Exploring the genetics of lithium response in bipolar disorders.

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=2,064) 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.
Competing Interests: Competing interests 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.