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

描述（由申请人提供）：最近的动物和人类神经影像学研究表明，抗精神病药物对大脑皮层结构具有潜在毒性。然而，在这方面， 人体研究未进行安慰剂对照，无法确定因果关系。此外，一些研究表明，抗精神病药物实际上是保护免受结构性大脑变化与未经治疗的精神障碍。随着越来越多的年轻和老年患者接受抗精神病药物，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，这个问题在精神分裂症患者中无法解决。我们建议在STOP-PD II的背景下进行一项MRI/DTI前/后神经影像学研究，STOP-PD II是一项新的NIMH资助的奥氮平持续/维持治疗伴精神病特征的重度抑郁症（“精神病性抑郁症”，PD）的随机、安慰剂对照试验。本申请的主要目的是评估与奥氮平治疗相关的灰质和白色物质的脑变化。使用混合模型回归分析，我们将比较奥氮平持续或停用患者的大脑结构和连接性随时间的变化。我们假设，与安慰剂相比，奥氮平持续治疗将与以下情况相关：所有脑叶皮质变薄;纹状体体积增加;白色物质微结构减少;表面积或海马和杏仁核体积无变化。我们的应用程序利用临床基础设施（即，筛选、招募、治疗和临床监测）：152名在舍曲林加奥氮平急性开放治疗12周后达到缓解并在随后8周内保持稳定的受试者将被随机分配至继续奥氮平组或转换至安慰剂组。这些受试者将接受首次（“术前”）MRI扫描，并在完成36周双盲试验或复发时重新扫描（“术后”）。这项研究是创新和独特的，它使用了随机安慰剂对照设计，结合先进的神经影像学技术：高分辨率MRI（包括DTI），皮质厚度，皮质表面积，白色物质束和皮质下微结构完整性的测量。 纹状体和边缘形态测量学。它将扩展和推进已用于人类和动物的常规体积方法，以评估抗精神病药物对大脑结构的纵向影响，提供对灰质和白色物质更具生物学意义的评估。

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.