Pitolisant-associated mania – a case report

Narcolepsy is a chronic neurological disorder treated with medications that promote wakefulness. Pitolisant, a histamine H3 receptor inverse agonist, is used to reduce excessive daytime sleepiness. Although pitolisant clinical trials describe mainly mild adverse effects, severe psychiatric reactions have been reported, yet detailed clinical descriptions remain limited. This case describes a first-onset manic episode with psychotic features shortly after pitolisant initiation in an adult without any psychiatric history, highlighting a rare but clinically significant potential reaction. A 51-year-old woman newly diagnosed with narcolepsy type 2 without psychiatric history began treatment with pitolisant, titrated up to 36 mg daily. She did not use recreational substances and had hypothyroidism well-managed with levothyroxine. After swift initial improvement in wakefulness, she developed behavioral changes including heightened sociability, impulsivity, and decreased need for sleep. Within weeks, the condition progressed to a severe manic state characterized by paranoid ideation, auditory hallucinations, and disinhibition. Primary care treatment with low-dose sedatives demonstrated minimal effect, resulting in referral for involuntary psychiatric admission. Comprehensive neurological, infectious, metabolic, and autoimmune evaluations were without remarks. Pitolisant was discontinued upon admission. Management included high-dose olanzapine, lorazepam, and subsequently electroconvulsive therapy, after which the manic episode resolved. She was stabilized on risperidone and olanzapine, which were gradually tapered as her condition improved. At follow-up two months after discharge, she remained euthymic and was referred to primary care. This case demonstrates a severe manic episode with psychotic symptoms emerging shortly after pitolisant initiation in an adult without prior psychiatric vulnerability. The temporal association, absence of alternative medical explanations, and resolution after drug discontinuation suggest a possible medication-related trigger. Clinicians prescribing pitolisant should closely monitor for early behavioral or mood changes, particularly during dose increases, and recognize that significant psychiatric reactions may occur even in individuals with no prior mental health history.