OBJECTIVE: Given recent reports about the off-label use of modafinil as an 
adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia 
patients and the recent interest in its putative cognitive-enhancing effects in 
this population, we present a systematic review of available data on trials of 
modafinil as an adjuvant in the treatment of cognitive deficits, negative 
symptoms, and antipsychotic-induced fatigue, and its tolerability.
DATA SOURCES: PubMed was searched for trials published in English up to January 
2008 evaluating modafinil's effects on fatigue, negative symptoms, and cognition 
in schizophrenia with combinations of the following terms: schizophrenia, 
modafinil, cognition, negative symptoms, and fatigue.
STUDY SELECTION: Six trials were identified: 2 randomized, prospective, 
double-blind placebo-controlled trials; 3 randomized, prospective, double-blind 
placebo-controlled crossover trials; and 1 open-label pilot study. Case series 
and case reports were excluded in the data analysis, except to identify 
potential adverse reactions to modafinil.
DATA EXTRACTION: Studies were examined for number of subjects, trial duration, 
design, dosing, and outcomes with respect to sedation, negative symptoms, 
cognitive function, and tolerability.
RESULTS: One of 4 reviewed studies found a significant effect of modafinil as an 
alerting agent for antipsychotic-induced fatigue and sedation. Neither of 2 
reviewed studies found modafinil to improve negative symptoms of schizophrenia. 
Three of 6 reviewed studies showed that modafinil may improve short-term memory, 
attention, and the ability to shift mental sets. Two neuroimaging studies 
identified functional correlates in areas associated with working memory 
functions. The main adverse effect was found to be a small risk of psychosis 
exacerbation, which was seen in 5 of 83 patients (6.0%) in the active treatment 
groups as compared to 2 of 70 patients (2.9%) in the placebo groups.
CONCLUSIONS: While the available data suggest that modafinil is generally well 
tolerated and may have some efficacy in the treatment of antipsychotic-induced 
sedation and cognitive domains, the small sample sizes, contradictory results, 
and methodological differences between trials, especially with respect to 
cognitive testing, make it difficult to draw firm conclusions about the overall 
effectiveness of modafinil as an adjunct in the treatment of schizophrenia. 
Well-powered, prospective, randomized placebo-controlled trials using the 
MATRICS battery concomitantly with functional outcome measures are necessary to 
elucidate modafinil's efficacy and effectiveness as an adjunctive treatment for 
sedation, negative symptoms, and cognitive deficits in schizophrenia. Hence, 
before prescribing modafinil to a schizophrenia patient, the possible risks and 
benefits of each particular case should be evaluated.