Unlike other
antidepressants,
mirtazapine does not inhibit the reuptake of
norepinephrine or
serotonin but acts as an antagonist at presynaptic alpha(2)-receptors, at postsynaptic 5-HT2 and 5-HT3 receptors, and at histaminergic
H1 receptors. Furthermore,
mirtazapine has been shown to acutely inhibit
cortisol secretion in healthy subjects. In the present study, the impact of
mirtazapine treatment on salivary
cortisol secretion was investigated in 12 patients (4 men, 8 women) suffering from major depression according to DSM-IV criteria. Patients were treated with
mirtazapine for 3 weeks, receiving 15 mg
mirtazapine on day 0, 30 mg on day 1 and 45 mg per day from day 2 up to the end of the study (day 21). Response to
mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of
therapy. Salivary
cortisol concentrations were measured before treatment (day -1), at the beginning of treatment (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with
mirtazapine. Saliva samples were collected hourly from 08.00 until 20.00 h. The area under the curve values served as parameter for the salivary
cortisol secretion. Following analysis of variance with a repeated measures design, tests with contrasts revealed a significant reduction of
cortisol concentrations already after 1 day of
mirtazapine treatment that was comparable in responders and nonresponders. In addition to new pharmacological approaches such as
CRH1 receptor antagonists,
mirtazapine therefore appears to be an effective strategy to decrease
hypercortisolism and restore HPA system dysregulation in depression. However, the importance of the acute inhibitory effects of
mirtazapine on
cortisol secretion for its
antidepressant efficacy has to be further clarified.