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Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.

ABSTRACT: BACKGROUND:A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence. This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect. METHODS:Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80, 120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores. RESULTS:Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence. CONCLUSIONS:A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.

SUBMITTER: Phelps LE

PROVIDER: S-EPMC2727595 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.

Phelps Laura E LE Brutsche Nancy N Moral Jazmin R JR Luckenbaugh David A DA Manji Husseini K HK Zarate Carlos A CA

Biological psychiatry 20081108 2

<h4>Background</h4>A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar ...[more]

PMID: 18996507

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Project description:Intravenous N-methyl-d-aspartate (NMDA) antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder.Adult outpatients with major depressive disorder and partial response or nonresponse to their current antidepressant (as indicated by a 17-item Hamilton Depression Rating Scale score of ? 16 at baseline) were randomized (from July 2006-December 2011) to add memantine (flexible dose 5-20 mg/d, with all memantine group participants reaching the dose of 20 mg/d) (n = 15) or placebo (n = 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated-measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects.84% of participants completed the trial, including 93% of participants receiving memantine. Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (? = 0.133, favoring placebo, P = .74) or at study completion (week 8 mean [SD] MADRS score change = -7.13 [6.61] [memantine]; -7.25 [11.14] [placebo]; P = .97). A minimal to small effect size (comparing change to baseline variability) favoring placebo was observed (Cohen d = 0.19). Similarly, no substantial effect sizes favoring memantine nor statistically significant between-group differences were observed on secondary efficacy outcomes.This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder.ClinicalTrials.gov identifier: NCT00344682.

Project description:BackgroundA previous genome-wide linkage study of alcohol dependence in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The KIAA0040 gene has been mapped to this region (1q24 - q25). A recent genome-wide association study using SAGE (the Study of Addiction: Genetics and Environment) and COGA (Collaborative Study on the Genetics of Alcoholism) found five SNPs within the KIAA0040 gene significantly associated with alcohol dependence. A meta-analysis using data from these sources also found the KIAA0040 gene significantly associated with alcohol dependence.MethodsUsing family data consisting of 1000 individuals with phenotypic data (762 with both phenotype and DNA), finer mapping of a 0.3 cM region that included the KIAA0040 gene and a flanking gene was undertaken using SNPs with minor allele frequency (MAF) ≥ 0.15 and pair-wise linkage disequilibrium (LD) of r2 < 0.8 using the HapMap CEU population.ResultsSignificant FBAT p-values were observed for six SNPs, four within the KIAA0040 gene (rs2269650, rs2861158, rs1008459, rs2272785) and two adjacent to KIAA0040 (rs10912899 and rs3753555). Five haplotype blocks of varying size were identified using HAPLOVIEW. Analysis using the haplotype-based test function of FBAT revealed one two-SNP block (rs1008459-rs2272785) associated with alcohol dependence. This block showed a pattern of transmission in which one haplotype, CT, with a frequency of 0.577 was found to be over-transmitted to affected offspring (p = 0.017) while another haplotype, AG, with a frequency of 0.238 was found to be under-transmitted to affected offspring (p = 0.006). A three-SNP block (rs1008459-rs2272785-rs375355) showed an overall significant association (p = 0.011) with alcohol dependence with the haplotype ACT over-transmitted to affected offspring (p = 0.016) and the haplotype GAG under-transmitted (p = 0.002).ConclusionsFamily-based association analysis shows the KIAA0040 gene significantly associated with alcohol dependence. The potential importance of the KIAA0040 gene for AD risk is currently unknown. However, the present results support earlier findings from a genome-wide association study.

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Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.

Publications

Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.

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