Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline

ABSTRACT

Introduction: Drug development and repurposing are urgently needed for individuals with autism spectrum disorders (ASD) and psychiatric comorbidity, which often presents as aggression and self-injury.

Areas covered: We review dopamine antagonists, including classical and atypical, as well as unconventional antipsychotics in ASD. The older antipsychotic loxapine is discussed in terms of preliminary albeit limited evidence in ASD. Emerging promise of amitriptyline in ASD is discussed, together with promising BDNF effects of loxapine and amitriptyline.

Expert opinion: In ASD, pharmacotherapy and specifically dopamine antagonist drugs are often prescribed for challenging behaviors including aggression. The novel antipsychotics risperidone and aripiprazole have received most study in ASD and are FDA-approved for irritability in children with ASD over age 5 years; individuals with ASD are prone to weight gain, Type II diabetes and associated side effects. Low dose loxapine has properties of classical and novel antipsychotics but importantly appears more weight neutral, and with promising use in adolescents and adults with ASD. Amitriptyline appears effective in ASD for irritability, aggression, gastrointestinal problems, and insomnia, in children, adolescents and adults however our adult data on amitriptyline in ASD is still in preparation for publication. Both loxapine and amitriptyline may stimulate BDNF; further studies are warranted.

KEYWORDS:

• Dopamine antagonists
• antipsychotics
• autism
• loxapine
• amitriptyline
• aggression
• BDNF

Article highlights

• Antipsychotic polypharmacy is common in ASD.

• Despite numerous old and new antipsychotic agents available, prescribing options are limited for treatment resistant aggression.

• Classical dopamine antagonists including haloperidol have received some study in ASD, but neuromotor side effects are limiting.

• Risperidone and aripiprazole have received most study in ASD, however individuals with ASD seem especially prone to weight gain and metabolic side effects.

• Preliminary evidence suggests loxapine in low dose of 5–10 mg/day resembles an atypical antipsychotic, but importantly with less weight gain.

• Limited preliminary evidence for amitriptyline suggests it may help many autistic interfering behaviors.

• Both old drugs may stimulate BDNF, in contrast to deleterious effects of most antipsychotics on brain health

This box summarizes key points contained in the article.

Declaration of interest

J Hellings is or has been an investigator for studies funded by NIMH, NICHD, Shire, Forest, Sunovion, Young Living, INSYS and has authorship collaborations with Roche. LE Arnold has received research funding from Curemark, Forest, Lilly, Neuropharm, Novartis, Noven, Shire, Supernus, and Young Living (as well as NIH and Autism Speaks) and has consulted with or been on advisory boards for Arbor, Gowlings, Ironshore, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Roche, Seaside Therapeutics, Sigma Tau, Shire, Tris Pharma, and Waypoint and received travel support from Noven. J Han has received research support from the Memphis Research Consortium and Rhythm Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.