The safety and efficacy of metformin in fragile X syndrome: An open-label study.

Fragile X syndrome (FXS) is a rare genetic disorder characterized by a deficit of the fragile X mental retardation protein (FMRP), encoded by the fragile X mental retardation gene (FMR1) on the X chromosome. It has been hypothesized that the absence of FRMP leads to higher levels of Insulin-like Growth Factor 1 (IGF-1) in the brain, possibly contributing to the intellectual impairment characteristic of the disorder. Preclinical studies have shown that metformin downregulates the insulin/IGF-1 signaling pathway, corrects dendritic defects, and improves repetitive behavior in Fmr1 knockout mice. Here, we conducted an open-label study to evaluate: (1) the safety of metformin in normoglycemic individuals with FXS; and (2) the efficacy of metformin to improve aberrant behavior, attention, and to modulate cortical functioning. Fifteen patients with FXS, aged from 17 to 44, received 500 mg of metformin twice/daily over a 9-week treatment period. The primary outcome measures were: (1) the incidence of adverse events (AE); (2) the decrease in IGF-1 levels; and (3) the global score of the Aberrant Behavior Checklist-Community, Fragile X. The secondary outcomes were: (1) the Test of Attentional Performance for children (KiTAP); and (2) the Transcranial Magnetic Stimulation (TMS) parameters measuring cortical excitability. The metformin treatment was well tolerated, with no significant related AE. The TMS data showed an increase in corticospinal inhibition mediated by GABAA and GABAB mechanisms. This study demonstrates the safety of metformin in normoglycemic patients with FXS, and suggests the potential of this medication in modifying GABA-mediated inhibition, a hallmark of FXS pathophysiology. Implications for future clinical trials are discussed.