Abstract
Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C16) score ⩽5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.
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References
Buetow KH, Edmonson M, MacDonald R, Clifford R, Yip P, Kelley J et al (2001). High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Natl Acad Sci USA 98: 581–584.
Crowley JJ, Brodkin ES, Blendy JA, Berrettini WH, Lucki I (2006). Pharmacogenomic evaluation of the antidepressant citalopram in the mouse tail suspension test. Neuropsychopharmacology 31: 2433–2442.
Crown WH, Finkelstein S, Berndt ER, Ling D, Poret AW, Rush AJ et al (2002). The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry 63: 963–971.
de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D (2005). Efficiency and power in genetic association studies. Nat Genet 37: 1217–1223.
Fava M (2003). Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 53: 649–659.
Fava M, Davidson KG (1996). Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 19: 179–200.
Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA et al (2003). Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am 26: 457–494, x.
Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C et al (1996). Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J 15: 6854–6862.
Gordon JA, Hen R (2006). TREKing toward new antidepressants. Nat Neurosci 9: 1081–1083.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62.
Heurteaux C, Lucas G, Guy N, El Yacoubi M, Thümmler S, Peng XD et al (2006). Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9: 1134–1141.
Honore E (2007). The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8: 251–261.
Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A (2005). Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br J Pharmacol 144: 821–829.
Lavori PW, Rush AJ, Wisniewski SR, Alpert J, Fava M, Kupfer DJ et al (2001). Strengthening clinical effectiveness trials: equipoise-stratified randomization. Biol Psychiatry 50: 792–801.
Lopes CM, Rohacs T, Czirjak G, Balla T, Enyedi P, Logothetis DE (2005). PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels. J Physiol 564: 117–129.
Malhotra AK, Murphy Jr GM, Kennedy JL (2004). Pharmacogenetics of psychotropic drug response. Am J Psychiatry 161: 780–796.
McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF et al (2006). Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78: 804–814.
Murbartian J, Lei Q, Sando JJ, Bayliss DA (2005). Sequential phosphorylation mediates receptor- and kinase-induced inhibition of TREK-1 background potassium channels. J Biol Chem 280: 30175–30184.
Murphy Jr GM, Kremer C, Rodrigues HE, Schatzberg AF (2003). Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry 160: 1830–1835.
Neale BM, Sham PC (2004). The future of association studies: gene-based analysis and replication. Am J Hum Genet 75: 353–362.
Ott J, Hoh J (2003). Set association analysis of SNP case–control and microarray data. J Comput Biol 10: 569–574.
Perlis RH, Purcell S, Fava M, Fagerness J, Rush AJ, Trivedi MH et al (2007). 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 64: 689–697.
Porsolt RD, Bertin A, Jalfre M (1977). Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229: 327–336.
Purcell S, Neale BM, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al (2007). PLINK: a toolset for whole genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.
Rush AJ, Bernstein IH, Trivedi MH, Carmody TJ, Wisniewski S, Mundt JC et al (2006a). An evaluation of the quick inventory of depressive symptomatology and the Hamilton rating scale for depression: a sequenced treatment alternatives to relieve depression trial report. Biol Psychiatry 59: 493–501.
Rush AJ, Carmody T, Reimitz P (2000). The inventory of depressive symptomatology (IDS): clinician (IDS-C) and self-report (IDS-SR) ratings of depressive symptoms. Int J Methods Psychiatr Res 9: 45–59.
Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA et al (2004). Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials 25: 119–142.
Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH (1996). The inventory of depressive symptomatology (IDS): psychometric properties. Psychol Med 26: 477–486.
Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN et al (2003). The 16-item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry 54: 573–583.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D et al (2006b). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163: 1905–1917.
Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME et al (2006c). Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 354: 1231–1242.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805–809.
Schafer WR (1999). How do antidepressants work? Prospects for genetic analysis of drug mechanisms. Cell 98: 551–554.
Serretti A, Cusin C, Rausch JL, Bondy B, Smeraldi E (2006). Pooling pharmacogenetic studies on the serotonin transporter: a mega-analysis. Psychiatry Res 145: 61–65.
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G et al (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 7: 579–593.
Souery D, Papakostas GI, Trivedi MH (2006). Treatment-resistant depression. J Clin Psychiatry 67 (Suppl 6): 16–22.
Sullivan PF (2007). Spurious genetic associations. Biol Psychiatry 61: 1121–1126.
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M et al (2006). Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311: 77–80.
Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA (2001). CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21: 7491–7505.
Tedlow J, Fava M, Uebelacker L, Nierenberg AA, Alpert JE, Rosenbaum J (1998). Outcome definitions and predictors in depression. Psychother Psychosom 67: 266–270.
Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D et al (2006a). Medication augmentation after the failure of SSRIs for depression. N Engl J Med 354: 1243–1252.
Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T et al (2004). The inventory of depressive symptomatology, clinician rating (IDS-C) and self-report (IDS-SR), and the quick inventory of depressive symptomatology, clinician rating (QIDS-C) and self-report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med 34: 73–82.
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L et al (2006b). Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163: 28–40.
Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9: 519–525.
Walsh BT, Seidman SN, Sysko R, Gould M (2002). Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287: 1840–1847.
Wisniewski SR, Fava M, Trivedi MH, Thase ME, Warden D, Niederehe G et al. Which second step treatments are acceptable to depressed outpatients and their clinicians? A STAR*D report. Am J Psychiatry (in press).
Acknowledgements
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study is supported by federal funds from NIMH under contract N01 MH-90003 to the University of TexasSouthwestern Medical Center at Dallas (AJ Rush, principal investigator). Dr Perlis is supported by NIMH K23MH67060, a NARSAD Young Investigator Award, and a Bowman Family Foundation award. We thank Rutgers Cell and DNA Repository for extracting DNA and for providing samples. We appreciate the support of Forest Laboratories, Wyeth, Pfizer, GlaxoSmithKline, and Bristol-Myers Squibb for providing medications at no cost to the STAR*D study. We also thank Stephen Wisniewski, PhD, and Heather Eng for providing the clinical data. We thank the STAR*D research team, who conducted the clinical study and obtained the clinical data and the blood samples for these analyses. Finally, we thank the study participants without whom this study would not have been possible.
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Roy H Perlis, MD
Research support: Eli Lilly & Company, Elan/Eisai, National Institute of Mental Health, NARSAD, Bowman Family Foundation, American Philosophical Society.
Advisory/consulting: AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly & Company, Pfizer Inc.
Speaking: AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly & Company, GlaxoSmithKline, Pfizer Inc.
Equity holdings: none.
Royalty/patent, other income: none.
Maurizio Fava, MD
Research support: Abbott Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, J&J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer Inc., Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals Inc., Wyeth-Ayerst Laboratories.
Advisory/consulting: Aspect Medical Systems, AstraZeneca, Bayer AG, Biovail Pharmaceuticals Inc., BrainCells Inc., Bristol-Myers Squibb Company, Cephalon, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Company, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals Inc., Forest Pharmaceuticals Inc., GlaxoSmithKline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J&J Pharmaceuticals, Knoll Pharmaceutical Company, Lundbeck, MedAvante Inc., Neuronetics, Novartis, Nutrition 21, Organon Inc., PamLab, LLC, Pfizer Inc., PharmaStar, Pharmavite, Roche, Sanofi/Synthelabo, Sepracor, Solvay Pharmaceuticals Inc., Somaxon, Somerset Pharmaceuticals, Wyeth-Ayerst Laboratories.
Speaking: AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, Novartis, Organon Inc., Pfizer Inc., PharmaStar, Wyeth-Ayerst Laboratories.
Equity holdings: Compellis, MedAvante.
Royalty/patent, other income: none.
Madhukar H Trivedi, MD
Research support: Bristol-Myers Squibb Company; Cephalon Inc., Corcept Therapeutics Inc., Cyberonics Inc., Eli Lilly & Company, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Merck, National Institute of Mental Health, National Alliance for Research in Schizophrenia and Depression, Novartis, Pfizer Inc., Predix Pharmaceuticals, Wyeth-Ayerst Laboratories.
Advisory/consulting: Abbott Laboratories Inc.; Akzo (Organon Pharmaceuticals Inc.); Bayer; Bristol-Myers Squibb Company; Cyberonics Inc.; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson PRD; Eli Lilly & Company; Meade Johnson; Parke-Davis Pharmaceuticals Inc.; Pfizer Inc.; Pharmacia & Upjohn; Sepracor; Solvay Pharmaceuticals Inc.; Wyeth-Ayerst Laboratories.
Speaking: Akzo (Organon Pharmaceuticals Inc.); Bristol-Myers Squibb Company; Cyberonics Inc.; Forest Pharmaceuticals; Janssen Pharmaceutica Products, LP; Eli Lilly & Company; Pharmacia & Upjohn; Solvay Pharmaceuticals Inc.; Wyeth-Ayerst Laboratories.
Equity holdings: none (exclude mutual funds/blinded trusts).
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A John Rush, MD
Speaker's bureau: Cyberonics Inc., Forest Pharmaceuticals Inc., GlaxoSmithKline, and Eli Lilly & Company.
Advisory boards/consulting: Advanced Neuromodulation Systems Inc., AstraZeneca, Best Practice Project Management Inc., Bristol-Myers Squibb Company, Cyberonics Inc., Eli Lilly & Company, Forest Pharmaceuticals Inc., Gerson Lehman Group, GlaxoSmithKline, Healthcare Technology Systems, Jazz Pharmaceuticals, Magellan Health Services, Merck & Company, Neuronetics, Ono Pharmaceuticals, Organon Pharmaceuticals Inc., PamLab, Personality Disorder Research Corp., Pfizer Inc., The Urban Institute, Wyeth-Ayerst Laboratories Inc.
Research support: Robert Wood Johnson Foundation, National Institute of Mental Health, Stanley Medical Research Institute.
Royalties: Guilford Publications, Healthcare Technology Systems.
Stock: Pfizer Inc.
Jordan W Smoller, MD, ScD
Dr Smoller has received honoraria from Hoffman-La Roche Inc. and has served on an advisory board for Roche Diagnostics Corporation. He has received research funding from the National Institute of Mental Health and the National Alliance for Research in Schizophrenia and Depression.
The other authors have no financial competing interest to disclose.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)
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Perlis, R., Moorjani, P., Fagerness, J. et al. Pharmacogenetic Analysis of Genes Implicated in Rodent Models of Antidepressant Response: Association of TREK1 and Treatment Resistance in the STAR*D Study. Neuropsychopharmacol 33, 2810–2819 (2008). https://doi.org/10.1038/npp.2008.6
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