Specific norepinephrine and serotonin uptake inhibitors in man: a crossover study with pharmacokinetic, biochemical, neuroendocrine and behavioral parameters

Eight depressed patients with major affective illness were treated with both zimelidine, a selective serotonin-uptake inhibitor, and with desipramine, a selective norepinephrine uptake inhibitor, following a double-blind crossover design. At steady-state the active metabolite of zimelidine, norzimelidine, predominated in the CSF by a factor of 7 to 1 over parent drug. As predicted, even high concentrations of norzimelidine were not associated with decreased 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the CSF. In the same individuals, desipramine concentrations were highly correlated with decreases of MHPG in the CSF. Despite specific effects on monoamine neurotransmitter systems which have been implicated in the control of neuroendocrine secretion, neither drug had consistent effects on plasma cortisol, luteinizing hormone, growth hormone or prolactin. Both drugs had a marked and unexpected common effect on the 24-hour rest-activity cycle. The excess activity during the normal rest period (0--700 hr.) which has been noted in severely depressed individuals was significantly reduced by both the serotonergic zimelidine and the noradrenergic desipramine. These findings suggest that effects on the rest-activity pattern may be a common pathway for antidepressant effect.