Zarate Carlos A, Singh Jaskaran, Manji Husseini K
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Bethesda, Maryland, USA.
Biol Psychiatry. 2006 Jun 1;59(11):1006-20. doi: 10.1016/j.biopsych.2005.10.021. Epub 2006 Feb 17.
For a number of patients with bipolar disorder, current pharmacotherapy is generally insufficient. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability, and significant medical and psychiatric comorbidity. Drug development for bipolar disorder may occur through one of two approaches: the first is by understanding the therapeutically relevant biochemical targets of currently effective medications. Two promising direct targets of lithium and valproate are glycogen synthase kinase-3 and histone deacetylase. The second path results from our understanding that severe mood disorders, although not classical neurodegenerative disorders, are associated with regional impairments of structural plasticity and cellular resilience. This suggests that effective treatments will need to provide both trophic and neurochemical support, which serves to enhance and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of mood disorders include inhibitors of glutamate release, N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid potentiators, cyclic adenosine monophosphate phosphodiesterase inhibitors, and glucocorticoid receptor antagonists.
对于许多双相情感障碍患者而言，当前的药物治疗通常并不充分。尽管接受了充分的治疗，但患者仍会反复出现情绪发作、残留症状、功能损害、心理社会残疾以及严重的医学和精神共病。双相情感障碍的药物研发可能通过两种途径之一进行：第一种是通过了解当前有效药物的治疗相关生化靶点。锂盐和丙戊酸盐的两个有前景的直接靶点是糖原合酶激酶-3和组蛋白脱乙酰酶。第二条途径源于我们的认识，即严重的情绪障碍虽然不是经典的神经退行性疾病，但与结构可塑性和细胞复原力的区域损害有关。这表明有效的治疗需要提供营养支持和神经化学支持，以增强和维持正常的突触连接，从而使化学信号恢复正常情感功能所需关键回路的最佳功能。对于许多难治性患者，模仿“传统”策略、直接或间接改变单胺能水平的药物可能益处有限。可能对治疗情绪障碍有用的更新的“增强可塑性”策略包括谷氨酸释放抑制剂、N-甲基-D-天冬氨酸拮抗剂、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸增强剂、环磷酸腺苷磷酸二酯酶抑制剂和糖皮质激素受体拮抗剂。
