Laasdai: Loxapine Add-On for Adolescents and Adults with Autism Spectrum Disorders, Aggression and Irritability

Background: Low dose loxapine (5-15mg/day) in our experience shows promising efficacy and safety superior to the newer atypical antipsychotics risperidone (RIS) and aripiprazole (ARI). The latter are currently FDA-approved for treating irritability and aggression in autism spectrum disorders (ASD) but carry black box warnings for weight gain and diabetes. We hypothesize that loxapine offers improved quality of life and fewer medical risks for this population, for whom new drug development is urgently needed. Side effects of weight gain, metabolic syndrome and diabetes appear much less with loxapine than those already well documented with RIS and ARI. With low dose loxapine, prolactin elevation does not occur, and extrapyramidal side effects are minimal. In addition, loxapine has recently been shown, using pluripotential stem cells, to produce neural sprouting.

Objectives: To study loxapine prospectively in doses of up to 15mg daily in adolescents and adults with ASD, aggression and irritability. Secondly, to measure brain derived neurotrophic factor (BDNF) as a potential biomarker of neurogenesis, controlling for platelet count and BMI.

 Methods: We performed an exploratory prospective 12-week open trial of add-on loxapine in subjects aged 13 to 65 years with ASD, aggression and irritability above 14 points on the Aberrant Behavior Checklist-Irritability (ABC-I) subscale. Loxapine was added and flexibly dosed up to 15mg daily, starting with 5mg alternate days for the first 3 weeks to minimize akathisia. From weeks 1 to 6 other medications were tapered if possible, while from weeks 6 to 12 all medication doses were held stable.The primary outcome response measure was the Clinical Global Impressions scale-Improvement (CGI-I), with response defined as CGI-I of Much Improved or Very Much Improved. Secondary outcome response measures were the ABC-I, Repetitive Behavior scale-Revised, and the Quality of Life scale. Serum BDNF was assayed from samples collected at baseline and final study visits.

Results: Sixteen subjects were enrolled; 13 completed. Eleven were males and 5 were females. Mean age was 21.6 years (range 13 to 39). Mean final loxapine dose was 8.6 mg/day(2.5to 15). By week 6, 8 (50%) were rated as Much Improved and by week 12, 15 (94%) were rated as Much Improved. On ABC-I, 6 subjects (38%) responded by week 6, and 8 (50%) by week 12, using a 25% score reduction as response. Mean BMI scores did not increase. Side effects were minimal. Prolactin elevation did not occur.  BDNF levels increased in all but one subject, to a significant degree, p=0.035.

Conclusions: Low dose loxapine shows promise as a new treatment for aggression and irritability in ASD. Loxapine response was rapid, however it could be started and increased to 5mg daily after a week in future trials for an even more rapid response. Prospective, double-blind placebo-controlled trials of loxapine dosed at 5 to 15 mg/day targeting aggression and irritability in ASD are warranted. Loxapine may increase BDNF as a potential biomarker of neurotrophic effects, although larger randomized controlled trials with placebo comparisons are needed.