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Translating GWAS findings into therapies for depression and anxiety disorders: gene-set analyses reveal enrichment of psychiatric drug classes and implications for drug repositioning

Published online by Cambridge University Press:  20 December 2018

Hon-Cheong So Open the ORCID record for Hon-Cheong So [Opens in a new window] ,
Carlos Kwan-Long Chau ,
Alexandria Lau ,
Sze-Yung Wong  and
Kai Zhao
Hon-Cheong So*
Affiliation:
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Zoology Institute of Zoology and The Chinese University of Hong Kong, Shatin, Hong Kong
Carlos Kwan-Long Chau
Affiliation:
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
Alexandria Lau
Affiliation:
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
Sze-Yung Wong
Affiliation:
Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
Kai Zhao
Affiliation:
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
*
Author for correspondence: Hon-Cheong So, E-mail: [email protected]
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Abstract

Background

Depression and anxiety disorders (AD) are the first and sixth leading causes of disability worldwide. Despite their high prevalence and significant disability resulted, there are limited advances in new drug development. Recently, genome-wide association studies (GWAS) have greatly advanced our understanding of the genetic basis underlying psychiatric disorders.

Methods

Here we employed gene-set analyses of GWAS summary statistics for drug repositioning. We explored five related GWAS datasets, including two on major depressive disorder (MDD2018 and MDD-CONVERGE, with the latter focusing on severe melancholic depression), one on AD, and two on depressive symptoms and neuroticism in the population. We extracted gene-sets associated with each drug from DSigDB and examined their association with each GWAS phenotype. We also performed repositioning analyses on meta-analyzed GWAS data, integrating evidence from all related phenotypes.

Results

Importantly, we showed that the repositioning hits are generally enriched for known psychiatric medications or those considered in clinical trials. Enrichment was seen for antidepressants and anxiolytics but also for antipsychotics. We also revealed new candidates or drug classes for repositioning, some of which were supported by experimental or clinical studies. For example, the top repositioning hit using meta-analyzed p values was fendiline, which was shown to produce antidepressant-like effects in mouse models by inhibition of acid sphingomyelinase.

Conclusion

Taken together, our findings suggest that human genomic data such as GWAS are useful in guiding drug discoveries for depression and AD.

Keywords

Anxiety disorderdrug repositioninggenome-wide association studymajor depressive disorder
Type
Original Articles
Information
Psychological Medicine , Volume 49 , Issue 16 , December 2019 , pp. 2692 - 2708
Copyright
Copyright © Cambridge University Press 2018 

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References

Al-Harbi, KS (2012) Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Preference and Adherence 6, 369–388.Google Scholar
Amador, M and Dani, JA (1991) Protein kinase inhibitor, H-7, directly affects N-methyl-D-aspartate receptor channels. Neuroscience Letters 124, 251–255.Google Scholar
Anighoro, A, Bajorath, J and Rastelli, G (2014) Polypharmacology: challenges and opportunities in drug discovery. Journal of Medicinal Chemistry 57, 7874–7887.Google Scholar
Antonaci, F, Nappi, G, Galli, F, Manzoni, GC, Calabresi, P and Costa, A (2011) Migraine and psychiatric comorbidity: a review of clinical findings. Journal of Headache and Pain 12, 115–125.Google Scholar
Artigas, F, Celada, P, Laruelle, M and Adell, A (2001) How does pindolol improve antidepressant action? Trends in Pharmacological Sciences 22, 224–228.Google Scholar
Bakshi, A, Zhu, ZH, Vinkhuyzen, AAE, Hill, WD, Mcrae, AF, Visscher, PM and Yang, J (2016) Fast set-based association analysis using summary data from GWAS identifies novel gene loci for human complex traits. Scientific Reports 6, 32894.Google Scholar
Ballenger, JC (2000) Anxiety and depression: optimizing treatments. Primary Care Companion Journal Clinical Psychiatry 2, 71–79.Google Scholar
Beaulieu, JM, Zhang, X, Rodriguiz, RM, Sotnikova, TD, Cools, MJ, Wetsel, WC, Gainetdinov, RR and Caron, MG (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proceedings of the National Academy of Sciences of the USA 105, 1333–1338.Google Scholar
Benjamini, Y and Hochberg, Y (1995) Controlling the false discovery rate – a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B-Methodological 57, 289–300.Google Scholar
Bigdeli, TB, Ripke, S, Peterson, RE, Trzaskowski, M, Bacanu, SA, Abdellaoui, A, Andlauer, TF, Beekman, AT, Berger, K, Blackwood, DH, Boomsma, DI, Breen, G, Buttenschon, HN, Byrne, EM, Cichon, S, Clarke, TK, Couvy-Duchesne, B, Craddock, N, De Geus, EJ, Degenhardt, F, Dunn, EC, Edwards, AC, Fanous, AH, Forstner, AJ, Frank, J, Gill, M, Gordon, SD, Grabe, HJ, Hamilton, SP, Hardiman, O, Hayward, C, Heath, AC, Henders, AK, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Hottenga, JJ, Ising, M, Jansen, R, Kloiber, S, Knowles, JA, Lang, M, Li, QS, Lucae, S, Macintyre, DJ, Madden, PA, Martin, NG, Mcgrath, PJ, Mcguffin, P, Mcintosh, AM, Medland, SE, Mehta, D, Middeldorp, CM, Milaneschi, Y, Montgomery, GW, Mors, O, Muller-Myhsok, B, Nauck, M, Nyholt, DR, Nothen, MM, Owen, MJ, Penninx, BW, Pergadia, ML, Perlis, RH, Peyrot, WJ, Porteous, DJ, Potash, JB, Rice, JP, Rietschel, M, Riley, BP, Rivera, M, Schoevers, R, Schulze, TG, Shi, J, Shyn, SI, Smit, JH, Smoller, JW, Streit, F, Strohmaier, J, Teumer, A, Treutlein, J, Van Der Auwera, S, Van Grootheest, G, Van Hemert, AM, Volzke, H, Webb, BT, Weissman, MM, Wellmann, J, Willemsen, G, Witt, SH, Levinson, DF, Lewis, CM, Wray, NR, Flint, J, Sullivan, PF and Kendler, KS (2017) Genetic effects influencing risk for major depressive disorder in China and Europe. Translational Psychiatry 7, e1074.Google Scholar
Blier, P and Bergeron, R (1995) Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. Journal of Clinical Psychopharmacology 15, 217–222.Google Scholar
Brown, MB (1975) 400: a method for combining non-independent, one-sided tests of significance. Biometrics 31, 987–992.Google Scholar
Cai, N, Bigdeli, TB, Kretzschmar, W, Li, YH, Liang, JQ, Song, L, Hu, JC, Li, QB, Jin, W, Hu, ZF, Wang, GB, Wang, LM, Qian, PY, Liu, Y, Jiang, T, Lu, Y, Zhang, XQ, Yin, Y, Li, YR, Xu, X, Gao, JF, Reimers, M, Webb, T, Riley, B, Bacanu, S, Peterson, RE, Chen, YP, Zhong, H, Liu, ZR, Wang, G, Sun, J, Sang, H, Jiang, GQ, Zhou, XY, Li, Y, Li, Y, Zhang, W, Wang, XY, Fang, X, Pan, RD, Miao, GD, Zhang, QW, Hu, J, Yu, FY, Du, B, Sang, WH, Li, KQ, Chen, GB, Cai, M, Yang, LJ, Yang, DL, Ha, BW, Hong, XH, Deng, H, Li, GY, Li, K, Song, Y, Gao, SG, Zhang, JB, Gan, ZY, Meng, HQ, Pan, JY, Gao, CG, Zhang, KR, Sun, N, Li, YH, Niu, QH, Zhang, YT, Liu, TQ, Hu, CM, Zhang, Z, Lv, LX, Dong, JC, Wang, XP, Tao, M, Wang, XM, Xia, J, Rong, H, He, Q, Liu, TB, Huang, GP, Mei, QY, Shen, ZM, Liu, Y, Shen, JH, Tian, T, Liu, XJ, Wu, WY, Gu, DH, Fu, GY, Shi, JG, Chen, YC, Gan, XC, Liu, LF, Wang, LN, Yang, FZ, Cong, EZ, Marchini, J, Yang, HM, Wang, J, et al. (2015) Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 523, 588– +.Google Scholar
Ceulemans, DL, Hoppenbrouwers, ML, Gelders, YG and Reyntjens, AJ (1985) The influence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind placebo-controlled study versus lorazepam. Pharmacopsychiatry 18, 303–305.Google Scholar
Chen, YC, Wang, HN, Zhang, RG, Wang, HH, Peng, ZW, Sun, RZ and Tan, QR (2012) Microinjection of sanguinarine into the ventrolateral orbital cortex inhibits Mkp-1 and exerts an antidepressant-like effect in rats. Neuroscience Letters 506, 327–331.Google Scholar
Cipriani, A, Saunders, K, Attenburrow, MJ, Stefaniak, J, Panchal, P, Stockton, S, Lane, TA, Tunbridge, EM, Geddes, JR and Harrison, PJ (2016) A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. Molecular Psychiatry 21, 1324–1332.Google Scholar
Corp, SA, Gitlin, MJ and Altshuler, LL (2014) A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. Journal of Clinical Psychiatry 75, 1010–1018.Google Scholar
Cross-Disorder Group of the Psychiatric Genomics C, Lee, SH, Ripke, S, Neale, BM, Faraone, SV, Purcell, SM, Perlis, RH, Mowry, BJ, Thapar, A, Goddard, ME, Witte, JS, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, OA, Anjorin, A, Anney, R, Anttila, V, Arking, DE, Asherson, P, Azevedo, MH, Backlund, L, Badner, JA, Bailey, AJ, Banaschewski, T, Barchas, JD, Barnes, MR, Barrett, TB, Bass, N, Battaglia, A, Bauer, M, Bayes, M, Bellivier, F, Bergen, SE, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, EB, Black, DW, Blackwood, DH, Bloss, CS, Boehnke, M, Boomsma, DI, Breen, G, Breuer, R, Bruggeman, R, Cormican, P, Buccola, NG, Buitelaar, JK, Bunney, WE, Buxbaum, JD, Byerley, WF, Byrne, EM, Caesar, S, Cahn, W, Cantor, RM, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, Cichon, S, Cloninger, CR, Collier, DA, Cook, EH, Coon, H, Cormand, B, Corvin, A, Coryell, WH, Craig, DW, Craig, IW, Crosbie, J, Cuccaro, ML, Curtis, D, Czamara, D, Datta, S, Dawson, G, Day, R, De Geus, EJ, Degenhardt, F, Djurovic, S, Donohoe, GJ, Doyle, AE, Duan, J, Dudbridge, F, Duketis, E, Ebstein, RP, Edenberg, HJ, Elia, J, Ennis, S, Etain, B, Fanous, A, Farmer, AE, Ferrier, IN, Flickinger, M, Fombonne, E, Foroud, T, Frank, J, Franke, B, et al. (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45, 984–994.Google Scholar
De Jong, S, Vidler, LR, Mokrab, Y, Collier, DA and Breen, G (2016) Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia. Journal of Psychopharmacology 30, 826–830.Google Scholar
De Leeuw, CA, Mooij, JM, Heskes, T and Posthuma, D (2015) MAGMA: generalized gene-set analysis of GWAS data. PLoS Computational Biology 11, e1004219.Google Scholar
De Leeuw, CA, Neale, BM, Heskes, T and Posthuma, D (2016) The statistical properties of gene-set analysis. Nature Reviews Genetics 17, 353–364.Google Scholar
De Oliveira, MR, Chenet, AL, Duarte, AR, Scaini, G and Quevedo, J (2017) Molecular mechanisms underlying the anti-depressant effects of resveratrol: a review. Molecular Neurobiology 55, 4543–4559.Google Scholar
Dell'Osso, B, Ketter, TA, Cremaschi, L, Spagnolin, G and Altamura, AC (2013) Assessing the roles of stimulants/stimulant-like drugs and dopamine-agonists in the treatment of bipolar depression. Current Psychiatry Reports 15, 378.Google Scholar
Dhingra, D and Chhillar, R (2012) Antidepressant-like activity of ellagic acid in unstressed and acute immobilization-induced stressed mice. Pharmacological Reports 64, 796–807.Google Scholar
Dubovsky, SL, Buzan, R, Thomas, M, Kassner, C and Cullum, CM (2001) Nicardipine improves the antidepressant action of ECT but does not improve cognition. Journal of ECT 17, 3–10.Google Scholar
Fedorova, I, Hashimoto, A, Fecik, RA, Hedrick, MP, Hanus, LO, Boger, DL, Rice, KC and Basile, AS (2001) Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems. Jouranl of Pharmacology and Expertimental Therapeutics 299, 332–342.Google Scholar
Flint, J, Chen, Y, Shi, S, Kendler, KS and Consortium, C (2012) Epilogue: lessons from the CONVERGE study of major depressive disorder in China. Journal of Affective Disorders 140, 1–5.Google Scholar
Florez, JC, Jablonski, KA, Mcateer, JB, Franks, PW, Mason, CC, Mather, K, Horton, E, Goldberg, R, Dabelea, D, Kahn, SE, Arakaki, RF, Shuldiner, AR, Knowler, WC and Diabetes Prevention Program Research G (2012) Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. PLoS ONE, 7, e44424.Google Scholar
Fournier, JC, Derubeis, RJ, Hollon, SD, Dimidjian, S, Amsterdam, JD, Shelton, RC and Fawcett, J (2010) Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 303, 47–53.Google Scholar
Frances, A, Manning, D, Marin, D, Kocsis, J, Mckinney, K, Hall, W and Kline, M (1992) Relationship of anxiety and depression. Psychopharmacology 106, S82–S86.Google Scholar
Freland, L and Beaulieu, JM (2012) Inhibition of GSK3 by lithium, from single molecules to signaling networks. Frontiers in Molecular Neuroscience 5, 14.Google Scholar
Fuller, RW, Snoddy, HD, Perry, KW, Roush, BW, Molloy, BB, Bymaster, FP and Wong, DT (1976) The effects of quipazine on serotonin metabolism in rat brain. Life Science 18, 925–933.Google Scholar
Fung, M (2001) Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets-1960 to 1999. Drug Information Journal 35, 293–317.Google Scholar
Gale, CR, Hagenaars, SP, Davies, G, Hill, WD, Liewald, DCM, Cullen, B, Penninx, BW, Boomsma, DI, Pell, J, Mcintosh, AM, Smith, DJ, Deary, IJ, Harris, SE and Gwas, ICBP (2016) Pleiotropy between neuroticism and physical and mental health: findings from 108038 men and women in UK Biobank. Translational Psychiatry 6, e791.Google Scholar
Gao, K, Muzina, D, Gajwani, P and Calabrese, JR (2006) Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review. Journal of Clinical Psychiatry 67, 1327–1340.Google Scholar
Gaspar, HA and Breen, G (2017) Drug enrichment and discovery from schizophrenia genome-wide association results: an analysis and visualisation approach. Scientific Reports 7, 12460.Google Scholar
Gaulton, A, Bellis, LJ, Bento, AP, Chambers, J, Davies, M, Hersey, A, Light, Y, Mcglinchey, S, Michalovich, D, Al-Lazikani, B and Overington, JP (2012) ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Research 40, D1100–D1107.Google Scholar
Ghabrash, MF, Comai, S, Tabaka, J, Saint-Laurent, M, Booij, L and Gobbi, G (2016) Valproate augmentation in a subgroup of patients with treatment-resistant unipolar depression. World of Journal Biological Psychiatry 17, 165–170.Google Scholar
Girish, C, Raj, V, Arya, J and Balakrishnan, S (2013) Involvement of the GABAergic system in the anxiolytic-like effect of the flavonoid ellagic acid in mice. European Journal of Pharmacology 710, 49–58.Google Scholar
Gold, PW and Chrousos, GP (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Molecular Psychiatry 7, 254–275.Google Scholar
Goldberg, D (2011) The heterogeneity of ‘major depression’. World Psychiatry 10, 226–228.Google Scholar
Goodwin, GM (2015) The overlap between anxiety, depression, and obsessive-compulsive disorder. Dialogues in Clinical Neuroscience 17, 249–260.Google Scholar
Gulbins, E, Palmada, M, Reichel, M, Luth, A, Bohmer, C, Amato, D, Muller, CP, Tischbirek, CH, Groemer, TW, Tabatabai, G, Becker, KA, Tripal, P, Staedtler, S, Ackermann, TF, Van Brederode, J, Alzheimer, C, Weller, M, Lang, UE, Kleuser, B, Grassme, H and Kornhuber, J (2013) Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nature Medicine 19, 934–+.Google Scholar
Harald, B and Gordon, P (2012) Meta-review of depressive subtyping models. Journal of Affective Disorders 139, 126–140.Google Scholar
Huang, L, Li, F, Sheng, J, Xia, X, Ma, J, Zhan, M and Wong, ST (2014) Drugcomboranker: drug combination discovery based on target network analysis. Bioinformatics (Oxford, England) 30, i228–i236.Google Scholar
Iyengar, RL, Gandhi, S, Aneja, A, Thorpe, K, Razzouk, L, Greenberg, J, Mosovich, S and Farkouh, ME (2013) NSAIDs are associated with lower depression scores in patients with osteoarthritis. American Journal of Medicine 126, 1017. e11–8.Google Scholar
Jardine, R, Martin, N, Henderson, A and Rao, D (1984) Genetic covariation between neuroticism and the symptoms of anxiety and depression. Genetic Epidemiology 1, 89–107.Google Scholar
Jue, SG, Dawson, GW and Brogden, RN (1982) Amoxapine – a review of its pharmacology and efficacy in depressed states. Drugs 24, 1–23.Google Scholar
Kanba, S (2004) Although antidepressants and anxiolytics are frequently used together to treat depression in the acute phase, how effective is the concomitant use of these drugs? Journal of Psychiatry and Neuroscience 29, 485–486.Google Scholar
Kessler, RC, Sampson, NA, Berglund, P, Gruber, MJ, Al-Hamzawi, A, Andrade, L, Bunting, B, Demyttenaere, K, Florescu, S, De Girolamo, G, Gureje, O, He, Y, Hu, C, Huang, Y, Karam, E, Kovess-Masfety, V, Lee, S, Levinson, D, Medina Mora, ME, Moskalewicz, J, Nakamura, Y, Navarro-Mateu, F, Browne, MA, Piazza, M, Posada-Villa, J, Slade, T, Ten Have, M, Torres, Y, Vilagut, G, Xavier, M, Zarkov, Z, Shahly, V and Wilcox, MA (2015) Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys. Epidemiology and Psychiatry Sciences 24, 210–226.Google Scholar
Kim, S, Thiessen, PA, Bolton, EE, Chen, J, Fu, G, Gindulyte, A, Han, LY, He, JE, He, SQ, Shoemaker, BA, Wang, JY, Yu, B, Zhang, J and Bryant, SH (2016) Pubchem substance and compound databases. Nucleic Acids Research 44, D1202–D1213.Google Scholar
Kirsch, I, Deacon, BJ, Huedo-Medina, TB, Scoboria, A, Moore, TJ and Johnson, BT (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine 5, e45.Google Scholar
Koch, HJ and Jurgens, TP (2009) Antidepressants in long-term migraine prevention. Drugs 69, 1–19.Google Scholar
Kohler, O, Gasse, C, Petersen, L, Ingstrup, KG, Nierenberg, AA, Mors, O and Ostergaard, SD (2016) The effect of concomitant treatment with SSRIs and statins: a population-based study. American Journal of Psychiatry 173, 807–815.Google Scholar
Lahey, BB (2009) Public health significance of neuroticism. American Psychologist 64, 241–256.Google Scholar
Lalonde, CD and Van Lieshout, RJ (2011) Treating generalized anxiety disorder with second generation antipsychotics: a systematic review and meta-analysis. Journal of Clinical Psychopharmacology 31, 326–333.Google Scholar
Lamb, J, Crawford, ED, Peck, D, Modell, JW, Blat, IC, Wrobel, MJ, Lerner, J, Brunet, JP, Subramanian, A, Ross, KN, Reich, M, Hieronymus, H, Wei, G, Armstrong, SA, Haggarty, SJ, Clemons, PA, Wei, R, Carr, SA, Lander, ES and Golub, TR (2006) The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935.Google Scholar
Lamers, F, Van Oppen, P, Comijs, HC, Smit, JH, Spinhoven, P, Van Balkom, AJ, Nolen, WA, Zitman, FG, Beekman, AT and Penninx, BW (2011) Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). Journal of Clinical Psychiatry 72, 341–348.Google Scholar
Lamers, F, Vogelzangs, N, Merikangas, KR, De Jonge, P, Beekman, ATF and Penninx, BWJH (2013) Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Molecular Psychiatry 18, 692–699.Google Scholar
Leost, M, Schultz, C, Link, A, Wu, YZ, Biernat, J, Mandelkow, EM, Bibb, JA, Snyder, GL, Greengard, P, Zaharevitz, DW, Gussio, R, Senderowicz, AM, Sausville, EA, Kunick, C and Meijer, L (2000) Paullones are potent inhibitors of glycogen synthase kinase-3 beta and cyclin-dependent kinase 5/p25. European Journal of Biochemistry 267, 5983–5994.Google Scholar
Lesser, IM, Myers, HF, Lin, KM, Bingham Mira, C, Joseph, NT, Olmos, NT, Schettino, J and Poland, RE (2010) Ethnic differences in antidepressant response: a prospective multi-site clinical trial. Depression and Anxiety 27, 56–62.Google Scholar
Lesser, IM, Zisook, S, Gaynes, BN, Wisniewski, SR, Luther, JF, Fava, M, Khan, A, Mcgrath, P, Warden, D, Rush, AJ and Trivedi, M (2011) Effects of race and ethnicity on depression treatment outcomes: the CO-MED trial. Psychiatry Service 62, 1167–1179.Google Scholar
Li, YH, Yu, CY, Li, XX, Zhang, P, Tang, J, Yang, Q, Fu, T, Zhang, X, Cui, X, Tu, G, Zhang, Y, Li, S, Yang, F, Sun, Q, Qin, C, Zeng, X, Chen, Z, Chen, YZ and Zhu, F (2018) Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic Acids Research 46, D1121–D1127.Google Scholar
Liu, JZ, Mcrae, AF, Nyholt, DR, Medland, SE, Wray, NR, Brown, KM, Hayward, NK, Montgomery, GW, Visscher, PM, Martin, NG, Macgregor, S and Investigators, A (2010) A versatile gene-based test for genome-wide association studies. American Journal of Human Genetics 87, 139–145.Google Scholar
Maciejewski, H (2014) Gene set analysis methods: statistical models and methodological differences. Briefings in Bioinformatics 15, 504–518.Google Scholar
Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Ripke, S, Wray, NR, Lewis, CM, Hamilton, SP, Weissman, MM, Breen, G, Byrne, EM, Blackwood, DH, Boomsma, DI, Cichon, S, Heath, AC, Holsboer, F, Lucae, S, Madden, PA, Martin, NG, McGuffin, P, Muglia, P, Noethen, MM, Penninx, BP, Pergadia, ML, Potash, JB, Rietschel, M, Lin, D, Müller-Myhsok, B, Shi, J, Steinberg, S, Grabe, HJ, Lichtenstein, P, Magnusson, P, Perlis, RH, Preisig, M, Smoller, JW, Stefansson, K, Uher, R, Kutalik, Z, Tansey, KE, Teumer, A, Viktorin, A, Barnes, MR, Bettecken, T, Binder, EB, Breuer, R, Castro, VM, Churchill, SE, Coryell, WH, Craddock, N, Craig, IW, Czamara, D, De Geus, EJ, Degenhardt, F, Farmer, AE, Fava, M, Frank, J, Gainer, VS, Gallagher, PJ, Gordon, SD, Goryachev, S, Gross, M, Guipponi, M, Henders, AK, Herms, S, Hickie, IB, Hoefels, S, Hoogendijk, W, Hottenga, JJ, Iosifescu, DV, Ising, M, Jones, I, Jones, L, Jung-Ying, T, Knowles, JA, Kohane, IS, Kohli, MA, Korszun, A, Landen, M, Lawson, WB, Lewis, G, Macintyre, D, Maier, W, Mattheisen, M, McGrath, PJ, McIntosh, A, McLean, A, Middeldorp, CM, Middleton, L, Montgomery, GM, Murphy, SN, Nauck, M, Nolen, WA, Nyholt, DR, O'Donovan, M, Oskarsson, H, Pedersen, N, Scheftner, WA, Schulz, A, Schulze, TG, Shyn, SI, Sigurdsson, E, Slager, SL, Smit, JH, Stefansson, H, Steffens, M, Thorgeirsson, T, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, EJ, Van Grootheest, G, Völzke, H, Weilburg, JB, Willemsen, G, Zitman, FG, Neale, B, Daly, M, Levinson, DF and Sullivan, PF (2012) A mega-analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry 18, 497–511.Google Scholar
Malouff, JM, Thorsteinsson, EB and Schutte, NS (2005) The relationship between the five-factor model of personality and symptoms of clinical disorders: a meta-analysis. Journal of Psychopathology and Behavioral Assessment 27, 101–114.Google Scholar
Mattingly, CJ, Colby, GT, Forrest, JN and Boyer, JL (2003) The Comparative Toxicogenomics Database (CTD). Environmental Health Perspectives 111, 793–795.Google Scholar
Mcgrath, PJ, Khan, AY, Trivedi, MH, Stewart, JW, Morris, DW, Wisniewski, SR, Miyahara, S, Nierenberg, AA, Fava, M and Rush, AJ (2008) Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report. Journal of Clinical Psychiatry 69, 1847–1855.Google Scholar
Melartin, T, Leskela, U, Rytsala, H, Sokero, P, Lestela-Mielonen, P and Isometsa, E (2004) Co-morbidity and stability of melancholic features in DSM-IV major depressive disorder. Psychological Medicine 34, 1443–1452.Google Scholar
Merino, J, Leong, A, Posner, DC, Porneala, B, Masana, L, Dupuis, J and Florez, JC (2017) Genetically driven hyperglycemia increases risk of coronary artery disease separately from type 2 diabetes. Diabetes Care 40, 687–693.Google Scholar
Murphy, E, Hou, L, Maher, BS, Woldehawariat, G, Kassem, L, Akula, N, Laje, G and Mcmahon, FJ (2013) Race, genetic ancestry and response to antidepressant treatment for major depression. Neuropsychopharmacology 38, 2598–2606.Google Scholar
Nappi, G, Sandrini, G, Granella, F, Ruiz, L, Cerutti, G, Facchinetti, F, Blandini, F and Manzoni, GC (1990) A New 5-Ht2 antagonist (Ritanserin) in the treatment of chronic headache with depression – a double-blind-study vs amitriptyline. Headache 30, 439–444.Google Scholar
Nierenberg, AA, Dougherty, D and Rosenbaum, JF (1998) Dopaminergic agents and stimulants as antidepressant augmentation strategies. Journal of Clinical Psychiatry 59, 60–64.Google Scholar
Okbay, A, Baselmans, BM, De Neve, JE, Turley, P, Nivard, MG, Fontana, MA, Meddens, SF, Linner, RK, Rietveld, CA, Derringer, J, Gratten, J, Lee, JJ, Liu, JZ, de Vlaming, R, Ahluwalia, TS, Buchwald, J, Cavadino, A, Frazier-Wood, AC, Furlotte, NA, Garfield, V, Geisel, MH, Gonzalez, JR, Haitjema, S, Karlsson, R, van der Laan, SW, Ladwig, KH, Lahti, J, van der Lee, SJ, Lind, PA, Liu, T, Matteson, L, Mihailov, E, Miller, MB, Minica, CC, Nolte, IM, Mook-Kanamori, D, van der Most, PJ, Oldmeadow, C, Qian, Y, Raitakari, O, Rawal, R, Realo, A, Rueedi, R, Schmidt, B, Smith, AV, Stergiakouli, E, Tanaka, T, Taylor, K, Thorleifsson, G, Wedenoja, J, Wellmann, J, Westra, HJ, Willems, SM, Zhao, W, LifeLines Cohort, S, Amin, N, Bakshi, A, Bergmann, S, Bjornsdottir, G, Boyle, PA, Cherney, S, Cox, SR, Davies, G, Davis, OS, Ding, J, Direk, N, Eibich, P, Emeny, RT, Fatemifar, G, Faul, JD, Ferrucci, L, Forstner, AJ, Gieger, C, Gupta, R, Harris, TB, Harris, JM, Holliday, EG, Hottenga, JJ, De Jager, PL, Kaakinen, MA, Kajantie, E, Karhunen, V, Kolcic, I, Kumari, M, Launer, LJ, Franke, L, Li-Gao, R, Liewald, DC, Koini, M, Loukola, A, Marques-Vidal, P, Montgomery, GW, Mosing, MA, Paternoster, L, Pattie, A, Petrovic, KE, Pulkki-Raback, L, Quaye, L, Raikkonen, K, Rudan, I, Scott, RJ, Smith, JA, Sutin, AR, Trzaskowski, M, Vinkhuyzen, AE, Yu, L, Zabaneh, D, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Boomsma, DI, Snieder, H, Chang, SC, Cucca, F, Deary, IJ, van Duijn, CM, Eriksson, JG, Bultmann, U, de Geus, EJ, Groenen, PJ, Gudnason, V, Hansen, T, Hartman, CA, Haworth, CM, Hayward, C, Heath, AC, Hinds, DA, Hypponen, E, Iacono, WG, Jarvelin, MR, Jockel, KH, Kaprio, J, Kardia, SL, Keltikangas-Jarvinen, L, Kraft, P, Kubzansky, LD, Lehtimaki, T, Magnusson, PK, Martin, NG, McGue, M, Metspalu, A, Mills, M, de Mutsert, R, Oldehinkel, AJ, Pasterkamp, G, Pedersen, NL, Plomin, R, Polasek, O, Power, C, Rich, SS, Rosendaal, FR, den Ruijter, HM, Schlessinger, D, Schmidt, H, Svento, R, Schmidt, R, Alizadeh, BZ, Sorensen, TI, Spector, TD, Starr, JM, Stefansson, K, Steptoe, A, Terracciano, A, Thorsteinsdottir, U, Thurik, AR, Timpson, NJ, Tiemeier, H, Uitterlinden, AG, Vollenweider, P, Wagner, GG, Weir, DR, Yang, J, Conley, DC, Smith, GD, Hofman, A, Johannesson, M, Laibson, DI, Medland, SE, Meyer, MN, Pickrell, JK, Esko, T, Krueger, RF, Beauchamp, JP, Koellinger, PD, Benjamin, DJ, Bartels, M and Cesarini, D (2016) Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nature Genetics 48, 624–633.Google Scholar
Onasanwo, S, Faborode, S, Agrawal, M, Ijiwola, O, Jaiyesimi, B and Narender, T (2014) Antidepressant and anxiolytic potentials of chebulinic acid in laboratory rodent. Annals of Depression and Anxiety 1, 1032.Google Scholar
Ostacher, MJ, Iosifescu, DV, Hay, A, Blumenthal, SR, Sklar, P and Perlis, RH (2014) Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome-wide association. Bipolar Disorders 16, 199–203.Google Scholar
Otowa, T, Hek, K, Lee, M, Byrne, EM, Mirza, SS, Nivard, MG, Bigdeli, T, Aggen, SH, Adkins, D, Wolen, A, Fanous, A, Keller, MC, Castelao, E, Kutalik, Z, Der Auwera, SV, Homuth, G, Nauck, M, Teumer, A, Milaneschi, Y, Hottenga, JJ, Direk, N, Hofman, A, Uitterlinden, A, Mulder, CL, Henders, AK, Medland, SE, Gordon, S, Heath, AC, Madden, PA, Pergadia, ML, Van Der Most, PJ, Nolte, IM, Van Oort, FV, Hartman, CA, Oldehinkel, AJ, Preisig, M, Grabe, HJ, Middeldorp, CM, Penninx, BW, Boomsma, D, Martin, NG, Montgomery, G, Maher, BS, Van Den Oord, EJ, Wray, NR, Tiemeier, H and Hettema, JM (2016 a) Meta-analysis of genome-wide association studies of anxiety disorders. Molecular Psychiatry 21, 1485.Google Scholar
Otowa, T, Hek, K, Lee, M, Byrne, EM, Mirza, SS, Nivard, MG, Bigdeli, T, Aggen, SH, Adkins, D, Wolen, A, Fanous, A, Keller, MC, Castelao, E, Kutalik, Z, Der Auwera, SV, Homuth, G, Nauck, M, Teumer, A, Milaneschi, Y, Hottenga, JJ, Direk, N, Hofman, A, Uitterlinden, A, Mulder, CL, Henders, AK, Medland, SE, Gordon, S, Heath, AC, Madden, PAF, Pergadia, ML, Van Der Most, PJ, Nolte, IM, Van Oort, FVA, Hartman, CA, Oldehinkel, AJ, Preisig, M, Grabe, HJ, Middeldorp, CM, Penninx, BWJH, Boomsma, D, Martin, NG, Montgomery, G, Maher, BS, Van Den Oord, EJ, Wray, NR, Tiemeier, H and Hettema, JM (2016 b) Meta-analysis of genome-wide association studies of anxiety disorders. Molecular Psychiatry 21, 1391–1399.Google Scholar
Pande, AC, Crockatt, JG, Feltner, DE, Janney, CA, Smith, WT, Weisler, R, Londborg, PD, Bielski, RJ, Zimbroff, DL, Davidson, JRT and Liu-Dumaw, M (2003) Pregabalin in generalized anxiety disorder: a placebo-controlled trial. American Journal of Psychiatry 160, 533–540.Google Scholar
Papassotiropoulos, A and De Quervain, DJF (2015) Failed drug discovery in psychiatry: time for human genome-guided solutions. Trends in Cognitive Sciences 19, 183–187.Google Scholar
Parker, G, Fink, M, Shorter, E, Taylor, MA, Akiskal, H, Berrios, G, Bolwig, T, Brown, WA, Carroll, B, Healy, D, Klein, DF, Koukopoulos, A, Michels, R, Paris, J, Rubin, RT, Spitzer, R and Swartz, C (2010) Issues for DSM-5: whither melancholia? The case for its classification as a distinct mood disorder. American Journal of Psychiatry 167, 745–747.Google Scholar
Peters, MF, Zacco, A, Gordon, J, Maciag, CM, Litwin, LC, Thompson, C, Schroeder, P, Sygowski, LA, Piser, TM and Brugel, TA (2011) Identification of short-acting kappa-opioid receptor antagonists with anxiolytic-like activity. European Journal of Pharmacology 661, 27–34.Google Scholar
Philip, NS, Carpenter, LL, Tyrka, AR and Price, LH (2012) The nicotinic acetylcholine receptor as a target for antidepressant drug development. Scientific World Journal 2012, 104105.Google Scholar
Poole, W, Gibbs, DL, Shmulevich, I, Bernard, B and Knijnenburg, TA (2016) Combining dependent p values with an empirical adaptation of Brown's method. Bioinformatics (Oxford, England) 32, 430–436.Google Scholar
Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MAR, Bender, D, Maller, J, Sklar, P, De Bakker, PIW, Daly, MJ and Sham, PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics 81, 559–575.Google Scholar
Rickels, K, Pollack, MH, Feltner, DE, Lydiard, RB, Zimbroff, DL, Bielski, RJ, Tobias, K, Brock, JD, Zornberg, GL and Pande, AC (2005) Pregabalin for treatment of generalized anxiety disorder – a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Archives of General Psychiatry 62, 1022–1030.Google Scholar
Ruderfer, DM, Charney, AW, Readhead, B, Kidd, BA, Kahler, AK, Kenny, PJ, Keiser, MJ, Moran, JL, Hultman, CM, Scott, SA, Sullivan, PF, Purcell, SM, Dudley, JT and Sklar, P (2016) Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. The Lancet. Psychiatry 3, 350–357.Google Scholar
Salagre, E, Fernandes, BS, Dodd, S, Brownstein, DJ and Berk, M (2016) Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials. Journal of Affective Disorders 200, 235–242.Google Scholar
Samuel, M, Zimovetz, EA, Gabriel, Z and Beard, SM (2011) Efficacy and safety of treatments for refractory generalized anxiety disorder: a systematic review. International Clinical Psychopharmacology 26, 63–68.Google Scholar
Sanseau, P, Agarwal, P, Barnes, MR, Pastinen, T, Richards, JB, Cardon, LR and Mooser, V (2012) Use of genome-wide association studies for drug repositioning. Nature Biotechnology 30, 317–320.Google Scholar
Sarkar, SK and Chang, C-K (1997) The Simes method for multiple hypothesis testing with positively dependent test statistics. Journal of the American Statistical Association 92, 1601–1608.Google Scholar
Simes, RJ (1986) An improved Bonferroni procedure for multiple tests of significance. Biometrika 73, 751–754.Google Scholar
Smith, LA, Cornelius, VR, Azorin, JM, Perugi, G, Vieta, E, Young, AH and Bowden, CL (2010) Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis. Journal of Affective Disorders 122, 1–9.Google Scholar
Smith, DJ, Escott-Price, V, Davies, G, Bailey, MES, Colodro-Conde, L, Ward, J, Vedernikov, A, Marioni, R, Cullen, B, Lyall, D, Hagenaars, SP, Liewald, DCM, Luciano, M, Gale, CR, Ritchie, SJ, Hayward, C, Nicholl, B, Bulik-Sullivan, B, Adams, M, Couvy-Duchesne, B, Graham, N, Mackay, D, Evans, J, Smith, BH, Porteous, DJ, Medland, SE, Martin, NG, Holmans, P, Mcintosh, AM, Pell, JP, Deary, IJ and O'Donovan, MC (2016) Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci. Molecular Psychiatry 21, 749–757.Google Scholar
So, HC and Sham, PC (2011) Multiple testing and power calculations in genetic association studies. Cold Spring Harbor Protocols 2011, pdb.top95.Google Scholar
So, HC, Chau, CK, Chiu, WT, Ho, KS, Lo, CP, Yim, SH and Sham, PC (2017) Analysis of genome-wide association data highlights candidates for drug repositioning in psychiatry. Nature Neuroscience 20, 1342–1349.Google Scholar
Spielmans, GI, Berman, MI, Linardatos, E, Rosenlicht, NZ, Perry, A and Tsai, AC (2013) Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Medicine 10, e1001403.Google Scholar
Steenen, SA, Van Wijk, AJ, Van Der Heijden, GJ, Van Westrhenen, R, De Lange, J and De Jongh, A (2016) Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis. Journal of Psychopharmacology 30, 128–139.Google Scholar
Stetler, C and Miller, GE (2011) Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosomatic Medicine 73, 114–126.Google Scholar
Strauss, WH and Klieser, E (1991) Psychotropic effects of ritanserin, a selective S2 antagonist: an open study. European Neuropsychopharmacology 1, 101–105.Google Scholar
Szmulewicz, AG, Angriman, F, Samame, C, Ferraris, A, Vigo, D and Strejilevich, SA (2017) Dopaminergic agents in the treatment of bipolar depression: a systematic review and meta-analysis. Acta Psychiatrica Scandinavica 135, 527–538.Google Scholar
Tamburella, A, Micale, V, Navarria, A and Drago, F (2009) Antidepressant properties of the 5-HT4 receptor partial agonist, SL65.0155: behavioral and neurochemical studies in rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry 33, 1205–1210.Google Scholar
Tang, TZ, Derubeis, RJ, Hollon, SD, Amsterdam, J, Shelton, R and Schalet, B (2009) Personality change during depression treatment a placebo-controlled trial. Archives of General Psychiatry 66, 1322–1330.Google Scholar
Touma, KTB, Zoucha, AM and Scarff, JR (2017) Liothyronine for depression: a review and guidance for safety monitoring. Innovations in Clinical Neuroscience 14, 24–29.Google Scholar
Trivedi, MH, Rush, AJ, Wisniewski, SR, Nierenberg, AA, Warden, D, Ritz, L, Norquist, G, Howland, RH, Lebowitz, B, Mcgrath, PJ, Shores-Wilson, K, Biggs, MM, Balasubramani, GK, Fava, M and Team, SS (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. American Journal of Psychiatry 163, 28–40.Google Scholar
Veena, J, Srikumar, BN, Mahati, K, Raju, TR and Shankaranarayana Rao, BS (2011) Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats. Psychopharmacology (Berl) 217, 239–253.Google Scholar
Wei, XY, Yang, JY, Dong, YX and Wu, CF (2007) Anxiolytic-like effects of oleamide in group-housed and socially isolated mice. Progress in Neuro-Psychopharmacology & Biological Psychiatry 31, 1189–1195.Google Scholar
Wei, WQ, Cronin, RM, Xu, H, Lasko, TA, Bastarache, L and Denny, JC (2013) Development and evaluation of an ensemble resource linking medications to their indications. Journal of American Medical Informatic Association 20, 954–961.Google Scholar
World Health Organization (2017) Depression and Other Common Mental Disorders Global Health Estimates. Available at http://apps.who.int/iris/bitstream/10665/254610/1/WHO-MSD-MER-2017.2-eng.pdf?ua=1.Google Scholar
Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TMF, Bacanu, SA, Baekvad-Hansen, M, Beekman, AFT, Bigdeli, TB, Binder, EB, Blackwood, DRH, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JIR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Crowley, CA, Dashti, HS, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Eriksson, N, Escott-Price, V, Kiadeh, FHF, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Giusti-Rodriguez, P, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hannon, E, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, JJ, Hougaard, DM, Hu, M, Hyde, CL, Ising, M, Jansen, R, Jin, F, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Lane, JM, Li, Y, Li, Y, Lind, PA, Liu, X, Lu, L, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mill, J, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Purcell, SM, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Saeed Mirza, S, Saxena, R, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GBC, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Stockmeier, CA, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Tian, C, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, eQtlgen, andMe, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, ECJ, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Hinds, DA, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PFA, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Muller-Myhsok, B, Nordentoft, M, Nothen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, B, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Winslow, AR, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF and Major Depressive Disorder Working Group of the Psychiatric Genomics C (2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics 50, 668–681.Google Scholar
Yadav, V, Chatterjee, SS, Majeed, M and Kumar, V (2015) Long lasting preventive effects of piperlongumine and a Piper longum extract against stress triggered pathologies in mice. Journal of Intercultural Ethnopharmacology 4, 277–283.Google Scholar
Yi, LT, Liu, BB, Li, J, Luo, L, Liu, Q, Geng, D, Tang, Y, Xia, Y and Wu, D (2014) BDNF signaling is necessary for the antidepressant-like effect of naringenin. Progress in Neuro-Psychopharmacology & Biological Psychiatry 48, 135–141.Google Scholar
Yoo, M, Shin, J, Kim, J, Ryall, KA, Lee, K, Lee, S, Jeon, M, Kang, J and Tan, AC (2015) DSigDB: drug signatures database for gene set analysis. Bioinformatics (Oxford, England) 31, 3069–3071.Google Scholar
You, H, Lu, W, Zhao, SP, Hu, ZP and Zhang, JN (2013) The relationship between statins and depression: a review of the literature. Expert Opinion on Pharmacotherapy 14, 1467–1476.Google Scholar
Zaminelli, T, Gradowski, RW, Bassani, TB, Barbiero, JK, Santiago, RM, Maria-Ferreira, D, Baggio, CH and Vital, MABF (2014) Antidepressant and antioxidative effect of ibuprofen in the rotenone model of Parkinson's disease. Neurotoxicity Research 26, 351–362.Google Scholar
Zhou, XY, Keitner, GI, Qin, B, Ravindran, AV, Bauer, M, Del Giovane, C, Zhao, JP, Liu, YY, Fang, YR, Zhang, YQ and Xie, P (2015) Atypical antipsychotic augmentation for treatment-resistant depression: a systematic review and network meta-analysis. International Journal of Neuropsychopharmacology 18, pyv060.Google Scholar
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