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: 10.25). 01/2008; 62(11):1205-7. DOI: 10.1016/j.biopsych.2007.09.016
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Available from: Francis J Mcmahon, Jul 28, 2015
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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 · 4.09 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 · 2.06 Impact Factor
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    • "Several studies have investigated the use of genetic markers to predict antidepressant treatment outcome in major depressive disorder (MDD) (Laje & McMahon, 2007). However, despite many interesting findings no consensus exists. "
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    ABSTRACT: In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [11C]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [11C]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [11C]DASB BPND in thalamus and three markers in a region spanning the 3' untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression.
    The International Journal of Neuropsychopharmacology 07/2010; 13(6):715-24. DOI:10.1017/S1461145709991027 · 5.26 Impact Factor
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