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Pharmacogenomic study of side-effects for antidepressant treatment options in STAR*D

  • S. L. Clark (a1), D. E. Adkins (a1), K. Aberg (a1), J. M. Hettema (a2), J. L. McClay (a1), R. P. Souza (a3) and E. J. C. G. van den Oord (a1)
  • DOI:
  • Published online: 01 November 2011

Understanding individual differences in susceptibility to antidepressant therapy side-effects is essential to optimize the treatment of depression.


We performed genome-wide association studies (GWAS) to search for genetic variation affecting the susceptibility to side-effects. The analysis sample consisted of 1439 depression patients, successfully genotyped for 421K single nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Outcomes included four indicators of side-effects: general side-effect burden, sexual side-effects, dizziness and vision/hearing-related side-effects. Our criterion for genome-wide significance was a prespecified threshold ensuring that, on average, only 10% of the significant findings are false discoveries.


Thirty-four SNPs satisfied this criterion. The top finding indicated that 10 SNPs in SACM1L mediated the effects of bupropion on sexual side-effects (p=4.98×10−7, q=0.023). Suggestive findings were also found for SNPs in MAGI2, DTWD1, WDFY4 and CHL1.


Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that could mediate adverse effects of antidepressant medication.

Corresponding author
*Address for correspondence: Dr S. L. Clark, Center for Biomarker Research and Personalized Medicine, School of Pharmacy, McGuire Hall, Room 216A, P.O. Box 980533, Richmond, VA 23298-0581, USA. (Email:
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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.

K Aberg , DE Adkins , J Bukszar , BT Webb , SN Caroff , DD Miller , J Sebat , S Stroup , AH Fanous , VI Vladimirov , JL McClay , JA Lieberman , PF Sullivan , EJ van den Oord (2010 a). Genomewide association study of movement-related adverse antipsychotic effects. Biological Psychiatry 67, 279282.

DE Adkins , K Aberg , JL McClay , J Bukszar , Z Zhao , P Jia , TS Stroup , D Perkins , JP McEvoy , JA Lieberman , PF Sullivan , EJ van den Oord (2011). Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Molecular Psychiatry 16, 321332.

DE Adkins , K Aberg , JL McClay , JM Hettema , SG Kornstein , J Bukszar , EJ van den Oord (2010). A genomewide association study of citalopram response in major depressive disorder – a psychometric approach. Biological Psychiatry 68, e25e27.

D Altshuler , MJ Daly , ES Lander (2008). Genetic mapping in human disease. Science 322, 881888.

ME Ayala (2009). Brain serotonin, psychoactive drugs, and effects on reproduction. Central Nervous System Agents in Medicinal Chemistry 9, 258276.

JG Barbee (1998). Mixed symptoms and syndromes of anxiety and depression: diagnostic, prognostic, and etiologic issues. Annals of Clinical Psychiatry 10, 1529.

JC Barrett , B Fry , J Maller , MJ Daly (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263265.

GW Beecham , ER Martin , YJ Li , MA Slifer , JR Gilbert , JL Haines , MA Pericak-Vance (2009). Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. American Journal of Human Genetics 84, 3543.

MF Berger , MS Lawrence , F Demichelis , Y Drier , K Cibulskis , AY Sivachenko , A Sboner , R Esgueva , D Pflueger , C Sougnez , R Onofrio , SL Carter , K Park , L Habegger , L Ambrogio , T Fennell , M Parkin , G Saksena , D Voet , AH Ramos , TJ Pugh , J Wilkinson , S Fisher , W Winckler , S Mahan , K Ardlie , J Baldwin , JW Simons , N Kitabayashi , TY Macdonald , PW Kantoff , L Chin , SB Gabriel , MB Gerstein , TR Golub , M Meyerson , A Tewari , ES Lander , G Getz , MA Rubin , LA Garraway (2011). The genomic complexity of primary human prostate cancer. Nature 470, 214220.

MA Black (2004). A note on the adaptive control of false discovery rates. Journal of the Royal Statistical Society. Series B 66, 297304.

A Blagoveshchenskaya , FY Cheong , HM Rohde , G Glover , A Knodler , T Nicolson , G Boehmelt , P Mayinger (2008). Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1. Journal of Cell Biology 180, 803812.

BW Brown , K Russell (1997). Methods correcting for multiple testing: operating characteristics. Statistics in Medicine 16, 25112528.

SA Bull , XH Hu , EM Hunkeler , JY Lee , EE Ming , LE Markson , B Fireman (2002 a). Discontinuation of use and switching of antidepressants: influence of patient-physician communication. Journal of the American Medical Association 288, 14031409.

SA Bull , EM Hunkeler , JY Lee , CR Rowland , TE Williamson , JR Schwab , SW Hurt (2002 b). Discontinuing or switching selective serotonin-reuptake inhibitors. Annals of Pharmacotherapy 36, 578584.

E Byun , SJ Caillier , X Montalban , P Villoslada , O Fernandez , D Brassat , M Comabella , J Wang , LF Barcellos , SE Baranzini , JR Oksenberg (2008). Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Archives of Neurology 65, 337344.

QY Chen , Q Chen , GY Feng , K Lindpaintner , Y Chen , X Sun , Z Chen , Z Gao , J Tang , L He (2005). Case-control association study of the close homologue of L1 (CHL1) gene and schizophrenia in the Chinese population. Schizophrenia Research 73, 269274.

AH Clayton , JK Warnock , SG Kornstein , R Pinkerton , A Sheldon-Keller , EL McGarvey (2004). A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. Journal of Clinical Psychiatry 65, 6267.

G Corona , M Maggi (2010). The role of testosterone in erectile dysfunction. Nature Reviews. Urology 7, 4656.

K Demyttenaere , A Albert , P Mesters , W Dewe , K De Bruyckere , M Sangeleer (2005). What happens with adverse events during 6 months of treatment with selective serotonin reuptake inhibitors? Journal of Clinical Psychiatry 66, 859863.

K Demyttenaere , L Jaspers (2008). Review: bupropion and SSRI-induced side effects. Journal of Psychopharmacology 22, 792804.

F Deng , MG Price , CF Davis , M Mori , DL Burgess (2006). Stargazin and other transmembrane AMPA receptor regulating proteins interact with synaptic scaffolding protein MAGI-2 in brain. Journal of Neuroscience 26, 78757884.

L Franchini , A Serretti , M Gasperini , E Smeraldi (1998). Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. Journal of Psychiatric Research 32, 255259.

J Frost , P Sandvik , O Spigset (2010). Sexual dysfunction induced by antidepressants [in Norwegian]. Tidsskrift for den Norske laegeforening 130, 19301931.

HA Garriock , JB Kraft , SI Shyn , EJ Peters , JS Yokoyama , GD Jenkins , MS Reinalda , SL Slager , PJ McGrath , SP Hamilton (2010). A genomewide association study of citalopram response in major depressive disorder. Biological Psychiatry 67, 133138.

KV Harvey , R Balon (1995). Augmentation with buspirone: a review. Annals of Clinical Psychiatry 7, 143147.

International HapMap Consortium (2005). A haplotype map of the human genome. Nature 437, 12991320.

M Kato , A Serretti (2010). Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular Psychiatry 15, 473500.

J Kirchheiner , K Nickchen , M Bauer , ML Wong , J Licinio , I Roots , J Brockmoller (2004). Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Molecular Psychiatry 9, 442473.

C Lavedan , L Licamele , S Volpi , J Hamilton , C Heaton , K Mack , R Lannan , A Thompson , CD Wolfgang , MH Polymeropoulos (2009). Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Molecular Psychiatry 14, 804819.

SF Lei , TL Yang , LJ Tan , XD Chen , Y Guo , YF Guo , L Zhang , XG Liu , H Yan , F Pan , ZX Zhang , YM Peng , Q Zhou , LN He , XZ Zhu , J Cheng , YZ Liu , CJ Papasian , HW Deng (2009). Genome-wide association scan for stature in Chinese: evidence for ethnic specific loci. Human Genetics 125, 19.

C Liu , F Batliwalla , W Li , A Lee , R Roubenoff , E Beckman , H Khalili , A Damle , M Kern , R Furie , J Dupuis , RM Plenge , MJ Coenen , TW Behrens , JP Carulli , PK Gregersen (2008 a). Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Molecular Medicine 14, 575581.

Y Liu , M Boukhelifa , E Tribble , E Morin-Kensicki , A Uetrecht , JE Bear , VA Bankaitis (2008 b). The Sac1 phosphoinositide phosphatase regulates Golgi membrane morphology and mitotic spindle organization in mammals. Molecular Biology of the Cell 19, 30803096.

YZ Liu , YF Guo , L Wang , LJ Tan , XG Liu , YF Pei , H Yan , DH Xiong , FY Deng , N Yu , YP Zhang , L Zhang , SF Lei , XD Chen , HB Liu , XZ Zhu , S Levy , CJ Papasian , BM Drees , JJ Hamilton , RR Recker , HW Deng (2009). Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. PLoS Genetics 5, e1000420.

JC Maddox , M Levi , C Thompson (1994). The compliance with antidepressants in general practice. Journal of Psychopharmacology 8, 4853.

AK Malhotra , Jr. GM Murphy , JL Kennedy (2004). Pharmacogenetics of psychotropic drug response. American Journal of Psychiatry 161, 780796.

JL McClay , DE Adkins , K Aberg , J Bukszar , AN Khachane , RS Keefe , DO Perkins , JP McEvoy , TS Stroup , RE Vann , PM Beardsley , JA Lieberman , PF Sullivan , EJ van den Oord (2011 a). Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. Neuropsychopharmacology 36, 616626.

JL McClay , DE Adkins , K Aberg , S Stroup , DO Perkins , VI Vladimirov , JA Lieberman , PF Sullivan , EJ van den Oord (2011 b). Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics. Molecular Psychiatry 16, 7685.

AJ Mitchell (2006). High medication discontinuation rates in psychiatry: how often is it understandable? Journal of Clinical Psychopharmacology 26, 109112.

A Morag , M Pasmanik-Chor , V Oron-Karni , M Rehavi , JC Stingl , D Gurwitz (2011). Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics 12, 171184.

RL Oreilly , L Bogue , SM Singh (1994). Pharmacogentic response to antidepressants in a multicase family with affective disorder. Biological Psychiatry 36, 467471.

GI Papakostas , M Fava (2009). Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. European Neuropsychopharmacology 19, 3440.

CMB Pare , JW Mack (1971). Differentiation of two genetically specific types of depression by response to antidepressant drugs. Journal of Medical Genetics 8, 306309.

JC Pinheiro , DM Bates (2000). Mixed-Effects Models in S and S-Plus. Springer: New York, NY.

S Porcelli , A Drago , C Fabbri , S Gibiino , R Calati , A Serretti (2011). Pharmacogenetics of antidepressant response. Journal of Psychiatry and Neuroscience 36, 87–113.

S Purcell , B Neale , K Todd-Brown , L Thomas , MA Ferreira , D Bender , J Maller , P Sklar , PI De Bakker , MJ Daly , PC Sham (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics 81, 559575.

HM Rohde , FY Cheong , G Konrad , K Paiha , P Mayinger , G Boehmelt (2003). The human phosphatidylinositol phosphatase SAC1 interacts with the coatomer I complex. Journal of Biological Chemistry 278, 5268952699.

AJ Rush , M Fava , SR Wisniewski , PW Lavori , MH Trivedi , HA Sackeim , ME Thase , AA Nierenberg , FM Quitkin , TM Kashner , DJ Kupfer , JF Rosenbaum , J Alpert , JW Stewart , PJ McGrath , MM Biggs , K Shores-Wilson , BD Lebowitz , L Ritz , G Niederehe (2004). Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Controlled Clinical Trials 25, 119142.

MR Safarinejad (2010). The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study. British Journal of Urology International 106, 840847.

K Sakurai , O Migita , M Toru , T Arinami (2002). An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Molecular Psychiatry 7, 412415.

SR Searle , G Casella , CE McCulloch (1992). Variance Components. Wiley: New York.

RT Segraves (1989). Effects of psychotropic drugs on human erection and ejaculation. Archives of General Psychiatry 46, 275284.

A Serretti , A Chiesa (2009). Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. Journal of Clinical Psychopharmacology 29, 259266.

D Souery , P Oswald , I Massat , U Bailer , J Bollen , K Demyttenaere , S Kasper , Y Lecrubier , S Montgomery , A Serretti , J Zohar , J Mendlewicz (2007). Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. Journal of Clinical Psychiatry 68, 10621670.

J Storey (2003). The positive false discovery rate: a Bayesian interpretation and the q-value. Annals of Statistics 31, 20132035.

JD Storey , R Tibshirani (2003). Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences USA 100, 94409445.

GR Uhl , QR Liu , T Drgon , C Johnson , D Walther , JE Rose , SP David , R Niaura , C Lerman (2008). Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Archives of General Psychiatry 65, 683693.

EJ van den Oord , DE Adkins , J McClay , J Lieberman , PF Sullivan (2009). A systematic method for estimating individual responses to treatment with antipsychotics in CATIE. Schizophrenia Research 107, 1321.

SR Wisniewski , AJ Rush , GK Balasubramani , MH Trivedi , AA Nierenberg (2006). Self-rated global measure of the frequency, intensity, and burden of side effects. Journal of Psychiatric Practice 12, 7179.

GJ Wright , JD Leslie , L Ariza-McNaughton , J Lewis (2004). Delta proteins and MAGI proteins: an interaction of Notch ligands with intracellular scaffolding molecules and its significance for zebrafish development. Development 131, 56595669.

A Zobel , W Maier (2010). Pharmacogenetics of antidepressive treatment. European Archives of Psychiatry and Clinical Neuroscience 260, 407417.

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