Inoue Takeshi, Kitaichi Yuji, Koyama Tsukasa
Department of Psychiatry, Neural Function, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
Nihon Shinkei Seishin Yakurigaku Zasshi. 2003 Feb;23(1):11-20.
Most antidepressants used in Japan are reuptake inhibitors of monoamine, such as noradrenaline and serotonin. Incidence of refractory depression, which is resistant to at least two monoamine reuptake inhibitors, is 10-20%. ECT and the addition of lithium, thyroid hormones or dopamine agonists is used for the treatment of refractory depression. Bupropion and MAO inhibitors are also effective for refractory depression but not approved in Japan. The presynaptic mechanism of action of these antidepressants has been studied by in vivo microdialysis studies. Serotonin reuptake inhibitors increase extracellular serotonin concentrations in the brain. Noradrenaline reuptake inhibitors increase extracellular noradrenaline concentrations in the brain, and increase extracellular dopamine concentrations in the frontal cortex, but not in the nucleus accumbens or striatum. ECT and MAO inhibitors increase extracellular serotonin concentrations in the brain, and ECT, bupropion and MAO inhibitors increase extracellular noradrenaline concentrations in the brain. In contrast to monoamine reuptake inhibitors, ECT, bupropion and MAO inhibitors increase extracellular dopamine concentrations not only in the frontal cortex but also in the nucleus accumbens and striatum. The facilitation of mesolimbic or nigrostriatal dopamine neurotransmission may be the mechanism of action behind these treatments' efficacies for refractory depression. Although there are only a few studies concerning the mechanism of action of augmentation therapy, recent studies demonstrated that subchronic lithium treatment increases basal concentrations of extracellular serotonin in the frontal cortex and hippocampus. Subchronic lithium further increases SSRI-induced increases in extracellular serotonin concentrations, and this effect is suggested to be the mechanism of action for lithium augmentation of antidepressants.
日本使用的大多数抗抑郁药都是单胺再摄取抑制剂，如去甲肾上腺素和血清素。难治性抑郁症（对至少两种单胺再摄取抑制剂耐药）的发病率为10%-20%。电休克疗法以及添加锂、甲状腺激素或多巴胺激动剂用于治疗难治性抑郁症。安非他酮和单胺氧化酶抑制剂对难治性抑郁症也有效，但在日本未获批准。这些抗抑郁药的突触前作用机制已通过体内微透析研究进行了探讨。血清素再摄取抑制剂会增加大脑细胞外血清素的浓度。去甲肾上腺素再摄取抑制剂会增加大脑细胞外去甲肾上腺素的浓度，并增加额叶皮质细胞外多巴胺的浓度，但伏隔核或纹状体中的浓度不会增加。电休克疗法和单胺氧化酶抑制剂会增加大脑细胞外血清素的浓度，电休克疗法、安非他酮和单胺氧化酶抑制剂会增加大脑细胞外去甲肾上腺素的浓度。与单胺再摄取抑制剂不同，电休克疗法、安非他酮和单胺氧化酶抑制剂不仅会增加额叶皮质细胞外多巴胺的浓度，还会增加伏隔核和纹状体中的浓度。中脑边缘或黑质纹状体多巴胺神经传递的促进作用可能是这些治疗难治性抑郁症有效性背后的作用机制。尽管关于增效疗法作用机制的研究很少，但最近的研究表明，亚慢性锂治疗会增加额叶皮质和海马体中细胞外血清素的基础浓度。亚慢性锂进一步增加了血清素再摄取抑制剂诱导的细胞外血清素浓度的增加，这种作用被认为是锂增强抗抑郁药作用的机制。
