Open-Label Treatment Trial of Lithium to Target the Underlying Defect in Fragile X Syndrome
Abstract
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.
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In a pilot trial of 15 patients with FXS, two months of lithium treatment produced positive effects on behavior and adaptive skills.
“used in a pilot trial of 15 patients with FXS, the twomonth treatment was found to have positive effects on behavior and adaptive skills (122).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [122]
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Self-citation
- Authors
- Berry-Kravis, E., Sumis, A., Hervey, C., Nelson, M., Porges, S. W., Weng, N., Weiler, I. J., & Greenough, W. T.
- Affiliations
- University of Illinois Chicago (US)
- University of Illinois Urbana-Champaign (US)
- ORCID
- Porges, Stephen W.
- Venue
- Journal of Developmental & Behavioral Pediatrics
- Published
- 2008-08
- Volume
- 29
- Issue
- 4
- Pages
- 293-302
- ISSN
- 0196-206X (ISSN-L)
- OpenAlex
- W2115110458
- Cited by
- 215
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 7 · 2017: 22 · 2016: 12 · 2015: 8 · 2014: 20 · 2013: 23 · 2012: 14
- FWCI
- 13.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Developmental & Behavioral Pediatrics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH-35321)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, lithium, FMRP, metabotropic glutamate receptor 5, ERK activation, irritability, adaptive behavior, cognitive function, polyuria and polydipsia, thyroid-stimulating hormone
- MeSH terms
- Administration, Oral, Adolescent, Adult, Antidepressive Agents, Blood Cell Count, Child, Cognition, Fragile X Syndrome, Humans, Learning, Pilot Projects, Psychiatric Status Rating Scales, Psychological Tests, Thyrotropin, Lithium Carbonate, Treatment Outcome, Receptors, Metabotropic Glutamate, Extracellular Signal-Regulated MAP Kinases
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