The relationship between the effects of metyrapone treatment on depressed mood and urinary steroid profiles.
In order to investigate mechanisms by which the adrenal 11 beta-hydroxylase inhibitor metyrapone might exert its antidepressant effect, we used gas chromatography to analyse the 24 h urinary steroid profiles from six females with major depression taking part in a trial of metyrapone (2-4 g/day) as an antidepressant. Due to concurrent administration of hydrocortisone (30 mg/day), plasma cortisol levels were not significantly reduced. Treatment with metyrapone resulted in greatly increased urinary excretion of 11-deoxy corticosteroids, including the GABA-modulatory steroid tetrahydro-11-deoxycorticosterone (from 68 +/- 34 to 219 +/- 75 micrograms/24 h, p < .05). Metyrapone also had multiple extra-adrenal effects on corticosteroid metabolism, including inhibition of the peripheral conversion of cortisone to cortisol as demonstrated by a significant decrease in the ratio of 11 beta-hydroxy/11-oxo metabolites of cortisol (from 0.81 +/- 0.08 to 0.46 +/- 0.04, p < .01). The decreased Montgomery-Asberg Depression Rating Scale scores seen during treatment with metyrapone did not correlate with changes in plasma cortisol, but did correlate significantly with total 11-deoxycortisol metabolites (r = 0.778, n = 12, p < .01). We conclude that, in addition to decreased cortisol synthesis, increased secretion of cortisol precursors and reduced local bioavailability of cortisol may play a role in the antidepressant effect of metyrapone.
Raven
P W
PW
Department of Psychiatry, Institute of Psychiatry, London, UK.
O'Dwyer
A M
AM
Taylor
N F
NF
Checkley
S A
SA
D000328:Adult; D000339:Affect / Q000187:drug effects* / Q000502:physiology*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000523:psychology / Q000652:urine; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D008797:Metyrapone / Q000627:therapeutic use*; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D013256:Steroids / Q000652:urine*
D000928:Antidepressive Agents; D013256:Steroids; D006854:Hydrocortisone; D008797:Metyrapone