An Open-Label Trial of Donepezil in Fragile X Syndrome

Fragile X syndrome is the most common known inherited cause of neurodevelopmental disability. Functional magnetic resonance imaging (fMRI) studies from our laboratory indicate that specific brain regions using the neurochemical, acetylcholine, show significantly reduced activation during learning. Since donepezil is a medication that enhances acetylcholine function in the brain, the purpose of this study is to determine if donepezil has any beneficial effect on behavior or cognition in subjects with fragile X syndrome.

Study Overview

• Status: Completed
• Conditions: Fragile X Syndrome
• Intervention / Treatment: Drug: donepezil

Detailed Description

Fragile X syndrome is the most common genetically inherited cause of neurodevelopmental disability in humans, affecting approximately 1:2000 to 4000 live births. Affected individuals have significant, long-term problems with learning, and often with behavior as well. The disorder is caused by the presence of a greatly expanded CGG repeat within the FMR1 gene on the long arm of the X chromosome. Abnormal methylation of this repeat, and adjacent areas within the FMR1 gene impedes transcription, ultimately resulting in reduced production of the FMR1 protein (FMRP). This protein is expressed in neurons, with particularly high levels of gene transcription occurring in the nucleus basalis (basal forebrain) and hippocampus. A recent functional imaging study from our group showed girls with fragile X to have greatly reduced levels of brain activation in the basal forebrain and hippocampal activation during a memory task. The nucleus basalis, is a cholinergic nucleus with widespread connections to the neocortex. It is critical to visuospatial attention in rodents and primates and is presumed to play a similar role in humans. The finding of decreased basal forebrain activation in girls with fragile X, considered in light of histological evidence showing high transcription levels of FMR1 in healthy nucleus basalis, suggests the possibility of a functional cholinergic deficit in fragile X syndrome.

Donepezil is an acetylcholinesterase inhibitor which slows the degradation of synaptic acetylcholine thereby increasing its availability. It is approved for the treatment of mild-moderate Alzheimer's disease. It has been studied in several other neurologic disorders--including vascular dementia, Lewy Body dementia, and Down's syndrome (with and without dementia)--where it has shown varying degrees of efficacy but consistently high degrees of safety and tolerability. The goal of the proposed study is to determine if enhancing cholinergic activity with donepezil has beneficial effects on behavior or cognition in subjects with fragile X syndrome.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:1. Confirmed genetic diagnosis of fragile X syndrome

2. Age e 14

3. Verbal IQ e 60 Exclusion Criteria:1. Currently taking any anticholinergic medications, tricyclic antidepressant medications, or diphenhydramine.

2. Presence of cardiac disease or bradycardia (< 60 beats/minute) at initial evaluation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open donepezil; open donepezil	Drug: donepezil; donepezil 5 mg daily for 3 weeks (days 1-21); 10 mg daily for 3 weeks (days 22-42); Other Names: Aricept; donepezil hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Scores on learning tests at baseline	baseline, day 21, day 42
score on test of attention	baseline, day 21, day 42
score on measures of behavior	baseline, day 21, day 42
scores on learning tests	baseline, day 21, day 42
scores on working memory tests	baseline, day 21, day 42

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Allan L Reiss, Stanford University

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: September 15, 2005
• First Submitted That Met QC Criteria: September 15, 2005
• First Posted (Estimate): September 22, 2005

Study Record Updates

• Last Update Posted (Estimate): December 13, 2012
• Last Update Submitted That Met QC Criteria: December 11, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Chromosome Disorders; Sex Chromosome Disorders; Syndrome; Fragile X Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Nootropic Agents; Cholinesterase Inhibitors; Donepezil
• Other Study ID Numbers: 96239