Seltorexant

Seltorexant came out of a Janssen medicinal-chemistry program and has been developed with Minerva Neurosciences [1]. It was first tested as an insomnia drug [5] and is now being developed as an add-on to antidepressants for major depression with insomnia symptoms [1]. As of June 2026 it had no marketing authorization anywhere [1].

Depression, early trials. In 47 people with depression, 20 mg at bedtime for 10 days lowered depression scores more than placebo (adjusted Hamilton score difference −2.2), the effect lasted to 28 days, and the sedating antihistamine diphenhydramine did not help, which argues against simple sedation as the explanation [6]. In a monotherapy trial, after a placebo lead-in, Hamilton scores fell 7.0 points on 20 mg, 5.5 on 40 mg and 4.4 on placebo; only 20 mg beat placebo, the effect was larger with worse baseline insomnia, and it stayed significant with the sleep items removed [7].

Add-on treatment. In a phase 2b adaptive trial in 287 people who had not responded adequately to 1–3 SSRIs or SNRIs, 20 mg added to their antidepressant lowered MADRS scores by 4.5 points more than placebo at week 3 and 3.1 points at week 6 (P = .083, judged against prespecified 90% confidence intervals); in people with an Insomnia Severity Index of 15 or more the week-6 difference was 4.9 points, against 0.7 in those with milder insomnia [3]. Response rates were 41.0% on 20 mg against 28.5% on placebo, and 40 mg was dropped at the interim analysis [3]. In the phase 3 trial MDD3001, 586 adults were randomized to 20 mg or placebo added to their antidepressant, about 70% with moderate-to-severe insomnia; MADRS scores improved 2.6 points more on seltorexant (P = .007), 2.0 points with the sleep item removed, and sleep disturbance scores 3.7 points more [4]. Those results were reported in press releases and posters rather than a full peer-reviewed paper [1][4]. A second phase 3 trial against quetiapine extended release over 26 weeks was reported at meetings as missing its primary endpoint of response rate, and a third, with a maintenance design, was due to finish in late 2026 [1].

Against quetiapine. In an exploratory 24-week trial in 107 people, time to stopping treatment for any reason did not differ between seltorexant and quetiapine extended release (41.2% against 47.1% stopped), MADRS scores improved numerically more in people mostly taking 20 mg, and adverse events were less common (65.4% against 80.8%) [8].

Pooled evidence. A 2026 meta-analysis of add-on orexin antagonists in depression found small improvements in MADRS scores (mean difference −1.96) and in sleep disturbance (PROMIS mean difference −3.39), with no clear excess of adverse events [9]. A 2026 review summarizing a separate meta-analysis attributes the class signal almost entirely to seltorexant 20 mg (standardized mean difference −0.36), with 40 mg and the non-selective antagonists showing no antidepressant effect [1]. A 2025 systematic review likewise found larger antidepressant effects in people with severe sleep disturbance and called for phase 3 confirmation [10].

Insomnia. In 27 people with insomnia, 40 mg for 5 nights raised sleep efficiency by 6–8 points and total sleep by 28–38 minutes and shortened sleep onset by 19–30 minutes against placebo [5]. In 364 adults with insomnia and no psychiatric illness, 10 and 20 mg shortened the time to persistent sleep on the first night by 36% and 49% against placebo, 20 mg beat zolpidem on this measure, and the gains held at night 13; the trial ran in 2017–2019 but was published in 2025 because of internal strategic decisions [11]. The 2022 Lancet network meta-analysis counted seltorexant among drugs that improved sleep quality and were well tolerated, but with too little data for firm conclusions [12].

Why orexin-2. Orexin neurons in the lateral hypothalamus drive wakefulness, and their loss causes narcolepsy [13][14]. The two receptors are spread differently: OX2 predominates in the histamine neurons of the tuberomammillary nucleus and in the hypothalamic paraventricular nucleus that drives the stress hormone axis, whereas OX1 is more prominent in the locus coeruleus [1]. Seltorexant blocks OX2 with about 100-fold selectivity over OX1 [1][2], a profile proposed to promote sleep while preserving normal sleep architecture [2].

In animals. Given to rats by mouth in the light phase, 3–30 mg/kg shortened the time to non-REM sleep and lengthened non-REM sleep in the first 2 hours with little effect on REM sleep; the effect held over 7 days of dosing and sleep returned to baseline after stopping [2]. It did not promote sleep in mice lacking the OX2 receptor, and it neither raised dopamine in the nucleus accumbens nor produced conditioned place preference, unlike zolpidem [2].

Depression and arousal. The rationale for depression is that excess arousal, linked to activation of the stress hormone axis, contributes to depressive symptoms and insomnia [6]. OX2 blockade blunted stress-induced ACTH release in rodents, and the daily rhythm of orexin-A in spinal fluid is flattened in depressed patients [1]. In depressed patients, 20 mg increased delta and reduced faster EEG activity in stage 2 sleep without obvious changes in the hypnogram [6], and lowered the cortisol awakening response [7]. A dual antagonist, filorexant, and a selective OX1 antagonist, tebideutorexant, failed to show antidepressant effects in their own trials, which is consistent with, though it does not prove, an OX2-specific effect [1].

An inverted dose–response. In depression trials 40 mg has repeatedly done worse than 20 mg [3][7]. In the monotherapy trial 40 mg increased total sleep more but also shortened the time to REM sleep and increased light N1 sleep, changes not seen at 20 mg, which the authors suggest may explain the curve [7].

No marketed product. Seltorexant has been given as oral capsules in trials [6][7].

Short-acting by design. It is absorbed within about 1.5 hours and eliminated with a half-life of 2–3 hours [15]. In healthy volunteers dosed in the morning for 10 days, 20 mg and above caused somnolence on every study day, while only a mild drop in attention at 4 hours appeared on other central tests [15]. No human receptor-occupancy study has been published [1].

Common effects. Across the phase 2 add-on trials the most common adverse events were somnolence, headache and nausea [3]. In the monotherapy trial adverse events affected 45.2% on 20 mg, 61.0% on 40 mg and 47.7% on placebo; abnormal dreams, sleep paralysis and nightmares affected 24.4% on 40 mg against 7.1% on 20 mg and 4.5% on placebo, and two people on 20 mg stopped because of raised liver enzymes [1]. In the insomnia trial adverse events were less common on seltorexant (33.8%) than on placebo (49.3%) or zolpidem (42.5%), and somnolence affected 5.6% on 20 mg [11].

Serious events. In the insomnia trial one person on 20 mg had a brain hemorrhage, and heart-rhythm problems (atrial fibrillation, PR prolongation and an arrhythmia) led four people on 5 or 20 mg to stop [11]. No clinically significant cataplexy has been reported at 20 mg, and suicidal ideation and behavior did not differ from comparators [1].

Next-day effects. In the insomnia trial next-day sleepiness rose slightly and similarly in all groups, and the largest loss of balance on waking at night was with zolpidem [11]. Healthy volunteers showed no clinically relevant residual central effects beyond mild attention changes at 4 hours [15].

What is unknown. No human abuse-potential study has been published, safety beyond 6 months has not been reported, and falls, driving and reproductive safety have not been formally studied [1].

Seltorexant is metabolized mainly by CYP3A4, so strong inhibitors would be expected to raise its levels and inducers to lower them, but no dedicated interaction studies have been published [1]. In its depression trials it was given on top of SSRIs or SNRIs [3][4].