Exploring the genetics of lithium response in bipolar disorders

Marisol Herrera-Rivero¹, Mazda Adli^{2

3}, Kazufumi Akiyama⁴, Nirmala Akula⁵, Azmeraw T Amare⁶, Raffaella Ardau⁷, Bárbara Arias⁸, Jean-Michel Aubry^{9

10}, Lena Backlund¹¹, Frank Bellivier¹², Antonio Benabarre¹³, Susanne Bengesser¹⁴, Abesh Kumar Bhattacharjee¹⁵, Joanna M Biernacka^{16

17}, Armin Birner¹⁴, Micah Cearns⁶, Pablo Cervantes¹⁸, Hsi-Chung Chen¹⁹, Caterina Chillotti⁷, Sven Cichon^{20

21

22}, Scott R Clark⁶, Francesc Colom^{23

24}, Cristiana Cruceanu²⁵, Piotr M Czerski²⁶, Nina Dalkner¹⁴, Franziska Degenhardt²⁷, Maria Del Zompo²⁸, J Raymond DePaulo²⁹, Bruno Etain¹², Peter Falkai³⁰, Ewa Ferensztajn-Rochowiak³¹, Andreas J Forstner^{22

27}, Josef Frank³², Louise Frisén³³, Mark A Frye¹⁷, Janice M Fullerton³⁴, Carla Gallo³⁵, Sébastien Gard³⁶, Julie S Garnham³⁷, Fernando S Goes²⁹, Maria Grigoroiu-Serbanescu³⁸, Paul Grof³⁹, Ryota Hashimoto⁴⁰, Roland Hasler⁹, Joanna Hauser²⁶, Urs Heilbronner⁴¹, Stefan Herms^{20

27}, Per Hoffmann^{20

27}, Liping Hou⁵, Yi-Hsiang Hsu⁴², Stephane Jamain⁴³, Esther Jiménez⁴⁴, Jean-Pierre Kahn⁴⁵, Layla Kassem⁵, Tadafumi Kato⁴⁶, John Kelsoe¹⁵, Sarah Kittel-Schneider⁴⁷, Po-Hsiu Kuo⁴⁸, Ichiro Kusumi⁴⁹, Barbara König⁵⁰, Gonzalo Laje⁵, Mikael Landén^{51

52}, Catharina Lavebratt¹¹, Marion Leboyer⁵³, Susan G Leckband⁵⁴, Mario Maj⁵⁵, Mirko Manchia^{56

57}, Cynthia Marie-Claire⁵⁸, Lina Martinsson⁵⁹, Michael J McCarthy^{15

60}, Susan L McElroy⁶¹, Vincent Millischer^{11

62}, Marina Mitjans^{24

63}, Francis M Mondimore²⁹, Palmiero Monteleone⁶⁴, Caroline M Nievergelt¹⁵, Tomas Novák⁶⁵, Markus M Nöthen²⁷, Claire O'Donovan³⁷, Norio Ozaki⁶⁶, Sergi Papiol^{30

41}, Andrea Pfennig⁶⁷, Claudia Pisanu²⁸, James B Potash²⁹, Andreas Reif⁶⁸, Eva Reininghaus¹⁴, Hélène Richard-Lepouriel^{9

10}, Gloria Roberts⁶⁹, Guy A Rouleau⁷⁰, Janusz K Rybakowski³¹, Martin Schalling¹¹, Peter R Schofield³⁴, Klaus Oliver Schubert^{6

71}, Eva C Schulte^{30

41

72}, Barbara W Schweizer²⁹, Giovanni Severino²⁸, Tatyana Shekhtman¹⁵, Paul D Shilling¹⁵, Katzutaka Shimoda⁷³, Christian Simhandl⁷⁴, Claire M Slaney³⁷, Alessio Squassina²⁸, Thomas Stamm², Pavla Stopkova⁶⁵, Fabian Streit³², Fasil Tekola-Ayele⁷⁵, Anbupalam Thalamuthu⁷⁶, Alfonso Tortorella⁷⁷, Gustavo Turecki²⁵, Julia Veeh⁶⁸, Eduard Vieta⁴⁴, Biju Viswanath⁷⁸, Stephanie H Witt³², Peter P Zandi⁷⁹, Martin Alda³⁷, Michael Bauer⁶⁷, Francis J McMahon⁵, Philip B Mitchell⁶⁹, Marcella Rietschel³², Thomas G Schulze^{29

41

80}, Bernhard T Baune^{81

82}

Affiliations

¹ Department of Psychiatry, University of Münster and Joint Institute for Individualisation in a Changing Environment (JICE), University of Münster and Bielefeld University, Albert-Schweitzer-Campus 1, Building A9, 48149, Münster, Germany.
² Department of Psychiatry and Psychotherapy, Charité, Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
³ Fliedner Klinik Berlin, Berlin, Germany.
⁴ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁵ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Baltimore, USA.
⁶ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
⁷ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
⁸ Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
⁹ Department of Psychiatry, Division of Psychiatric Specialities, Geneva University Hospitals, Geneva, Switzerland.
¹⁰ Faculty of Medicine, University of Geneva, Geneva, Switzerland.
¹¹ Department of Molecular Medicine and Surgery and Center for Molecular Medicine at Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
¹² 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.
¹³ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
¹⁴ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
¹⁵ Department of Psychiatry, University of California San Diego, San Diego, USA.
¹⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, USA.
¹⁷ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, USA.
¹⁸ The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada.
¹⁹ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁰ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²¹ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²² Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
²³ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Spain.
²⁴ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
²⁵ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
²⁶ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznań, Poland.
²⁷ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
²⁸ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
²⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, USA.
³⁰ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
³¹ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznań, Poland.
³² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
³³ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁴ Neuroscience Research, Australia and School of Biomedical Sciences, University of New South Wales, Sydney, Australia.
³⁵ Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, San Martín de Porres, Peru.
³⁶ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
³⁷ Department of Psychiatry, Dalhousie University, Halifax, Canada.
³⁸ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁹ Mood Disorders Center of Ottawa, Ottawa, Canada.
⁴⁰ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁴¹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
⁴² Program for Quantitative Genomics, Harvard School of Public Health and HSL Institute for Aging Research, Harvard Medical School, Boston, USA.
⁴³ Univ. Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Créteil, France.
⁴⁴ Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, ISCIII, Barcelona, Spain.
⁴⁵ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université, Nancy, France.
⁴⁶ Department of Psychiatry & Behavioral Science, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁴⁷ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
⁴⁸ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁴⁹ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁵⁰ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁵¹ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵³ Univ. Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, AP-HP, Mondor University Hospital, DMU Impact, Fondation FondaMental, Créteil, France.
⁵⁴ Office of Mental Health, VA San Diego Healthcare System, California, USA.
⁵⁵ Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Caserta, Italy.
⁵⁶ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁷ Department of Pharmacology, Dalhousie University, Halifax, Canada.
⁵⁸ Université Paris Cité, Inserm UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006, Paris, France.
⁵⁹ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁶⁰ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁶¹ Department of Psychiatry, Lindner Center of Hope/University of Cincinnati, Cincinnati, USA.
⁶² Department of Psychiatry and Psychotherapy, Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
⁶³ Department of Genetics, Microbiology and Statistics, Faculty of Biology, Institut de Biomedicina de La Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain.
⁶⁴ Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi, Italy.
⁶⁵ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁶ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁷ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁸ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁶⁹ School of Psychiatry, University of New South Wales, Sydney, Australia.
⁷⁰ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁷¹ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, Australia.
⁷² Department of Psychiatry and Psychotherapy, University Hospital Bonn, Medical Faculty University of Bonn, Bonn, Germany.
⁷³ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁷⁴ Medical Faculty, Bipolar Center Wiener Neustadt, Sigmund Freud University, Vienna, Austria.
⁷⁵ 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.
⁷⁶ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, Australia.
⁷⁷ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁷⁸ Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India.
⁷⁹ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
⁸⁰ Department of Psychiatry and Behavioral Sciences, Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.
⁸¹ Department of Psychiatry, University of Münster and Joint Institute for Individualisation in a Changing Environment (JICE), University of Münster and Bielefeld University, Albert-Schweitzer-Campus 1, Building A9, 48149, Münster, Germany. Bernhard.Baune@ukmuenster.de.
⁸² Department of Psychiatry, Melbourne Medical School, University of Melbourne and The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia. Bernhard.Baune@ukmuenster.de.

PMID: 38865039
PMCID: PMC11169116
DOI: 10.1186/s40345-024-00341-y

Exploring the genetics of lithium response in bipolar disorders

Marisol Herrera-Rivero et al. Int J Bipolar Disord. 2024.

. 2024 Jun 12;12(1):20.

doi: 10.1186/s40345-024-00341-y.

Authors

Affiliations

¹ Department of Psychiatry, University of Münster and Joint Institute for Individualisation in a Changing Environment (JICE), University of Münster and Bielefeld University, Albert-Schweitzer-Campus 1, Building A9, 48149, Münster, Germany.
² Department of Psychiatry and Psychotherapy, Charité, Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
³ Fliedner Klinik Berlin, Berlin, Germany.
⁴ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁵ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Baltimore, USA.
⁶ Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
⁷ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
⁸ Unitat de Zoologia i Antropologia Biològica (Dpt. Biologia Evolutiva, Ecologia i Ciències Ambientals), Facultat de Biologia and Institut de Biomedicina (IBUB), University of Barcelona, CIBERSAM, Barcelona, Spain.
⁹ Department of Psychiatry, Division of Psychiatric Specialities, Geneva University Hospitals, Geneva, Switzerland.
¹⁰ Faculty of Medicine, University of Geneva, Geneva, Switzerland.
¹¹ Department of Molecular Medicine and Surgery and Center for Molecular Medicine at Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
¹² 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.
¹³ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
¹⁴ Department of Psychiatry and Psychotherapeutic Medicine, Research Unit for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
¹⁵ Department of Psychiatry, University of California San Diego, San Diego, USA.
¹⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, USA.
¹⁷ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, USA.
¹⁸ The Neuromodulation Unit, McGill University Health Centre, Montreal, Canada.
¹⁹ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁰ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²¹ Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²² Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
²³ Mental Health Research Group, IMIM-Hospital del Mar, Barcelona, Spain.
²⁴ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
²⁵ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
²⁶ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznań, Poland.
²⁷ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
²⁸ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
²⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, USA.
³⁰ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany.
³¹ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznań, Poland.
³² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
³³ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁴ Neuroscience Research, Australia and School of Biomedical Sciences, University of New South Wales, Sydney, Australia.
³⁵ Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, San Martín de Porres, Peru.
³⁶ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
³⁷ Department of Psychiatry, Dalhousie University, Halifax, Canada.
³⁸ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
³⁹ Mood Disorders Center of Ottawa, Ottawa, Canada.
⁴⁰ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁴¹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
⁴² Program for Quantitative Genomics, Harvard School of Public Health and HSL Institute for Aging Research, Harvard Medical School, Boston, USA.
⁴³ Univ. Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, Créteil, France.
⁴⁴ Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, ISCIII, Barcelona, Spain.
⁴⁵ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université, Nancy, France.
⁴⁶ Department of Psychiatry & Behavioral Science, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁴⁷ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
⁴⁸ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
⁴⁹ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁵⁰ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁵¹ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵³ Univ. Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, AP-HP, Mondor University Hospital, DMU Impact, Fondation FondaMental, Créteil, France.
⁵⁴ Office of Mental Health, VA San Diego Healthcare System, California, USA.
⁵⁵ Department of Psychiatry, University of Campania 'Luigi Vanvitelli', Caserta, Italy.
⁵⁶ Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁷ Department of Pharmacology, Dalhousie University, Halifax, Canada.
⁵⁸ Université Paris Cité, Inserm UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006, Paris, France.
⁵⁹ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁶⁰ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁶¹ Department of Psychiatry, Lindner Center of Hope/University of Cincinnati, Cincinnati, USA.
⁶² Department of Psychiatry and Psychotherapy, Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
⁶³ Department of Genetics, Microbiology and Statistics, Faculty of Biology, Institut de Biomedicina de La Universitat de Barcelona (IBUB), University of Barcelona, Barcelona, Spain.
⁶⁴ Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi, Italy.
⁶⁵ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁶ Department of Psychiatry & Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁷ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶⁸ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁶⁹ School of Psychiatry, University of New South Wales, Sydney, Australia.
⁷⁰ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁷¹ Northern Adelaide Local Health Network, Mental Health Services, Adelaide, Australia.
⁷² Department of Psychiatry and Psychotherapy, University Hospital Bonn, Medical Faculty University of Bonn, Bonn, Germany.
⁷³ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁷⁴ Medical Faculty, Bipolar Center Wiener Neustadt, Sigmund Freud University, Vienna, Austria.
⁷⁵ 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.
⁷⁶ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, Australia.
⁷⁷ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁷⁸ Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India.
⁷⁹ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
⁸⁰ Department of Psychiatry and Behavioral Sciences, Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.
⁸¹ Department of Psychiatry, University of Münster and Joint Institute for Individualisation in a Changing Environment (JICE), University of Münster and Bielefeld University, Albert-Schweitzer-Campus 1, Building A9, 48149, Münster, Germany. Bernhard.Baune@ukmuenster.de.
⁸² Department of Psychiatry, Melbourne Medical School, University of Melbourne and The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia. Bernhard.Baune@ukmuenster.de.

PMID: 38865039
PMCID: PMC11169116
DOI: 10.1186/s40345-024-00341-y

Abstract

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.

Keywords: Bipolar disorder; Comorbidity; Genetics; Lithium treatment; Psychiatric symptoms.

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Conflict of interest statement

Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbvie, Almirall, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GH Research, Glaxo-Smith-Kline, Janssen, Lundbeck, Orion, Otsuka, Pfizer, Roche, Rovi, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Stanley Medical Research Institute and Viatris. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Takeda. Bernhard Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co, Ltd, Eli Lilly Japan K.K., Otsuka Pharmaceutical Co, Ltd, GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co, Ltd, Dainippon Sumitomo Pharma Co, Ltd, Meiji Seika Pharma Co, Ltd, Pfizer Japan Inc., Mochida Pharmaceutical Co, Ltd, Shionogi & Co, Ltd, Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc, Wako Pure Chemical Industries, Ltd, Wiley Publishing Japan, Nippon Boehringer Ingelheim Co Ltd, Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co, Ltd and Takeda Pharmaceutical Co, Ltd. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén has received lecture honoraria from Lundbeck. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. Scott Clark has received grants, or data and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia,Viatris. Bruno Etain received honoraria from Sanofi Aventis. The rest of authors have no conflicts of interest to disclose.

Figures

**Fig. 1**
Links between phenotypes and Li responses in ConLiGen. A Association test results between total Alda scores and psychiatric symptoms. Shown are the nominal p-values (−log10) and z-values (effect) obtained from robust linear/logistic regression models. B Correlation test results between total Alda scores and PGSs for comorbid conditions. Shown are the nominal p-values (−log10) and correlation coefficients (effect) obtained from partial correlation models using the Spearman method

**Fig. 2**
Visual integration of nominal findings for Li response genes. Shapes depict the diagnostic group analyzed while colors refer to the phenotypes nominally associated with the gene in our analyses, except for the blue color, which localized even the genes not analyzed in this study that were reported by Amare et al. as contributors to Li response in ConLiGen

See this image and copyright information in PMC

Update of

Exploring the genetics of lithium response in bipolar disorders.
Herrera-Rivero M, Adli M, Akiyama K, Akula N, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O'Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Sta… See abstract for full author list ➔ Herrera-Rivero M, et al. Res Sq [Preprint]. 2023 Dec 2:rs.3.rs-3677630. doi: 10.21203/rs.3.rs-3677630/v1. Res Sq. 2023. Update in: Int J Bipolar Disord. 2024 Jun 12;12(1):20. doi: 10.1186/s40345-024-00341-y. PMID: 38077040 Free PMC article. Updated. Preprint.

References

1. Amare AT, Schubert KO, International Consortium on Lithium Genetics (ConLi+Gen), 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(1):65–74. 10.1001/jamapsychiatry.2017.3433 - PMC - PubMed
1. Amare AT, Thalamuthu A, Schubert KO, et al. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. Mol Psychiatry. 2023 doi: 10.1038/s41380-023-02149-1.10.1038/s41380-023-02149-1. - DOI - PMC - PubMed
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1. Chen PH, Hsiao CY, Chiang SJ, et al. Cardioprotective potential of lithium and role of fractalkine in euthymic patients with bipolar disorder. Aust N Z J Psychiatry. 2023;57(1):104–114. doi: 10.1177/00048674211062532. - DOI - PubMed

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Exploring the genetics of lithium response in bipolar disorders

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Exploring the genetics of lithium response in bipolar disorders

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