Randomized Controlled Study of Donepezil in Fragile X Syndrome
Condition: Fragile X Syndrome
MeSH terms: Fragile X Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Fragile X syndrome (FraX) is the most common known heritable cause of human intellectual
      disability. Though recent research has revealed much about the genetic and neurobiological
      bases of FraX, knowledge about specific and effective treatments for affected individuals is
      lacking. Based on information from both human and animal studies, one cause of intellectual
      disability in FraX may be related to deficits in a particular brain neurotransmitter system
      (the "cholinergic" system). Thus, the investigators propose to use a specific medication,
      donepezil, to augment cholinergic system in adolescents affected by FraX. If found to be
      effective, the knowledge generated by this research may also be relevant to other
      developmental disorders that share common disease pathways with FraX.
    

Detailed description: 
      Fragile X syndrome (FraX), a neurodevelopmental disorder caused by mutations of the FMR1
      gene, is the most common known heritable cause of cognitive and behavioral disability in
      humans. Though research progress pertaining to FraX has been extraordinary in many areas,
      many critical gaps in knowledge remain. In particular, there is a dearth of information on
      treatments designed to address the often-serious cognitive and behavioral symptoms of FraX.
      Like many other developmental disorders, descriptions of treatments for FraX that do exist in
      the literature are primarily derived from uncontrolled case studies or series, with both
      pharmacological and behavioral interventions targeted to symptoms associated with
      phenomenologically defined "co-morbid" diagnoses such as AD/HD, autism spectrum disorders
      (ASD) or anxiety disorders. These circumstances are suboptimal as such symptom-based
      treatments represent a low level of specificity with respect to the underlying pathogenesis
      of cognitive and behavioral problems. Accordingly, new research to develop more effective,
      disease-specific treatments for persons with FraX is greatly needed.

      Converging evidence from our research group and others strongly support a hypothesis of
      functional cholinergic deficits contributing to cognitive-behavioral dysfunction in FraX.
      This evidence includes: (1) abnormalities of cholinergic pathway function and neurochemistry
      observed with functional MRI and 1H-MRS, respectively, in FraX, (2) an analysis of FMR1
      expression during human fetal development indicating particularly high expression in
      cholinergic brain regions, (3) cholinergic system abnormalities detected in the mouse and fly
      models of FraX, (4) an analysis of the specific profile of cognitive and behavioral deficits
      in FraX in relation to current knowledge of cholinergic system functions, and, (5)
      significant improvements in cognition and behavior observed in 12 individuals with FraX
      during an open-label trial of donepezil, a cholinesterase inhibitor. Accordingly, the
      proposed project will consist of a double blind, placebo controlled trial of donepezil in 50
      individuals with FraX, ages 12 to 29 years. The primary hypothesis is that subjects receiving
      donepezil will show greater improvements in specific measures of behavior and cognition,
      relative to the placebo group. In addition to direct benefit to persons affected by FraX,
      findings from the proposed research are likely to be highly relevant to subgroups of
      (currently) idiopathic developmental disorders, such as autism, that might share common
      pathophysiological mechanisms of disease with FraX. Such shared mechanisms could occur
      through intersecting pathways involving FMR1 protein function or as a result of similarities
      in the contribution of cholinergic dysfunction to cognitive and behavioral disability.
    

Intervention name(s): donepezil; sugar pill
Intervention type(s): Drug; Drug
Intervention description(s): donepezil (2.5 mg to 10.0 mg per day for 12 weeks); sugar pill (2.5 mg to 10.0 mg per day for 12 weeks)
Other intervention name(s): Aricept; lactose
Intervention MeSH terms: Donepezil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment