The pharmacogenetics of major depression: past, present, and future.

Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, Bethesda, MD 20892, USA.
Biological Psychiatry (Impact Factor: 9.47). 01/2008; 62(11):1205-7.
Source: PubMed
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    ABSTRACT: We examined the pharmacogenetic association between a variant in the κ-opioid receptor (OPRK1) gene and the response to treatment with a cocaine vaccine tested in a recent clinical trial (October 2003 to April 2005). This gene has a protective allele for opioid addiction that may act by the inhibiting dopamine activation associated with reinforcement. Sixty-nine DNA samples were obtained from 114 cocaine-dependent and opioid-dependent patients who were enrolled in a 16-week phase IIb randomized double-blind placebo-controlled trial and received five vaccinations over the first 12 weeks. We genotyped 66 of these patients for the rs6473797 variant of the OPRK1 gene and compared vaccine patients with placebo patients in terms of cocaine-free urines over time. Using repeated measures analysis of variance corrected for population structure, it was seen that vaccine pharmacotherapy reduced cocaine-positive urines significantly on the basis of the OPRK1 genotype. Among patients treated with the cocaine vaccine, those who were homozygous for the protective A allele of rs6473797 had the proportion of positive urines drop from 78 to 51% on using the vaccine (point-wise P<0.0001, experiment-wise P<0.005), whereas the positive urines of individuals carrying the nonprotective, risk G allele dropped from 82 to 77%. Strong treatment by single nucleotide polymorphism interactions reflected a lower baseline and significant reduction for placebo patients with the risk G allele (P<0.00001). This study indicates that a patient's OPRK1 genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence.
    Psychiatric genetics 08/2013; 23(6). · 2.33 Impact Factor
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    ABSTRACT: In clinical practice, ketamine, an antagonist of the N-methyl-D-aspartate receptor (NMDAR), is used to alleviate depressive symptoms in patients with major depressive disorder (MDD), especially in those with treatment-resistant depression (TRD). Accordingly, the human gene coding for the 2B subunit of the NMDAR (GRIN2B) is considered a promising candidate gene for MDD susceptibility. The primary aim of this study is to examine whether potentially functional polymorphisms of GRIN2B confer risk for MDD, and second to investigate whether GRIN2B acts as a genetic predictor for TRD in MDD patients. We enrolled 178 TRD and 612 non-TRD patients as well as 779 healthy controls. Four potentially functional polymorphisms (rs1805502, rs890, rs1806201, and rs7301328) within GRIN2B were genotyped in all participants. The haplotype analysis found significant differences in the distribution of the G-T haplotype between the TRD and control groups (corrected P = 0.007), and the frequency of the G-T haplotype in TRD group was significantly higher than that in the controls (TRD/control ratio 0.31:0.21). Statistically significant differences in allele and genotype frequencies were detected between TRD and non-TRD groups for the rs1805502 polymorphism within GRIN2B. There was a significant allelic association between rs1805502 and TRD with an excess of the G allele in the TRD group, compared to non-TRD group (OR = 1.55, 95 % CI = 1.18-2.05, corrected P = 0.008). These initial findings strengthen the hypothesis that GRIN2B not only confers susceptibility to TRD, but also plays a genetic predictor for TRD in MDD patients.
    Psychopharmacology 10/2013; · 3.99 Impact Factor
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    ABSTRACT: Major depression is a serious mental illness frequently associated with devastating consequences for those affected. Suicide rates are significantly elevated, creating a sense of urgency to identify effective yet safe treatment options. A plethora of antidepressants are available on the market today, designed to act on different neurotransmitter systems in the brain, providing the clinician with several treatment strategies. There is, however, very little guidance as to which antidepressant may be most successful in a certain individual. Biomarkers that can predict treatment outcome would thus be of great value, shortening the time until remission and reducing costs for the healthcare system by reducing unsuccessful treatment attempts. The proven contribution of heredity to major depression risk suggests that genetic markers may be good biomarkers for treatment outcome. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and a large ancillary pharmacogenetic study in 1953 STAR*D participants constitute the largest effort to date to identify genetic predictors of antidepressant treatment outcome. In this review, the results of candidate gene studies carried out so far are summarized and discussed, and some future directions are proposed.
    Molecular Diagnosis & Therapy 09/2012; 12(5). · 2.59 Impact Factor

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