Effects of Antiglucocorticoid Treatment on 5-HT1A Function in Depressed Patients and Healthy Subjects

Abstract

Clinical studies suggest that 5-HT1A receptor function may be blunted in depression, while 5-HT1A agonists may possess antidepressant activity. Preclinical findings implicate changes in 5-HT1A receptor sensitivity in the mechanism of antidepressant action. The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression could be related to those observations, since 5-HT1A receptors are inhibited by glucocorticoids. To evaluate the interaction of the HPA and 5-HT1A systems, we pretreated 15 unipolar depressed patients and 12 healthy control subjects with the antiglucocorticoid ketoconazole (KTCZ) prior to administration of a test dose of the 5-HT1A agonist ipsapirone (IPS). Neuroendocrine (ACTH, cortisol, growth hormone), physiological (hypothermia), and behavioral responses to IPS were assessed. As expected, KTCZ inhibited cortisol biosynthesis, but non-HPA responses to IPS were not enhanced. This study failed to show that glucocorticoid modulation of 5-HT1A receptor function is altered in depression.

An increased hypothermic response to buspirone in patients with major depression

“…This finding with buspirone challenge was not reported before in depressed patients. However, it is in agreement with a previous challenge study with ipsapirone (Price et al 1997) and in contrast with others with ipsapirone (Lesch et al 1990a;Meltzer and Maes 1995;Shin Shiah et al 1998;Shapira et al 2000) and buspirone (Cowen et al 1994), which showed a decreased hypothermic response (Lesch et al 1990a;Cowen et al 1994;Shapira et al 2000) or no differences (Meltzer and Maes 1995;Shin Shah et al 1998). Multiple confounder factors could explain the differences among studies.…”

“…Second, in studies in which a reduced or no differences in the hypothermic response were observed, the samples were mostly formed by inpatients or melancholic patients (Shin Shiah et al 1998;Shapira et al 2000). Similar to the study of Price et al (1997), most of our patients were of the nonmelancholic subtype. Third, it was suggested that the attenuated hypothermic response to 5-HT 1A receptor agonists in depressed patients is an adaptive response to cortisol hypersecretion (Cowen et al 1994).…”

Cortisol, Hypothermic, and Behavioral Responses to Ipsapirone in Patients with Bipolar Depression and Normal Controls

“…Evidence in support of this hypothesis comes from the fact that previous positive studies have in general involved inpatients or melancholic patients [9][10][11][12]25] while negative studies have comprised outpatients or nonmelancholic patients (table 2) [14,15]. This was further supported by the observation that there was a significant positive correlation between the HAMD scores and the hypothermic response to ipsapirone but not with other variables such as age, sex, BMI, dose of ipsapirone, Shiah/Yatham/Lam/Tam/Zis and medication, etc.…”

“…Furthermore, a subsensitivity of postsynaptic 5-HT 1A receptors in depression has also been suggested by the studies that showed a reduction in prolactin response to buspirone [11], and a reduction in cortisol response to ipsapirone [12,13] in patients with major depression compared to normal controls. Some other investigators, however, were unable to find such a significant reduction in the hypothermic [14] or hormonal responses [9,14,15] to 5-HT 1A receptor agonists in patients with major depression compared to normal controls.…”

Adult brain neurogenesis and psychiatry: a novel theory of depression

“…Nonetheless, there is evidence that 5-HT 1A partial agonists have anxiolytic properties (anxiety is often considered an important antecedent to depression) and some antidepressant efficacy. 62,63 Unfortunately, there has been little direct examination of altered brain 5-HT 1A function in depressed patients. One study reported a decreased number of 5-HT 1 binding sites in the hippocampus of depressed suicide victims, but specific 5-HT 1A binding in the hippocampus was not examined.…”