Effects of Maintenance Treatment with Olanzapine vs. Placebo on Brain Structure

描述(申请人提供)：最近的动物和人类神经成像研究表明，抗精神病药物对大脑皮质结构有潜在的毒性。然而， 这些人体研究并不是安慰剂对照，也不能确定因果关系。此外，一些研究表明，抗精神病药物实际上对未经治疗的精神障碍相关的结构性大脑变化具有保护作用。随着越来越多的年轻和老年患者接受抗精神病药物的治疗，确定这些药物对大脑结构的总体影响是公共卫生的当务之急。出于伦理原因，这个问题不能在精神分裂症患者身上得到解决。我们建议在Stop-PD II的背景下进行一项前后MRI/DTI神经成像研究，Stop-PD II是一项新的由NIMH资助的随机、安慰剂对照试验，奥氮平用于继续/维持治疗具有精神病特征的主要抑郁症(“精神性抑郁症”，PD)。该应用的主要目的是评估与奥氮平治疗相关的大脑灰质和白质的变化。使用混合模型回归分析，我们将比较奥氮平持续或停药患者的脑结构和连接性随时间的变化。我们假设，与安慰剂相比，继续使用奥氮平治疗将与以下方面相关：所有脑叶的皮质变薄；纹状体体积增加；白质微结构减少；表面积或海马体和杏仁体体积没有变化。我们的应用利用了STOP-PD II提供的临床基础设施(即筛查、招募、治疗和临床监测)：152名患者在接受舍曲林和奥氮平的急性开放治疗12周后获得缓解，并在接下来的8周内保持稳定，他们将被随机分为继续服用奥氮平和改用安慰剂。这些受试者将接受第一次(“前”)MRI扫描，并将在36周的双盲试验结束时或复发时重新扫描(“后”)。这项研究在使用随机安慰剂对照设计和先进的神经成像技术方面是创新和独特的：高分辨率磁共振成像(包括DTI)、测量皮质厚度、皮质表面积、白质束微结构完整性和皮质下 纹状体和边缘形态测量。它将扩展和发展已用于人类和动物的传统体积方法，以评估抗精神病药物对大脑结构的纵向影响，为灰质和白质提供更有生物学意义的评估。

DESCRIPTION (provided by applicant): Recent animal and human neuroimaging studies suggest that antipsychotic medications are potentially toxic to cortical brain structures. However, the human studies have not been placebo-controlled and cannot establish causality. Also, some studies suggest that antipsychotics are actually protective against structural brain changes associated with untreated psychotic disorders. With the growing number of younger and older patients receiving antipsychotics, determining the overall effect of these medications on brain structure is a public health imperative. For ethical reasons, this question cannot be resolved in patients with schizophrenia. We are proposing to conduct a pre/post MRI/DTI neuroimaging study in the context of STOP- PD II, a newly NIMH-funded randomized, placebo-controlled trial of olanzapine in the continuation/maintenance treatment of major depression with psychotic features ("psychotic depression", PD). The main aims of this application are to assess brain changes in gray and white matter associated with olanzapine treatment. Using a mixed model regression analysis, we will compare changes in brain structure and connectivity over time in patients in whom olanzapine has been continued or discontinued. We hypothesize that, compared to placebo, continuing treatment with olanzapine will be associated with: cortical thinning throughout all lobes; increase in striatal volumes; reductions in white matter microstructure; and no change in surface area or hippocampal and amygdala volumes. Our application leverages the clinical infrastructure (i.e., screening, recruitment, treatment, and clinical monitoring) provided by STOP-PD II: 152 subjects who achieve remission after 12 weeks of acute open treatment with sertraline plus olanzapine and remain stable over the following 8 weeks will be randomized to continuing olanzapine vs. being switched to placebo. These subjects will undergo a first ("pre") MRI scan and will be rescanned ("post") at the completion of the 36-week double-blind trial or at the time of relapse. This study is innovative and unique in its use of a randomized placebo-controlled design combined with advanced neuroimaging techniques: high resolution MRI (including DTI), measurements of cortical thickness, cortical surface area, microstructural integrity of white matter tracts, and subcortical striatal and limbic morphometry. It will extend and advance conventional volumetric approaches that have been used in humans and animals to assess longitudinal effects of antipsychotics on brain structure, providing a more biologically meaningful assessment of both gray and white matter.