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: 10.26). 01/2008; 62(11):1205-7. DOI: 10.1016/j.biopsych.2007.09.016
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Available from: Francis J Mcmahon,
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    • "Multiple factors, including environmental and genetic, are likely involved in the pathophysiology of TRD. However, mounting evidence has demonstrated that genetic variations associated with antidepressant responses appear to cluster in families, supporting a more critical role for genetic variations in mechanisms underlying TRD (Laje and McMahon, 2007; O'Reilly et al., 1994). Recently, the neurotrophin hypothesis of MDD has attracted more attention (Dunham et al., 2009; Fernandes et al., Contents lists available at SciVerse ScienceDirect "
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    ABSTRACT: Background: Although genetic variants may play a key role in development of treatment-resistant depression (TRD), relevant research is scarce. Methods: To examine whether the polymorphisms of BDNF (rs6265) and NTRK2 (rs1387923, rs2769605 and rs1565445) genes confer risk for TRD in major depressive disorder (MDD), a total of 948 MDD patients were recruited in a 12-week, multicenter, prospective longitudinal study. Results: Our study showed a significant allelic association between rs1565445 and TRD with an excess of the T allele in the TRD group, compared to non-TRD group (OR = 1.43, 95%CI: 1.16-1.76, p = 0.0008); while patients with genotype C/C and T/C in rs1565445 were less likely to develop TRD than those carrying T/T (OR = 0.52, 95%CI: 0.33-0.82; OR = 0.72, 95%CI: 0.54-0.97, respectively; p = 0.005). Haplotype T-T (rs1565445 and rs1387923) had 1.41-fold increased risk of TRD (p = 0.0014). Furthermore, significant four-locus (rs1387923-rs1565445-rs2769605-rs6265) gene-gene interactions were detected by the Multifactor-dimensionality reduction (MDR) method. Discussion: These results suggest that the interactions of BDNF (rs6265) with NTRK2 (rs1387923, rs2769605 and rs1565445) gene polymorphisms likely play an essential role in the development of TRD in Han Chinese MDD patients.
    Journal of Psychiatric Research 11/2012; 47(1). DOI:10.1016/j.jpsychires.2012.10.003 · 3.96 Impact Factor
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    • "One factor that further might have biased our results is the medication of depressed patients. Antidepressants are known to have antinociceptive effects, although most studies on analgesic effects of antidepressants were performed on tricyclic antidepressants [16] [31]. Furthermore, recent studies indicate that modern antidepressants such as selective serotonine reuptake inhibitors SSRI or norepinephrine and serotonine reuptake inhibitors NaSRI can influence pain perception (i.e., neuropathic pain) in healthy subjects or animal models [32]. "
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    ABSTRACT: Depression and clinical pain have been shown being strongly associated with each other. However, recent studies have demonstrated that depressed patients are less sensitive to experimental pain than healthy individuals. Reasons for this phenomenon are still elusive. The study investigates whether cutaneous C- and/or Aδ-fibers might contribute to this phenomenon. C- and Aδ-fiber systems were assessed in 12 depressed patients and 12 sex- and age-matched healthy controls using stimulation of tiny skin areas by laser heat stimuli. Detection and pain thresholds as well as proportions of trials associated with C- and Aδ-fiber stimulation as well as of non-perceived trials were compared between groups. Patients showed elevated pain thresholds and significantly less C-fiber responses. They also failed significantly more often to recognize the noxious laser-heat stimuli. Thus, higher pain thresholds to experimental stimuli in depressed patients are not only associated with reduced perception of cutaneous Aδ-, but also with decreased perception of selective C-fiber input. The physiological underpinnings of the phenomenon remain elusive and should be examined in the future to understand whether it is based on changes in the periphery or in central processing or both.
    Neuroscience Letters 07/2011; 498(1):89-92. DOI:10.1016/j.neulet.2011.04.069 · 2.03 Impact Factor
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    • "Despite evidence that pharmacokinetic factors under genetic control are correlated with response and toxicity to tricyclic antidepressants, there has been little evidence to suggest that this is the case with response to or tolerance of the SSRIs [64]. The current widespread use of SSRIs in treatment of depression has resulted in a large body of literature on SSRI pharmacogenetics [65]. Most of these studies focus on candidate genes related to monoamine function, including the serotonin transporter (the molecular target for SSRIs), tryptophan hydroxylase-1, monoamine oxidase A, and the type 2A serotonin receptor. "
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    ABSTRACT: During the past several years, we have achieved a deeper understanding of the etiology/pathophysiology of major depressive disorder (MDD). However, this improved understanding has not translated to improved treatment outcome. Treatment often results in symptomatic improvement, but not full recovery. Clinical approaches are largely trial-and-error, and when the first treatment does not result in recovery for the patient, there is little proven scientific basis for choosing the next. One approach to enhancing treatment outcomes in MDD has been the use of standardized sequential treatment algorithms and measurement-based care. Such treatment algorithms stand in contrast to the personalized medicine approach, in which biomarkers would guide decision making. Incorporation of biomarker measurements into treatment algorithms could speed recovery from MDD by shortening or eliminating lengthy and ineffective trials. Recent research results suggest several classes of physiologic biomarkers may be useful for predicting response. These include brain structural or functional findings, as well as genomic, proteomic, and metabolomic measures. Recent data indicate that such measures, at baseline or early in the course of treatment, may constitute useful predictors of treatment outcome. Once such biomarkers are validated, they could form the basis of new paradigms for antidepressant treatment selection.
    Current Psychiatry Reports 10/2010; 12(6):553-62. DOI:10.1007/s11920-010-0160-4 · 3.24 Impact Factor
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