Loxapine add-on for adolescents and adults with autism spectrum disorders and irritability

Abstract

Objectives: Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation.

Methods: We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores >14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped.

Results: Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype.

Conclusions: Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study.

FIG. 1.

Change in Clinical Global Impressions-Severity (CGI-S) during the trial. Results are least squares means±standard errors from mixed models. Light gray lines are individual trajectories (with a small amount of noise added so that overlapping lines are visible).

FIG. 2.

Change in Aberrant Behavior Checklist (ABC) subscales during the trial. Results are least squares means from mixed models. Subscales with significant changes over time are denoted with bolded text and an asterisk.

FIG. 3.

Change in Repetitive Behavior Scale-Revised (RBS-R) during the trial. Results are least squares means from mixed models. Subscales with significant changes over time are denoted with bolded text and an asterisk.

FIG. 4.

Change in quality of life (QOL) during the trial. Results are least squares means from mixed models. Subscales with significant changes over time are denoted with bolded text and an asterisk.

FIG. 5.

Brain-derived neurotrophic factor (BDNF) changes.