Amitriptyline use in individuals with KCNQ2/3 gain-of-function variants: A retrospective cohort study.

Objective: Heterozygous gain-of-function (GOF) variants in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channel subunits Kv7.2 and Kv7.3, lead to neurodevelopmental disorders for which no established treatments are available. Amitriptyline, an antidepressant, blocks Kv7.2/Kv7.3 and has previously been reported to be effective in a single individual with a KCNQ2 GOF variant. We designed a retrospective, single-arm, multicenter study to investigate the effects of amitriptyline in a real-world setting.

Methods: We used a 7-point Likert scale to measure seizure frequency, clinical examination, motor function, alertness, skill acquisition, communication, mood, behavior, self-care, sleep, tiredness, and electroencephalogram at baseline, after a minimum of 6 weeks of intervention, and, if applicable, after discontinuation. Adverse events were assessed in all participants, and the effectiveness of the treatment was evaluated in 11 individuals who received a minimum dosage of .5 mg/kg/day for at least 6 weeks. Data were collected from October 2023 to August 2024.

Results: Thirteen individuals, eight with a pathogenic KCNQ2 GOF variant and five with a pathogenic KCNQ3 GOF variant, were included. Nine were female, and the median age at start of amitriptyline was 7.1 years (range = 1.5-20 years). Eleven individuals received a minimum dosage of .5 mg/kg/day for at least 6 weeks. The median dosage of amitriptyline administered was 1 mg/kg/day, with a median treatment duration of 29 weeks. Although amitriptyline was ineffective in two individuals (18%), eight (72%) demonstrated at least minimal improvement in two or more domains, with improvements in alertness and communication being the most frequently reported. In those with reported improvements, amitriptyline was discontinued in four individuals, but continued improvements were seen, to the same or greater extent compared to treatment. The remaining five individuals are on continued treatment because of perceived benefits.

Significance: Overall, the effect of amitriptyline remains unclear, and formal n-of-1 trials are needed to investigate the precise effects of amitriptyline in KCNQ GOF-related neurodevelopmental disorders.