Serotonin hypothesis of winter depression: behavioral and neuroendocrine effects of the 5-HT 1A receptor partial agonist ipsapirone in patients with seasonal affective disorder and healthy control subjects

Abstract

Winter depressions in seasonal affective disorder (SAD) are associated with central serotonergic (5-HT) dysfunction. SAD patients demonstrate rather specific, state-dependent, abnormal increases in `activation-euphoria' ratings following intravenous infusion of the 5-HT receptor agonist meta-chlorophenylpiperazine ( m-CPP). Several studies are also consistent with abnormal serotonergic regulation of the hypothalamic–pituitary–adrenal (HPA) axis in SAD. Here, we investigated the effects of the 5-HT 1A receptor partial agonist ipsapirone, which produces behavioral effects and HPA-axis activation, to further characterize the 5-HT receptor subtype-specificity of these disturbances in SAD. Eighteen SAD patients and 18 control subjects completed two drug challenges (ipsapirone 0.3 mg/kg and placebo) separated by 3–5 days in randomized order. We measured behavioral responses with the NIMH self-rating scale, and plasma ACTH, cortisol, and prolactin concentrations. Compared with placebo, ipsapirone was associated with significant increases in self-rated `functional deficit' and `altered self-reality', and in each of the hormones. There were no differences between groups on any measures. The level of depression in SAD patients was inversely correlated with their ipsapirone-induced cortisol responses. There were significant drug×order effects on baseline `anxiety' scores, ACTH and cortisol concentrations, such that subjects were significantly more stressed (higher `anxiety', ACTH and cortisol) prior to their first challenge compared with their second. In conclusion, post-synaptic 5-HT 1A receptors appear to function normally in SAD. The previously observed m-CPP-induced behavioral abnormality may be mediated by either 5-HT 2C or 5-HT 7 receptors.