The Pharmacogenetics of Major Depression: Past, Present, and Future

  • Gonzalo Laje
    Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, Bethesda, Maryland.
    Search for articles by this author
  • Francis J. McMahon
    Address reprint requests to Francis J. McMahon, M.D., 35 Convent Drive, Room 1A202, Bethesda, MD 20892-3719
    Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, Bethesda, Maryland.
    Search for articles by this author
      Much has been said and written in recent years about the promise of pharmacogenetics. The vision is one of a world where we will be able to match medications with patients, maximizing efficacy while minimizing—or eliminating—adverse effects. This vision has been widely embraced out of a real desire to better help patients. But we are now some years into the pharmacogenetics enterprise, and we are beginning to accumulate real-world data in juxtaposition to our perhaps somewhat idealistic expectations. Some of the assumptions underlying the vision are beginning to be scrutinized more closely. Can we really match medications with patients when the range of available treatments is still quite small compared with the range of clinical presentations? Can genetics really provide the keys? How much of the difference between patients in efficacy and adverse effects will actually be attributable to differences in life experience and circumstances that we can neither measure biologically nor address medically? The technological advances of human genetics over the past decade, along with the recent availability of large treatment cohorts for study, are beginning to answer these questions. Pharmacogenetics is being transformed from a small field of promising leads into one of the foundations of evidence-based medicine. Few specialties stand to benefit as much as psychiatry, where all of our treatment options are empirical and the matching of patients with treatments is largely a question of clinical judgment.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Swen J.J.
        • Huizinga T.W.
        • Gelderblom H.
        • de Vries E.G.
        • Assendelft W.J.
        • Kirchheiner J.
        • et al.
        Translating pharmacogenomics: Challenges on the road to the clinic.
        PLoS Med. 2007; 4: e209
        • Wadelius M.
        • Chen L.Y.
        • Downes K.
        • Ghori J.
        • Hunt S.
        • Eriksson N.
        • et al.
        Common VKORC1 and GGCX polymorphisms associated with warfarin dose.
        Pharmacogenomics J. 2005; 5: 262-270
        • Murray C.J.
        • Lopez A.D.
        Evidence-based health policy—lessons from the Global Burden of Disease Study.
        Science. 1996; 274: 740-743
        • Perlis R.H.
        Pharmacogenetic studies of antidepressant response: How far from the clinic?.
        Psychiatr Clin North Am. 2007; 30: 125-138
        • Trivedi M.H.
        • Rush A.J.
        • Wisniewski S.R.
        • Nierenberg A.A.
        • Warden D.
        • Ritz L.
        • et al.
        Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice.
        Am J Psychiatry. 2006; 163: 28-40
        • Nierenberg A.A.
        Predictors of response to antidepressants: General principles and clinical implications.
        Psychiatr Clin North Am. 2003; 26: 345-352
        • Gibbons R.D.
        • Brown C.H.
        • Hur K.
        • Marcus S.M.
        • Bhaumik D.K.
        • Erkens J.A.
        • et al.
        Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents.
        Am J Psychiatry. 2007; 164: 1356-1363
        • Binder E.B.
        • Holsboer F.
        Pharmacogenomics and antidepressant drugs.
        Ann Med. 2006; 38: 82-94
        • Lesch K.P.
        • Bengel D.
        • Heils A.
        • Sabol S.Z.
        • Greenberg B.D.
        • Petri S.
        • et al.
        Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.
        Science. 1996; 274: 1527-1531
        • Serretti A.
        • Kato M.
        • De R.D.
        • Kinoshita T.
        Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients.
        Mol Psychiatry. 2007; 12: 247-257
        • Rush A.J.
        • Fava M.
        • Wisniewski S.R.
        • Lavori P.W.
        • Trivedi M.H.
        • Sackeim H.A.
        • et al.
        Sequenced treatment alternatives to relieve depression (STAR*D): Rationale and design.
        Control Clin Trials. 2004; 25: 119-142
        • Ioannidis J.P.
        • Trikalinos T.A.
        • Ntzani E.E.
        • Contopoulos-Ioannidis D.G.
        Genetic associations in large versus small studies: An empirical assessment.
        Lancet. 2003; 361: 567-571
        • Hu X.Z.
        • Rush A.J.
        • Charney D.
        • Wilson A.F.
        • Sorant A.J.
        • Papanicolaou G.J.
        • et al.
        Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression.
        Arch Gen Psychiatry. 2007; 64: 783-792
        • Laje G.
        • Buervenich S.
        • Manji H.
        • Rush A.J.
        • Wilson A.F.
        • McMahon F.J.
        Genetic markers of suicidal ideation emerging during antidepressant treatment.
        Am J Psychiatry. 2007; 164: 1530-1538
        • McMahon F.J.
        • Buervenich S.
        • Charney D.
        • Lipsky R.
        • Rush A.J.
        • Wilson A.F.
        • et al.
        Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment.
        Am J Hum Genet. 2006; 78: 804-814
        • Paddock S.
        • Laje G.
        • Charney D.
        • Rush A.J.
        • Wilson A.F.
        • Sorant A.J.
        • et al.
        Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort.
        Am J Psychiatry. 2007; 164: 1181-1188
        • Perlis R.H.
        • Purcell S.
        • Fava M.
        • Fagerness J.
        • Rush A.J.
        • Trivedi M.H.
        • et al.
        Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D study.
        Arch Gen Psychiatry. 2007; 64: 689-697
        • Kraft J.B.
        • Peters E.J.
        • Slager S.L.
        • Jenkins G.D.
        • Reinalda M.S.
        • McGrath P.J.
        • et al.
        Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample.
        Biol Psychiatry. 2007; 61: 734-742
        • Birney E.
        • Stamatoyannopoulos J.A.
        • Dutta A.
        • Guigo R.
        • Gingeras T.R.
        • Margulies E.H.
        • et al.
        Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.
        Nature. 2007; 447: 799-816
        • Feuk L.
        • Carson A.R.
        • Scherer S.W.
        Structural variation in the human genome.
        Nat Rev Genet. 2006; 7: 85-97
        • Duman R.S.
        • Newton S.S.
        Epigenetic marking and neuronal plasticity.
        Biol Psychiatry. 2007; 62: 1-3
        • Nemeroff C.B.
        • Vale W.W.
        The neurobiology of depression: Inroads to treatment and new drug discovery.
        J Clin Psychiatry. 2005; 66: 5-13