Modafinil for schizophrenia

Review question: Is adding modafinil to antipsychotic treatment effective and safe for people with schizophrenia?


Schizophrenia is a complicated and chronic mental disorder that usually presents with a wide range of symptoms. The standard treatment (antipsychotics) is considered to be effective for the positive symptoms (such as delusions and hallucinations or bizarre thoughts). However, there are negative and cognitive symptoms (such as social withdrawal, lack of affect, problems with memory) that are not adequately treated with these medications. These symptoms tend to be chronic and can therefore have a long-term impact on an individual's quality of life. Additional treatments are often added to antipsychotic treatment, of which one is modafinil, a wakefulness-promoting medication usually used for sleep disorders.

Searching for evidence

We ran an electronic search of Cochrane Schizophrenia's register of trials in April 2015, May 2017, and October 2019 for trials that randomised (allocated participants to treatment groups using a random method) people with schizophrenia to receive add-on modafinil (modafinil added to their standard care) or to receive add-on placebo. We identified 67 records that referred to 25 studies.

Evidence found

Eleven studies met the review requirements and reported data that could be used in analyses. However, the trials included small numbers of participants and were of short duration; schizophrenia is a long-term health problem that ideally requires studies of longer duration. Our analysis of the data showed there is no clear difference between add-on modafinil and add-on placebo for improving mental state or global state, changing cognitive functioning, causing participants to leave a study early, producing adverse effects, or affecting rates of hospitalisation. However, most of these results were based on very low- or low-quality data, therefore it is uncertain if these statistical effect sizes found by our data analyses are true effects.


The results of this review indicate no clear difference in effectiveness and safety between add-on modafinil and add-on placebo, however these results are not conclusive as they are based low- or very low-quality evidence. Based on the current evidence we were unable to provide an answer to our review question as to whether modafinil is better than placebo for improving the symptoms of schizophrenia, or if it is safe to use for people with schizophrenia. More high-quality research is needed.

Authors' conclusions: 

Due to methodological issues, low sample size, and short duration of the clinical trials as well as high risk of bias for outcome reporting, most of the evidence available for this review is of very low or low quality. For results where quality is low or very low, we are uncertain or very uncertain if the effect estimates are true effects, limiting our conclusions. Specifically, we found that modafinil is no better or worse than placebo at preventing worsening of psychosis; however, we are uncertain about this result. We have more confidence that participants receiving modafinil are no more likely to leave a trial early than participants receiving placebo. However, we are very uncertain about the remaining equivocal results between modafinil and placebo for outcomes such as improvement in global state or cognitive function, incidence of adverse events, and changes in quality of life. More high-quality data are needed before firm conclusions regarding the effects of modafinil for people with schizophrenia or related disorders can be made.

Read the full abstract...

People with schizophrenia have a range of different symptoms, including positive symptoms (hallucinations and delusions), negative symptoms (such as social withdrawal and lack of affect), and cognitive impairment. The standard medication for people with schizophrenia is antipsychotics. However, these medications may not be effective for all symptoms of schizophrenia, as cognitive and negative symptoms are usually hard to treat. Additional therapies or medications are available for the management of these symptoms. Modafinil, a wakefulness-promoting agent most frequently used in narcolepsy or shift work sleep disorder, is one intervention that is theorised to have an effect of these symptoms.


The primary objective of this review was to assess the effects of modafinil for people with schizophrenia or related disorders.

Search strategy: 

On 27 April 2015, 24 May 2017, and 31 October 2019, we searched the Cochrane Schizophrenia Group's register of trials, which is based on regular searches of CENTRAL, MEDLINE, Embase, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials. There are no language, time, document type, or publication status limitations for the inclusion of records in the register.

Selection criteria: 

We selected all randomised controlled trials comparing modafinil with placebo or other treatments for people with schizophrenia or schizophrenia-spectrum disorders.

Data collection and analysis: 

We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CI. We used a random-effects model for the meta-analysis. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for the included studies.

Main results: 

Eleven studies including a total of 422 participants contributed to data analyses. Most studies had a small population size (average 38 people per study) and were of short duration. We also detected a high risk of bias for selective outcome reporting in just under 50% of the trials. We therefore rated the overall methodological quality of the included studies as low. We considered seven main outcomes of interest: clinically important change in overall mental state, clinically important change in cognitive functioning, incidence of a clinically important adverse effect/event, clinically important change in global state, leaving the study early for any reason, clinically important change in quality of life, and hospital admission. All studies assessed the effects of adding modafinil to participants' usual antipsychotic treatment compared to adding placebo to usual antipsychotic treatment.

Six studies found that adding modafinil to antipsychotic treatment may have little or no effect on overall mental state of people with schizophrenia, specifically the risk of worsening psychosis (RR 0.91, 95% CI 0.28 to 2.98; participants = 209; studies = 6, low-quality evidence). Regarding the effect of modafinil on cognitive function, the trials did not report clinically important change data, but one study reported endpoint scores on the MATRICS Consensus Cognitive Battery (MCCB): in this study we found no clear difference in scores between modafinil and placebo treatment groups (MD −3.10, 95% CI −10.9 to 4.7; participants = 48; studies = 1, very low-quality evidence). Only one study (N = 35) reported adverse effect/event data. In this study one serious adverse event occurred in each group (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence).

One study measured change in global state using the Clinical Global Impression - Improvement Scale. This study found that adding modafinil to antipsychotic treatment may have little or no effect on global state (RR 6.36, 95% CI 0.94 to 43.07, participants = 21; studies = 1, very low-quality evidence). Nine studies found that modafinil has no effect on numbers of participants leaving the study early (RR 1.26, 95% CI 0.63 to 2.52 participants = 357; studies = 9, moderate-quality evidence). None of the trials reported clinically important change in quality of life, but one study did report quality of life using endpoint scores on the Quality of Life Inventory, finding no clear difference between treatment groups (MD −0.2, 95% CI −1.18 to 0.78; participants = 20; studies = 1, very low-quality evidence). Finally, one study reported data for number of participants needing hospitalisation: one participant in each group was hospitalised (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence).