Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial

J Clin Psychiatry. 2009 Dec;70(12):1674-80. doi: 10.4088/JCP.08m04683. Epub 2009 Aug 11.


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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / therapeutic use*
  • Benzhydryl Compounds / administration & dosage
  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / therapeutic use*
  • Central Nervous System Stimulants / administration & dosage*
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / therapeutic use*
  • Clozapine / administration & dosage
  • Clozapine / therapeutic use*
  • Cognition Disorders / diagnosis
  • Cognition Disorders / drug therapy
  • Cognition Disorders / psychology
  • Double-Blind Method
  • Drug Therapy, Combination
  • Fatigue / drug therapy
  • Female
  • Humans
  • Male
  • Middle Aged
  • Modafinil
  • Neuropsychological Tests
  • Pilot Projects
  • Placebos
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / psychology
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology
  • Treatment Outcome
  • Wakefulness / drug effects


  • Antipsychotic Agents
  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Placebos
  • Clozapine
  • Modafinil

Associated data