Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome.
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.
Berry-Kravis
Elizabeth
E
Department of Pediatrics, Rush University Medical Center, University of Illinois at Chicago, IL 60612, USA. elizabeth_M_berry-kravis@rush.edu
Sumis
Allison
A
Hervey
Crystal
C
Nelson
Michael
M
Porges
Stephen W
SW
Weng
Ning
N
Weiler
Ivan Jeanne
IJ
Greenough
William T
WT
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001772:Blood Cell Count; D002648:Child; D003071:Cognition / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000523:psychology; D006801:Humans; D007858:Learning / Q000187:drug effects; D016651:Lithium Carbonate / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D010865:Pilot Projects; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D011581:Psychological Tests / Q000706:statistics & numerical data; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013972:Thyrotropin / Q000097:blood; D016896:Treatment Outcome
D000928:Antidepressive Agents; D018094:Receptors, Metabotropic Glutamate; D016651:Lithium Carbonate; D013972:Thyrotropin; D048049:Extracellular Signal-Regulated MAP Kinases