Antipsychotic drug effects on brain morphology in first-episode psychosis

Jeffrey A. Lieberman, Gary D. Tollefson, Cecil Charles, Robert Zipursky, Tonmoy Sharma, Rene S. Kahn, Richard S.E. Keefe, Alan I. Green, Raquel E. Gur, Joseph Patrick McEvoy, Diana Perkins, Robert M. Hamer, Hongbin Gu, Mauricio Tohen

Research output: Contribution to journalArticle

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Abstract

Background: Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. Objective: To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. Design: Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. Setting: Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). Participants: Patients with first-episode psychosis (DSM-IV) and healthy volunteers. Interventions: Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). Main Outcome Measures: Brain volume changes assessed by MRI. Results: Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n=58) examined contemporaneously showed no change in gray matter volume. Conclusions: Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Original languageEnglish (US)
Pages (from-to)361-370
Number of pages10
JournalArchives of General Psychiatry
Volume62
Issue number4
DOIs
StatePublished - Apr 1 2005

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olanzapine
Psychotic Disorders
Antipsychotic Agents
Haloperidol
Magnetic Resonance Imaging
Brain
Schizophrenia
Lateral Ventricles
Psychopathology
Healthy Volunteers
Drug Effects
Psychosis
Therapeutic Uses
Therapeutics
Random Allocation
Double-Blind Method
Diagnostic and Statistical Manual of Mental Disorders
England
Netherlands
Canada

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

Cite this

Lieberman, J. A., Tollefson, G. D., Charles, C., Zipursky, R., Sharma, T., Kahn, R. S., ... Tohen, M. (2005). Antipsychotic drug effects on brain morphology in first-episode psychosis. Archives of General Psychiatry, 62(4), 361-370. https://doi.org/10.1001/archpsyc.62.4.361

Antipsychotic drug effects on brain morphology in first-episode psychosis. / Lieberman, Jeffrey A.; Tollefson, Gary D.; Charles, Cecil; Zipursky, Robert; Sharma, Tonmoy; Kahn, Rene S.; Keefe, Richard S.E.; Green, Alan I.; Gur, Raquel E.; McEvoy, Joseph Patrick; Perkins, Diana; Hamer, Robert M.; Gu, Hongbin; Tohen, Mauricio.

In: Archives of General Psychiatry, Vol. 62, No. 4, 01.04.2005, p. 361-370.

Research output: Contribution to journalArticle

Lieberman, JA, Tollefson, GD, Charles, C, Zipursky, R, Sharma, T, Kahn, RS, Keefe, RSE, Green, AI, Gur, RE, McEvoy, JP, Perkins, D, Hamer, RM, Gu, H & Tohen, M 2005, 'Antipsychotic drug effects on brain morphology in first-episode psychosis', Archives of General Psychiatry, vol. 62, no. 4, pp. 361-370. https://doi.org/10.1001/archpsyc.62.4.361
Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Archives of General Psychiatry. 2005 Apr 1;62(4):361-370. https://doi.org/10.1001/archpsyc.62.4.361
Lieberman, Jeffrey A. ; Tollefson, Gary D. ; Charles, Cecil ; Zipursky, Robert ; Sharma, Tonmoy ; Kahn, Rene S. ; Keefe, Richard S.E. ; Green, Alan I. ; Gur, Raquel E. ; McEvoy, Joseph Patrick ; Perkins, Diana ; Hamer, Robert M. ; Gu, Hongbin ; Tohen, Mauricio. / Antipsychotic drug effects on brain morphology in first-episode psychosis. In: Archives of General Psychiatry. 2005 ; Vol. 62, No. 4. pp. 361-370.
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abstract = "Background: Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. Objective: To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. Design: Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. Setting: Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). Participants: Patients with first-episode psychosis (DSM-IV) and healthy volunteers. Interventions: Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). Main Outcome Measures: Brain volume changes assessed by MRI. Results: Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n=58) examined contemporaneously showed no change in gray matter volume. Conclusions: Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.",
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AU - Kahn, Rene S.

AU - Keefe, Richard S.E.

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N2 - Background: Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. Objective: To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. Design: Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. Setting: Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). Participants: Patients with first-episode psychosis (DSM-IV) and healthy volunteers. Interventions: Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). Main Outcome Measures: Brain volume changes assessed by MRI. Results: Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n=58) examined contemporaneously showed no change in gray matter volume. Conclusions: Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

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