Abstract
Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS17). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.
Highlights
Introduction In2010 major depressive disorder (MDD) accounted for8.2 percent of the global years lived with disability and 2.5 percent of the global disability-adjusted life years, thereby identifying MDD as a leading cause of the global burden of disease[1]
That arousal-related sleep disturbances contributed to depression in our patient population is suggested by the significant correlation between sleep efficiency, time spent in stage 2 sleep, and wake after sleep onset with the total HDRS17 score and the HDRS score with sleep items subtracted measured at baseline
Baseline total sleep time (TST) and latency to persistent sleep (LPS) measures correlated with the effect of seltorexant on these parameters suggesting that insomnia symptoms improved in subjects who entered the study with sleep disturbance
Summary
Introduction In2010 major depressive disorder (MDD) accounted for8.2 percent of the global years lived with disability and 2.5 percent of the global disability-adjusted life years, thereby identifying MDD as a leading cause of the global burden of disease[1]. Certain MDD subpopulations demonstrate sustained negative affect This hyperarousal that characterizes patients with MDD contributes to difficulties with falling asleep, staying asleep, and early morning awakening and may reflect a reduced ability to downregulate brain activity in limbic structures such as the amygdala during the sleep period[8]. This state of hyperarousal has been implicated mechanistically with hypothalamic–pituitary–adrenal (HPA)-axis hyperactivation[9,10,11], and is supported by chronically elevated central nervous system (CNS) activation[12,13] and, in Recourt et al Translational Psychiatry (2019) 9:216 certain MDD subtypes, sustained sympathetic nervous system activity[14]. The neuropeptide orexin (OX) regulates arousal and wakefulness by modulating two distinct G-
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