Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Bipolar Center Wiener Neustadt Sigmund Freud University Medical Faculty Vienna Austria

Bipolar Disorder Program Institute of Neuroscience Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Barcelona Catalonia Spain

Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Centro de Investigación Biomédica en Red de Salud Mental Instituto de Salud Carlos 3 Madrid Spain

Clinical Neuroscience Max Planck Institute of Experimental Medicine Göttingen Germany

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Biological Psychiatry and Neuroscience Dokkyo Medical University School of Medicine Mibu Tochigi Japan

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Department of Health Sciences Research Mayo Clinic Rochester MN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Molecular Medicine and Surgery Karolinska Institute Stockholm Sweden

Department of Neurobiology Care Sciences and Society Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore MD USA

Department of Psychiatry and Center of Sleep Disorders National Taiwan University Hospital Taipei Taiwan

Department of Psychiatry and Department of Child and Adolescent Psychiatry Nagoya University Graduate School of Medicine Nagoya Japan

Department of Psychiatry and Psychology Mayo Clinic Rochester MN USA

Department of Psychiatry and Psychotherapeutic Medicine Landesklinikum Neunkirchen Neunkirchen Austria

Department of Psychiatry and Psychotherapeutic Medicine Research Unit for bipolar affective disorder Medical University of Graz Graz Austria

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany

Department of Psychiatry and Psychotherapy Ludwig Maximilian University Munich Munich Germany

Department of Psychiatry and Psychotherapy University Hospital Carl Gustav Carus Medical Faculty Technische Universität Dresden Dresden Germany

Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen Germany

Department of Psychiatry and Psychotherapy University of Münster Münster Germany

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Dokkyo Medical University School of Medicine Mibu Tochigi Japan

Department of Psychiatry Hokkaido University Graduate School of Medicine Sapporo Japan

Department of Psychiatry Lindner Center of Hope University of Cincinnati Mason OH USA

Department of Psychiatry Melbourne Medical School University of Melbourne Parkville VIC Australia

Department of Psychiatry Mood Disorders Unit HUG Geneva University Hospitals Geneva Switzerland

Department of Psychiatry Osaka University Graduate School of Medicine Osaka Japan

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt Germany

Department of Psychiatry University of Basel Basel Switzerland

Department of Psychiatry University of California San Diego San Diego CA USA

Department of Psychiatry University of Campania Luigi Vanvitelli Naples Italy

Department of Psychiatry University of Perugia Perugia Italy

Department of Psychiatry VA San Diego Healthcare System San Diego CA USA

Department of Public Health and Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan

Discipline of Psychiatry School of Medicine University of Adelaide Adelaide SA Australia

Douglas Mental Health University Institute McGill University Montreal QC Canada

Epidemiology Branch Division of Intramural Population Health Research Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD USA

HSL Institute for Aging Research Harvard Medical School Boston MA USA

Human Genomics Research Group Department of Biomedicine University Hospital Basel Basel Switzerland

Inserm U955 Translational Psychiatry laboratory Fondation FondaMental Créteil France

Inserm U955 Translational Psychiatry laboratory Université Paris Est Créteil Department of Psychiatry and Addictology of Mondor University Hospital AP HP Fondation FondaMental Créteil France

INSERM UMR S 1144 Université Paris Diderot Département de Psychiatrie et de Médecine Addictologique AP HP Groupe Hospitalier Saint Louis Lariboisière F Widal Paris France

Institute of Human Genetics University of Bonn and Department of Genomics Life and Brain Center Bonn Germany

Institute of Neuroscience and Physiology the Sahlgrenska Academy at the Gothenburg University Gothenburg Sweden

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany

Intramural Research Program National Institute of Mental Health National Institutes of Health US Department of Health and Human Services Bethesda MD USA

Laboratory for Molecular Dynamics of Mental Disorders RIKEN Center for Brain Science Saitama Japan

Mental Health Research Group IMIM Hospital del Mar Barcelona Catalonia Spain

Molecular Research Center for Children's Mental Development United Graduate School of Child Development Osaka University Osaka Japan

Montreal Neurological Institute and Hospital McGill University Montreal QC Canada

Mood Disorders Center of Ottawa Ottawa ON Canada

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney NSW Australia

Neurosciences Section Department of Medicine Surgery and Dentistry Scuola Medica Salernitana University of Salerno Salerno Italy

Northern Adelaide Local Health Network Mental Health Services Adelaide SA Australia

Office of Mental Health VA San Diego Healthcare System San Diego CA USA

Program for Quantitative Genomics Harvard School of Public Health Boston MA USA

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

School of Medical Sciences University of New South Wales Sydney NSW Australia

School of Psychiatry University of New South Wales and Black Dog Institute Sydney NSW Australia

Section of Psychiatry Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy

Service de Psychiatrie et Psychologie Clinique Centre Psychothérapique de Nancy Université de Lorraine Nancy France

Service de psychiatrie Hôpital Charles Perrens Bordeaux France

South Australian Academic Health Science and Translation Centre South Australian Health and Medical Research Institute Adelaide SA Australia

The Florey Institute of Neuroscience and Mental Health The University of Melbourne Parkville VIC Australia

The Neuromodulation Unit McGill University Health Centre Montreal QC Canada

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

Unitat de Zoologia i Antropologia Biològica University of Barcelona CIBERSAM Barcelona Spain

Zobrazit více v PubMed

Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18:440–50. PubMed DOI

Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry. 2014;13:153–60. PubMed DOI PMC

Schulze TG, Alda M, Adli M, Akula N, Ardau R, Bui ET, et al. 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;62:72–8. PubMed DOI PMC

Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49:1087–206. PubMed DOI

Hou L, Heilbronner U, Degenhardt F, Adli M, Akiyama K, Akula N, et al. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. The Lancet. 2016;387:1085–93. DOI

Grof P, Duffy A, Cavazzoni P, Grof E, Garnham J, MacDougall M, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002;63:942–7. PubMed DOI

Garnham J, Munro A, Slaney C, Macdougall M, Passmore M, Duffy A, et al. Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study. J Affect Disord. 2007;104:185–90. PubMed DOI

Lahteenvuo M, Tanskanen A, Taipale H, Hoti F, Vattulainen P, Vieta E, et al. Real-world effectiveness of pharmacologic treatments for the prevention of rehospitalization in a finnish nationwide cohort of patients with bipolar disorder. JAMA Psychiatry. 2018;75:347–55. PubMed DOI PMC

Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet (London, England). 2016;387:1561–72. DOI

Bauer M, Gitlin M. Practical management of lithium. In: The essential guide to lithium treatment. Springer International Publishing: Cham, 2016, pp 113–28.

Oedegaard KJ, Alda M, Anand A, Andreassen OA, Balaraman Y, Berrettini WH, et al. The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample. BMC Psychiatry. 2016;16:129. PubMed DOI PMC

Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, Bauer M, et al. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord. 2014;2:15. PubMed DOI PMC

Joas E, Karanti A, Song J, Goodwin GM, Lichtenstein P, Landen M. Pharmacological treatment and risk of psychiatric hospital admission in bipolar disorder. Br J Psychiatry. 2017;210:197–202. PubMed DOI

Chen CH, Lee CS, Lee MT, Ouyang WC, Chen CC, Chong MY, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med. 2014;370:119–28. PubMed DOI

Song J, Bergen SE, Di Florio A, Karlsson R, Charney A, Ruderfer DM, et al. Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder. Molecular Psychiatry. 2016;21:1290–7. PubMed DOI

Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Heilbronner U, et al. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: a genome-wide association study. JAMA Psychiatry. 2018;75:65–74. PubMed

Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry. 1999;60:733–40. PubMed DOI

Calkin C, van de Velde C, Ruzickova M, Slaney C, Garnham J, Hajek T, et al. Can body mass index help predict outcome in patients with bipolar disorder? Bipolar Disorders. 2009;11:650–6. PubMed DOI PMC

Calkin CV, Ruzickova M, Uher R, Hajek T, Slaney CM, Garnham JS, et al. Insulin resistance and outcome in bipolar disorder. Brit J Psychiatry. 2015;206:52–7. DOI

Mitchell PB, Frankland A, Hadzi-Pavlovic D, Roberts G, Corry J, Wright A, et al. Comparison of depressive episodes in bipolar disorder and in major depressive disorder within bipolar disorder pedigrees. Brit J Psychiatry. 2011;199:303–9. DOI

Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM. Cross-Disorder Group of the Psychiatric Genomics C et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45:984–94. PubMed DOI

Cross-Disorder Group of the Psychiatric Genomics C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. The Lancet. 2013;381:1371–9. DOI

Amare AT, Schubert KO, Klingler-Hoffmann M, Cohen-Woods S, Baune BT. The genetic overlap between mood disorders and cardiometabolic diseases: a systematic review of genome wide and candidate gene studies. Transl Psychiatry. 2017;7:e1007. PubMed DOI PMC

Amare AT, Schubert KO, Baune BT. Pharmacogenomics in the treatment of mood disorders: strategies and opportunities for personalized psychiatry. EPMA J. 2017;8:211–27. PubMed DOI PMC

Abou-Saleh MT, Muller-Oerlinghausen B, Coppen AJ. Lithium in the episode and suicide prophylaxis and in augmenting strategies in patients with unipolar depression. Int J Bipolar Disord. 2017;5:11. PubMed DOI PMC

Zhou X, Ravindran AV, Qin B, Del Giovane C, Li Q, Bauer M, et al. Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis. J Clin Psychiatry. 2015;76:e487–98. PubMed DOI

Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtala J, et al. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry. 2017;4:547–53. PubMed DOI

Popovic D, Reinares M, Goikolea JM, Bonnin CM, Gonzalez-Pinto A, Vieta E. Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder. Eur Neuropsychopharmacol. 2012;22:339–46. PubMed DOI

Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, et al. Bipolar disorders. Nat Rev Dis Primers. 2018;4:18008. PubMed DOI

Colom F, Vieta E, Daban C, Pacchiarotti I, Sanchez-Moreno J. Clinical and therapeutic implications of predominant polarity in bipolar disorder. J Affect Disord. 2006;93:13–7. PubMed DOI

Kessing LV, Hellmund G, Andersen PK. Predictors of excellent response to lithium: results from a nationwide register-based study. Int Clin Psychopharmacol. 2011;26:323–8. PubMed DOI

Kleindienst N, Engel R, Greil W. Which clinical factors predict response to prophylactic lithium? A systematic review for bipolar disorders. Bipolar Disorders. 2005;7:404–17. PubMed DOI

Pfennig A, Schlattmann P, Alda M, Grof P, Glenn T, Muller-Oerlinghausen B, et al. Influence of atypical features on the quality of prophylactic effectiveness of long-term lithium treatment in bipolar disorders. Bipolar Disorders. 2010;12:390–6. PubMed DOI

Fountoulakis KN, Kontis D, Gonda X, Siamouli M, Yatham LN. Treatment of mixed bipolar states. Int J Neuropsychopharmacol. 2012;15:1015–26. PubMed DOI

Sportiche S, Geoffroy PA, Brichant-Petitjean C, Gard S, Khan JP, Azorin JM, et al. Clinical factors associated with lithium response in bipolar disorders. Aust N Z J Psychiatry. 2017;51:524–30. PubMed DOI

Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics 2018;50:668–81.

Duffy A, Alda M, Milin R, Grof P. A consecutive series of treated affected offspring of parents with bipolar disorder: is response associated with the clinical profile? Can J Psychiatry. 2007;52:369–76. PubMed DOI

Manchia M, Adli M, Akula N, Ardau R, Aubry JM, Backlund L, et al. Assessment of response to lithium maintenance treatment in bipolar disorder: a consortium on lithium genetics (ConLiGen) report. PloS ONE. 2013;8:e65636. PubMed DOI PMC

Scott J, Etain B, Manchia M, Brichant-Petitjean C, Geoffroy PA, Schulze T et al. An examination of the quality and performance of the Alda scale for classifying lithium response phenotypes. Bipolar Disorders. 2019. https://doi.org/10.1111/bdi.12829 .

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. PubMed DOI PMC

Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48:1284–7. PubMed DOI PMC

Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52. PubMed DOI

Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet. 2019;51:793–803. PubMed DOI PMC

Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526:112–7. PubMed DOI PMC

Amare AT, Vaez A, Hsu YH, Direk N, Kamali Z, Howard DM et al. Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-018-0336-6 .

Choi SW, O’Reilly PF. PRSice-2: polygenic risk score software for biobank-scale data. GigaScience. 2019;8:giz082. PubMed DOI PMC

Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ. 1995;310:170. PubMed DOI PMC

Malhi GS, Tanious M, Das P, Berk M. The science and practice of lithium therapy. Aust N Z J Psychiatry. 2012;46:192–211. PubMed DOI

Grof E, Haag M, Grof P, Haag H. Lithium response and the sequence of episode polarities: preliminary report on a Hamilton sample. Prog Neuropsychopharmacol Biol Psychiatry. 1987;11:199–203. PubMed DOI

Hui TP, Kandola A, Shen L, Lewis G, Osborn DPJ, Geddes JR, et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. Acta Psychiatr Scand. 2019;140:94–115. PubMed DOI PMC

Grof P, Alda M, Grof E, Zvolsky P, Walsh M. Lithium response and genetics of affective disorders. J Affect Disord. 1994;32:85–95. PubMed DOI

Bschor T. Lithium in the treatment of major depressive disorder. Drugs. 2014;74:855–62. PubMed DOI

Alevizos B, Alevizos E, Leonardou A, Zervas I. Low dosage lithium augmentation in venlafaxine resistant depression: an open-label study. Psychiatriki. 2012;23:143–8. PubMed

Bauer M, Döpfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. Prim Care Companion J Clin Psych. 2000;2:31.

Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs. 2014;28:331–42. PubMed DOI

Bauer M, Bschor T, Kunz D, Berghofer A, Strohle A, Muller-Oerlinghausen B. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry. 2000;157:1429–35. PubMed DOI

Bauer M, Adli M, Baethge C, Berghöfer A, Sasse J, Heinz A, et al. Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms. Can J Psychiatry. 2003;48:440–8. PubMed DOI

Bschor T, Bauer M. Efficacy and mechanisms of action of Lithium augmentation in refractory major depression. Curr Pharm Des. 2006;12:2985–92. PubMed DOI

Kan C, Pedersen NL, Christensen K, Bornstein SR, Licinio J, MacCabe JH, et al. Genetic overlap between type 2 diabetes and depression in Swedish and Danish twin registries. Mol Psychiatry. 2016;21:903. PubMed DOI PMC

Bigdeli TB, Ripke S, Peterson RE, Trzaskowski M, Bacanu SA, Abdellaoui A, et al. Genetic effects influencing risk for major depressive disorder in China and Europe. Transl Psychiatry. 2017;7:e1074. PubMed DOI PMC

Shan GW, Makmor-Bakry M, Omar MS. Long term use of lithium and factors associated with treatment response among patients with bipolar disorder. Psychiatr Danub. 2016;28:146–53. PubMed

Wray NR, Lee SH, Mehta D, Vinkhuyzen AA, Dudbridge F, Middeldorp CM. Research review: polygenic methods and their application to psychiatric traits. J Child Psychol Psychiatry Allied Discip. 2014;55:1068–87. DOI

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

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