International Meeting for Autism Research: Pilot Study of Minocycline Treatment for Autism

Pilot Study of Minocycline Treatment for Autism

Friday, May 21, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
2:00 PM
S. E. Swedo , Pediatrics & Developmental Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
A. W. Buckley , Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
A. Thurm , Pediatrics and Developmental Neuropsychiatry, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
L. C. Lee , Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
A. Azhagiri , Neurology, Jonhs Hopkins University School of Medicine, Baltimore, MD
C. A. Pardo , Neurology & Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
Minocycline is a member of the tetracycline class of antibiotics that has been found to have beneficial effects on neuroinflammation, microglial activation and neuroprotection in disorders such as multiple sclerosis, Parkinson’s disease and neuroAIDS.  The CNS effects of minocycline appear to be facilitated by modulation of microglial activation and regulation of critical factors in inflammatory pathways such as matrix metalloproteinases (MMPs), nitric oxide production, and apoptotic cell death.  Because microglial activation and neuroinflammation have been reported to be associated with autism, we hypothesized that minocycline might be of value in the treatment of children with autism, particularly if they had a history of developmental regression – a potential marker of the onset of neuroinflammation.
To evaluate the effects of minocycline treatment on autistic symptomatology and markers of neuroinflammation  
IRB approval was received for an open-label preliminary trial of 6 months of minocycline therapy (1.4 mg/kg) in 10 children (8 boys, 2 girls; mean age 7.58yrs; range 3-12 yrs).  CSF, serum and plasma were obtained  before and at the end of minocycline treatment (1 child withdrew at 3 months and CSF was obtained then).  All subjects met ADOS, ADI-R and DSM-IV criteria for autism.  Developmental regression was an inclusionary requirement with loss of social skills and/or language occurring at 18.4 months, on average (range 12 to 28 mos).  Symptom severity was rated at baseline and monthly intervals using the Clinical Global Impression Severity Scale (CGI-S) and change was recorded with the CGI-Improvement (CGI-I) scale.   In addition, adaptive functioning was measured using the Vineland Adaptive Behavior Scale, 2nd edition, with a mean composite score at baseline of 57.8 (SD 8.6).
Clinical improvements were negligible, with CGI-S scores remaining stable and only 2 of 10 children demonstrating “minimal improvement” on the CGI-I.  The Vineland composite scores also showed little or no change.  In contrast to the clinical findings, the laboratory assays demonstrated significant changes in the expression profile of the proform of BDNF (p=0.042) and HGF (p=0.028) in CSF and the proform of  BDNF (p=0.028) and IL-8 (p=0.047) in  serum when pre- and post-treatment levels of these proteins were compared. No significant changes were observed in chemokines such as  CCL2 (MCP-1) or cytokines such as TNF-α, CD40L, IL-6, IFN-γ and IL-1β. No significant pre- and post-treatment changes were seen in the profiles of markers of microbial translocation or MMPs, although there was a trend towards change in MMP7, one of the MMPs that appears to be a target of the effects of minocycline.
No significant clinical effects were seen in this small group of children with autism in response to minocycline treatment. However, changes in the pre-/post-treatment profiles of the  proform of BDNF in CSF and blood, HGF in CSF  and IL8  in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotropic growth factors.   Larger studies are needed to determine if minocycline treatment could be helpful for children with autism, and particularly for those with baseline evidence of neuroinflammation.
See more of: Treatment
See more of: Mandell
See more of: Clinical & Genetic Studies