Randomized Controlled Study of Donepezil in Fragile X Syndrome

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.

Inclusion Criteria:

1. confirmed genetic diagnosis of fragile X syndrome

2. age >=12, <=29

3. Verbal IQ >= 50, <=75

4. Tanner pubertal stage >= 3

Exclusion Criteria:

1. Current or lifetime DSM-IV diagnosis of bipolar disorder, schizophrenia,
schizoaffective disorder, or psychotic disorder, NOS based upon reported history

2. Poorly controlled seizure disorder or taking more than one anticonvulsant (subjects
cannot be prescribed carbamazepine, phenytoin, or phenobarbital due to potential
interaction effects with donepezil). The investigators will permit one anticonvulsant
as monotherapy for seizures if the seizure disorder is well controlled with no
evidence of break through seizures within the past year

3. Concomitant or anticipated use of other medications having prominent effects on the
cholinergic system (e.g., bethanechol, benztropine, atropine, succinylcholine)

4. Medications or nutritional supplements that have the potential to significantly alter
donepezil levels, clinical effects or adverse reactions (antifungal agents,
corticosteroids, erythromycin, beta-blockers, calcium channel blockers, NSAIDs,
gingko biloba, St. John's wort)

5. Medical illnesses where donepezil could worsen the condition such as asthma, cardiac
conduction abnormalities, urinary obstruction or gastrointestinal disease with
gastric bleeding

6. Pregnancy or sexually active females not using a reliable method of contraception

7. If considering participation in brain MRI part of the study, then any
contraindications for MRI (e.g., orthodontia, metal in or on the body, etc.)