Antipsychotic drug effects on brain morphology in first-episode psychosis.
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.


METHODS
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.


METHODS
Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1).


METHODS
Patients with first-episode psychosis (DSM-IV) and healthy volunteers.


METHODS
Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d).


METHODS
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.
Lieberman
Jeffrey A
JA
Departments of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA. jlieberman@pi.cpmc.columbia.edu
Tollefson
Gary D
GD
Charles
Cecil
C
Zipursky
Robert
R
Sharma
Tonmoy
T
Kahn
Rene S
RS
Keefe
Richard S E
RS
Green
Alan I
AI
Gur
Raquel E
RE
McEvoy
Joseph
J
Perkins
Diana
D
Hamer
Robert M
RM
Gu
Hongbin
H
Tohen
Mauricio
M
D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000033:anatomy & histology* / Q000187:drug effects*; D002421:Caudate Nucleus / Q000033:anatomy & histology / Q000187:drug effects; D003072:Cognition Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000523:psychology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D000077152:Olanzapine; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D006220:Haloperidol; D000077152:Olanzapine