Skip to main content
    • Aa
    • Aa

Pharmacogenetics of mood disorders: what clinicians need to know

  • Gonzalo Laje (a1)

Pharmacogenetics brought the promise of matching individuals with treatments that would be efficacious while minimizing adverse events. This has been long needed in psychiatry, where treatment options have been empirical and treatment choices have been made largely based on clinical judgment. The efficacy and tolerability of antidepressants, the most common drugs used in mood disorders, have been widely studied in pharmacogenetics. Genetic association studies have been reported for pharmacokinetic genes such as the CYP450 isoenzymes or MDR1, and pharmacodynamic genes such as the serotonin transporter (SLC6A4) or the serotonin 2A receptor (HTR2A). However, despite the large number of reports, clinically useful predictors are still scarce for antidepressant monotherapy. Pharmacogenetic predictors of efficacy for mood stabilizers such as lithium and anticonvulsants have not had a dissimilar fate, and clinically meaningful markers are yet to emerge. The lack of consistent results may be in part due to small samples of heterogeneous populations and lack of consensus on phenotype definitions. Current pharmacogenetic recommendations include testing for HLA-B*1502 when using carbamazepine in Asian ancestry populations to prevent Stevens–Johnson syndrome, CYP2D6 genotypes when using pimozide, and CYP2D6 in polypharmacy to minimize drug interactions. This review, which is aimed at clinicians, lays the basis for understanding strengths and weaknesses of pharmacogenetic studies and outlines current clinical uses of these biomarkers.

Corresponding author
*Address for correspondence: Gonzalo Laje, 5480 Wisconsin Avenue, #228 Chevy Chase, MD 20815, USA.(Email
Hide All

I would like to express my deepest gratitude to Drs. McMahon and Zarate for their mentorship and support over the past several years.

Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2. J Angst . A clinical analysis of the effects of tofranil in depression: longitudinal and follow-up studies: treatment of blood-relations. Psychopharmacologia. 1961; 2: 381407.

3. CM Pare , JW Mack . Differentiation of two genetically specific types of depression by the response to antidepressant drugs. J Med Genet. 1971; 8(3): 306309.

4. M Wadelius , LY Chen , K Downes , etal. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005; 5(4): 262270.

5. RS Duman , SS Newton . Epigenetic marking and neuronal plasticity. Biol Psychiatry. 2007; 62(1): 13.

6. HJ Kang , YI Kawasawa , F Cheng , etal. Spatio-temporal transcriptome of the human brain. Nature. 2011; 478(7370): 483489.

7. G Laje , DM Cannon , AS Allen , etal. Genetic variation in HTR2A influences serotonin transporter binding potential as measured using PET and [11C]DASB. Int J Neuropsychopharmacol. 2010; 13(6): 715724.

8. XZ Hu , AJ Rush , D Charney , etal. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007; 64(7): 783792.

9. IM Lesser , DB Castro , BN Gaynes , etal. Ethnicity/race and outcome in the treatment of depression: results from STAR*D. Med Care. 2007; 45(11): 10431051.

10. G Laje , RH Perlis , AJ Rush , FJ McMahon . Pharmacogenetics studies in STAR*D: strengths, limitations, and results. Psychiatr Serv. 2009; 60(11): 14461457.

11. A Khan , M Detke , SR Khan , C Mallinckrodt . Placebo response and antidepressant clinical trial outcome. J Nerv Ment Dis. 2003; 191(4): 211218.

12. JC Fournier , RJ DeRubeis , SD Hollon , etal. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010 ; 303(1): 4753.

13. MH Trivedi , AJ Rush , SR Wisniewski , etal. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006; 163(1): 2840.

14. A Serretti , M Kato , JL Kennedy . Pharmacogenetic studies in depression: a proposal for methodologic guidelines. Pharmacogenomics J. 2008; 8(2): 90100.

15. FJ McMahon , S Buervenich , D Charney , etal. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006; 78(5): 804814.

16. EJ Peters , SL Slager , JB Kraft , etal. Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample. PLoS One. 2008; 3(4): e1872.

17. DA Mrazek , AJ Rush , JM Biernacka , etal. SLC6A4 variation and citalopram response. Am J Med Genet B Neuropsychiatr Genet. 2009; 150B(3): 341351.

18.GENDEP Investigators, MARS Investigators, STAR*D Investigators. Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies. Am J Psychiatry. 2013; 170(2): 207217.

19. HB Rasmussen , TM Werge . Novel procedure for genotyping of the human serotonin transporter gene-linked polymorphic region (5-HTTLPR)—a region with a high level of allele diversity. Psychiatr Genet. 2007; 17(5): 287291.

21. MJ Taylor , S Sen , Z Bhagwagar . Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biol Psychiatry. 2010; 68(6): 536543.

22. GM Murphy Jr, SB Hollander , HE Rodrigues , C Kremer , AF Schatzberg . Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry. 2004; 61(11): 11631169.

24. JB Kraft , EJ Peters , SL Slager , etal. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry. 2007; 61(6): 734742.

25. S Paddock , G Laje , D Charney , etal. Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry. 2007; 164(8): 11811188.

26. S Horstmann , S Lucae , A Menke , etal. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010; 35(3): 727740.

27. E Green , N Craddock . Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: evidence, limitations, and implications. Curr Psychiatry Rep. 2003; 5(6): 469476.

29. MF Egan , M Kojima , JH Callicott , etal. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003; 112(2): 257269.

30. M Ventriglia , L Bocchio Chiavetto , L Benussi , etal. Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol Psychiatry. 2002; 7(2): 136137.

31. JP Hwang , SJ Tsai , CJ Hong , etal. The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiology Aging. 2006; 27(12): 18341837.

32. L Ribeiro , JV Busnello , RM Cantor , etal. The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in Mexican-Americans. Neuroreport. 2007; 18(12): 12911293.

33. J Schumacher , RA Jamra , T Becker , etal. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry. 2005; 58(4): 307314.

34. CJ Hong , SJ Huo , FC Yen , etal. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology. 2003; 48(4): 186189.

36. L Chen , DA Lawlor , SJ Lewis , etal. Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2008; 147B(6): 814821.

37. MJ Choi , RH Kang , SW Lim , KS Oh , MS Lee . Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res. 2006; 1118(1): 176182.

38. S Anttila , K Huuhka , M Huuhka , etal. Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J Neural Transm. 2007; 114(8): 10651068.

39. K Domschke , B Lawford , G Laje , etal. Brain-derived neurotrophic factor (BDNF) gene: no major impact on antidepressant treatment response. Int J Neuropsychopharmacol. 2010; 13(1): 93101.

40. CA Zarate Jr., JB Singh , PJ Carlson , etal. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8): 856864.

41. RJ Liu , FS Lee , XY Li , etal. Brain-derived neurotrophic factor Val66Metallele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012; 71(11): 9961005.

42. G Laje , N Lally , D Mathews , etal. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry. 2012; 72(11): e27e28.

43. HA Garriock , JB Kraft , SI Shyn , etal. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry. 2010; 67(2): 133138.

44. M Ising , S Lucae , EB Binder , etal. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry. 2009; 66(9): 966975.

45. R Uher , N Perroud , MY Ng , etal. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am J Psychiatry. 2010; 167(5): 555564.

46. G Laje , FJ McMahon . Genome-wide association studies of antidepressant outcome: a brief review. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(7): 15531557.

47.Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors. Genet Med. 2007; 9(12): 819825.

48. P Huezo-Diaz , N Perroud , EP Spencer , etal. CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. J Psychopharmacol. 2012; 26(3): 398407.

50. RH Perlis , S Purcell , M Fava , etal. 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(6): 689697.

51. G Laje , S Paddock , H Manji , etal. Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry. 2007; 164(10): 15301538.

52. A Menke , S Lucae , S Kloiber , etal. Genetic markers within glutamate receptors associated with antidepressant treatment-emergent suicidal ideation. Am J Psychiatry. 2008; 165(7): 917918.

53. G Laje , AS Allen , N Akula , etal. Genome-wide Association Study of Suicidal Ideation Emerging During Citalopram Treatment of Depressed Outpatients. Pharmacogenet Genomics. 2009; 19(9): 666674.

54. A Menke , K Domschke , D Czamara , etal. Genome-wide association study of antidepressant treatment-emergent suicidal ideation. Neuropsychopharmacology. 2012; 37(3): 797807.

55. N Perroud , R Uher , MY Ng , etal. Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project. Pharmacogenomics J. 2012; 12(1): 6877.

56. N Perroud , KJ Aitchison , R Uher , etal. Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project. Neuropsychopharmacology. 2009; 34(12): 25172528.

57. P Grof , A Duffy , P Cavazzoni , etal. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002; 63(10): 942947.

58. MJ McCarthy , SG Leckband , JR Kelsoe . Pharmacogenetics of lithium response in bipolar disorder. Pharmacogenomics. 2010; 11(10): 14391465.

59. PE Brandish , M Su , DJ Holder , etal. Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex. Neuron. 2005; 45(6): 861872.

60. AP Popkie , LC Zeidner , AM Albrecht , etal. Phosphatidylinositol 3-kinase (PI3 K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. J Biol Chem. 2010; 285(53): 4133741347.

62. RH Perlis , EB Dennehy , DJ Miklowitz , etal. Retrospective age at onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study. Bipolar Disord. 2009; 11(4): 391400.

63. A Squassina , M Manchia , J Borg , etal. Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. Pharmacogenomics. 2011; 12(11): 15591569.

64. TG Schulze , M Alda , M Adli , etal. The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment. Neuropsychobiology. 2010; 62(1): 7278.

65. WH Chung , SI Hung , HS Hong , etal. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004; 428(6982): 486.

66. M McCormack , A Alfirevic , S Bourgeois , etal. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011; 364(12): 11341143.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 2
Total number of PDF views: 34 *
Loading metrics...

Abstract views

Total abstract views: 168 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd May 2017. This data will be updated every 24 hours.