Old Antibiotic May Improve Behavior, Mood in Fragile X Kids

Caroline Cassels

April 17, 2013

An old, and widely used, broad-spectrum antibiotic may provide meaningful clinical improvement in behavior and mood disturbances in children with fragile X syndrome (FXS), new research shows.

A randomized controlled trial showed that 3 months of treatment with minocycline resulted in greater global improvement and less anxiety and mood-related behaviors in children with FXS compared with those who received placebo.

"This study provides evidence of the efficacy of this medication as targeted treatment for fragile X syndrome with a long history of use and that can currently be prescribed," lead author Mary Jacena Leigh, MD, from the University of California, Davis, MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, said in a statement.

The study was published online April 8 in the Journal of Developmental and Behavioral Pediatrics.

FXS is the most common inherited cause of intellectual impairment and is the leading known single-gene cause of autism spectrum disorder. It is caused by a mutation in a single gene, FMR1, found on the X chromosome. The Centers for Disease Control and Prevention estimates that about 1 in 4000 individuals have the disorder.

In addition to physical features such as prominent ears, hyperextensible finger joints, and macroorchidism, FXS includes both behavioral and cognitive deficits. Behavioral problems typically include "attention-deficit hyperactivity disorder (ADHD), anxiety and intermittent aggression, which can cause significant difficulties for the families," the researchers note.

A semisynthetic tetracycline derivative, minocycline has been available since the 1970s. Its potential as a neuroprotective agent was first investigated in 1999, at which time it was shown to reduce inflammation in patients with cerebral ischemia.

Subsequent animal and clinical research suggested the drug may be effective in FXS. However, the researchers note that its efficacy in patients had not previously been assessed in a controlled trial.

To determine the behavioral effects of minocycline, the researchers conducted a randomized, double-blind, crossover trial that included 66 children with FXS aged 3.5 to 16 years (mean age, 9.2). Study participants were randomly assigned to receive either minocycline or placebo for 3 months and were then switched to the alternate treatment for the remaining 3 months of the trial.

The study's primary outcome was improvement on the Clinical Global Impression Scale–Improvement (CGI-I) and the Visual Analog Scale (VAS), which assessed the most significant symptom that caregivers wanted to see improve (VAS1).

Secondary outcome measures included the VAS for severity of target symptoms rated second (VAS2) and third (VAS3) by the parents as well as Aberrant Behavior Checklist Community Edition (ABC-C) composite score and subscales validated for the FXS population to assess severity of patients' behaviors, the Expressive Vocabulary Test Second edition (EVT-2) to assess language development, and Vineland Adaptive Behavior Scale (VABS)–II to assess adaptive skills.

Participants were followed up in person twice during the study period but were also assessed via regular telephone calls throughout the study to review concomitant medications and assess common side effects associated with minocycline.

Of the 66 original participants, 55 (83.3%) completed at least the first period of the trial, and 48 (72.7%) completed the second period.

The investigators found that minocycline resulted in statistically significant improvement in CGI-I (2.49 ± 0.13) vs placebo (2.97 ± 0.13, P = .0173). However, they found no difference between treatment groups with respect to VAS1. They also note that "although statistically significant, the CGI-I improvement (average of 0.5 points) was modest."

The investigators also note that although the average VAS scores were rated as more improved on minocycline vs placebo, the difference was not significant.

An ad hoc analysis by investigators by VAS scores according to behavior category revealed that minocycline was associated with a significantly greater improvement in anxiety and mood-related behaviors.

They also note that greater improvement was observed for the "other" category, which included being organized, potty training, self-calming/self-soothing, verbal initiation for play, chewing objects, overstuffing, scratching stomach, belching, running away, noncompliance/defiance, and self-injury.

However, they note that there was no significant treatment effect with respect to secondary outcome measures, including the ABC-C, VABS-II, EVT-2, or VAS2 and VAS3.

Overall, the researchers report, minocycline was safe, with the majority of adverse events rated mild, with no difference when compared with placebo. The most common side effects were gastrointestinal symptoms, which included loose stools and decreased appetite.

Five patients experienced tooth discoloration, a typical side effect of tetracyclines. However, it was noteworthy that most of these cases resolved, an unusual finding, as tooth-staining associated with these drugs is usually permanent.

"Further studies examining the long-term benefits and side effects are needed, perhaps in combination with other educational and medication treatments currently being developed for individuals with [FXS]," said Dr. Leigh.

Study author Randi J. Hagerman, MD, reports receiving funding from Hoffman LaRoche, Novartis, Seaside Therapeutics, Forest, and Curemark for treatment trials in patients with fragile X syndrome, autism, and fragile X–associated tremor ataxia syndrome. She is also on the Treatment Advisory Board for Novartis regarding fragile X syndrome treatment studies. Study investigator David Hessl, PhD, reports that he has received financial support from Hoffman LaRoche, Novartis, and Seaside Therapeutics for clinical trials of patients with fragile X syndrome. The other authors report no relevant financial relationships.

J Dev Behav Pediatr. Published online April 8, 2013. Abstract

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