Pitolisant May Allow for Discontinuation of Other Psychiatric Medications

Clinicians often prescribe antidepressants such as selective serotonin reuptake inhibitors (SSRI’s) to individuals with Prader-Willi Syndrome (PWS) to help with ongoing symptoms of obsessive-compulsive disorder, anxiety disorders, and mood disorders. These medications are prescribed despite a lack of evidence in support of their use in patients with PWS and a concern about their adverse effects. The lack of a good solution for psychiatric challenges in individuals with PWS has caused some psychiatrists to take a novel approach. They have prescribed pitolisant, a H3 receptor antagonist and inverse agonist that crosses the blood brain barrier and results in widespread release of histamine throughout the CNS.

Pitolisant, available as 4.5- and 18-mg film-coated tablets, is approved in the US for the treatment of narcolepsy with or without cataplexy. It is not currently approved for any neuropsychiatric indication. New research linking histamine in neuropsychiatric conditions, have stimulated the hypothesis that pitolisant may play a unique role in the management of PWS. Now, early results suggest that pitolisant may be an option for individuals with PWS who fail a psychostimulant trial.

The case report describes the safe and effective use of pitolisant in a pediatric patient with PWS, obsessive-compulsive disorder, autism spectrum disorder, mild intellectual disability, hypothyroidism, and scoliosis. The 15-year-old female (65 kg) was followed by outpatient psychiatry and had ongoing complaints of irritability, anxiety, aggression, rigid thinking, and excessive daytime sleepiness. The patient also experienced ongoing restlessness, difficulty with transition, insistence on sameness, daytime sleepiness accompanied by distractibility/irritability, and behavioral outbursts. The clinical team started the patient at 4.5 mg and slowly titrated pitolisant over six months up to a dose of 36 mg per day. During this time, they also weaned the patient off escitalopram and down from buspirone 10 mg in the morning, 5 mg in the evening, and 10 mg at bedtime to buspirone 5 mg twice daily.

Within ten days of starting pitolisant, the patients’ mother noted that her daughter could more easily complete academic tasks. After two months of receiving a dose of 4.5 mg, the dose of pitolisant was increased from 4.5 mg to 9 mg and the patient experienced improved muscle tone, was walking more quickly with less hyperflexibility, had reductions in daytime sleepiness, was more alert and engaged with others, and had fewer behavioral outbursts and aggression. Three months later the dose of pitolisant was increased to 18 mg and following this increase the parents reported that the patient was better able to reason through situations. While she continued to have behavioral outbursts at home and school, she had improved frustration tolerance. As family and teachers at school continued to notice improvements, the dose of pitolisant was increased from 27 mg to 36 mg daily. Clinical rating scales in depression, irritability, lethargy, and hyperactivity significantly improved post-pitolisant.

While the adolescent tolerated pitolisant, each dose increase was associated with several days of a notable increase in anxiety, restlessness, and irritability. The patient also experienced increased sweating, salivation, and drooling, although these adverse effects did not seem to worsen with an increased dosage of pitolisant. The authors note that pitolisant is metabolized via phase I metabolism to an inactive metabolite through CYP3A4 and CYP2D6 and patients who take potent CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) or CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s Wort) should be closely monitored.

Reference

S Pennington, D Stutzman, and E Sannar. Pitolisant in an adolescent with Prader-Willi Syndrome. J Pediatr Pharmacol Ther. 2021. 26 (4): 405-410.