BIOL PSYCHIATRY 1990;28:73-78
73
Cortisol and Growth Hormone Responses to the 5-HT1A Agonist Gepirone in Depressed Patients Jeffrey L. Rausch, Stephen M. Stahl, and Richard L. Hauger
The 5-HTIA agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 rain after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Sert,tm cortisol levels were significantly higher 90 rain after gepirone compared to placebo (p < 0.05). Baseline Hamilton depression rating~ were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p < 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p < 0.02) ~tten~ated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may corre~aw with depression severity. Furthermore, a desensitization to gepirone' s effects on cortisol may occur after chronic gepirone administration.
Introduction Gepirone is a buspirone analogue which, unlike buspirone, has less affinity for dopamine receptors (McMillen et al. 1987), Within the known subtypes of serotonin receptors, gepirone has selective affinity for the 5-HT1A subtype, binding to central 5-HTIA receptors with nanon,,olar affinities (Hamon et al. 1986; Traber and Glaser 1987). 5-HTIA receptors are implicated in the actions of antidepressant treatment (Green 1988). In rodents, there is evidence that certain 5-HT1A receptors may desensitize after different antidepressants (Goodwin et al. 1986; Green 1987; Goodwin et al. 1987; Sleight et al. i988; Mizuta and Segawa 1988), or electroconvulsive shock (Goodwin et al. 1987; Green 1987; Mizuta and Segawa 1988). Also, chronic adraiaistration of 5-HT1A agonists may decrease some 5oHT1A receptor-medi,~ted responses (De Souza et al. 1986; Blier and de Montigny 1987). Some aspects of aypotl,,alamic pituitary axis activity may be mediated by 5-HTIA receptors. In rats, increases in adrenocorticotropic hormone (ACTH) and corticosterone are found after administration of 5-HT1A ligands, and these increases can be stereoselectively blocked by 5-HT1A antagonism (Gilbert et al. 1988; Koenig et al. 1988). In
From the Department of Psychiatry M-003, San Diego VAMC, School of Medicine, University of California at San Diego, La Jolla, CA. Address reprint requests to Dr. Rausch, Department of Psych:arty, M-003, San Diego VAMC, School of Medicine, University of California at San Diego, La Jolla, CA 92093. This work was supported by the Veterans Administration. I~"tl/NIMH 5 R29 MH43388-02, arA a grant from Bristol.Myers Company. Received July I l, i989; revised October 27, 1989. This article is in the Public Domain.
0006-3223/90/$00.00
74
BIOL PSYCHIATRY 1990;28:73-78
J.L. Rausch et al.
the present study, we examined whether (1) gepirone might increase cortisol levels in depressed patients compared to placebo; (2) such increase~ might be related to symptom severity, and (3) the cortisol levels after gepirone challenge would decrease after chronic administration of the drug.
Methods
Subjects The study was conducted in 14 consenting outpatients (11 men, 3 women) aged 35-64, meeting DSM-III criteria for major depressive disorder, with 24-item Hamilton Depression Rating scores (HDRS) of ~>20. Subjects were excluded for organic brain syndrome, primary diagnoses other than depression, history of mania, other significant medical illness, or substance use disorder duri,g the last year, or for use of antipsychet.,.'cs, antidepressants, anxiolytics, or sedativeti~ypnotics other than chloral hydrate for a period of 14 days prior to the study.
Design The study was initiated during an ongoing trial of gepirone in the treatment of depression. All subjects received a single-blind, placebo lead-in during the first week of one placebo capsule bid, followed by identical capsules containing active drug for 6 weeks. All subjects were kept blind to the design of the study, with the understanding that on any given week, they would be receiving either active drug or placebo. The daily divided doses of gepirone were titrated to 10-20 mg during the first week, and 30-70 mg daily during weeks 2-6 in an attempt to achieve an antidepressant response. Each week, an oral endocrine challenge was done to assess hormone levels 90 min postcaailenge beginning with placebo challenge the first week. To control for time of days a'd subiects were studied between 8 AM and 2 PM, and the time of day was kept constant within subjects by ~
73
Cortisol and Growth Hormone Responses to the 5-HT1A Agonist Gepirone in Depressed Patients Jeffrey L. Rausch, Stephen M. Stahl, and Richard L. Hauger
The 5-HTIA agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 rain after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Sert,tm cortisol levels were significantly higher 90 rain after gepirone compared to placebo (p < 0.05). Baseline Hamilton depression rating~ were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p < 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p < 0.02) ~tten~ated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may corre~aw with depression severity. Furthermore, a desensitization to gepirone' s effects on cortisol may occur after chronic gepirone administration.
Introduction Gepirone is a buspirone analogue which, unlike buspirone, has less affinity for dopamine receptors (McMillen et al. 1987), Within the known subtypes of serotonin receptors, gepirone has selective affinity for the 5-HT1A subtype, binding to central 5-HTIA receptors with nanon,,olar affinities (Hamon et al. 1986; Traber and Glaser 1987). 5-HTIA receptors are implicated in the actions of antidepressant treatment (Green 1988). In rodents, there is evidence that certain 5-HT1A receptors may desensitize after different antidepressants (Goodwin et al. 1986; Green 1987; Goodwin et al. 1987; Sleight et al. i988; Mizuta and Segawa 1988), or electroconvulsive shock (Goodwin et al. 1987; Green 1987; Mizuta and Segawa 1988). Also, chronic adraiaistration of 5-HT1A agonists may decrease some 5oHT1A receptor-medi,~ted responses (De Souza et al. 1986; Blier and de Montigny 1987). Some aspects of aypotl,,alamic pituitary axis activity may be mediated by 5-HTIA receptors. In rats, increases in adrenocorticotropic hormone (ACTH) and corticosterone are found after administration of 5-HT1A ligands, and these increases can be stereoselectively blocked by 5-HT1A antagonism (Gilbert et al. 1988; Koenig et al. 1988). In
From the Department of Psychiatry M-003, San Diego VAMC, School of Medicine, University of California at San Diego, La Jolla, CA. Address reprint requests to Dr. Rausch, Department of Psych:arty, M-003, San Diego VAMC, School of Medicine, University of California at San Diego, La Jolla, CA 92093. This work was supported by the Veterans Administration. I~"tl/NIMH 5 R29 MH43388-02, arA a grant from Bristol.Myers Company. Received July I l, i989; revised October 27, 1989. This article is in the Public Domain.
0006-3223/90/$00.00
74
BIOL PSYCHIATRY 1990;28:73-78
J.L. Rausch et al.
the present study, we examined whether (1) gepirone might increase cortisol levels in depressed patients compared to placebo; (2) such increase~ might be related to symptom severity, and (3) the cortisol levels after gepirone challenge would decrease after chronic administration of the drug.
Methods
Subjects The study was conducted in 14 consenting outpatients (11 men, 3 women) aged 35-64, meeting DSM-III criteria for major depressive disorder, with 24-item Hamilton Depression Rating scores (HDRS) of ~>20. Subjects were excluded for organic brain syndrome, primary diagnoses other than depression, history of mania, other significant medical illness, or substance use disorder duri,g the last year, or for use of antipsychet.,.'cs, antidepressants, anxiolytics, or sedativeti~ypnotics other than chloral hydrate for a period of 14 days prior to the study.
Design The study was initiated during an ongoing trial of gepirone in the treatment of depression. All subjects received a single-blind, placebo lead-in during the first week of one placebo capsule bid, followed by identical capsules containing active drug for 6 weeks. All subjects were kept blind to the design of the study, with the understanding that on any given week, they would be receiving either active drug or placebo. The daily divided doses of gepirone were titrated to 10-20 mg during the first week, and 30-70 mg daily during weeks 2-6 in an attempt to achieve an antidepressant response. Each week, an oral endocrine challenge was done to assess hormone levels 90 min postcaailenge beginning with placebo challenge the first week. To control for time of days a'd subiects were studied between 8 AM and 2 PM, and the time of day was kept constant within subjects by ~
