The challenges of clinical trials in fragile X syndrome

Sébastien Jacquemont, Elizabeth Berry-Kravis, Randi J Hagerman, Florian Von Raison, Fabrizio Gasparini, George Apostol, Mike Ufer, Vincent Des Portes, Baltazar Gomez-Mancilla

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Rationale: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement. Objectives: We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders. Results: Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains. Conclusion: Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.

Original languageEnglish (US)
Pages (from-to)1237-1250
Number of pages14
JournalPsychopharmacology
Volume231
Issue number6
DOIs
StatePublished - Mar 2014

Fingerprint

Fragile X Syndrome
Clinical Trials
Fragile X Mental Retardation Protein
Outcome Assessment (Health Care)
Pharmaceutical Preparations
Patient Selection
Methylation
Therapeutics
Biomarkers
Phenotype
Research
Population

Keywords

  • AFQ056
  • Arbaclofen
  • Autism spectrum disorder
  • Disease modification
  • FMR1
  • FMRP
  • Fragile X syndrome
  • GABA
  • Mavoglurant
  • mGluR5

ASJC Scopus subject areas

  • Pharmacology

Cite this

Jacquemont, S., Berry-Kravis, E., Hagerman, R. J., Von Raison, F., Gasparini, F., Apostol, G., ... Gomez-Mancilla, B. (2014). The challenges of clinical trials in fragile X syndrome. Psychopharmacology, 231(6), 1237-1250. https://doi.org/10.1007/s00213-013-3289-0

The challenges of clinical trials in fragile X syndrome. / Jacquemont, Sébastien; Berry-Kravis, Elizabeth; Hagerman, Randi J; Von Raison, Florian; Gasparini, Fabrizio; Apostol, George; Ufer, Mike; Des Portes, Vincent; Gomez-Mancilla, Baltazar.

In: Psychopharmacology, Vol. 231, No. 6, 03.2014, p. 1237-1250.

Research output: Contribution to journalArticle

Jacquemont, S, Berry-Kravis, E, Hagerman, RJ, Von Raison, F, Gasparini, F, Apostol, G, Ufer, M, Des Portes, V & Gomez-Mancilla, B 2014, 'The challenges of clinical trials in fragile X syndrome', Psychopharmacology, vol. 231, no. 6, pp. 1237-1250. https://doi.org/10.1007/s00213-013-3289-0
Jacquemont S, Berry-Kravis E, Hagerman RJ, Von Raison F, Gasparini F, Apostol G et al. The challenges of clinical trials in fragile X syndrome. Psychopharmacology. 2014 Mar;231(6):1237-1250. https://doi.org/10.1007/s00213-013-3289-0
Jacquemont, Sébastien ; Berry-Kravis, Elizabeth ; Hagerman, Randi J ; Von Raison, Florian ; Gasparini, Fabrizio ; Apostol, George ; Ufer, Mike ; Des Portes, Vincent ; Gomez-Mancilla, Baltazar. / The challenges of clinical trials in fragile X syndrome. In: Psychopharmacology. 2014 ; Vol. 231, No. 6. pp. 1237-1250.
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