Influence of reboxetine and mirtazapine on hypothalamic-pituitary-adrenocortical activity in depressed patients

Objective: It has been hypothesized that antidepressants may act via gradual normalization of hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity in depression. In healthy subjects, cortisol and ACTH secretions are acutely stimulated by reboxetine and inhibited by mirtazapine. However, it has not been investigated so far whether reboxetine and mirtazapine may also differ in their impact on HPA axis activity in depressed patients. Method: 40 drug-free patients suffering from major depression (DSM-IV criteria) were treated with either reboxetine (8mg/day; n=20) or mirtazapine (45mg/day; n=20) for 5 weeks. Before (week 0), after 1 week and after 5 weeks of therapy, the combined dexamethasone/CRH-test was performed. Results: Both drugs were comparable in their antidepressant efficacy (65% responders after 5 weeks, respectively). During reboxetine treatment, a gradual but non-significant reduction in HPA axis function was seen being the lowest after 5 weeks. In contrast, mirtazapine significantly downtuned HPA axis activity already within one week both in responders and non-responders; however, after 5 weeks of mirtazapine treatment the cortisol and ACTH secretions increased again. Conclusions: Our finding that the mirtazapine-induced rapid diminution of the cortisol and ACTH overshoot is not necessarily followed by a favourable clinical response challenge the hypothesis that reduction of HPA axis activity is a causally linked prerequisite for antidepressant efficacy.