The neurobiology of depression: inroads to treatment and new drug discovery.
The neurobiology of depression: inroads to treatment and new drug discovery.
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发表时间：
2005-08
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通讯作者：
C. Nemeroff;W. Vale
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作者：
C. Nemeroff;W. Vale
大多数情绪和焦虑症的根本原因仍然未知。精神疾病有很强的遗传因素，再加上环境影响，导致脆弱性增加。为了更好地描述精神疾病的遗传基础，已经进行了大量的研究工作。然而，大多数精神疾病，包括情绪和焦虑症，本质上是多基因的，而不是由传统的常染色体显性孟德尔遗传学决定的。最近的技术进步，包括人类基因组清单的完成，染色体作图，高通量DNA测序等，为有朝一日确定精神疾病的遗传基础提供了希望。与此同时，在理解情绪和焦虑症的神经生物学基础以及生活事件对风险和弹性的影响方面取得了巨大进展。来自临床前、流行病学和临床研究的证据已经令人信服地证明，早期生活中发生的压力或创伤性事件会显著增加成年后患抑郁症和其他精神疾病的风险。含有促肾上腺皮质激素释放因子（CRF）的神经回路已被确定为应激反应的重要介质。早期生活中的逆境，例如儿童时期的身体虐待或性虐待，会导致CRF介导的压力反应发生长期变化，并大大增加遗传易感人群患抑郁症的风险。CRF受体的鉴定和克隆及其在应激反应中作用的表征使人们能够更好地理解对早期逆境的适应不良反应。此外，CRF系统的研究已经提出了新药开发的分子靶点、生物学风险因素和治疗反应的预测因子。
The underlying causes of most mood and anxiety disorders remain unknown. There is a strong heritable component to psychiatric illnesses that, when coupled with environmental influences, results in increased vulnerability. Intensive research efforts have been expended to better characterize the genetic underpinnings of mental illness. However, most psychiatric disorders, including mood and anxiety disorders, are polygenetic in nature rather than determined by traditional autosomal-dominant Mendelian genetics. Recent technological advances, including the completion of the human genome inventory, chromosome mapping, high throughput DNA sequencing, and others, offer the promise of someday identifying the genetic basis of mental illnesses. In parallel, tremendous inroads have been made into understanding the neurobiological basis of mood and anxiety disorders and the influence of life events on risk and resilience. Evidence from preclinical, epidemiologic, and clinical studies has converged to convincingly demonstrate that stressful or traumatic events occurring in early life significantly increase the risk for depression and other psychiatric illnesses in adulthood. Neural circuits containing corticotropin-releasing factor (CRF) have been identified as an important mediator of the stress response. Early-life adversity, such as physical or sexual abuse during childhood, results in long-lasting changes in the CRF-mediated stress response and a greatly increased risk of depression in genetically predisposed persons. Identification and cloning of CRF receptors and characterization of their role in the stress response have enabled a better understanding of maladaptive responses to early-life adversity. In addition, studies of the CRF system have suggested molecular targets for new drug development, biological risk factors, and predictors of treatment response.