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 ct-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] ormazindol [n=2]) or serotonin reuptake inhibitors (fluoxetine hydrochloride [n=9] or sertraline hydrochloride [n=l]). Because of considerable sedation associated with α-methylparatyrosine testing, diphenhydramine was used as an active control rather than an inactive placebo. The effects of α-methylparatyrosine and diphenhydramine on depression, anxiety, and plasma catecholamine metabolites were assessed.
α-Methylparatyrosine produced similar significant decreases in plasma 3-methoxy-4-hydroxyphenyl-ethyleneglycol and homovanillic acid levels in the treatment groups. a-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.
Miller HL, Delgado PL, Salomon RM, Berman R, Krystal JH, Heninger GR, Charney DS. Clinical and Biochemical Effects of Catecholamine Depletion on Antidepressant-Induced Remission of Depression. Arch Gen Psychiatry. 1996;53(2):117-128. doi:10.1001/archpsyc.1996.01830020031005