Translational Evaluation of JNJ-18038683, a 5-Hydroxytryptamine Type 7 Receptor Antagonist, on Rapid Eye Movement Sleep and in Major Depressive Disorder

Abstract

In rodents 5-hydroxytryptamine type 7 (5-HT 7 ) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT 7 receptor antagonist, (3-(4-chlorophenyl)-1, 4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo [3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT 7 blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drugdrug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS) Ͻ ϭ 12] and from sites with no placebo response (MADRS Ͼ ϭ 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.

Lurasidone Suppresses Rapid Eye Movement Sleep and Improves Sleep Quality in Rats

“…Indeed, Monti et al reported that administration of buspirone or ipsapirone, both of which are 5-HT 1A receptor partial agonists, suppresses REM in rats. In addition, the 5-HT 7 receptor antagonists, SB-269970 and JNJ-18038683, have been reported to exhibit REM-suppressive and antidepressant-like effects in animals and humans (12,14,15). Consistent with these findings, our unpublished data show that tandospirone, a 5-HT 1A receptor partial agonist, and SB-258741, a 5-HT 7 receptor antagonist, suppress REM sleep (data not shown).…”

“…It has been reported that REM sleep increases in the depressive state and that antidepressants ameliorate REM sleep concomitant with depressive symptoms. As some antidepressants also suppress REM sleep even in healthy subjects and naïve animals, it is believed that REM suppression may be a useful biomarker for antidepressant effect (9,10,12). Indeed, paroxetine at a dose of 10 mg/kg significantly decreased REM sleep duration and prolonged REM sleep latency under the current experimental conditions (data not shown).…”

In the search for a lead structure among series of potent and selective hydantoin 5‐HT7R agents: The drug‐likeness in vitro study

“…[3] Moreover, experiments that involved 5-HT 7 R knockout mice led to observation, that its blockade may reduce immobility effect of animals in forced swim test (FST), making searching for 5-HT 7 R antagonists a promising direction for future depression treatment. [7] Compound SB-269970A (2, Figure 1), another promising and one of the most active and selective 5-HT 7 R antagonists, used very often as a pharmacological tool for 5-HT 7 receptor examination, has been also rejected from further in vivo studies, because of extremely high blood clearance and short in vivo half-life (t 1/2 < 0.5 h). Unfortunately, this double-blind, active, and placebo-controlled clinical trial in patients with depression has failed.…”

The sleep effects of lurasidone: a placebo‐controlled cross‐over study using a 4‐h phase‐advance model of transient insomnia

“…It is the only such agent that has 5‐HT 7 antagonism as its most potent effect. As such, this study offers the only opportunity to evaluate the sleep effects of 5‐HT 7 antagonism other than the prior study of the effects of a selective 5‐HT 7 antagonist on REM sleep in undisturbed healthy volunteers (Bonaventure et al ., ). We found that 5‐HT 7 antagonism does not affect REM or slow‐wave sleep, at least in the phase advance paradigm, and appears to have a potent effect on sleep maintenance without improving sleep onset.…”

“…We found that 5‐HT 7 antagonism does not affect REM or slow‐wave sleep, at least in the phase advance paradigm, and appears to have a potent effect on sleep maintenance without improving sleep onset. The finding of an absence of an effect on REM differs from what was reported with the previously studied selective 5‐HT 7 antagonist (Bonaventure et al ., ). However, it should be noted that in the prior study the dosage was selected so as to be equivalent to a dosage that suppressed REM sleep in animals.…”