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. DOI: 10.1016/j.biopsych.2007.09.016
Source: PubMed
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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; DOI:10.1007/s00213-013-3297-0 · 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). DOI:10.1007/BF03256297 · 2.59 Impact Factor
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    ABSTRACT: Major depressive disorder (MDD) is estimated by the World Health Organization to be the fourth leading cause of loss of disability-adjusted life years. In the National Comorbidity Survey, MDD is the most common mental illness and is one of the most common and disabling of all illnesses (Kessler et al., 1994). The lifetime risk for MDD is 10–25% in women and 5–12% in men, and at any point its prevalence is 5–9% in women and 2–3% in men. Given the widespread and disabling nature of the illness, MDD is of great public health concern. The first useful antidepressants, imipramine and isoniazid, were serendipitously found to have antidepressant properties in the 1950s. These discoveries – coupled with the observation that reserpine, which depletes monoamines, induced depres-sion – led to the development of the monoamine hypothesis of depression. This led to the rational development of drugs which affect central nervous system monoamines, primarily norepinephrine (noradrenaline), serotonin (5-HT), and dopamine. The tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) formed the foundation for several decades of pharmacologic treat-ments for depression, although their side-effects (including lethality in overdose in the case of TCAs, and strict dietary restriction to avoid hypertensive crises in the case of MAOIs) limited their utility and tolerability. Pharmaceutical research focused on the development of drugs with improved tolerability and safety. Next-generation drugs such as trazodone, a 5-HT 2 -receptor antagonist, were an incre-mental improvement, but not until the arrival to the market in 1988 of the first selective serotonin reuptake inhibitor (SSRI), fluoxetine (Prozac), did the use of antidepressants markedly change. Several other SSRIs followed, including parox-etine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro).

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Jun 4, 2014