Pilot study of flesinoxan, a 5‐HT1A agonist, in major depression: Effects on sleep REM latency and body temperature

Abstract

Flesinoxan is a highly potent and selective 5-HTlA full agonist, active in several models of depression. In this pilot open study, flesinoxan (4 mdd) was administered orally for 4 weeks in 16 major depressive, mostly treatmentresistant inpatients exhibiting a score of at least 19 on the Hamilton depression sale. Weekly ratings included Hamilton depression scale, Montgomery and Asberg depression scale (MADRS), and Clinical Global Impressions (CGI). Results showed considerable improvement in depressive symptomatology, with mean MADRS scores (SD) dropping from 35.7 (10.0) to 13.0 (11.9) and CGI-illness severity from 5.69 (1.14) to 2.73 (1.62) after 4 weeks of treatment. Moreover, 13 patients were classified as much or very much improved on the CGI-global improvement. The tolerance of flesinoxan was excellent, with only four patients exhibiting side-effects. In contrast to acute studies with 5HTlA agonists, flesinoxan induced no significant decrease in daily oral temperature over the Cweek period.In eight melancholic patients, the mean REM latency (SD) of respectively 35.6 (15.9) and 40.2 (17.9) min during two baseline nights significantly increased to 51-9 (20-9) min during a double-blind challenge night with flesinoxan 1 mg as compared to 42.0 (16.1) min with placebo, and to respectively 55.6 (29.9) and 55.6 (30.2) min during the last two treatment nights. All these findings encourage further developments of flesinoxan as a promising antidepressant.woms-Flesinoxan, 5-HTl A agonists, antidepressant, major depression, REM latency, body temperature.

Serotonin1A Receptor Activation by Flesinoxan in Humans Body Temperature and Neuroendocrine Responses

“…The potential antldepressant propertlcs of flesinoxan have been assessed in several animal models of depression (van Hest et al 1992). ln h umans with anxiety disorders or wlth major depression, flesinoxan showed therapeutic effects (Graf et al 1993;Ansseau et al 1993;Bradford, 1992). …”

Towards a Functional Understanding of PGO Waves

“…Given the anticipated role that 5-HT receptor subtypes play in the expression of psychopathological illness, such as body dysmorphic disorders and unipolar depression (Celada et al, 2004; Bailer et al, 2007), the role these receptors also play in REM sleep (Ansseau et al, 1993; Landolt and Wehrle, 2009), and the growing consensus that features of agency and self-reflection characterized in psychopathology depend on network level changes similarly produced REM sleep (Lysaker et al, 2011; Filevich et al, 2015), there is considerable clinical potential in further understanding the mechanisms that underpin PGO waves. Indeed, PGO wave research may eventually provide an important link in explaining how the systems that allow internally generated imagery to unconsciously modulate and override retinal visual input synchronize in healthy perception, and subsequently break down in psychopathology.…”