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, Perkins Diana, Hamer Robert M, Gu Hongbin, Tohen Mauricio
Departments of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Arch Gen Psychiatry. 2005 Apr;62(4):361-70. doi: 10.1001/archpsyc.62.4.361.
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.
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.
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.
Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1).
Patients with first-episode psychosis (DSM-IV) and healthy volunteers.
Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d).
Brain volume changes assessed by MRI.
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.
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.
早在首发精神分裂症时就已广泛描述了大脑的病理形态学变化。纵向研究表明，这些变化可能是渐进性的，并与临床结局相关。这就增加了抗精神病药物可能改变早期精神分裂症这种病理形态学进展的可能性。
预先检验以下假设：与接受氟哌啶醇治疗的患者相比，接受奥氮平治疗的患者全脑灰质体积和侧脑室体积随时间的变化更小，且灰质和侧脑室体积变化与精神病理学和神经认知的变化相关。
纵向、随机、对照、多中心、双盲研究。对患者进行治疗并随访长达104周。在第0周（基线）、12周、24周、52周和104周进行神经认知和磁共振成像（MRI）评估。采用含时间依存性协变量的混合模型分析评估治疗对MRI终点的影响，并探讨MRI、精神病理学和神经认知结局之间的关系。
14个学术医疗中心（美国11个；加拿大1个；荷兰1个；英国1个）。
首发精神病（DSM-IV）患者和健康志愿者。
随机分配至传统抗精神病药物氟哌啶醇（2 - 20毫克/天）或非典型抗精神病药物奥氮平（5 - 20毫克/天）。
通过MRI评估脑体积变化。
在263例随机分组的患者中，161例有基线及至少1次基线后MRI评估。接受氟哌啶醇治疗的患者灰质体积显著减少，而接受奥氮平治疗的患者则未出现这种情况。同期检查的匹配健康志愿者样本（n = 58）灰质体积无变化。
首发精神病患者在MRI体积变化方面存在显著的治疗间差异。氟哌啶醇与灰质体积显著减少相关，而奥氮平则不然。事后分析表明，治疗对精神分裂症脑体积和精神病理学的影响可能相关。对脑形态的不同治疗效果可能是由于氟哌啶醇相关的毒性或奥氮平更大的治疗效果。
