BLUNTED 5-HTLA-RECEPTOR AGONIST-INDUCED CORTICOTROPIN AND CORTISOL RESPONSES AFTER LONG-TERM IPSAPIRONE AND FLUOXETINE ADMINISTRATION TO HEALTHY-SUBJECTS

Objectives: To assess whether acute 5-hydroxytryptamine-1A (5-HT1A)-re ceptor-mediated corticotropin, cortisol, and temperature responses are maintained after 3 weeks of treatment with controlled-release (CR) ip sapirone and fluoxetine compared with placebo and whether changes are reversible after cessation of treatment. Methods: This was a randomize d parallel-group study. Ten healthy subjects received ipsapirone CR or fluoxetine, and eight received placebo in a double-blind manner. An. ipsapirone challenge test with 20 mg ipsapirone immediate-release form ulation (IR) was pet-formed before treatment (day 0) and after 20 days of treatment with placebo, SO mg/day ipsapirone CR, or 20 mg/day fluo xetine (day 21). From day 22 to day 34 all subjects received placebo i n a simple-blind manner. A third ipsapirone challenge test was perform ed on day 35. Results.-Before treatment, resting plasma corticotropin and cortisol concentrations and increases ha plasma corticotropin and cortisol concentrations after challenge with 20 mg ipsapirone IR were similar for the three groups. After 20 days of treatment, plasma corti cotropin and cortisol concentrations were similar before challenge, bu t ipsapirone IR-induced increases in plasma corticotropin and cortisol concentrations were significantly lower in both the ipsapirone CR gro up (corticotropin, 6.5 +/- 2 pg/ml; cortisol, 1.5 +/- 0.7 mu g/dl) and the fluoxetine group (corticotropin, 4.4 +/- 2 pg/ml; cortisol, 1.5 /- 0.7 mu g/dl) compared with placebo (corticotropin, 34 +/- 14 pg/ml; cortisol, 5.8 +/- 2 mu g/dl, mean i SEM). After 2 weeks of placebo ad ministration, plasma corticotropin and cortisol responses to ipsapiron e IR again became identical in all three groups. Plasma ipsapirone con centrations were similar in all groups during each challenge. The hypo thermic response to ipsapirone IR showed no difference before treatmen t, at the end of the treatment period, or 2 weeks after cessation of t reatment. Long-term administration of antidepressants to the healthy s ubjects did not lead to any serious adverse effects. Conclusions: Long -term administration of fluoxetine and ipsapirone did not influence re sting plasma corticotropin and cortisol concentrations in the morning, Stimulation of corticotropin and cortisol release by a selective 5-HT 1A-agonist is reduced with long-term administration of these serotonin ergic antidepressants. This subsensitivity of postsynaptic 5-HT1A-rece ptors is reversible.