Pitolisant
Pitolisant (Wakix) is a histamine H3 receptor inverse agonist/antagonist approved for excessive daytime sleepiness and cataplexy in narcolepsy. It is the first non-controlled wakefulness promoter of its class, boosting histaminergic tone rather than acting as a catecholamine stimulant, and carries no abuse scheduling.
01 Overview
By blocking presynaptic H3 autoreceptors, pitolisant increases the synthesis and release of histamine in the brain, enhancing wakefulness through a mechanism distinct from amphetamines or modafinil. The HARMONY trials demonstrated significant improvement in Epworth scores and cataplexy rate.
It is metabolised by CYP2D6/CYP3A4 and can prolong the QT interval. Because it lacks catecholaminergic reinforcement, it is not a controlled substance in most jurisdictions.
02 Mechanism
Selective histamine H3 receptor inverse agonist/antagonist that disinhibits histaminergic neurons, raising cortical histamine and downstream acetylcholine and dopamine release to promote wakefulness.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Starting | 8.9 mg/day | Oral | Start 8.9 mg once daily in the morning, titrate weekly. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Reduced daytime sleepinessSignificant improvement in Epworth Sleepiness Scale in narcolepsy. | -3 ESS points vs placebo | Clinical | |
| Reduced cataplexyMarked reduction in weekly cataplexy attacks in HARMONY-CTP. | ~-75% attack rate | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| InsomniaDifficulty sleeping, particularly with higher doses. | Mild | Common | Clinical | |
| Headache and nauseaHeadache, nausea and anxiety during titration. | Mild | Common | Clinical | |
| QT prolongationDose-dependent QT interval prolongation. | Moderate | Uncommon | Clinical |