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Jeffrey A. Lieberman, MD; Gary D. Tollefson, MD, PhD; Cecil Charles, PhD; Robert Zipursky, MD; Tonmoy Sharma, MD; Rene S. Kahn, MD, PhD; Richard S. E. Keefe, PhD; Alan I. Green, MD; Raquel E. Gur, MD, PhD; Joseph McEvoy, MD; Diana Perkins, MD, MPH; Robert M. Hamer, PhD; Hongbin Gu, PhD; Mauricio Tohen, MD, DrPH; for the HGDH Study Group

Arch Gen Psychiatry. 2005;62:361-370.

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.

Author Affiliations: Departments of Psychiatry, University of North Carolina School of Medicine, Chapel Hill (Drs Lieberman, Perkins, Hamer, and Gu); University of Utrecht Medical School, Utrecht, the Netherlands (Dr Kahn); Duke University School of Medicine, Durham, NC (Drs Keefe and McEvoy); Dartmouth Medical School, Hanover, NH (Dr Green); University of Pennsylvania School of Medicine, Philadelphia (Dr Gur); Harvard Medical School, Boston, Mass (Dr Tohen); Lilly Research Laboratories, Indianapolis, Ind (Drs Tollefson and Tohen); Department of Radiology, Duke University School of Medicine (Dr Charles); University of Toronto Faculty of Medicine, Toronto, Ontario (Dr Zipursky); and Clinical Neuroscience Research Centre, Kent, England (Dr Sharma). Dr Lieberman is now with the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and New York State Psychiatric Institute, New York.

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