit, brain tumor, psychostimulant, stimulant treatment]

“A Novel, Functional and Replicable Risk Gene Region for Alcohol Dependence Identified by Genome-Wide Association Study”, Zuo et al 2011

“A Novel, Functional and Replicable Risk Gene Region for Alcohol Dependence Identified by Genome-Wide Association Study”⁠, Lingjun Zuo, Clarence K. Zhang, Fei Wang, Chiang-Shan R. Li, Hongyu Zhao, Lingeng Lu, Xiang-Yang Zhang et al (2011-10-01; ; backlinks; similar):

Several genome-wide association studies (GWASs) reported tens of risk genes for alcohol dependence, but most of them have not been replicated or confirmed by functional studies. The present study used a GWAS to search for novel, functional and replicable risk gene regions for alcohol dependence. Associations of all top-ranked SNPs identified in a discovery sample of 681 African-American (AA) cases with alcohol dependence and 508 AA controls were retested in a primary replication sample of 1,409 European-American (EA) cases and 1,518 EA controls. The replicable associations were then subjected to secondary replication in a sample of 6,438 Australian family subjects. A functional expression quantitative trait locus (eQTL) analysis of these replicable risk SNPs was followed-up in order to explore their cis-acting regulatory effects on gene expression. We found that within a 90 Mb region around PHF3-PTP4A1 locus in AAs, a linkage disequilibrium (LD) block in PHF3-PTP4A1 formed the only peak associated with alcohol dependence at p < 10−4. Within this block, 30 SNPs associated with alcohol dependence in AAs (1.6×10−5p ≤ 0.050) were replicated in EAs (1.3×10−3p ≤ 0.038), and 18 of them were also replicated in Australians (1.8×10−3p ≤ 0.048). Most of these risk SNPs had strong cis-acting regulatory effects on PHF3-PTP4A1 mRNA expression across three HapMap samples. The distributions of −log(p) values for association and functional signals throughout this LD block were highly consistent across AAs, EAs, Australians and three HapMap samples. We conclude that the PHF3-PTP4A1 region appears to harbor a causal locus for alcohol dependence, and proteins encoded by PHF3 and/​or PTP4A1 might play a functional role in the disorder.

“Psychopathology, Childhood Trauma, and Personality Traits in Patients With Borderline Personality Disorder and Their Sisters”, Laporte et al 2011

2011-laporte.pdf: “Psychopathology, Childhood Trauma, and Personality Traits in Patients with Borderline Personality Disorder and Their Sisters”⁠, Lise Laporte, Joel Paris, Herta Guttman, Jennifer Russell (2011-08-01; ; similar):

The aim of this study was to document and compare adverse childhood experiences, and personality profiles in women with borderline personality disorder (BPD) and their sisters, and to determine how these factors impact current psychopathology.

56 patients with BPD and their sisters were compared on measures assessing psychopathology, personality traits, and childhood adversities.

Most sisters showed little evidence of psychopathology. Both groups reported dysfunctional parent-child relationships and a high prevalence of childhood trauma. Subjects with BPD reported experiencing more emotional abuse and intrafamilial sexual abuse, but more similarities than differences between probands and sisters were found. In multilevel analyses, personality traits of affective instability and impulsivity predicted DIB-R scores and SCL-90-R scores, above and beyond trauma. There were few relationships between childhood adversities and other measures of psychopathology.

Sensitivity to adverse experiences, as reflected in the development of psychopathology, appears to be influenced by personality trait profiles.

“About Henry Darger”, Nostalgebraist 2011

“About Henry Darger”⁠, Nostalgebraist (2011-05-26; ; backlinks; similar):

[On why Henry Darger⁠, an elderly, solitary dishwasher, wrote and illustrated a 15,000+ page unpublished fantasy novel.]

I’m here today to tell you about a book I read recently, namely Henry Darger: In The Realms Of The Unreal, by John MacGregor. It’s a study of Henry Darger⁠, a man I instantly became obsessed with upon encountering his Wikipedia entry sometime last fall.

Here’s a quick sketch of who Darger was, which will hopefully give you an idea of why I find him so fascinating. He was a reclusive man who worked various dishwashing jobs for most of his life. He only had one real friend in the course of his life, and although he occasionally interacted with the other residents of his apartment complex, they just saw him as a peculiar, taciturn eccentric. But when Darger was on his deathbed, his landlord Nathan Lerner began to clean out his room and discovered something incredible. Unknown to everyone around him, Darger had been writing and painting. Writing and painting a lot. Among the objects Lerner discovered were fifteen massive volumes comprising one continuous fictional work entitled The Story of the Vivian Girls, in What is Known as the Realms of the Unreal, of the Glandeco-Angelinian War Storm Caused by the Child Slave Rebellion. In total, the typed, single-spaced text was 15,145 pages long—one of the longest fictional works ever produced by a human being, if not the longest. (Whether it is the longest or not depends on what counts as a single work; there are some long works of serial pulp fiction that, in total, are longer, but that’s only if you add up the length of hundreds of installments.) This was not Darger’s only writing project. There was also a sort of sequel, Crazy House, which ran to around 10,000 pages, and the 5000-page autobiography The History of My Life, as well as numerous journals and other miscellany. And then there were the paintings, hundreds of huge, odd-looking, compositions depicting battles, scenes of torture, and heroic adventures. (You can see some of Darger’s art thanks to Google Image Search here).

It turned out that the paintings were illustrations for Darger’s 15,145-page masterwork, called In The Realms Of The Unreal for short. In The Realms Of The Unreal is, in some very broad sense, a fantasy novel. It takes place on a planet far larger than Earth, which Earth is said to orbit as a moon. This planet is mostly composed of Catholic nations, of which the most important to the plot are Angelinia, Calverinia and Abbieannia. (Protestants do not appear to exist in this world, though—confusingly enough—one of the Catholic nations is called Protestantia.) The story is about a war between the Catholic nations and the atheist nation Glandelinia, which is inhabited by evil, sadistic people who practice institutionalized child slavery. Shortly before the time period described in the text, some of the child slaves mounted a rebellion, led by a heroic 10-year-old named Annie Aronburg. The Glandelineans quashed the rebellion and killed Aronburg, but this started a chain of events that led to a Glandelinean invasion of Calverinia and eventually a full-scale war between the Catholic nations and Glandelinia. In The Realms Of The Unreal tells the story of this war, an incredibly long succession of huge battles, espionage missions, scenes of torture in the Glandelinean slave camps, and so on. The protagonists, curiously enough, are a set of seven prepubescent sisters—the titular Vivian girls—who follow the Christian armies, spy on the Glandelineans, and narrowly escape mortal danger on innumerable occasions. The battles are mostly realistic in nature—though they involve millions of combatants—but the world is an enchanted one, filled with chimeric beasts called “Blengiglomenean creatures” (or “Blengins”, for short) which assist and protect the Vivian girls.

…The problem comes when MacGregor tries to interpret the text psychologically, which happens often. MacGregor is a Freudian analyst—he studied with Anna Freud, in fact—and he is mainly interested in Darger as a psychological subject. Now, this is not the time or place to hash out whether Freudian psychology does or doesn’t succeed, generally speaking, at explaining the human mind. But even if I withhold judgment on MacGregor’s Freudian premises, his account of Darger’s psychology is just really, really bad and frustrating…So, without further ado, here are some interesting things about Henry Darger:

  • In the Realms, there are numerous characters named after Darger…These Dargers do not all seem to be distinct in the author’s mind, and it’s often confusing which one is being referred to in any given instance.
  • Darger’s paintings are filled with prepubescent girls—usually the Vivian girls, but there are also sometimes anonymous child slaves, etc. They are usually depicted naked, even when there is no good reason for this…The little girls usually, but not always, have penises…
  • Darger collected lots of random junk in the course of his menial job. He was particularly fond of photographs of children…
  • The inspiration for writing the Realms was the loss of a particular newspaper clipping, a photo of Elsie Paroubek, a little girl who had been murdered, and whose murder was all over the Chicago papers for a short time. Darger’s journals express no particular interest in this picture until he discovered that he had lost it. After that, he spent much of the rest of his life in a profound state of anger at God, who he believed had taken the picture from him. He saw the fictional war between Christians and Glandelineans as a way of punishing God for taking the picture by causing harm to millions of (fictional?) Christians.
  • …Darger’s 5000-page work The History Of My Life is putatively an autobiography. However, that word does not accurately describe the vast majority of its contents. The first several hundred pages of the work are indeed an account of Darger’s early life. However, after describing a scene in which his younger self is entranced by the sight of a powerful storm, he apparently gets distracted by the storm and spends the remaining 4000-some pages of the text describing the wake of destruction caused by a fictional twister called “Sweetie Pie”, with no further mention of his own life whatsoever.
  • …Near the end of his life, Darger apparently spent a lot of time playing with string. In his journal he recounts collecting string and coiling and uncoiling it, and huge amounts of string were found in his room after his death.

…Any account of Darger’s psychology is going to have to explain this weirdness. This is what, I contend, John MacGregor’s account fails to do. Fails pretty massively, in fact—massively enough that Darger seems less, rather than more, comprehensible after you read MacGregor try to “explain” him…But MacGregor also tells us that the battles sometimes lasted for hundreds of pages, and that they include vast amounts of bureaucratic detail (about particular regiments, commanders, tactical maneuvers, etc.—lots and lots of proper names), but that none of this detail is in any way self-consistent (so that it is impossible, for instance, to form a mental picture of the shape of the battlefield that does not distort over time). And that Darger is obsessed with what some might consider the more “boring” details of war—he spends huge amounts of time describing the way the supply lines work, for instance. It’s still conceivable that this sort of ridiculously long bureaucratic catalogue could be an expression of pent-up rage, but if so, it’s a very odd one, and naturally raises the question of just what sort of guy would deal with his frustrations by going home from his job every night and writing about the tedious technical details of a fictional war. But that’s exactly the question MacGregor does not want to answer…If writing this stuff was somehow pornographic for Darger, then how is it that so much of the text is composed of moralizing about the glorious Christians and the wicked Glandelineans, describing military maneuvers in mind-numbing detail, and so on, rather than talking about anything that smacks in any way of overt sexuality? Remember that this is a 15,000-page text in which no one ever gets it on; if we’re looking at a sexual fantasy, it must be the coyest sexual fantasy ever produced by the human race.

“Christopher Smart’s "Jubilate Agno"”, Key 2011

“Christopher Smart’s "Jubilate Agno"”⁠, Frank Key (2011-01-31; ⁠, ⁠, ; similar):

The poet Christopher Smart—also known as “Kit Smart”, “Kitty Smart”, “Jack Smart” and, on occasion, “Mrs Mary Midnight”—was a well known figure in 18th-century London. Nowadays he is perhaps best known for considering his cat Jeoffry⁠. Writer and broadcaster Frank Key looks at Smart’s weird and wonderful Jubilate Agno

It was not until 1939 that his masterpiece, written during his confinement in St Luke’s, was first published.

Jubilate Agno is one of the most extraordinary poems in the English language, and almost certainly the reason we remember Christopher Smart today. It has been described as a vast hymn of praise to God and all His works, and also as the ravings of a madman. Indeed, that first edition was published under the title Rejoice In The Lamb: A Song From Bedlam, clearly marking it as a curio from the history of mental illness. It was W. H. Bond’s revised edition of 1954 which gave order to Smart’s surviving manuscript, restoring the Latin title Jubilate Agno, bringing us the poem in the form we know it today.

Christopher Smart never completed the work, which consists of four fragments making a total of over 1,200 lines, each beginning with the words “Let” or “For”. For example, Fragment A is all “Let”s, whereas in Fragment B the “Let”s and “For”s are paired, which may have been the intention for the entire work, modelled on antiphonal Hebrew poetry⁠. References and allusions abound to Biblical (especially Old Testament) figures, plants and animals, gems, contemporary politics and science, the poet’s family and friends, even obituary lists in current periodicals. The language is full of puns, archaisms, coinages, and unfamiliar usages. Dr. Johnson famously said “Nothing odd will do long; Tristram Shandy did not last”. Jubilate Agno is, if anything, “odder” than Sterne’s novel, and perhaps we are readier to appreciate it in the 21st century than when it was written…one of the great joys of Jubilate Agno is in its sudden dislocations and unexpected diversions. The “my cat Jeoffrey” passage is justly famous, but the poem is cram-packed with similar wonders, and must be read in full to appreciate its inimitable genius.

“Why Are Children in the Same Family so Different from One Another?”, Plomin & Daniels 2011

“Why are children in the same family so different from one another?”⁠, Robert Plomin, Denise Daniels (2011; ⁠, ⁠, ; backlinks; similar):

One of the most important findings that has emerged from human behavioral genetics involves the environment rather than heredity, providing the best available evidence for the importance of environmental influences on personality, psychopathology, and cognition. The research also converges on the remarkable conclusion that these environmental influences make two children in the same family as different from one another as are pairs of children selected randomly from the population. The theme of the target article is that environmental differences between children in the same family (called “nonshared environment”) represent the major source of environmental variance for personality, psychopathology, and cognitive abilities. One example of the evidence that supports this conclusion involves correlations for pairs of adopted children reared in the same family from early in life. Because these children share family environment but not heredity, their correlation directly estimates the importance of shared family environment. For most psychological characteristics, correlations for adoptive “siblings” hover near zero, which implies that the relevant environmental influences are not shared by children in the same family. Although it has been thought that cognitive abilities represent an exception to this rule, recent data suggest that environmental variance that affects IQ is also of the nonshared variety after adolescence. The article has three goals: (1) To describe quantitative genetic methods and research that lead to the conclusion that nonshared environment is responsible for most environmental variation relevant to psychological development, (2) to discuss specific nonshared environmental influences that have been studied to date, and (3) to consider relationships between nonshared environmental influences and behavioral differences between children in the same family. The reason for presenting this article in BBS is to draw attention to the far-reaching implications of finding that psychologically relevant environmental influences make children in a family different from, not similar to, one another.

“Modafinil Use in Patients With a Primary Psychiatric Illness”, Black et al 2010

2010-black.pdf: “Modafinil Use in patients with a Primary Psychiatric Illness”⁠, Warwick Black, Peter Hoey, Thomas Mayze (2010-05-20; ; similar):

We report 4 individuals with a variety of psychiatric diagnoses whose symptoms of fatigue, sleepiness or hypoarousal were treated successfully with modafinil⁠. In each case the patient remains on modafinil therapy, with no important adverse events reported to date.

…The first patient had a 30 year history of bipolar disorder type 1…The second patient had experienced massive cerebral trauma requiring a long period of rehabilitation…The third patient is a 70 year old male with treatment-resistant depression characterized by severe fatigue and a possible obsessive-compulsive spectrum disorder…Finally, a 32 year old female patient presented with severe uncontrolled trichotillomania, and depressive symptoms.

“Stability, Change, and Heritability of Borderline Personality Disorder Traits from Adolescence to Adulthood: a Longitudinal Twin Study”, Bornovalova et al 2009

“Stability, change, and heritability of borderline personality disorder traits from adolescence to adulthood: a longitudinal twin study”⁠, Marina A. Bornovalova, Brian M. Hicks, William G. Iacono, Matt McGue (2009; ⁠, ; similar):

Although personality disorders are best understood in the context of lifetime development, there is a paucity of work examining their longitudinal trajectory. An understanding of the expected course and the genetic and environmental contributions to these disorders is necessary for a detailed understanding of risk processes that lead to their manifestation. The current study examined the longitudinal course and heritability of borderline personality disorder (BPD) over a period of 10 years starting in adolescence (age 14) and ending in adulthood (age 24). In doing so, we built on existing research by using a large community sample of adolescent female twins, a sensitive dimensional measure of BPD traits, an extended follow-up period, and a longitudinal twin design that allowed us to investigate the heritability of BPD traits at four discrete ages spanning mid-adolescence to early adulthood. Results indicated that mean-level BPD traits significantly decline from adolescence to adulthood, but rank order stability remained high. BPD traits were moderately heritable at all ages, with a slight trend for increased heritability from age 14 to age 24. A genetically informed latent growth curve model indicated that both the stability and change of BPD traits are highly influenced by genetic factors and modestly by nonshared environmental factors. Our results indicate that as is the case for other personality dimensions, trait BPD declines as individuals mature from adolescence to adulthood, and that this process is influenced in part by the same genetic factors that influence BPD trait stability.

“Linking Antisocial Behavior, Substance Use, and Personality: an Integrative Quantitative Model of the Adult Externalizing Spectrum”, Krueger et al 2007

“Linking antisocial behavior, substance use, and personality: an integrative quantitative model of the adult externalizing spectrum”⁠, Robert F. Krueger, Kristian E. Markon, Christopher J. Patrick, Stephen D. Benning, Mark D. Kramer (2007; backlinks; similar):

Antisocial behavior, substance use, and impulsive and aggressive personality traits often co-occur, forming a coherent spectrum of personality and psychopathology. In the current research, the authors developed a novel quantitative model of this spectrum. Over 3 waves of iterative data collection, 1,787 adult participants selected to represent a range across the externalizing spectrum provided extensive data about specific externalizing behaviors. Statistical methods such as item response theory and semiparametric factor analysis were used to model these data. The model and assessment instrument that emerged from the research shows how externalizing phenomena are organized hierarchically and cover a wide range of individual differences. The authors discuss the utility of this model for framing research on the correlates and the etiology of externalizing phenomena.

“The Effects of Attention-deficit/hyperactivity Disorder on Employment and Household Income”, Biederman et al 2006

“The effects of attention-deficit/hyperactivity disorder on employment and household income”⁠, Biederman, Joseph Faraone, Stephen V (2006; ; backlinks; similar):

Many children with attention-deficit/​hyperactivity disorder (ADHD) continue to exhibit symptoms of the disorder into adolescence and adulthood. Although ADHD may have a profound impact on activities of daily living, including educational achievement and work performance, limited research exists on ADHD’s impact on individual income loss and overall economic effect. Evaluate ADHD’s impact on individual employment and income, and quantify costs of ADHD on workforce productivity for the US population.

Two telephone surveys were conducted between April 18, 2003, and May 11, 2003, to collect demographic, educational, employment, and income information. Two groups of adults aged 18–64 years were interviewed: those diagnosed with ADHD (n = 500) derived from a national list of mail-paneled members who identified themselves or a household member as having been diagnosed with ADHD, and an age-matched and gender-matched control group (n = 501) derived from a random digital-dialing sample of a national cross-section not diagnosed with ADHD. Statistically fewer subjects in the ADHD group achieved academic milestones beyond some high school (p < 0.05). In addition, fewer subjects with ADHD were employed full time (34%) compared with controls (59%; p < 0.001). Except for the subgroup of subjects aged 18–24 years, average household incomes were statistically-significantly lower among individuals with ADHD compared with controls, regardless of academic achievement or personal characteristics.

On the basis of these findings, loss of workforce productivity associated with ADHD was estimated between $96.4$67.02006 billion and $166.8$116.02006 billion. Decreased individual income among adults with ADHD contributes to substantial loss in US workforce productivity.

“Self-management of Fatal Familial Insomnia. Part 2: Case Report”, Schenkein & Montagna 2006

“Self-management of fatal familial insomnia. Part 2: case report”⁠, Joyce Schenkein, Pasquale Montagna (2006; ⁠, ; similar):

Context: Fatal familial insomnia (FFI) is a genetically transmitted neurodegenerative prion disease that incurs great suffering and has neither a treatment nor cure. The clinical literature is devoid of management plans (other than palliative). Part 1 of this article reviews the sparse literature about FFI, including case descriptions. Part 2 describes the efforts of one patient (with the rapid-course Met-Met subtype) who contended with his devastating symptoms and improved the quality of his life.

Design: Interventions were based on the premise that some symptoms may be secondary to insomnia and not a direct result of the disease itself. Strategies (derived by trial and error) were devised to induce sleep and increase alertness. Interventions included vitamin supplementation, narcoleptics, anesthesia, stimulants, sensory deprivation, exercise, light entrainment, growth hormone, and electroconvulsive therapy (ECT).

Results: The patient exceeded the average survival time by nearly 1 year, and during this time (when most patients are totally incapacitated), he was able to write a book and to successfully drive hundreds of miles.

Conclusion: Methods to induce sleep may extend and enhance life during the disease course, although they do not prevent death. It is hoped that some of his methods will inspire further clinical studies.

“Fluvoxamine Impairs Single-dose Caffeine Clearance without Altering Caffeine Pharmacodynamics”, Culm-Merdek et al 2005

“Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics”⁠, Kerry E. Culm-Merdek, Lisa L. von Moltke, Jerold S. Harmatz, David J. Greenblatt (2005-11; similar):

Background: Coadministration of fluvoxamine impairs the clearance of caffeine and prolongs its elimination half-life⁠, which is attributable to inhibition of CYP1A2 by fluvoxamine. The clinical importance of this interaction is not established.

Aim: To evaluate the effects of fluvoxamine on the kinetics and dynamics of single doses of caffeine.

Methods: 7 healthy subjects received single 250 mg doses of caffeine (or matching placebo) together with fluvoxamine (four doses of 100 mg over 2 days) or with matching placebo in a double-blind, 4-way crossover study. For 24 h after caffeine or placebo administration, plasma caffeine and fluvoxamine concentrations were determined. Psychomotor performance, sedation, and electroencephalographic (EEG) “beta” frequency activity were also assessed.

Results: Fluvoxamine substantially reduced apparent oral clearance of caffeine (105 vs. 9.1 mL min(-1), p < 0.01; mean difference: 95.7 mL min(-1), 95% CI: 54.9–135.6), and prolonged its elimination half-life (4.9 vs. 56 h, p < 0.01; mean difference: 51 h, 95% CI: 26–76). Caffeine produced CNS-stimulating effects compared with placebo. However, psychomotor performance, alertness, or EEG effects attributable to caffeine were not augmented by coadministration of fluvoxamine.

Conclusions: Fluvoxamine greatly impaired caffeine clearance, but without detectable changes in caffeine pharmacodynamics. However, this study does not rule out possible adverse effects due to extensive accumulation of caffeine with daily ingestion in fluvoxamine-treated individuals.

“Sleep Paralysis, Sexual Abuse, and Space Alien Abduction”, McNally & Clancy 2005

2005-mcnally.pdf: “Sleep Paralysis, Sexual Abuse, and Space Alien Abduction”⁠, Richard J. McNally, Susan A. Clancy (2005-03-01; ; similar):

Sleep paralysis accompanied by hypnopompic (‘upon awakening’) hallucinations is an often-frightening manifestation of discordance between the cognitive/​perceptual and motor aspects of rapid eye movement (REM) sleep⁠. Awakening sleepers become aware of an inability to move, and sometimes experience intrusion of dream mentation into waking consciousness (eg. seeing intruders in the bedroom).

In this article, we summarize 2 studies:

  1. In the first study, we assessed 10 individuals who reported abduction by space aliens and whose claims were linked to apparent episodes of sleep paralysis during which hypnopompic hallucinations were interpreted as alien beings.
  2. In the second study, adults reporting repressed, recovered, or continuous memories of childhood sexual abuse more often reported sleep paralysis than did a control group. Among the 31 reporting sleep paralysis, only one person linked it to abuse memories. This person was among the 6 recovered memory participants who reported sleep paralysis (ie. 17% rate of interpreting it as abuse-related).

People rely on personally plausible cultural narratives to interpret these otherwise baffling sleep paralysis episodes.

“Personality Traits As Intermediary Phenotypes in Suicidal Behavior: Genetic Issues”, Baud 2005

2005-baud.pdf: “Personality traits as intermediary phenotypes in suicidal behavior: Genetic issues”⁠, Patrick Baud (2005-01-12; ⁠, ⁠, )

“The Incremental Validity of the MMPI–2: When Does Therapist Access Not Enhance Treatment Outcome?”, Lima et al 2005

2005-lima.pdf: “The incremental validity of the MMPI–2: When does therapist access not enhance treatment outcome?”⁠, Elizabeth N. Lima, Sheila Stanley, Beth Kaboski, Lorraine R. Reitzel, J. Anthony Richey, Yezzennya Castro et al (2005; ; similar):

The present study examined whether therapist access to the Minnesota Multiphasic Personality Inventory (MMPI-2) predicted favorable treatment outcome, above and beyond other assessment measures.

A manipulated assessment design was used, in which patients were randomly assigned either to a group in which therapists had access to their MMPI-2 data or to a group without therapist access to such information. Illness severity, improvement ratings, number of sessions attended, and premature termination were indicators of therapy outcome.

Results: indicated that therapist access to the MMPI-2 data did not add to the prediction of positive treatment outcome beyond that predicted by other measures in this setting. Findings from this initial study suggest that, compared with other resources, perhaps in clinical settings with an emphasis on diagnosis-based and evidence-based treatment, the MMPI-2 may not provide incrementally valid information.

However, these effects warrant replication across different settings and samples. Guidelines for future studies are discussed.

“Clinical Outcomes of Hemispherectomy for Epilepsy in Childhood and Adolescence”, Devlin et al 2003

“Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence”⁠, A. M. Devlin, J. H. Cross, W. Harkness, W. K. Chong, B. Harding, F. Vargha-Khadem, B. G. R. Neville (2003-03-01; ⁠, ; backlinks; similar):

Hemispherectomy has been performed in the treatment of epilepsy in association with hemiplegia for over 50 years. However, the optimal timing of surgery with respect to age at presentation and the influence of underlying pathology on outcome is only slowly emerging.

This study reports on the clinical course and outcomes of 33 children who underwent hemispherectomy at Great Ormond Street Hospital⁠, London, between 1991 and 1997. Age at surgery was 0.33–17 years (median 4.25) with 1–8 years follow-up (median 3.4). The underlying pathology was developmental in 16 (10 hemimegalencephaly⁠, 2 polymicrogyria⁠, 2 focal cortical dysplasia⁠, one diffuse cortical dysplasia and one microdysgenesis), acquired in 11 (six middle cerebral artery infarct⁠, 3 post encephalitis/​trauma, and one each of hemiconvulsion-hemiplegia epilepsy and perinatal ischaemic insult) and progressive in 6 children (four Rasmussen encephalitis⁠, 2 Sturge-Weber syndrome).

At follow-up, 52% were seizure free, 9% experienced rare seizures, 30% showed >75% reduction in seizures and 9% showed <75% seizure reduction or no improvement. Seizure freedom was highest in those with acquired pathology (82%), followed by those with progressive pathology (50%) and those with developmental pathology (31%). However, seizure freedom, rare seizures or >75% reduction in seizures occurred in 100% of those with progressive pathology, 91% of those with acquired and 88% of those with developmental pathology, indicating a worthwhile seizure outcome in all groups. Hemiplegia remained unchanged following surgery in 22 out of 33 children, improved in 5 and was worse in 6. No large cognitive deterioration or loss of language occurred, and 4 children showed large cognitive improvement. Behavioural improvement was reported in 92% of those who had behaviour problems pre-operatively.

…The cognitive category of the patients pre-operatively assessed according to IQ or DQ is shown in Figure 1. Figure 1 shows that the majority of children (88%) with developmental pathology, including all 10 subjects with hemimegalencephaly, exhibited severe cognitive/​developmental delay. The majority of patients with acquired pathology (64%) also showed severe delay and a further 27% showed moderate delay. Those with Rasmussen encephalitis were most likely to have normal levels of cognitive function (three out of 4) whilst the 2 children with Sturge-Weber syndrome were in the severe and moderate impairment groups. 12 children (36%) had shown evidence of developmental regression prior to surgery.

Particular difficulty with expressive language was noted in 6 subjects and was anticipated in 2 subjects with Rasmussen encephalitis of the left hemisphere who came to surgery at 3.8 and 4.2 years of age, respectively. One was developmentally normal and the other was only mildly developmentally delayed prior to surgery. One showed very slurred speech, which was reduced in quantity during formal assessment, but developed clear speech immediately prior to surgery and the other became aphasic 2 weeks prior to surgery. One further subject with left-sided pathology resulting from a congenital MCA infarction was 2.3 years at the time of surgery with severe developmental delay. The 3 remaining subjects showed abnormal pathology of the right hemisphere and when assessed at age 1.5, 2.6 and 12 years, respectively, were thought to be severely developmentally delayed thereby making language assessment difficult particularly in the 2 younger patients. In the opinion of experienced examiners, however, these children exhibited expressive language difficulties beyond those which would have been predicted from cognitive performance and comprehension. The pathology was developmental in one, acquired in one and the other child had Sturge-Weber syndrome.

Behaviour difficulties were present in 12 children (36%). The most common problem was difficulty with concentration (75%), followed by fluctuating mood with or without socially intrusive behaviour (66%). 25% showed temper tantrums or aggression. The duration of seizures prior to surgery (median 7.38 years) and hence age at surgery was statistically-significantly greater in those with behaviour problems compared with those without (median duration of seizures 2 years, Mann-Whitney U test p = 0.0033). The median duration of seizures prior to surgery in those with acquired pathology was statistically-significantly longer at 7.75 years compared with 2.6 years and 1.9 years in the developmental and progressive pathology groups, respectively (Kruskal-Wallis p = 0.0004). Behaviour problems were most common in the group with acquired pathology (73%), followed by the group with progressive pathology (33%) and least common in those with developmental pathology (12.5%). There was no apparent association between the category of cognitive performance and the presence or absence of behaviour problems.

Figure 1: Summary of pre-operative developmental categories of patients. The percentage of individuals in each developmental category on the vertical axis is plotted against underlying pathology on the horizontal axis.

“The Hazards of Predicting Divorce Without Crossvalidation”, Heyman & Slep 2001

“The Hazards of Predicting Divorce Without Crossvalidation”⁠, Richard E. Heyman, Amy M. Smith Slep (2001; ; similar):

Divorce prediction studies (eg. Gottman, Coan, Carrere, & Swanson, 1998) suggest that couples’ eventual divorce can be very accurately predicted from a number of different variables. Recent attention to these studies has failed to consider the need to cross-validate prediction equations and to consider the prevalence of divorce in the population. We analyze archival data to demonstrate that accuracy and predictive value drops precipitously during crossvalidation. We conclude that results of studies without crossvalidation analyses should be interpreted with extreme caution, no matter how impressive the initial results appear to be.

“Melatonin for the Treatment of Sleep Disturbances in Major Depressive Disorder”, Dolberg et al 1998

“Melatonin for the Treatment of Sleep Disturbances in Major Depressive Disorder”⁠, Ornah T. Dolberg, Schmuel Hirschmann, Leon Grunhaus (1998-08-01; ; backlinks; similar):

Objective: The authors’ goal was to examine the hypnotic effects of slow-release melatonin during the initial 4 weeks of treatment with fluoxetine in 19 patients with major depressive disorder.

Method: 24 outpatients with major depressive disorder were included in the study; 19 completed the study. 10 patients were treated with fluoxetine plus slow-release melatonin and 9 were given fluoxetine plus placebo in a double-blind protocol for 4 weeks. Response was assessed by using rating scales for depression and sleep.

Results: The 10 patients given slow-release melatonin reported statistically-significantly better scores on the Pittsburgh Sleep Quality Index (PSQI) than the 9 patients given placebo. No statistically-significant differences in the rate of improvement in depressive symptoms were noted between the 2 groups. No particular side effects were noted from the combination of fluoxetine and slow-release melatonin.

Conclusions: Slow-release melatonin was effective in improving the sleep of patients with major depressive disorder. Slow-release melatonin had no effect on the rate of improvement in symptoms of major depressive disorder. The authors conclude that the role of slow-release melatonin for sleep disturbances in major depressive disorder should be investigated further.

“Simon Browne: the Soul-murdered Theologian”, Berman 1996

1996-berman.pdf: “Simon Browne: the soul-murdered theologian”⁠, David Berman (1996-06-01; ⁠, )

“Heritability of MMPI Personality Indicators of Psychopathology in Twins Reared Apart”, DiLalla et al 1996

1996-dilalla.pdf: “Heritability of MMPI personality indicators of psychopathology in twins reared apart”⁠, David L. DiLalla, Gregory Carey, Irving I. Gottesman, Thomas J. Bouchard Junior (1996; ; backlinks):

This report presents Minnesota Multiphasic Personality Inventory (MMPI) findings from the Minnesota Study of Twins Reared Apart (MISTRA).

Data from 65 unique pairs of monozygotic twins reared apart (MZA) and 54 unique pairs of dizygotic twins reared apart (DZA) were analyzed.

As in other results from this sample, MZA twins evidenced substantial similarity, highlighting the influence of shared genes. Biometric modeling yielded estimates of heritability for the MMPI’s standard validity and clinical scales and for the Wiggins content scales ranging from 0.26 to 0.62 (M = 0.44), echoing previous findings from the twin and adoption literature on personality.

The pattern of MZA and DZA correlations suggested nonadditive genetic effects for 3 MMPI scales. Multivariate profile analyses also suggested genetic influence on both profile elevation and shape.

“Rhinotillexomania: Psychiatric Disorder or Habit?”, Jefferson & Thompson 1995

1995-jefferson.pdf: “Rhinotillexomania: Psychiatric disorder or habit?”⁠, James W. Jefferson, Trent D. Thompson (1995-02; ; similar):

Background: Conditions once considered bad habits are now recognized as psychiatric disorders (trichotillomania⁠, onychopagia). We hypothesized that nose picking is another such “habit”, a common benign practice in most adults but a time-consuming, socially compromising, or physically harmful condition (rhinotillexomania) in some.

Methods: We developed the Rhinotillexomania Questionnaire, mailed it to 1,000 randomly selected adult residents of Dane County, Wisconsin, and requested anonymous responses. The returned questionnaires were analyzed according to age, sex, marital status, living arrangement, and educational level. Nose picking was characterized according to time involved, level of distress, location, attitudes toward self and others regarding the practice, technique, methods of disposal, reasons, complications, and associated habits and psychiatric disorders.

Results: 254 subjects responded. 91% were current nose pickers although only 49.2% felt it was common among adults and only 75% felt “almost everyone does it”; 1.2% picked at least every hour…The amount of personal distress caused by nose picking was “mild to none” in all respondents, but 4.6% (n = 11 of 239) felt that their nose picking was “very disturbing” to others…For 2 subjects (0.8%), nose picking caused moderate to marked interferences with daily functioning. 2 subjects spent between 15 and 30 minutes and 1 over 2 hours a day picking their nose. For 2 others, perforation of the nasal septum was a complication. Associated “habits” included picking cuticles (25%), picking at skin (20%), biting fingernails (18%), and pulling out hair (6%).

Conclusion: This first population survey of nose picking suggests that it is an almost universal practice in adults but one that should not be considered pathologic for most. For some, however, the condition may meet criteria for a disorder—rhinotillexomania.

…43% acknowledged some public picking, but only 4.2% made no effort to avoid being seen. The most common public settings were automobiles and office.

Tolerance of public nose picking was related to age of the picker with 2⁄3rds of the respondents not being disturbed by a child under the age of 6 but well over 2⁄3rds being upset by teenagers, adults, and the elderly picking in public.

Public pickers were felt to be socially unskilled by 59.2% of respondents, while only 3.8% held this opinion about private pickers. Nose picking in public was considered a sign of mental illness by only 1.7% of respondents

“The Lifetime History of Major Depression in Women: Reliability of Diagnosis and Heritability”, Kendler et al 1993

1993-kendler.pdf: “The Lifetime History of Major Depression in Women: Reliability of Diagnosis and Heritability”⁠, Kenneth S. Kendler, Michael C. Neale, Ronald C. Kessler, Andrew C. Heath, Lindon J. Eaves (1993-11-01; ; similar):

Background: In epidemiology samples, the assessment of lifetime history (LTH) of major depression (MD) is not highly reliable. In female twins, we previously found that LTH of MD, as assessed at a single personal interview, was moderately heritable (approximately 40%). In that analysis, errors of measurement could not be discriminated from true environmental effects.

Methods: In 1,721 female twins from a population-based register, including both members of 742 pairs, LTH of MD, covering the same time period, was obtained twice, once by self-administered questionnaire and once at personal interview.

Results: Reliability of LTH of MD was modest (κ = + 0.34, tetrachoric r = + 0.56) and was predicted by the number of depressive symptoms, treatment seeking, number of episodes, and degree of impairment. Deriving an “index of caseness” from these predictors, the estimated heritability of LTH of MD was greater for more restrictive definitions. Incorporating error of measurement into a structural equation model including both occasions of measurement, the estimated heritability of the liability to LTH of MD increased substantially (approximately 70%). More than half of what was considered environmental effects when LTH of MD was analyzed on the basis of one assessment appeared, when 2 assessments were used, to reflect measurement-error⁠.

Conclusions: Major depression, as assessed over the lifetime, may be a rather highly heritable disorder of moderate reliability rather than a moderately heritable disorder of high reliability.

“Estimated Lifetime Prevalence of Trichotillomania in College Students”, Christenson et al 1991

1991-christenson.pdf: “Estimated Lifetime Prevalence of Trichotillomania in College Students”⁠, Gary A. Christenson, Richard L. Pyle, James E. Mitchell (1991-10-01; similar):

Background: Trichotillomania⁠, a disorder of hair pulling, has been considered a rare condition. Estimations of the prevalence of this disorder have been based largely on clinical experience, and there have been no estimates of its prevalence based on data collected from a large, nonclinical population.

Method: 2,579 freshman college students at two state universities and one liberal arts college were asked to provide written responses to questions designed to practically apply DSM-III-R criteria for trichotillomania and estimate the prevalence of trichotillomania in this population.

Results: 2,534 students (97.9% of the study population) responded. We found a 0.6% lifetime prevalence of DSM-III-R trichotillomania for both male and female respondents. Hair pulling resulting in visible hair loss, but failing to meet full DSM-III-R criteria, was identified in 1.5% of males and 3.4% of females.

Conclusion: Trichotillomania may not be as rare as previously suspected and may affect males as often as females.

“Alcohol Input and Creative Output”, Ludwig 1990

1990-ludwig.pdf: “Alcohol input and creative output”⁠, Arnold M. Ludwig (1990-07-01; ; backlinks; similar):

Is alcohol use a help or a hindrance for creativity? And, conversely, what effect does creative activity have on alcohol use?

In order to answer these questions, relevant information was obtained from the biographies of 34 well known, heavy drinking, 20th century writers, artists or composers/​performers.

Analysis of this information yielded a number of interesting findings. Alcohol use proved detrimental to productivity in over 75% of the sample, especially in the latter phases of their drinking careers. However, it appeared to provide direct benefit for about 9% of the sample, indirect benefit for 50% and no appreciable effect for 40% at different times in their lives. Creative activity, conversely, can also affect drinking behavior, leading, for instance, to increased alcohol consumption in over 30% of the sample.

Because of the complexities of this relationship, no simplistic conclusions are possible.

…Previous studies on the incidence of alcoholism in creative individuals offer little help. For example, Ellis2 reports no alcoholism in a sampling of over 1,000 British ‘geniuses’. Juda3 reports rates of 2.7% and 0.6%, respectively, in a sampling of pre-World War I, German ‘artists’ and 181 ‘scientists’. But Andreasen,4 using strict diagnostic criteria, reports a rate of 30% in a sample of American writers (n = 30) compared to 7% in controls (n = 30). From this range of findings, in entirely different samples, it is difficult to determine the importance of alcohol in the creative process, especially when most of the individuals evaluated manage to be productive and creative without any obvious dependence on alcohol…The only study, to my knowledge, specifically devoted to the effects of actual drinking habits on productivity in creative individuals—in this case, artists—was conducted more than 40 years ago by Roe,8 but the results are largely anecdotal in nature. All of the established artists interviewed drank, but most avoided drinking while painting. All but one of 17 artists regarded the short-term effects of alcohol as deleterious to their work and none used alcohol to overcome technical difficulties. The general sentiment was that alcohol provided the freedom for painting but impaired the discipline. Interestingly enough, alcohol consumption also appeared to play a role in artistic style. All of the moderate drinkers, who also were the most well adjusted, were realistic painters. The steady social drinkers had a wide range of styles. And the excessive drinkers showed greater shifts in their style of painting.

“Factors and Primes: a Specific Numerical Ability”, Hermelin & O’Connor 1990

1990-hermelin.pdf: “Factors and primes: a specific numerical ability”⁠, B. Hermelin, N. O’Connor (1990-02-01):

SYNOPSIS: An autistic young man and a normal control were asked to factorize numbers and to recognize and generate primes. Both subjects made a similar of errors and employed similar strategies, but they differed markedly in the speeds at which the arithmetical operations were carried out.

“Differences in Nocturnal Melatonin Secretion between Melancholic Depressed Patients and Control Subjects”, Brown et al 1985

1985-brown.pdf: “Differences in nocturnal melatonin secretion between melancholic depressed patients and control subjects”⁠, Richard Brown, James H. Kocsis, Stanley Caroff, Jay Amsterdam, Andrew Winokur, Peter E. Stokes, Alan Frazer et al (1985-07; ; backlinks):

The authors took multiple serum samples for measurement of melatonin between 4:30PM and 7:30AM in 7 male depressed patients with melancholia and 5 healthy male control subjects and found that:

melancholic patients had a statistically-significantly lower rise of melatonin. They also compared a second, separate group of 14 women and 5 men suffering from melancholic depression with 7 healthy male control subjects and 9 depressed women without melancholia. The melancholic patients had a statistically-significantly lower concentration of serum melatonin at 11:00PM than either the control subjects or the non-melancholic depressed patients.

These findings support the possibility that the functioning of the pineal gland is altered in these patients.

“Infantile Autism: A Genetic Study Of 21 Twin Pairs”, Folstein & Rutter 1977

1977-folstein.pdf: “Infantile Autism: A Genetic Study Of 21 Twin Pairs”⁠, Susan Folstein, Michael Rutter (1977-09-01; ; similar):

A systematic study was made of a representative group of 21 same-sexed twin pairs (11 MZ and 10 DZ) in which at least one twin showed the syndrome of infantile autism⁠.

There was a 36% pair-wise concordance rate for autism in MZ pairs compared with 0% concordance in DZ pairs. The concordance for cognitive abnormalities was 82% in MZ pairs and 10% in DZ pairs. It was concluded that there were important hereditary influences concerning a cognitive deficit which included but was not restricted to autism. In 12 out of 17 pairs discordant for autism, the presence of autism was associated with a biological hazard liable to cause brain damage.

It was concluded that brain injury in the infancy period may lead to autism on its own or in combination with a genetic predisposition. Uncertainty remains on both the mode of inheritance and exactly what is inherited.

“Maternal Deprivation Reconsidered”, Rutter 1972

1972-rutter.pdf: “Maternal deprivation reconsidered”⁠, Michael Rutter (1972; similar):

In studying the results of maternal-deprivation⁠, children’s responses to separation experiences were noted and tests related to intellect were given. Children were also observed at various stages in their growth on other hypothesized maternal-deprivation factors. While further research is required, evidence to date indicates that the syndrome of acute distress is probably due in part to a disruption of the bonding process (not necessarily to the mother). Developmental retardation and intellectual impairment are both a consequence of experiential privation; dwarfism is usually due to nutritional privation; delinquency follows family discord; and affectionless psychopathy may be the end-product of a failure to develop bonds or attachments in the 1st–3rd yrs of life.

The purpose of this paper is to question these assumptions. It will be suggested that “maternal deprivation” includes many different types of experiences involving lack, loss and distortion; that little progress is likely to occur until the separate effects of each experience are determined;6 that different psychological mechanisms account for different types of outcome; and finally that the term “maternal deprivation” is misleading in that in most cases the deleterious influences are not specifically tied to the mother and are not due to deprivation. Reference to the Shorter Oxford English Dictionary shows that deprivation means “dispossession” or “loss”. While loss is probably an important factor in one of the syndromes associated with “maternal deprivation” a review of the evidence suggests that in most cases the damage comes from “lack” or “distortion” of care rather than from any form of “loss”.

“Coprophagia and Allied Phenomena”, Tarachow 1966

1966-tarachow.pdf: “Coprophagia and Allied Phenomena”⁠, Sidney Tarachow (1966-08-01; )

“Identical Twin—’Idiot Savants’—Calendar Calculators”, Horwitz et al 1965

1965-horwitz.pdf: “Identical Twin—‘Idiot Savants’—Calendar Calculators”⁠, William A. Horwitz, Clarice Kestenbaum, Ethel Person (1965-05-01)

“The Sense of Smell in the Neuroses and Psychoses”, Brill 1932

1932-brill.pdf: “The Sense of Smell in the Neuroses and Psychoses”⁠, A. A. Brill (1932-01-01; )

Wake therapy


Tickling § Self-tickling




Pathological lying


Ketamine § Depression




Fatal insomnia


Alien hand syndrome