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

AbstractOBJECTIVE:
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.
AuthorsElizabeth Berry-Kravis, Allison Sumis, Crystal Hervey, Michael Nelson, Stephen W Porges, Ning Weng, Ivan Jeanne Weiler, William T Greenough
JournalJournal of developmental and behavioral pediatrics : JDBP (J Dev Behav Pediatr) Vol. 29 Issue 4 Pg. 293-302 (Aug 2008) ISSN: 1536-7312 [Electronic] United States
PMID18698192 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antidepressive Agents
  • Receptors, Metabotropic Glutamate
  • Lithium Carbonate
  • Thyrotropin
  • Extracellular Signal-Regulated MAP Kinases
Topics
  • Administration, Oral
  • Adolescent
  • Adult
  • Antidepressive Agents (administration & dosage, adverse effects, therapeutic use)
  • Blood Cell Count
  • Child
  • Cognition (drug effects)
  • Extracellular Signal-Regulated MAP Kinases (drug effects)
  • Fragile X Syndrome (drug therapy, psychology)
  • Humans
  • Learning (drug effects)
  • Lithium Carbonate (adverse effects, blood, 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

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