BACKGROUND: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. RESULTS: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. CONCLUSIONS: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

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

Bipolar and Depressive Disorders Unit Institute of Neuroscience Hospital Clinic University of Barcelona IDIBAPS CIBERSAM ISCIII Barcelona Spain

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

Centre for Healthy Brain Ageing School of Psychiatry University of New South Wales Sydney Australia

Centre for Psychiatry Research Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

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

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

Department of Adult Psychiatry Poznan University of Medical Sciences Poznań 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 Heidelberg Germany

Department of Genetics Microbiology and Statistics Faculty of Biology Institut de Biomedicina de La Universitat de Barcelona University of Barcelona Barcelona Spain

Department of Health Sciences Research Mayo Clinic Rochester USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medicine Surgery and Dentistry 'Scuola Medica Salernitana' University of Salerno Baronissi Italy

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

Department of Molecular Medicine and Surgery and Center for Molecular Medicine at Karolinska University Hospital Karolinska Institute 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 Canada

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

Department of Psychiatry and Behavioral Sciences Johns Hopkins University Baltimore USA

Department of Psychiatry and Behavioral Sciences Norton College of Medicine SUNY Upstate Medical University Syracuse NY 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 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 Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna Vienna Austria

Department of Psychiatry and Psychotherapy Ludwig Maximilian University Munich Munich Germany

Department of Psychiatry and Psychotherapy University Hospital Bonn Medical Faculty University of Bonn Bonn Germany

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

Department of Psychiatry Dalhousie University Halifax Canada

Department of Psychiatry Division of Psychiatric Specialities Geneva University Hospitals Geneva Switzerland

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 Cincinnati USA

Department of Psychiatry Melbourne Medical School University of Melbourne and The Florey Institute of Neuroscience and Mental Health The University of Melbourne Melbourne Australia

Department of Psychiatry National Institute of Mental Health and Neurosciences Bangalore 560029 India

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

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

Department of Psychiatry University of California San Diego San Diego USA

Department of Psychiatry University of Campania 'Luigi Vanvitelli' Caserta Italy

Department of Psychiatry University of Münster and Joint Institute for Individualisation in a Changing Environment University of Münster and Bielefeld University Albert Schweitzer Campus 1 Building A9 48149 Münster Germany

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 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 USA

Faculty of Medicine University of Geneva Geneva Switzerland

Fliedner Klinik Berlin Berlin Germany

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

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 LMU Munich Munich Germany

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

Laboratorios de Investigación y Desarrollo Facultad de Ciencias y Filosofía Universidad Peruana Cayetano Heredia San Martín de Porres Peru

Medical Faculty Bipolar Center Wiener Neustadt Sigmund Freud University Vienna Austria

Mental Health Research Group IMIM Hospital del Mar Barcelona Spain

Montreal Neurological Institute and Hospital McGill University Montreal Canada

Mood Disorders Center of Ottawa Ottawa Canada

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia and School of Biomedical Sciences University of New South Wales Sydney Australia

Northern Adelaide Local Health Network Mental Health Services Adelaide Australia

Office of Mental Health VA San Diego Healthcare System California USA

Program for Quantitative Genomics Harvard School of Public Health and HSL Institute for Aging Research Harvard Medical School Boston USA

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznań Poland

School of Psychiatry University of New South Wales Sydney 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 Nancy France

Service de Psychiatrie Hôpital Charles Perrens Bordeaux France

The Neuromodulation Unit McGill University Health Centre Montreal Canada

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

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

Univ Paris Est Créteil INSERM IMRB Translational Neuropsychiatry AP HP Mondor University Hospital DMU Impact Fondation FondaMental Créteil France

Univ Paris Est Créteil INSERM IMRB Translational Neuropsychiatry Fondation FondaMental Créteil France

Université Paris Cité Inserm UMR S 1144 Optimisation Thérapeutique en Neuropsychopharmacologie 75006 Paris France

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Res Sq. 2023 Dec 02:rs.3.rs-3677630. doi: 10.21203/rs.3.rs-3677630/v1. PubMed

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