Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression

Arch Gen Psychiatry. 1996 Feb;53(2):117-28. doi: 10.1001/archpsyc.1996.01830020031005.


Background: 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.

Method: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Naphthylamine / analogs & derivatives
  • 1-Naphthylamine / pharmacology
  • 1-Naphthylamine / therapeutic use
  • Adrenergic Uptake Inhibitors / pharmacology
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Brain / metabolism*
  • Brain Chemistry / drug effects*
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / metabolism
  • Desipramine / pharmacology
  • Desipramine / therapeutic use
  • Diphenhydramine / pharmacology
  • Dopamine / chemistry*
  • Dopamine / metabolism
  • Fluoxetine / pharmacology
  • Fluoxetine / therapeutic use
  • Humans
  • Mazindol / pharmacology
  • Mazindol / therapeutic use
  • Methyltyrosines / pharmacology
  • Norepinephrine / chemistry*
  • Norepinephrine / metabolism
  • Psychiatric Status Rating Scales
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Sertraline


  • Adrenergic Uptake Inhibitors
  • Antidepressive Agents
  • Methyltyrosines
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Diphenhydramine
  • 1-Naphthylamine
  • Mazindol
  • Sertraline
  • Desipramine
  • Dopamine
  • Norepinephrine