Miller H L, Delgado P L, Salomon R M, Berman R, Krystal J H, Heninger G R, Charney D S
Department of Psychiatry, Yale University School of Medicine, New Haven, Conn, USA.
Arch Gen Psychiatry. 1996 Feb;53(2):117-28. doi: 10.1001/archpsyc.1996.01830020031005.
Most hypotheses of the therapeutic mechanism of action of antidepressant drugs have focused on the role of the monoamines. We examined the effect of catecholamine depletion on antidepressant-induced remission.
The tyrosine hydroxylase inhibitor alpha-methylparatyrosine and the antihistamine diphenhydramine hydrochloride were administered, during separate test sessions, to depressed patients in remission maintained with either norepinephrine reuptake inhibitors (desipramine [n = 7] or mazindol [n = 2]) or serotonin reuptake inhibitors (fluoxetine hydrochloride [n = 9] or sertraline hydrochloride [n = 1]). Because of considerable sedation associated with alpha-methylparatyrosine testing, diphenhydramine was used as an active control rather than an inactive placebo. The effects of alpha-methylparatyrosine and diphenhydramine on depression, anxiety, and plasma catecholamine metabolites were assessed.
alpha-Methylparatyrosine produced similar significant decreases in plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels in the treatment groups. alpha-Methylparatyrosine produced a robust increase in depressive symptoms on the Hamilton Depression Rating Scale, including depressed mood, decreased concentration, anhedonia, loss of interest, and feelings of worthlessness, helplessness, and hopelessness, in the desipramine-mazindol but not in the fluoxetine-sertraline group. Diphenhydramine had no effects on mood in either treatment group.
The therapeutic effects of norepinephrine reuptake inhibitors, but not serotonin reuptake inhibitors, are reversed by catecholamine depletion. Considered with previous reports that serotonin depletion produces depressive relapses in patients in remission maintained with serotonin reuptake inhibitors, but not norepinephrine reuptake inhibitors, these findings suggest that antidepressants may not work via a single monoamine-related mechanism.
大多数关于抗抑郁药物治疗作用机制的假说都集中在单胺的作用上。我们研究了儿茶酚胺耗竭对抗抑郁药诱导缓解的影响。
在单独的测试阶段，将酪氨酸羟化酶抑制剂α-甲基对酪氨酸和抗组胺药盐酸苯海拉明分别给予用去甲肾上腺素再摄取抑制剂（地昔帕明[n = 7]或马吲哚[n = 2]）或5-羟色胺再摄取抑制剂（盐酸氟西汀[n = 9]或盐酸舍曲林[n = 1]）维持缓解的抑郁症患者。由于与α-甲基对酪氨酸测试相关的显著镇静作用，使用苯海拉明作为活性对照而非无活性安慰剂。评估了α-甲基对酪氨酸和苯海拉明对抑郁、焦虑和血浆儿茶酚胺代谢产物的影响。
α-甲基对酪氨酸在各治疗组中使血浆3-甲氧基-4-羟基苯乙二醇和高香草酸水平出现类似的显著下降。在去甲肾上腺素再摄取抑制剂（地昔帕明-马吲哚）组而非5-羟色胺再摄取抑制剂（氟西汀-舍曲林）组中，α-甲基对酪氨酸使汉密尔顿抑郁量表上的抑郁症状显著增加，包括情绪低落、注意力下降、快感缺失、兴趣丧失以及无价值感、无助感和绝望感。苯海拉明在两个治疗组中均对情绪无影响。
儿茶酚胺耗竭可逆转去甲肾上腺素再摄取抑制剂的治疗效果，但不能逆转5-羟色胺再摄取抑制剂的治疗效果。结合先前的报道，即5-羟色胺耗竭会使使用5-羟色胺再摄取抑制剂维持缓解的患者出现抑郁复发，但使用去甲肾上腺素再摄取抑制剂维持缓解的患者不会出现这种情况，这些发现表明抗抑郁药可能并非通过单一的单胺相关机制起作用。
