Abstract

In rodents, 5-HT7 receptor blockade has been shown to be effective in models of depression and to increase the latency to 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 selective 5-HT7 receptor antagonist, 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-HT7 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 drug-drug 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 citalopram separated from placebo indicating a failed study lacking assay sensitivity. A post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response and from sites with no placebo response are removed, there was a clinically meaningful and statistically significant difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.