Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome

J Dev Behav Pediatr. 2008 Aug;29(4):293-302. doi: 10.1097/DBP.0b013e31817dc447.


Objective: In fragile X syndrome (FXS), it is hypothesized that absence of the fragile X mental retardation protein (FMRP) disrupts regulation of group 1 metabotropic glutamate receptor (mGluR and mGluR5)-dependent translation in dendrites. Lithium reduces mGluR-activated translation and reverses phenotypes in the dfxr mutant fly and fmr1 knockout mouse. This pilot add-on trial was conducted to evaluate safety and efficacy of lithium in humans with FXS.

Methods: Fifteen individuals with FXS, ages 6-23, received lithium titrated to levels of 0.8-1.2 mEq/L. The primary outcome measure, the Aberrant Behavior Checklist --Community Edition (ABC-C) Irritability Subscale, secondary outcome measures (other ABC-C subscales, clinical global improvement scale (CGI), visual analog scale for behavior (VAS), Vineland Adaptive Behavior Scale (VABS)), exploratory cognitive and psychophysiological measures and an extracellular signal-regulated kinase (ERK) activation assay were administered at baseline and 2 months of treatment. Side effects were quantified with a standardized checklist and lithium level, complete blood count (CBC), thyroid stimulating hormone (TSH), and chemistry screen were done at baseline, 2 weeks, 4 weeks and 2 months.

Results: The only significant treatment-related side effects were polyuria/polydipsia (n = 7) and elevated TSH (n = 4). Although the ABC-C Irritability Subscale showed only a trend toward improvement, there was significant improvement in the Total ABC-C score (p = 0.005), VAS (p = 0.003), CGI (p = 0.002), VABS Maladaptive Behavior Subscale (p = 0.007), and RBANS List Learning (p = 0.03) and an enhanced ERK activation rate (p = 0.007). Several exploratory tasks proved too difficult for lower-functioning FXS subjects.

Conclusions: Results from this study are consistent with results in mouse and fly models of FXS, and suggest that lithium is well-tolerated and provides functional benefits in FXS, possibly by modifying the underlying neural defect. A placebo-controlled trial of lithium in FXS is warranted.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / therapeutic use
  • Blood Cell Count
  • Child
  • Cognition / drug effects
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / psychology
  • Humans
  • Learning / drug effects
  • Lithium Carbonate / adverse effects
  • Lithium Carbonate / blood
  • Lithium Carbonate / therapeutic use*
  • Pilot Projects
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Psychological Tests / statistics & numerical data
  • Receptors, Metabotropic Glutamate / drug effects*
  • Thyrotropin / blood
  • Treatment Outcome


  • Antidepressive Agents
  • Receptors, Metabotropic Glutamate
  • Lithium Carbonate
  • Thyrotropin
  • Extracellular Signal-Regulated MAP Kinases