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.

When GWAS meets the Connectivity Map: drug repositioning for seven psychiatric disorders

“…Both showed effectiveness in ameliorating behavioral problems 78,79 . Another drug loxapine, a typical anti-psychotic, was effectiveness as an add-on therapy for irritability in ASD 80 . Ribavirin is another interesting 15 candidate.…”

Off-label psychopharmacological interventions for autism spectrum disorders: strategic pathways for clinicians

“…An open-label 12-week study 147 studied add-on loxapine (BDNF stimulator) doses of 5–15 mg in 16 participants with ASD who were on one or more psychotropics of different types. Most improved in their Clinical Global Impression-Improvement scale (CGI-I) scores and their Aberrant Behavior Checklist- irritability (ABC-I) subscale scores with minimal side effects.…”

Metabolic Side Effects of Antipsychotic Medications in Children and Adolescents with Autism Spectrum Disorder (ASD)

“…First generation antipsychotics (FGAs), also called typical antipsychotics, primarily haloperidol, may still be used occasionally, but most studies have used second generation antipsychotics (SGAs), also called atypical antipsychotics because of a lessened chance of extrapyramidal side effects, dystonic reactions, withdrawal dyskinesia, and tardive dyskinesia (Posey, Stigler, Erickson, & Mc-Dougle, 2008). More recently, an FGA, loxapine, that to some degree resembles an SGA, has found new favor (Hellings, Jadhav, Jain, Jadhov, & Genovese, 2015;Hellings, Reed et al, 2015;Jain, Andridge, & Hellings, 2016). SGAs block postsynaptic serotonin receptors that may provide relative protection against extrapyramidal symptoms (Glick, Murray, Vasudevan, Marder, & Hu, 2001).…”

“…Extrapyramidal side effects were found, but again no significant weight change (Hellings, Jadhav et al, 2015). These investigators then used loxapine as an add-on in adolescents and adults with ASD, with doses of 5 to 15 mg/day in a 12-week study: they found that a number of other psychotropics could be tapered, that there was high efficacy, and that BMI scores actually decreased (Hellings, Reed et al, 2015). Given the favorable metabolic profile, the authors then reviewed 15 charts of adults with ASD who had antipsychotic drug-related weight gain and had loxapine added to their regime.…”