title: Loxapine add-on for adolescents and adults with autism spectrum disorders and irritability.
abstract: OBJECTIVE
  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.
authors.affiliation: 1 The Ohio State University Nisonger Center , Columbus, Ohio.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hellings
authors.forename: Gregory
authors.initials: G
authors.lastname: Reed
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Cain
authors.forename: Xinghua
authors.initials: X
authors.lastname: Zhou
authors.forename: Francis X
authors.initials: FX
authors.lastname: Barth
authors.forename: Michael G
authors.initials: MG
authors.lastname: Aman
authors.forename: Gladys I
authors.initials: GI
authors.lastname: Palaguachi
authors.forename: Dmytro
authors.initials: D
authors.lastname: Mikhnev
authors.forename: Rujia
authors.initials: R
authors.lastname: Teng
authors.forename: Rebecca
authors.initials: R
authors.lastname: Andridge
authors.forename: Marilyn
authors.initials: M
authors.lastname: Logan
authors.forename: Merlin G
authors.initials: MG
authors.lastname: Butler
authors.forename: Joan C
authors.initials: JC
authors.lastname: Han
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D000067877:Autism Spectrum Disorder / Q000097:blood / Q000188:drug therapy* / Q000523:psychology*; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007508:Irritable Mood / Q000187:drug effects*; D008152:Loxapine / Q000008:administration & dosage*; D008297:Male; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human; D008152:Loxapine