Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

AP HP Hôpital Henri Mondor Département Médico Universitaire de Psychiatrie et d'Addictologie Créteil France

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 Spain

Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Centre for Human Genetics University of Marburg Marburg Germany

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

Centro de Investigación Biomédica en Salud Mental Madrid Spain

Departament de Genètica Microbiologia i Estadística Facultat de Biologia Universitat de Barcelona Barcelona Spain

Department for Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Biological Psychiatry and Neuroscience Dokkyo Medical University School of Medicine Mibu 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 Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore Maryland 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 Pathology of Mental Diseases National Institute of Mental Health National Center of Neurology and Psychiatry Tokyo Japan

Department of Pharmacology Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry and Behavioral Science Juntendo University Graduate School of Medicine Tokyo Japan

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

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

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

Department of Psychiatry and Psychology Mayo Clinic Rochester Minnesota 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 Medical University of Vienna Vienna Austria

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 Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Dokkyo Medical University School of Medicine Mibu Japan

Department of Psychiatry Hokkaido University Graduate School of Medicine Sapporo Japan

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

Department of Psychiatry Melbourne Medical School The University of Melbourne Melbourne Victoria 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 California San Diego La Jolla California USA

Department of Psychiatry University of Campania Luigi Vanvitelli Naples Italy

Department of Psychiatry University of Münster Münster Germany

Department of Psychiatry University of Perugia Perugia Italy

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

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

Department of Quantitative Health Sciences Mayo Clinic Rochester Minnesota USA

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

Douglas Mental Health University Institute McGill University Montreal Québec Canada

Fondation FondaMental Créteil France

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

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

Institut de Biomedicina de la Universitat de Barcelona Barcelona Spain

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Neuroscience and Medicine Research Center Jülich Jülich Germany

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

Institute of Psychiatric Phenomics and Genomics University Hospital Munich Germany

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

Mental Health Research Group IMIM Hospital del Mar Barcelona Spain

Montreal Neurological Institute and Hospital McGill University Montreal Québec Canada

Mood Disorders Center of Ottawa Ottawa Ontario Canada

National Institute of Mental Health Klecany Czechia

Neuroscience Research Australia Sydney New South Wales 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 South Australia Australia

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

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

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

School of Psychiatry University of New South Wales Sydney New South Wales 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 South Australia Australia

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

The Neuromodulation Unit McGill University Health Centre Montreal Québec Canada

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

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

Université Paris Est Créteil INSERM U955 IMRB Laboratoire Neuro Psychiatrie Translationnelle Créteil France

Zobrazit více v PubMed

Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007 May;64((5)):543–52. PubMed PMC

Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011 Mar;68((3)):241–51. PubMed 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 Dec;49((12)):1087–206. PubMed

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 Dec;104((1–3)):185–90. PubMed

Lähteenvuo 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 Apr 1;75((4)):347–55. PubMed PMC

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. Lancet. 2016 Mar 12;387((10023)):1085–93. PubMed PMC

Bauer M, Gitlin M. The essential guide to lithium treatment [Internet] 2016.

Nunes A, Ardau R, Berghöfer A, Bocchetta A, Chillotti C, Deiana V, et al. Prediction of lithium response using clinical data. Acta Psychiatr Scand. 2020 Feb;141((2)):131–41. PubMed

Ho AM-C, Coombes BJ, Nguyen TTL, Liu D, McElroy SL, Singh B, et al. Mood-stabilizing antiepileptic treatment response in bipolar disorder: a Genome-Wide Association Study. Clin Pharmacol Ther. 2020 Jul 5;108((6)):1233–42. PubMed PMC

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 Jan 9;370((2)):119–28. PubMed

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. Mol Psychiatry. 2017 Aug;22((8)):1223. PubMed PMC

Jacobs A, Hagin M, Shugol M, Shomron N, Pillar N, Fañanás L, et al. The black sheep of the family- whole-exome sequencing in family of lithium response discordant bipolar monozygotic twins. Eur Neuropsychopharmacol. 2020 May;34:19–27. PubMed

International Consortium on Lithium Genetics (ConLi+Gen) Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, 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 Jan 1;75((1)):65–74. PubMed PMC

Amare AT, Schubert KO, Hou L, Clark SR, Papiol S, Cearns M, et al. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Mol Psychiatry. 2021;26((6)):2457–70. PubMed

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 Aug;140((2)):94–115. PubMed PMC

Duffy A. The nature of the association between childhood ADHD and the development of bipolar disorder: a review of prospective high-risk studies. Am J Psychiatry. 2012 Dec;169((12)):1247–55. PubMed

Cross-Disorder Group of the Psychiatric Genomics Consortium Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell. 2019 Dec 12;179((7)):1469–82.e11. PubMed PMC

O'Connell KS, Shadrin A, Bahrami S, Smeland OB, Bettella F, Frei O, et al. Identification of genetic overlap and novel risk loci for attention-deficit/hyperactivity disorder and bipolar disorder. Mol Psychiatry. 2019 Dec 2 PubMed

Strober M, DeAntonio M, Schmidt-Lackner S, Freeman R, Lampert C, Diamond J. Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania. J Affect Disord. 1998 Nov;51((2)):145–51. PubMed

Heilbronner U, Schulze TG. ConLiGen - A consortium investigating the genetic underpinnings of lithium response in bipolar disorder. Ann Méd Psychol Rev Psychiatr. 2014;172((3)):197–8.

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 Disord. 2020;22((3)):255–65. PubMed

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 Jun 19;8((6)):e65636. PubMed PMC

Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010 Nov 15;26((22)):2867–73. PubMed PMC

Loh PR, Danecek P, Palamara PF, Fuchsberger C, Reshef AY, Finucane KH, et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat Genet. 2016 Nov;48((11)):1443–8. PubMed PMC

Das S, Forer L, Schönherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016 Oct;48((10)):1284–7. PubMed PMC

Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019 Jan;51((1)):63–75. PubMed PMC

Howard DM, Adams MJ, Clarke TK, Hafferty JD, Gibson J, Shirali M, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci. 2019 Mar;22((3)):343–52. PubMed PMC

Schizophrenia Working Group of the Psychiatric Genomics Consortium Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014 Jul 24;511((7510)):421–7. PubMed PMC

Mak TSH, Porsch RM, Choi SW, Zhou X, Sham PC. Polygenic scores via penalized regression on summary statistics. Genet Epidemiol. 2017 Sep;41((6)):469–80. PubMed

Coombes BJ, Ploner A, Bergen SE, Biernacka JM. A principal component approach to improve association testing with polygenic risk scores. Genet Epidemiol. 2020 Jul 21;44((7)):676–86. PubMed PMC

Nierenberg AA, Miyahara S, Spencer T, Wisniewski SR, Otto MW, Simon N, et al. Clinical and diagnostic implications of lifetime attention-deficit/hyperactivity disorder comorbidity in adults with bipolar disorder: data from the first 1000 STEP-BD participants. Biol Psychiatry. 2005 Jun 1;57((11)):1467–73. PubMed

Skirrow C, Hosang GM, Farmer AE, Asherson P. An update on the debated association between ADHD and bipolar disorder across the lifespan. J Affect Disord. 2012 Dec 10;141((2–3)):143–59. PubMed

Sandstrom A, Perroud N, Alda M, Uher R, Pavlova B. Prevalence of attention-deficit/hyperactivity disorder in people with mood disorders: a systematic review and meta-analysis. Acta Psychiatr Scand. 2021 Feb 2;143((5)):380–91. PubMed

Uchida M, Spencer TJ, Faraone SV, Biederman J. Adult outcome of ADHD: an overview of results from the MGH longitudinal family studies of pediatrically and psychiatrically referred youth with and without ADHD of both sexes. J Atten Disord. 2018 Apr;22((6)):523–34. PubMed

Marangoni C, De Chiara L, Faedda GL. Bipolar disorder and ADHD: comorbidity and diagnostic distinctions. Curr Psychiatry Rep. 2015 Aug;17((8)):604. PubMed

Grigoroiu-Serbanescu M, Giaroli G, Thygesen JH, Shenyan O, Bigdeli TB, Bass NJ, et al. Predictive power of the ADHD GWAS 2019 polygenic risk scores in independent samples of bipolar patients with childhood ADHD. J Affect Disord. 2020 Mar 15;265:651–9. PubMed

van Hulzen KJE, Scholz CJ, Franke B, Ripke S, Klein M, McQuillin A, et al. Genetic overlap between attention-deficit/hyperactivity disorder and bipolar disorder: evidence from genome-wide Association Study Meta-analysis. Biol Psychiatry. 2017 Nov 1;82((9)):634–41. PubMed PMC

State RC, Frye MA, Altshuler LL, Strober M, DeAntonio M, Hwang S, et al. Chart review of the impact of attention-deficit/hyperactivity disorder comorbidity on response to lithium or divalproex sodium in adolescent mania. J Clin Psychiatry. 2004;65:1057–63. PubMed

Kim TT, Dufour S, Xu C, Cohen ZD, Sylvia L, Deckersbach T, et al. Predictive modeling for response to lithium and quetiapine in bipolar disorder. Bipolar Disord. 2019 Aug;21((5)):428–36. PubMed

Vitiello B, Riddle MA, Yenokyan G, Axelson DA, Wagner KD, Joshi P, et al. Treatment moderators and predictors of outcome in the Treatment of Early Age Mania (TEAM) Study [Internet] J Am Acad Child Adolesc Psychiatry. 2012;Vol. 51:867–78. PubMed PMC

Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell. 2018 Jun 14;173((7)):1705–15.e16. PubMed PMC

Coombes BJ, Markota M, John Mann J, Colby C, Stahl E, Talati A, et al. Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores [Internet] Translational Psychiatry. 2020;10 PubMed PMC

Markota M, Coombes BJ, Larrabee BR, McElroy SL, Bond DJ, Veldic M, et al. Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder. Transl Psychiatry. 2018 Sep 10;8((1)):188. PubMed PMC

Leppert B, Millard LAC, Riglin L, Davey Smith G, Thapar A, Tilling K, et al. A cross-disorder PRS-pheWAS of 5 major psychiatric disorders in UK Biobank. PLoS Genet. 2020 May;16((5)):e1008185. PubMed PMC

Grof P, Alda M, Grof E, Zvolsky P, Walsh M. Lithium response and genetics of affective disorders. J Affect Disord. 1994 Oct;32((2)):85–95. PubMed

Nunes A, Stone W, Ardau R, Berghöfer A, Bocchetta A, Chillotti C, et al. Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder. Transl Psychiatry. 2021 Jan 11;11((1)):36. PubMed PMC

Zhang JP, Robinson D, Yu J, Gallego J, Fleischhacker WW, Kahn RS, et al. Schizophrenia polygenic risk score as a predictor of antipsychotic efficacy in first-episode psychosis. Am J Psychiatry. 2019 Jan 1;176((1)):21–8. PubMed PMC

Fanelli G, Benedetti F, Kasper S, Zohar J, Souery D, Montgomery S, et al. Higher polygenic risk scores for schizophrenia may be suggestive of treatment non-response in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2020 Nov 9;:110170. PubMed

Santoro ML, Ota V, de Jong S, Noto C, Spindola LM, Talarico F, et al. Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort [Internet] Translational Psychiatry. 2018;8 PubMed PMC

Gasse C, Wimberley T, Wang Y, Mors O, Børglum A, Als TD, et al. Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia. Schizophr Res. 2019 Oct;212:79–85. PubMed

Exploring the genetics of lithium response in bipolar disorders