Clinical trial NCT00662571: Acamprosate: Genes Associated With Response
Official title: A Probe Study of Acamprosate: Genes Associated With Response
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Alcoholism
Keywords: nucleotide polymorphisms
disequilibrium haplotype
acamprosate
differentiate
pharmacogenomic
effective individualized treatment
alcohol dependent
N-methyl-D-aspartate receptor (NMDA)
metabotropic glutamate receptor
decreasing craving
abstinence maintenance
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: Samuel C. Johnson Foundation
First posted: 2008-04-21
Enrollment: 485
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects selected from Mayo Clinics Addiction programs.

Brief summary: In 2004, acamprosate was approved in the U.S. for abstinence maintenance, by decreasing craving, in alcoholic patients who have undergone detoxification. while a new anti-craving drug was encouraging, only 36.1% of the subjects treated with acamprosate remained abstinent for 6 months. Having the ability to identify treatment responsive individuals would have a major impact on the use of acamprosate.

Detailed description: The primary objective of this pharmacogenomic probe study of acamprosate is to identify genetic variations that predict response. Our hypothesis is that effective acamprosate response in alcohol dependent subjects may be influenced by genetically controlled variation in the functionality of the N-methyl-D-aspartate receptor (NMDA) and/or the type 5 metabotropic glutamate receptor (mGluR5). Hypothesis confirmation could lead to development of effective individualized treatment recommendations for alcohol dependent patients based on pharmacogenomically relevant genetic variations.

The general goal is to identify genetic polymorphic variants that differentiate subjects continuously abstinent for six months while taking acamprosate from relapsed subjects. The initial analysis will determine whether any of ten polymorphisms in four target genes (GRIN1, GRIN2A and GRIN2B that code for the NMDA receptor and GRM5 that codes for the type mGluR5 receptor) are associated with successful abstinence. Subsequent analyses will examine whether variation in a comprehensive set of 383 linkage disequilibrium haplotype tagged single nucleotide polymorphisms of these four genes predicts successfully abstinent subjects.

Eligibility criteria: Inclusion Criteria:

1. Male or females, Age 18-80.
2. 2. Primary diagnosis of alcohol dependence based on DSM-IV-TR criteria and determined by the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) (stable mood and anxiety disorders will not be exclusionary).
3. Prior enrollment in the IRB approved protocol "Developing a DNA Repository for Genomic Studies of Addiction: A Pilot Study".

Exclusion Criteria:

1. Inability to provide informed consent.
2. Inability to speak English.
3. History of hypersensitivity or allergic reaction to acamprosate.
4. Moderate to severe renal impairment, as determined by a creatinine level \> 1.5 mg/dL.
5. Diagnosis of primary biliary cirrhosis, chronic active hepatitis, and drug-induced hepatic insufficiency, as noted in the medical record.
6. Women who are pregnant, lactating, or are planning to become pregnant during the next year.
7. Any unstable active medical or additional psychiatric condition as determined by the investigator.

9. Active suicidal ideation as determined by responses provided during PRISM or as determined by the investigator.

Primary outcomes:
measure: Aim 1: To determine the relationship between genetically determined variation in the NMDA receptor and treatment response to acamprosate.
timeFrame: 6 months
Secondary outcomes:
measure: Aim 2: To determine the relationship between genetically determined variation in the mGluR5 receptor and treatment response to acamprosate.
timeFrame: 6months
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic, Department of Psychiatry
name: David Mrazek, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ho MF, Zhang C, Moon I, Wei L, Coombes B, Biernacka J, Skime M, Choi DS, Frye M, Schmidt K, Gliske K, Braughton J, Ngo Q, Skillon C, Seppala M, Oesterle T, Karpyak V, Li H, Weinshilboum R. Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism. Mol Metab. 2022 Sep;63:101534. doi: 10.1016/j.molmet.2022.101534. Epub 2022 Jun 22.
citation: Karpyak VM, Biernacka JM, Geske JR, Abulseoud OA, Brunner MD, Chauhan M, Hall-Flavin DK, Lewis KA, Loukianova LL, Melnyk GJ, Onsrud DA, Proctor BD, Schneekloth TD, Skime MK, Wittkopp JE, Frye MA, Mrazek DA. Gender-specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states. Addiction. 2016 Aug;111(8):1366-75. doi: 10.1111/add.13386. Epub 2016 May 5.