Could orexin drugs offer psychiatry a new path beyond SSRIs and stimulants?

In May 2026, the US Department of Health and Human Services launched an action plan to “curb” psychiatric overprescribing and promote deprescribing when clinically indicated. The initiative calls for regular review of psychiatric medications and guidance on tapering and discontinuation, including antidepressants.^[][]

Although SSRIs have substantial evidence supporting their use in major depressive disorder and several anxiety disorders, physicians and researchers are looking beyond traditional monoamine targets for new ways to treat psychiatric disease. 

One of the more unusual candidates is orexin, a neuropeptide system best known for regulating wakefulness.

Why is orexin attracting attention?

“The orexin, or hypocretin, system is compelling because it sits at the intersection of things like arousal, attention, motivation, reward processing, stress responsivity, and sleep–wake regulation,” says Barry K. Herman, MD, Chief Medical Officer at Mentavi Health.

Dr. Herman describes the system as “pharmacologically bidirectional.” OX2R agonists increase orexin signaling, while orexin receptor antagonists suppress the pathway. “The strong results obtained with orexin-2 receptor agonism in narcolepsy type 1 provide the important human proof-of-concept that this system can be manipulated therapeutically,” he adds.

Narcolepsy

Takeda reported phase 3 improvements in wakefulness, cognition, daily functioning, and nighttime sleep in narcolepsy type 1. China approved oveporexton in July 2026. The US application received priority review and had a third-quarter 2026 target action date.^[][]

“Narcolepsy type 1 is fundamentally an orexin-deficiency disorder whereas most psychiatric illnesses are not,” says Dr. Herman. “Consequently, translating the mechanism into psychiatry will require evidence that modulating orexin signaling improves clinically relevant symptoms rather than simply increasing wakefulness.”

Psychiatry is now testing whether the same circuitry has relevance outside narcolepsy.

Role in ADHD

Alkermes is developing ALKS 7290, an OX2R agonist, for adult ADHD.^[] Preclinical work has provided evidence of effects on sustained attention and impulsive responding.

A randomized, placebo-controlled phase 1b study is enrolling approximately 50 adults and assessing safety alongside quantitative EEG and neuropsychological measures of sustained attention, vigilance, and impulse control. Results are expected in the fourth quarter of 2026. 

Sam Zand, DO, psychiatrist and founder and CEO of Anywhere Clinic, explains the rationale. “ADHD is not only an inability to concentrate, but [includes] difficulties with arousal, motivation, and sustained attention. This raises interest in whether targeting the orexin system can alleviate symptoms,” he says.

But neither physician sees orexin agonists as ready to replace stimulants.

Dr. Zand concurs. “I would not necessarily view orexin agonists in place of stimulants at this point.”

Other molecules under development 

Seltorexant, an OX2R antagonist rather than an agonist, has been studied as adjunctive treatment for major depressive disorder with insomnia symptoms: 

• In phase 3 MDD3001, the drug improved depressive symptoms and sleep disturbance outcomes in patients with inadequate responses to SSRI or SNRI treatment.^[]

• A later phase 3 comparison with quetiapine XR found a numerically higher response rate with seltorexant (although not statistically significant), alongside lower rates of somnolence and weight gain.^[]

Centessa’s cleminorexton, OX2R agonist, now part of Lilly’s pipeline, is also being developed across narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia.^[][] Alkermes is advancing alixorexton through phase 3 studies in narcolepsy type 1 and type 2, with a phase 2 program in idiopathic hypersomnia.^[]

Safety considerations 

“The biggest questions raised include long-term safety, effectiveness, dosing, and what types of patients will benefit most,” Dr. Zand says. 

He commented that the earlier OX2R agonist, TAK-994, was discontinued after drug-induced liver injury, “although that toxicity appears to have been related to the molecule and its metabolites rather than necessarily representing a class effect,” he says.