IN VIVO BRAIN MECHANISMS UNDERLYING REMISSION IN BIPOLAR DEPRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：双相情感障碍在普通人群中的终生患病率约为1.5%。它与相当大的发病率和死亡率有关，其病理生理机制尚不清楚。双相抑郁是疾病的抑郁阶段，越来越多地被认为是双相患者管理中的主要挑战，也是慢性损害的常见原因。这项拟议研究的具体目的是：(1)调查抑郁症双相II型患者涉及情绪调节的额叶边缘脑区是否存在解剖和神经化学异常；(2)检查情绪稳定剂(拉莫曲辛)治疗是否具有显著的抗抑郁效果，以及是否与改善或逆转已发现的双相II型抑郁症的大脑变化有关；以及(3)检查拉莫三嗪治疗的临床反应是否与抑郁双相II型患者的特定大脑异常有关。 研究计划：这项研究将在一组抑郁症双相II型患者和健康对照组中检测涉及情绪调节的额叶边缘脑结构的特定异常，并将开始调查疾病阶段和治疗对已发现的异常的影响。我们将利用磁共振成像(MRI)和磁共振波谱(MRS)对大脑进行活体解剖和神经化学测量。我们将在体内研究大脑形态和N-乙酰天冬氨酸(NAA)的区域水平，N-乙酰天冬氨酸(NAA)是神经元存活/功能的非特异性标记物，在前额叶和内侧颞叶。 方法：本研究将检验的具体假设是：(1)在双相II型抑郁患者中，参与情绪调节的额叶边缘脑区存在特定的形态和神经化学异常；具体而言，我们预测背外侧前额叶皮质的NAA水平降低，杏仁核增大，这两个结构的损害，类似于双相I型患者的描述；(2)拉莫三嗪治疗后杏仁核扩大和背外侧前额叶皮质NAA水平的下降将逆转；(3)与治疗无效的患者相比，治疗有效的患者在基线时的解剖和神经化学异常较少。我们将招募30名抑郁症双相II型受试者和30名匹配的健康对照组，为期3年。受试者将根据DSM-IV标准进行诊断，该标准是在SCID-IV访谈中确立的。所有患者都将在进入研究时接受脑部MRI/MRS扫描，然后作为单一疗法，公开接受拉莫三嗪治疗，每天最多200毫克，为期12周。在疗程结束时，将完成另一次MRI/MRS扫描。 临床意义：本研究将研究额叶-边缘异常在双相II型抑郁症发病机制和治疗反应中的作用。对相关机制的阐明可以开始阐明双相抑郁治疗反应和难治性的具体过程。这些研究有相当大的潜力来阐明双相情感障碍的病理生理学机制，并最终有助于开发新的、更有效的治疗这种严重精神疾病的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Bipolar disorder has a lifetime prevalence of approximately 1.5% in the general population. It is related to substantial morbidity and mortality, and its pathophysiology is still not known. Bipolar depression, the depressive phase of the illness, has been increasingly recognized as a major challenge in the management of bipolar patients and is the frequent cause of chronic impairment. The specific aims of the proposed study are: (1) Investigate the presence of anatomical and neurochemical brain abnormalities in fronto-limbic brain regions involved in mood regulation in depressed bipolar type II patients; (2) Examine whether treatment with a mood stabilizer (lamotragine) has a pronounced antidepressant effect and is related to improvement or reversal of identified brain changes in bipolar type II depression; and (3) Examine whether clinical response to lamotrigine treatment is related to specific brain abnormalities in depressed bipolar type II patients. RESEARCH PLAN: The study will examine specific abnormalities in fronto-limbic brain structures involved in mood regulation in a group of depressed bipolar type II patients and healthy controls, and it will begin to investigate the effects of illness phase and treatment on identified abnormalities. We will utilize in vivo anatomical and neurochemical brain measurements with magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). We will conduct an in vivo investigation of brain morphology and regional levels of N-Acetyl Aspartate (NAA), a non-specific marker of neuronal viability/function, in the prefrontal cortex and medial temporal lobe. METHODS: The specific hypotheses that will be examined in this study are: (1) There are specific morphometric and neurochemical abnormalities in fronto-limbic brain regions involved in mood regulation in depressed bipolar type II patients; specifically, we predict a reduction in NAA levels in dorsolateral prefrontal cortex, and an enlargement of the amygdala, indicating impairment of these two structures, similarly to what has been described in bipolar type I patients; (2) Enlargement of amygdala, and decreased levels of NAA in dorsolateral prefrontal cortex will reverse after lamotrigine treatment; (3) Patients who respond to lamotrigine treatment will have less pronounced anatomical and neurochemical brain abnormalities at baseline compared to ones who do not respond to treatment. We will recruit 30 depressed bipolar type II subjects and 30 matched healthy controls over a 3-year period. Subjects will be diagnosed according to the DSM-IV criteria, as established in a SCID-IV interview. All patients will undergo a brain MRI/MRS scan at the time of entry in the study, and will then be treated openly with lamotrigine up to 200 mg/day for a period of 12 weeks, as monotherapy. At the end of the treatment period, another MRI/MRS scan will be completed. CLINICAL RELEVANCE: The study will examine the role of fronto-limbic abnormalities in mechanisms involved in bipolar type II depression and treatment response. The elucidation of involved mechanisms could begin to shed light into the specific processes underlying treatment response and refractoriness in bipolar depression. These studies have considerable potential to elucidate the pathophysiology of bipolar disorder and ultimately contribute to the development of novel and more effective treatments for this severe psychiatric illness.