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Original Research

Modafinil for Clozapine-Treated Schizophrenia Patients: A Double-Blind, Placebo-Controlled Pilot Trial

Oliver Freudenreich, MD; David C. Henderson, MD; Eric A. Macklin, PhD; A. Eden Evins, MD, MPH; Xiaoduo Fan, MD; Cori Cather, PhD; Jared P. Walsh, BA; and Donald C. Goff, MD

Published: August 11, 2009

Article Abstract

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: Identifier: NCT00573417

Submitted: September 6, 2008; accepted November 11, 2008.

Online ahead of print: August 11, 2009.

Corresponding author: Oliver Freudenreich, MD, MGH Schizophrenia Program, Freedom Trail Clinic, 25 Staniford St, 2nd Floor, Boston, MA 02114 (

Volume: 70

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