Cochrane Database of Systematic Reviews Protocol - Intervention

Modafinil for schizophrenia

This is not the most recent version

Collapse all Expand all

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The primary objective of this review is to assess the effectiveness of modafinil for people with schizophrenia.

If possible, this systematic review aims to regroup studies that investigated the effects of modafinil on people with schizophrenia to extract statistically more powerful results from individual studies and ascertain a summary conclusion from the global body of data. It also enables the characterisation of any potential biases from these studies.

Background

Description of the condition

Schizophrenia is a heterogeneous mental syndrome characterised by two main categories of symptoms: positive symptoms that generally include hallucinations, delusions and thought disorders; and negative symptoms, which present a diminution or loss of function in higher functions such as cognition and emotion. Such features lead to blunted affect, poverty of speech and lack of motivation.

Schizophrenia ranks in the top ten illnesses responsible for the global burden of disease (Murray 1996). This disorder is often extremely debilitating, first appears in young adulthood, at the beginning of an individual's independent and working life and unfortunately frequently continues to afflict sufferers throughout their lives despite the best currently available treatment. As a consequence, schizophrenia has a significant impact on the affected individual and their family and results in meaningful societal and economic costs (Knapp 2005).

Schizophrenia results from abnormalities in the brain, as a consequence of dysregulations in various neurotransmitter systems. Past studies revealed that individuals with schizophrenia had an excess of dopamine in subcortical regions and a deficit of this neurotransmitter in more prefrontal regions of the brain (Meyer‐Lindenberg 2002), which might explain emotional and cognitive impairments. Other neurotransmitters are also involved in the pathophysiology of the disease, and the glutamate system has received a particular interest as it exerts a potent excitatory effect on dopaminergic neurons (Floresco 2001) and it has been shown to be involved in schizophrenia (Coyle 2003). This suggests a combination of neurotransmitters are dysregulated in the brain of individuals with schizophrenia.

Description of the intervention

Current pharmacological treatment essentially targets the dopaminergic system, by blocking D2 receptors, and all antipsychotics have this property. This helps the moderation of positive symptoms, but does not help other symptoms that sufferers might experience, such as blunted affect, memory, attention and executive function impairments. Moreover, antipsychotics have side effects from its D2 blockade itself, because D2 receptors are in pathways other than the relevant ascending mesolimbic circuit, and also block numerous other neurotransmitter systems (Moller 2005). Consequently, antipsychotics might worsen symptoms that are not their primary target. It is, therefore, vital to consider alternative additional pharmaceutical treatments to help people with schizophrenia cope with their cognitive and emotional symptoms, which seem to be primary drivers of disability and outcome

Modafinil is a central nervous system wake‐promoting agent indicated for the treatment of excessive daytime sleepiness for people suffering from narcolepsy, obstructive sleep apnoea and other sleeping disorders. Although its mechanisms are still relatively unknown, human and other animal research suggest that it directly or indirectly activates the dopaminergic (De Saint 2001, Volkow 2009, Wisor 2001), glutamatergic (Ferraro 1999), noradrenergic De Saint 2001, Madras 2006, Minzenberg 2008) and serotonergic (Ferraro 2005, De Saint 2001) systems  in several regions of the brain, including the prefrontal cortex, hippocampus, hypothalamus, and striatum; whereas it inhibits GABAergic pathways in the same cerebral regions (Ferraro 1999). The hippocampus and its interplay with the prefrontal cortex, controls brain states associated with memory (Laroche 2000) and it is most likely that modafinil improves this function by inducing changes in the neurotransmitters composition in these areas. Modafinil is able to improve working memory in animals (Pierard 2007), healthy humans (Turner 2003) and individuals with neuropsychiatric disorders (Turner 2004aTurner 2004b); there is evidence that modafinil enhances learning processes in animals (Beracochea 2002), attention, memory, inhibition control, and executive function in healthy non‐sleep deprived (Turner 2003) and sleep deprived individuals (Wesensten 2005), as well as narcoleptic (Saletu 2007) and ADHD (Turner 2004a) patients. Studies in healthy individuals and bipolar depressive people showed improvements in mood, fatigue and depressive symptoms (Randall 2003, Frye 2007).

How the intervention might work

Studies in chronic schizophrenia show that modafinil improves cognitive deficits such as attention (Park 2007), working memory (Hunter 2006), fluency, inhibition control (Minzenberg 2009) and executive function (Turner 2004b). Modafinil also showed improvements in tasks related to emotional processing in first episode psychosis patients (Scoriels 2010). Thus, modafinil might act as a cognitive and emotional enhancer for people suffering from schizophrenia, thus ameliorating symptoms and leading to improvements in social and occupational functioning.

Why it is important to do this review

Results regarding the benefits of modafinil in schizophrenia are not unequivocal. Although the studies mentioned above and some others claim the benefits of modafinil’s use for symptoms of schizophrenia, especially regarding cognitive deficits, these results are very mild and based on quite small samples. Moreover, there are studies that failed to find any association between modafinil administration and improvement of function in people with schizophrenia (Freudenreich 2009, Sevy 2005).

Objectives

The primary objective of this review is to assess the effectiveness of modafinil for people with schizophrenia.

If possible, this systematic review aims to regroup studies that investigated the effects of modafinil on people with schizophrenia to extract statistically more powerful results from individual studies and ascertain a summary conclusion from the global body of data. It also enables the characterisation of any potential biases from these studies.

Methods

Criteria for considering studies for this review

Types of studies

All relevant randomised controlled trials will be included. Where trials are described as ‘double‐blind’ but are only implied as being randomised, they will be included in a sensitivity analysis. If there are no substantive differences within primary outcomes (Types of outcome measures) when these ‘implied randomisation’ studies are added, then we will include these in the final analysis. If there are substantive differences, these studies will not be included in the analysis and we will describe the results of the sensitivity analysis in the text. Randomised cross‐over studies will be eligible but only data up to the point of first cross‐over because of the likely carry‐over effects of all treatments (Elbourne 2002). We will exclude quasi randomised studies such as those allocating by using alternate days of the week.

Types of participants

Participants will be adults (18‐65 years) diagnosed with schizophrenia and other types of schizophrenia‐like psychoses (e.g. schizophreniform and schizoaffective disorders), irrespective of the diagnostic criteria used. There is no clear evidence that the schizophrenia‐like psychoses are caused by fundamentally different disease processes or require different treatment approaches (Carpenter 1994).

Types of interventions

1. Modafinil: any dose/administration
2. Placebo
Both interventions are in addition to care as usual.

Types of outcome measures

We will group outcomes into single dose, short‐term (chronic dose for up to 12 weeks), medium‐term (chronic dose for up to 26 weeks) and long‐term (chronic dose for over 26 weeks).

Primary outcomes

1. Mental state (with particular reference to the positive and negative symptoms of schizophrenia)
1.1 No clinically important change in general mental state score
1.2 Average endpoint general mental state score
1.3 Average change in general mental state scores
1.4 No clinically important change in positive symptoms of schizophrenia
1.5 Average endpoint positive symptom score
1.6 Average change in positive symptom scores
1.7 No clinically important change in negative symptoms of schizophrenia
1.8 Average endpoint negative symptom score
1.9 Average change in negative symptom scores

2. Cognitive functioning
2.1 No clinically important change in overall cognitive functioning
2.2 No clinically important change in specific aspects of cognitive functioning (e.g., IQ, memory, learning, attention, fluency, control, executive functioning)
2.3 Average endpoint of overall cognitive functioning score
2.4 Average change of overall cognitive functioning scores
2.5 Average endpoint specific cognitive functioning score
2.6 Average change specific cognitive functioning scores

Secondary outcomes

1. Behaviour/Emotional state
1.1 No clinically important change in overall behaviour
1.2 No clinically important change in specific aspects of behaviour/emotion (e.g., anxiety, aggression, mood)
1.3 Average endpoint behaviour score
1.4 Average change in behaviour scores

2. Global state
2.1 Relapse
2.2 Time to relapse
2.3 No clinically important change in global state
2.4 Not any change in global state
2.5 Average endpoint global state score
2.6 Average change in global state scores

3. Social/General functioning
3.1 Average endpoint general functioning score
3.2 Average change in general functioning scores
3.3 No clinically important change in specific aspects of functioning, such as social or life skills
3.4 Not any change in specific aspects of functioning, such as social or life skills
3.5 Average endpoint specific aspects of functioning, such as social or life skills
3.6 Average change in specific aspects of functioning, such as social or life skills
3.7 Employment status (employed/unemployed)

4. Quality of life
4.1 No clinically important change in general quality of life
4.2 Average endpoint general quality of life score
4.3 Average change in general quality of life scores

5. Service Use
5.1 Mean days in hospital
5.2 Number of participants admitted to hospital/re‐hospitalised

6. Satisfaction with treatment
6.1 Recipient of care not satisfied with treatment
6.2 Recipient of care average satisfaction score
6.3 Recipient of care average change in satisfaction scores
6.4 Carer not satisfied with treatment
6.5 Carer average satisfaction score
6.6 Carer average change in satisfaction scores

7. Adverse effects
7.1 Number of participants with at least one treatment‐emergent adverse effect
7.2 Clinically important specific adverse effects (e.g. cardiac effects, death, movement disorders, probating increase
and associated effects, fatigue, sedation, seizures, weight gain, effects on white blood cell count)
7.3 Average endpoint in specific adverse effects
7.4 Average change in specific adverse effects
7.5 Death (natural or suicide)

8. Leaving the study early (any reason, adverse events, inefficacy of treatment)

Search methods for identification of studies

Electronic searches

The Cochrane Schizophrenia Group Trials Register (March 2010) will be searched using the phrase:

[*modafinil* in interventions of STUDY field]

This register is compiled by systematic searches of major databases, hand searches and conference proceedings (see Group Module)

Searching other resources

Studies will also be identified by cross‐referencing of reviews and included studies. We will also contact laboratories that are in the process of studying these effects. Studies will also be identified from conferences and congresses.

Data collection and analysis

Selection of studies

Two authors (LS and JHB) will independently read citations identified from the search and include studies according to the criteria for review. Irrelevant articles will be discarded by a review of the title and its abstract. In the presence of any suggestion that the article could possibly be relevant, it will be retrieved for further assessment. Any disagreements will be resolved by discussion. If it is impossible to resolve disagreements these studies will be added to those awaiting assessment and the authors of the papers will be contacted for clarification. Non‐concurrence in trial selection will be reported.

Data extraction and management

1. Extraction
Two independent reviewers (LS and JHB) will extract data from the selected trials using the double entry method. In the event of a difference between the reviewers, they will seek to resolve the difference by further scrutiny of the original trial reports, and may involve a third reviewer and/or contact the authors for further information.

2. Management
Data will be extracted onto standard, simple forms.

3. Scale‐derived data
We will include continuous data from rating scales only if: (a) the psychometric properties of the measuring instrument have been described in a peer‐reviewed journal (Marshall 2000); (b) the measuring instrument was not written or modified by one of the trialist; (c) the measuring instrument is either (i) a self‐report or (ii) completed by an independent rater or relative.

Assessment of risk of bias in included studies

Two review authors (LS and JHB) will independently assess risk of bias in accordance with the Cochrane Collaboration’s tools for assessing quality and risk of bias (Higgins 2008). This tool encourages consideration of how the sequence was generated, how allocation was concealed, the integrity of blinding, the completeness of outcome data, selective reporting and other biases. The risk of bias in each domain, and overall, are assessed and categorised into:
A. Low risk of bias: plausible bias unlikely to seriously alter the results (categorised as 'Yes' in Risk of Bias table)
B. High risk of bias: plausible bias that seriously weakens confidence in the results (categorised as 'No' in Risk of Bias table)
C. Unclear risk of bias: plausible bias that raises some doubt about the results (categorised as 'Unclear' in Risk of Bias table)

Trials with high risk of bias (defined as at least 3 out of 5 domains categorised as 'No') will not be included in the meta‐analysis. If the raters disagree, the final rating will be made by consensus with the involvement of another member of the review group. Where inadequate details of randomisation and other characteristics of trials are provided, authors of the studies will be contacted in order to obtain further information. Non‐concurrence in quality assessment will be reported.

Measures of treatment effect

1. Binary outcomes
Where binary outcomes (proportions) are used, we will calculate fixed‐effects model relative risks (RR) (Furukawa 2002), and 95% confidence intervals for each outcome. We will perform a sensitivity analysis for heterogeneity, and if this is significant, we will use a random effects model. The relative risk will be chosen over the odds ratio because the latter tends to overstate effect size when event rates are high (Higgins 2008).

2. Continuous data
2.1 Summary statistic
For continuous outcomes we will estimate a Weighted Mean Difference (WMD) between groups. WMDs are based on the fixed‐effects model, unless there is significant heterogeneity, in which case we will use the random‐effects model. We will calculate Standardised Mean Differences (SMD) for continuous outcomes measured with different scales.

2.2 Endpoint versus change data
Since there is no principal statistical reason why endpoint and change data should measure different effects (Higgins 2008), we will use scale endpoint data which is easier to interpret from clinical point of view. If endpoint data are not available, we will use change data.

2.3 Skewed data
Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non‐parametric data, we aim to apply the following standards to all data before inclusion: (a) standard deviations (SD) and means (M) are reported in the paper or obtainable from the authors; (b) when a scale starts from the finite number zero, the SD, when multiplied by two, is less than the mean (as otherwise the mean is unlikely to be an appropriate measure of the centre of the distribution (Altman 1996)); (c) if a scale starts from a positive value the calculation described above will be modified to take the scale starting point into account. In these cases skew is present if 2SD>(S‐S min), where S is the mean score and S min is the minimum score. Endpoint scores on scales often have a finite start and end point and these rules can be applied. When continuous data are presented on a scale which includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not. These skewed data will be excluded and then included to see if they make a substantive difference in the results. If it does, data will be excluded. If it does not, data will be included and results discussed.

2.4 Data synthesis
When standard errors instead of standard deviations are presented, the former will be converted to the standard deviations. If standard deviations are not reported and cannot be calculated from available data, authors will be asked to supply the data. In the absence of data from authors, we will calculate the SD using the p‐values and the sample size of the group(s) present in individual studies (Chapter 8.5.2.5 "P‐values" from the Cochrane Handbook version 4.2.6).

Unit of analysis issues

1. Cluster trials
Studies increasingly employ ‘cluster randomisation’ (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intra class correlation in clustered studies, leading to a ‘unit of analysis’ error (Divine 1992) whereby p‐values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes Type I errors (Bland 1997;Gulliford 1999). Where clustering has not been accounted for in primary studies, we will present the data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of studies to obtain intra class correlation coefficients of their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, we will also present these data as if from a non‐cluster randomised study, but adjusted for the clustering effect. The binary data as presented in a report should be divided by a ‘design effect’. This is calculated using the mean number of participants per cluster (m) and the intra‐class correlation coefficient (ICC) [Design effect = 1+(m‐1)*ICC] (Donner 2002). If the ICC has not been reported it will be assumed to be 0.1(Ukoumunne 1999).

2. Studies with multiple treatment groups
Where a study involved more than two treatment groups, if relevant, the additional treatment groups will be presented in additional relevant comparisons. Groups will either be combined in two categories of treatment‐no treatment, where appropriate, to create a single pair‐wise comparison. Alternatively, if groups differ among them, groups will be split so they can be compared to each group. However data will not be double‐counted. Where the additional treatment groups were not relevant, these data will not be reproduced.

Dealing with missing data

1. Overall loss of credibility
At some degree of loss of follow up data must lose credibility (Xia 2007). Should more than 40% of data be unaccounted for we will not reproduce these data or use them within analyses, with the exception of the analysis of numbers leaving the study early.

2. Binary
In the case where attrition for a binary outcome is between 0 and 40% and outcomes of these people are described, we will include these data as reported. Where these data are not clearly described, data will be presented on a 'once‐randomised‐always‐analyse' basis, assuming an intention to treat analysis. Those lost to follow up will be all assumed to have a negative outcome. For example, for the outcome of employment, those who were lost to follow up will be considered all unemployed. A final sensitivity analysis will be undertaken testing how prone the primary outcomes are to change when 'completer' data only are compared to the intention to treat analysis using the negative assumption.

3. Continuous
In the case where attrition for a continuous outcome is between 0 and 40% and completer‐only data are reported, we will reproduce these.

4. Intention‐to‐treat (ITT)
Intention‐to‐treat (ITT) will be used when available. We anticipate that in some studies, in order to do an ITT analysis, the method of last observation carried forward (LOCF) would be employed within the study report. As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results. Therefore, where LOCF data have been used in the analysis, it will be indicated in the review.

Assessment of heterogeneity

Overall, if possible, results will be calculated based on the fixed‐effects model. We plan to quantify the impact of statistical heterogeneity in the meta‐analysis using I2, a measure of the degree of inconsistency in the studies' results. This measure describes the percentage of total variation across studies due to heterogeneity rather than chance. The values of I2 lie between 0% and 100%, and a simplified categorisation of heterogeneity that we plan to use is of low (I2 value of 25%); moderate (I2 value of 50%); and high (I2 value of 75%) (Higgins 2003). In addition, a Chi2 test will be included to assess whether observed differences in results are compatible with chance alone. A low p‐value provides evidence of heterogeneity of intervention effects.

Assessment of reporting biases

A funnel plot will be used to assess whether the review is subject to publication bias where 10 or more studies are available. If asymmetry is detected we will also assess other possible causes such as selection bias, reporting bias, true heterogeneity and artefact. The possible existence of small study effects will be examined by Egger’s regression method (Egger 1997) as well as by visual inspection of the graph.
Where available we will compare the study protocols to published reports to assess for outcome reporting bias. Otherwise we will compare the 'Methods' section of the study to the 'Results' section of the report. If we suspect outcome reporting bias we will contact authors for data.

Data synthesis

We will synthesise data performing meta‐analysis using the fixed‐effects model. If heterogeneity is present among the included studies, we will use the random‐effects model. Where available, the analyses will be based on intention‐to‐treat data from the individual studies. The data from included trials will be combined in a meta‐analysis if they are sufficiently homogeneous, both clinically and statistically.

Subgroup analysis and investigation of heterogeneity

If necessary, we will perform subgroup analysis in order to investigate heterogeneity in the case scenario I2 was superior to 50%. If the number of studies allows, analyses will be performed taking factors that may contribute to the existence of clinical heterogeneity into account. These might include diagnosis, age, sex or different doses of modafinil administered.

Sensitivity analysis

We will perform sensitivity analyses to determine the impact of study quality on outcome, including and excluding studies with missing data. We will also investigate the effect of including studies with implied randomisation and high attrition rates by sensitivity analyses. In addition, different doses of modafinil will be compared with regard to the primary outcomes of mental state and cognitive function using sensitivity analyses.