A Pilot Naturalistic Trial of Acamprosate In Idiopathic and Fragile X-Associated Autism Spectrum Disorders

Background: The central impairment in autism spectrum disorders (ASDs) is a disturbance in social relatedness. In persons with ASD, numerous systematic drug trials targeting core social impairment have yielded negative results. Acamprosate is approved for use in adults with alcohol dependence. Acamprosate has a novel mechanism of action including potential modulation of metabotropic glutamate receptor type 5 (mGluR5) and GABA neurotransmission. Dysregulation in glutamate and GABA neurotransmission has been implicated in the pathophysiology of idiopathic ASDs.  Fragile X syndrome (FXS) is the most common single gene cause of ASDs. Excessive mGluR5 neurotransmission has been demonstrated in animal models of FXS.   

Objectives: To complete a naturalistic pilot investigation of acamprosate in youth with idiopathic and FXS-associated ASDs.

Methods: Subjects were the first 13 persons with ASD treated with acamprosate at our clinic. Concomitant psychotropic drug use (except glutamatergic agents) was allowed with stable dosing for at least 8 weeks prior to the trial. Acamprosate was dosed starting at 333 mg per day increased as tolerated weekly by 333 mg/day up to a maximum of 1332 mg/day (weight ≤ 50 kg) or 1998 mg/day (weight ≥ 50 kg).  Rating measures including the Aberrant Behavior Checklist (ABC), Clinical Global Impressions  Improvement (CGI-I) and Severity (CGI-S) subscales, and Social Responsiveness Scale (SRS) were prospectively obtained at baseline, four weeks, eight weeks, and at last clinical visit.  Treatment response was defined by a ≥ 30% improvement on the Social Withdrawal subscale of the ABC and a CGI-I score of 1 “very much improved” or 2 “much improved”.   

Results: The treatment group included 7 persons (6 adults, 1 youth) with FXS-associated ASD, and 6 youth with idiopathic autistic disorder. Mean age for subjects with FXS-associated ASD was 20 ± 6.5 years, and 9.8 ± 2.4 years for those with idiopathic ASD; group mean 15 ± 7 years. Mean acamprosate dosing was 1284 ± 520 mg/day.  Mean length of treatment was 22 ± 11.6 weeks. Mean CGI-I score at end point was 2; “much improved”. CGI-S scores changed from a mean of 4.29 ± 0.47 at baseline to 3.57 ± 0.51 at endpoint (p< 0.0001; effect size= 1.46).  The ABC-Social Withdrawal subscale scores changed from a mean 15.2 ± 6.4 at baseline to 8.2 ± 4.8 at endpoint (p<0.0001; effect size= 1.57). The SRS total raw score changed from a baseline mean of 104.2 ± 22 to 89.5 ± 22.7 at endpoint (p<0.001; effect size= 0.7). Using our definition of treatment response, 10 of 13 subjects (77%) were treatment responders. Separate analysis of subjects with FXS-associated or idiopathic ASD did not yield significantly different results on any measure employed. Acamprosate was well tolerated with no drug discontinuations due to adverse effects noted. Adverse effects experienced by six (43%) subjects were primarily related to gastrointestinal function including nausea (n=4), reduced appetite (n=2), diarrhea (n=1), and sedation (n=1).  

Conclusions: Acamprosate shows initial potential to improve social behavior in persons with ASD. Future systematic controlled study of acamprosate in FXS and idiopathic ASDs is warranted.