Modulation of the Locus Coeruleus-Noradrenergic System with Milnacipran Vs Placebo in Autism Spectrum Disorder

Background:  Developmental dysfunction of the locus coeruleus/noradrenergic (LC-NA) system has been proposed as a possible cause of autism spectrum disorders (ASD).  Anecdotal parent reports, clinical observations and formal studies have found that up to 40% of children with ASD experience improvement of autistic behavior during fever, which may provide clues to the pathophysiology and potential therapeutic interventions for ASD.  Accordingly, we posit that the dramatic fluctuations in behavioral states observed during febrile episodes suggest the involvement of the LC-NA system, a widespread and versatile neuromodulatory system that we suggest is common to febrigenesis and the modulation of autistic behaviors. Milnacipran (MLN) is predominantly a norepinephrine reuptake inhibitor that may enhance function of the LC-NA system.  We hypothesize that MLN will re-activate the LC-NA system in patients with autism in a fashion similar to that seen with fever, thus resulting in improvement in attention, irritability, repetitive behaviors and social cognition.

Objectives:  To determine whether MLN improves attention dysfunction, irritability, repetitive behaviors and social cognition in patients with autism.

Methods:  A 12 week randomized, double-blind, placebo-controlled trial of MLN up to 200mg/ was performed in  subjects aged 18 – 50 with a DSM-IV TR ASD diagnosis, confirmed by ADI-R and ADOS. Comorbid medical, neurological and psychiatric illnesses with the exception of ADHD and OCD were excluded. Conners Adults ADHD Rating Scale-Observer Version (CAARS-O), Aberrant Behavior Checklist (ABC), and Clinical Global Impressions Improvement Scale (CGI-I) were measured.

Results:  Interim analyses revealed clinically meaningful improvement on milnacipran versus placebo in CGI-I, CAARS-O Inattention/Memory Hyperactivity/Restlessness, Problems with self-concept, DSM-IV Inattentive Symptoms, ADHD Symptoms Total and ADHD Index.  Improvements on milnacipran versus placebo were also observed on the ABC Irritability, Stereotypy, and Hyperactivity subscales.  No significant differences between treatment groups were found on the CAARS Impulsivity/Emotional Lability and DSM-IV Hyperactive-Impulsive Symptoms subscales or the ABC-Social Withdrawal or Inappropriate Speech subscales.

Conclusions:  Treatment with MLN versus placebo produced clinically meaningful improvements in several domains of the core symptoms of ASD.  We posit that this was accomplished via activation of the LC-NA system by MLN mimicking the effects of fever, however more research is needed.