Before Treating Excessive Sleepiness, Make Sure You Know What You're Treating

CONFERENCE REPORTER

At the 2026 Jersey City Psychiatry Conference, Lisa Harding, MD, told attendees that psychiatrists play an investigative role in sleep-wake disorders. She called for careful history-taking, safe deprescribing, and well-informed referrals to sleep medicine specialists before treatment starts. Harding said a referral should never be a "blind referral," and that clinicians can make the process much easier for patients by collecting key information from the start.

Orexin and the REM-Wake Boundary

Harding described orexin (hypocretin) as the main stabilizer of the boundary between REM sleep and wakefulness. In narcolepsy, she explained, physiological features that should stay confined to REM sleep cross into waking hours. Cataplexy is the clearest example. Muscle atonia, which normally happens only during REM sleep, appears in a waking patient after an intense emotional surge, such as heavy laughter followed by buckling knees.

She reviewed the immune hypothesis for this neuronal loss. It rests on an association with the genetic marker HLA-DQB1*06:02, and on evidence that T cells target orexin-producing neurons in the lateral hypothalamus. According to Harding, imaging and preclinical studies support orexin loss as the core pathology.

Harding noted that a normal sleep cycle lasts about 90 to 110 minutes and repeats through the night. She also pointed out that loss of atonia during REM sleep has long been studied as a marker for Parkinson disease in older adults. Almost 90% of psychiatric medications affect sleep architecture, she said. That is not always pathological, though, and the direction of cause and effect is often unclear.

Clinical Clues and Testing

Harding cited a mean gap of 12 years between symptom onset and diagnosis. She urged clinicians to ask targeted questions:

• Does the patient fall asleep involuntarily?
• Are short naps briefly refreshing?
• When during the day do the symptoms happen?

Hypnagogic and hypnopompic hallucinations can overlap with thought disorders. In adolescents, attention problems can resemble ADHD, so histories from both parents and children are needed. Screening for body mass index and neck circumference helps identify metabolic contributors to sleepiness. She also cautioned that a patient who sleeps 5 hours a night and feels refreshed may not have a disorder. The focus should be on the symptoms that cause impairment.

Harding reminded attendees that over-the-counter supplements and cannabis are not benign. She noted that THC and CBD affect the cytochrome P450 enzymes CYP2C19 and CYP2C9.

Diagnostic testing has 2 phases. Overnight polysomnography is followed the next day by the multiple sleep latency test (MSLT). In the MSLT, patients get 5 nap opportunities spaced 2 hours apart. Harding pointed out a counterintuitive feature: if the patient does not fall asleep, the nap opportunity ends after 20 minutes. She said medications should be tapered to a safe point before testing, never stopped abruptly, and patients should get clear instructions ahead of the consultation.

Safety and Monitoring

Harding said every patient on a central nervous system depressant needs a safety plan. That plan includes checking the prescription drug monitoring program, reviewing concomitant medications, and asking about alcohol and sedative-hypnotic use. It also means asking whether the patient has secure, locked storage, especially for sodium oxybate products, given their potential for diversion. She noted that the original sodium oxybate formulation carried a high sodium load (about 1600 mg, she said), which required monitoring for hypertension and kidney function.

For patients on wake-promoting agents, Harding stressed correct blood pressure technique. Patients should be seated, avoid caffeine for 30 minutes beforehand, and have serial readings taken. Clinicians can also prescribe a home monitor so patients record readings at the same time each day for 3 to 5 days. Other risk factors she listed included QT-prolonging medications such as some antidepressants and second-generation antipsychotics, substance use disorders, cardiovascular risk, and polypharmacy.

The Orexin Agonist Era

Harding contrasted orexin receptor agonism with the orexin antagonism used to treat insomnia. She said agonism targets the missing pathophysiology in narcolepsy type 1. She cited two 12-week randomized phase 3 trials in which orexin agonist treatment improved wakefulness and reduced sleepiness and cataplexy compared with placebo. The US Food and Drug Administration (FDA) approved oveporexton (Orzeyful; Takeda), an orexin receptor 2 agonist, for adults with narcolepsy type 1 in August 2026.^1,2 Harding added that clinicians still need to wait for long-term safety signals.

"Make sure you know what you're treating," Harding emphasized.

She contrasted 2 kinds of referral. In the first, a patient is sent to a sleep specialist while taking diphenhydramine, paroxetine, an opioid, and a Z-drug. In the second, the clinician takes a history, schedules a taper of medications that are not working, and passes a clear description of symptoms to the specialist. Harding also suggested having patients complete a sleep questionnaire in the waiting room and reviewing data from wearable devices before appointments. Both steps can speed up diagnosis and support co-management with sleep specialists.

She warned against escalating doses of off-label agents such as quetiapine or trazodone to target sleep. Receptor effects change with dose, and higher doses may overshoot what the patient needs.

"It is completely okay to use medications off label because we don't have a lot of choices in psychiatry," Harding said. "But the overarching thing is: Ask the patients questions."

References

1. Takeda. FDA approves Orzeyful for adults with narcolepsy type 1. News release. August 5, 2026. Accessed October 2, 2026. https://www.takeda.com/en-us/newsroom/news-releases/2026/orzeyful-approved-narcolepsy/

2. Walters J. FDA approves oveporexton for narcolepsy type 1, first drug to treat full range of NT1 symptoms. Psychiatric Times. August 5, 2026. https://www.psychiatrictimes.com/view/fda-approves-oveporexton-for-narcolepsy-type-1-first-drug-to-treat-full-range-of-nt1-symptoms