Modafinil for Clozapine-Treated Schizophrenia Patients: A Double-Blind, Placebo-Controlled Pilot Trial
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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.
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In the Freudenreich et al trial, modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared with placebo.
“• Modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared with placebo.”
From Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far? (2013) · cites this paper as [43]
The Freudenreich et al trial had limited power to detect a treatment effect, with a clear possibility of a type II error.
“• Given the 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”
From Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far? (2013) · cites this paper as [43]
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Learned lessons from patients who take clozapine: A case study
Lee, H., Scolieri, B. B., & Mullick, P. K. (2017) · Perspectives In Psychiatric Care · doi:10.1111/ppc.12245 · Cited by 2 · see citing works
Khalafi, M., Rostami, H., Malekpour, N., Behrouzian, F., & Boostani, H. (2024) · Jundishapur Journal of Chronic Disease Care · doi:10.5812/jjcdc-143232 · Cited by 1 · see citing works
A Call to Action for Starting Clozapine: Increasing Clozapine Use and Safety in a Post-REMS Era
Leung, J. G., & Cotes, R. O. (2025) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.20250023 · Cited by 2 · see citing works
Management of Negative Symptoms in Schizophrenia
Rado, J. T. (2011) · Psychiatric Annals · doi:10.3928/00485713-20110425-05 · Cited by 1 · see citing works
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The management of negative symptoms
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The ethics of prescribing low- to no-efficacy stimulants
Langston, C. (2021) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2021.103386
Developmental Manipulation-Induced Changes in Cognitive Functioning
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- Authors
- Freudenreich, O., Henderson, D. C., Macklin, E. A., Evins, A. E., Fan, X., Cather, C., Walsh, J. P., & Goff, D. C.
- Affiliations
- Massachusetts General Hospital (US)
- Boston University (US)
- Corresponding author
- Freudenreich, Oliver
- ORCID
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2009-08-11
- Volume
- 70
- Issue
- 12
- Pages
- 1674-1680
- ISSN
- 0160-6689 (ISSN-L)
- PMC
- PMC5038350
- OpenAlex
- W2059569476
- Cited by
- 78
- References
- 36
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 3 · 2014: 8 · 2013: 7 · 2012: 6
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K24MH002025)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Keywords
- modafinil, clozapine, schizophrenia, negative symptoms, cognitive impairment, wakefulness, fatigue, adjunctive therapy, safety and tolerability
- MeSH terms
- Modafinil, Adolescent, Adult, Central Nervous System Stimulants, Benzhydryl Compounds, Clozapine, Cognition Disorders, Double-Blind Method, Drug Therapy, Combination, Fatigue, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Pilot Projects, Placebos, Psychotic Disorders, Schizophrenia, Schizophrenic Psychology, Antipsychotic Agents, Wakefulness, Treatment Outcome
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