Research Article For reprint orders, please contact: reprints@futuremedicine.com Differences in telomere length between patients with bipolar disorder and controls are infuenced by lithium treatment Claudia Pisanu 1 , Donatella Congiu 1 , Mirko Manchia 2,3,4 , Paola Caria 5 , Cristina Cocco 6 , Tinuccia Dettori 5 , Daniela Virginia Frau 5 , Elias Manca 6 , Anna Meloni 1 , Mariella Nieddu 5 , Barbara Noli 6 , Federica Pinna 2,3 , Renato Robledo 5 , Valeria Sogos 7 , Gian Luca Ferri 6 , Bernardo Carpiniello 2,3 , Roberta Vanni 5 , Alberto Bocchetta 1,8 , Giovanni Severino 1 , Raffaella Ardau 8 , Caterina Chillotti 8 , Maria Del Zompo 1,8 & Alessio Squassina* ,1 1 Department of Biomedical Science, Section of Neuroscience & Clinical Pharmacology, University of Cagliari, Monserrato, Cagliari, 09042, Italy 2 Unit of Psychiatry, Department of Public Health, Clinical & Molecular Medicine, University of Cagliari, Cagliari, 09100, Italy 3 Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, 09100, Italy 4 Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada 5 Department of Biomedical Sciences, Unit of Biology & Genetics, University of Cagliari, Monserrato, Cagliari, 09042, Italy 6 Department of Biomedical Sciences, NEF Laboratory, University of Cagliari, Monserrato, Cagliari, 09042, Italy 7 Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Monserrato, Cagliari, 09042, Italy 8 Unit of Clinical Pharmacology, University Hospital Agency of Cagliari, Cagliari, 09100, Italy *Author for correspondence: Tel.: +39 070 675 4323; squassina@unica.it Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leuko- cyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and sim- ilar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genet- ically determined LTL. Conclusion: Our data support previous fndings showing that long-term lithium treatment might protect against telomere shortening. First draft submitted: 24 February 2020; Accepted for publication: 16 March 2020; Published online: 6 May 2020 Keywords: aging • mendelian randomization mood disorders • mood stabilizers • pharmacogenetics • telomeres • telomere shortening Bipolar disorder (BD) is a severe mental illness characterized by recurrent episodes of depressive and manic or hypomanic symptoms. Being associated with high morbidity and premature mortality, BD has a major socioeco- nomic impact and is one of the leading causes of disability [1]. Indeed, patients with BD are characterized by a decreased life expectancy compared with the general population [2], mainly due to suicide and increased frequency of comorbid medical illnesses, including cardiovascular and metabolic disorders, cancer and dementia [3]. These observations have prompted the hypothesis that BD might be associated with accelerated aging. In fact, several studies have shown an association between BD and molecular markers of aging [4–11], including reduced telomere length (TL) [12–14], which represents the most investigated marker of cellular aging [15]. In humans, telomeres consist of 5 ′ -TTAGGG-3 ′ DNA tandem repeats regulated by the associated protein complexes and located at the end of eukaryotic chromosomes [15]. Telomeres play a crucial role to ensure chromosome stability due to their protective properties against degradation of the terminal region of chromosomes, chromosome fusions or recombination [16]. Telomeres physiologically shorten with each cell division and when they reach a critical threshold the cell undergoes senescence. This physiological shortening can be counteracted by the enzyme telomerase (which is, however, active in adult stem cells). It has been hypothesized that chronic disorders, such as mental illness, might be associated Pharmacogenomics (Epub ahead of print) ISSN 1462-2416 10.2217/pgs-2020-0028 C  2020 Future Medicine Ltd