Minocycline Promising in Fragile X Syndrome

Megan Brooks

September 07, 2010

September 7, 2010 — In the eyes of their parents at least, children with fragile X syndrome who are treated with minocycline often show improvements in language, attention levels, and behavior while experiencing mostly mild gastrointestinal-related adverse effects.

"This is the first survey of the clinical response to minocycline in patients with fragile X syndrome with the intention to document side effects and determine the parents' impression of treatment benefits and problems," the researchers, with lead study author Randi J. Hagerman, MD, medical director of the University of California, Davis, Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, in Sacramento, report.

The promising preliminary data from this survey, Dr. Hagerman told Medscape Medical News, prompted the National Fragile X Foundation to fund a controlled study of minocycline that is now in progress.

"This is a 2-year, double-blind, placebo-controlled, crossover study, 3 months on each arm," she noted. "We have a couple of patients who have finished and, in general, we are seeing some pretty positive effects."

Their report appears in the September issue of the American Journal of Intellectual and Developmental Disabilities.

Minocycline and Fragile X: A Brief History

Fragile X syndrome is a genetic disorder resulting from a defect on the X chromosome. It is estimated to affect 1 in 3600 males and 1 in 4000 females. One-third of all children with fragile X syndrome develop autism, and about 5% of children with an autism-spectrum disorder have fragile X.

It was recently shown that the fragile X knockout mouse, given minocycline for 3 weeks starting at birth, normalized their synaptic connections, Dr. Hagerman noted in a telephone interview.

"Usually in fragile X, the synaptic connections are weak and that is thought to be the cause of intellectual disability and autism," she said. "Minocycline treatment in the fragile X knockout mouse completely reversed that, and it had some good effects on cognition and learning tasks too," she explained.

The publication of this animal study, Dr. Hagerman said, led to calls from parents who wanted their child with fragile X to take minocycline. "This is a relatively benign FDA [US Food and Drug Administration]–approved medication with a lot of pediatric use, so many doctors decided to prescribe it off label just to see what would happen, and we decided to survey parents on what they were seeing," Dr. Hagerman pointed out.

The Survey

The researchers used a questionnaire to survey the parents of 53 patients with fragile X syndrome who received minocycline for between 2 weeks and 20 months at doses of 25 to 200 mg/day. The patients with fragile X syndrome ranged in age from 4 months to 25 years (mean age, 13.3 years).

The questionnaire used a Likert scale to measure changes in language, academic abilities, attention, behavior, physical features, and adverse effects after taking minocycline. The parents were asked to report any adverse effects of minocycline treatment using a list of all reported associated problems in addition to an open-ended question about perceived problems with the drug.

The researchers report that 3 patients dropped out after taking minocycline for 1 to 4 days because of gastrointestinal-related adverse effects, including stomachache and vomiting.

The most common reported adverse effects in the 50 remaining patients were loss of appetite (8 of 50 patients, 16%), gastrointestinal upset (6 patients, 12%), and diarrhea (4 patients, 8%). Most of these resolved after the first few days of treatment.

One teenage boy had darkening of his nails after treatment with minocycline for about 12 months. "Because he had a good response to minocycline, the family wanted to continue the treatment," the study authors note in their report.

There were no reports of sun sensitivity, blue-gray teeth, hearing loss, fever, swelling rash, drowsiness, or dizziness. "The side effects were minimal in terms of the improvements the family was seeing," Dr. Hagerman said.

Significant Placebo Effect "Likely"

On the basis of responses to the questionnaire, 54% of parents said their child showed improvements in the use of language, 50% reported improved attention span, 44% noticed improved social communication, and 30% noticed a lessening of anxiety levels. "We also had some indication that maybe cognition was better," Dr. Hagerman said.

The results were mixed for hyperactivity, with 14% of parents reporting their child's hyperactivity got "mildly worse" with minocycline and 12% reporting it got "somewhat better." Twelve percent of parents thought their child's moodiness or irritability and sleep disturbances got mildly worse with minocycline.

Dr. Hagerman and her colleagues emphasize in their report that this was not a controlled trial and there is likely a significant placebo effect in the family reports. "Clearly the efficacy of minocycline in treating individuals with fragile X syndrome cannot be determined," they note.

However, the parent-reported data on adverse effects and clinical response "provide important information for monitoring and designing outcome measures in future clinical studies," they say.

"Excellent" Data

Reached for outside comment, Robert L Hendren, DO, professor and vice chair of the Department of Psychiatry and director of Child and Adolescent Psychiatry at the University of California, San Francisco, said, "This paper presents an excellent in-depth review of the potential benefits, mechanisms of action, and adverse events from minocycline for the treatment of neurodevelopmental disorders, particularly fragile X.

"It also presents a survey of families where a member with fragile X has taken minocycline, identifying safety and tolerability issues and potential benefits, [which] is very helpful in providing a fully informed consent to family members," he added.

This background and the survey results, Dr. Hendren said, "strongly support the value of doing a randomized controlled trial of minocycline for fragile X. This experienced team also offers a number of useful design suggestions for this promising clinical trial."

The study was funded by grants from the US National Center for Research Resources, National Institutes of Health, Health and Human Services Administration of Developmental Disabilities, and the National Fragile X Foundation. Funding also was received from the Center for Biomedical Research, Diponegoro University, and the Bureau of Foreign Planning and Cooperation, Ministry of National Education, Republic of Indonesia. Dr. Hagerman and colleagues and Dr. Hendren have disclosed no relevant financial relationships.

Am J Intellect Dev Disabil. 2010;115:433-443.


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