BACKGROUND: Patients with schizophrenia often suffer from cognitive deficits and 
negative symptoms that are poorly responsive to antipsychotics including 
clozapine. Clozapine-induced sedation can worsen cognition and impair social and 
occupational functioning.
OBJECTIVES: To evaluate the efficacy, tolerability, and safety of modafinil for 
negative symptoms, cognition, and wakefulness/fatigue in DSM-IV-diagnosed 
schizophrenia patients treated with clozapine.
METHOD: A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial 
was conducted between September 2003 and September 2007, adding modafinil up to 
300 mg/d to stabilized schizophrenia outpatients receiving clozapine. 
Psychopathology, cognition, and wakefulness/fatigue were assessed with standard 
rating scales.
RESULTS: Thirty-five patients were randomly assigned to treatment with study 
drug and included in the analysis. Modafinil did not reduce negative symptoms or 
wakefulness/fatigue or improve cognition compared to placebo. Modafinil was well 
tolerated and did not worsen psychosis.
CONCLUSIONS: Results of this pilot trial do not support routine use of modafinil 
to treat negative symptoms, cognitive deficits, or wakefulness/fatigue in 
patients on clozapine. However, given our limited power to detect a treatment 
effect and the clear possibility of a type II error, larger trials are needed to 
resolve or refute a potential therapeutic effect of uncertain magnitude.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00573417.