The Flesinoxan 5-HT1A Receptor Challenge in Major Depression and Suicidal Behavior

Abstract

The prevailing neurochemical theory about biological correlates of suicidal behavior focuses on the serotonergic system. In this study, we assessed the cortisol, ACTH, GH, prolactin and temperature responses to flesinoxan, a5-HT1A agonist, in 30 DSM-III-R major depressed inpatients subgrouped into suicide attempters (n = 15) and nonattempters (n = 15). The patients were assessed after a drug-free period of at least 3 weeks. A subsample of 16 patients completed the Buss-Durkee Hostility Inventory as a measure of impulsive aggressive behavior. Mean delta cortisol responses to flesinoxan were significantly lower in the group of depressed patients with a history of suicide attempts than in the group without history of suicidal behavior: for the delta cortisol values 14.5 +/- 16.3 micrograms/l vs 101 +/- 94 micrograms/l (F = 8.9, df = 5.25, p = 0.006). There was also a very significant difference between suicide attempters and nonattempters for the temperature (delta T degrees) responses to flesinoxan: 0.20 +/- 0.24 degrees C vs. 0.60 +/- 0.24 degrees C (F = 18.1, df = 5.25, p = 0.0003). Hormonal and temperature responses to flesinoxan were not correlated with BDHI irritability or assault subscale scores. The results of the present study support the implication of the serotonergic system, particularly 5-HT1A receptors, in the control of self-directed aggressive behavior. Moreover, in depressed patients, serotonergic abnormalities do not appear to be related to aggressive behavior.

Serotonin and Dopamine as Mediators of Sensation Seeking Behavior

“…If we follow Coccarro's [47] line of reasoning that a constantly low serotonergic transmis sion may (a) lead to upregulation of postsynaptic and/or subsensitivity of presynaptic 5-HT|a receptors and (b) to a lowering of the threshold of sensitivity to aversive stimuli with the consequence of increased hypersensitivity and hyperirritability, then the increased cortisol responses to the 5-HThl agonist in subjects with high trait aggression and irritability could be plausibly related to their low 5-HT activity. The opposite would hold true for high ES subjects (high 5-HT transmission, subsensitive postsy naptic receptors, low cortisol response: this must not be mistaken for the blunted cortisol response observed in depressives [48][49][50], which is interpreted as a reduced responsivity of the HPA axis similar to nonsuppression of cortisol by the dexamethasone inhibition test in depressed patients).…”

Endocrine Responses after <i>d</i>-Fenfluramineand Ipsapirone Challenge: Further Support for Cloninger’s Tridimensional Model of Personality

“…This led to the development of (partial) 5-HT 1a agonists like flesinoxan, buspirone or ipsapirone (IPS). After treatment with flesinoxan, CORT as well as thermoregulatory responses were significantly different between depressed patients with a history of suicide as compared to those without suicidal behavior, whereas both responses were not correlated with measures of irritability or assault [38]. For buspirone it was shown that the responses of PRL and CORT were not different between major depressives and healthy controls or between melancholic and nonmelancholic patients.…”

“…In these, precursors [9,10], agonists [11] or releasers [12] were investigated with respect to changes in the concentrations of pituitary hormones: growth hormone, adrenocorticotropic hormone (ACTH), prolactin (PRL) or adrenocortical hormones like cortisol (CORT). The basic idea is that the amount of change in hormone concentrations reflects the reactivity of the neurotransmitter system which can be related to clinical states like depression [13][14][15][16][17][18][19][20], impulsive aggression [21][22][23], obsessive-compulsive disorders [24,25] and other psychiatric diseases.…”

HPA Axis Dysfunction in Major Depression: Relationship to 5-HT_1A Receptor Activity

“…Recently, we developed a serotonergic challenge test using flesinoxan [12]. We demonstrated that flesinoxan, which is a highly potent and selective 5-HT 1A agonist, induced a very significant and dose-dependent increase in anterior pituitary hormones (PRL, ACTH, cortisol, and growth hormone) and a decrease in oral temperature.…”