Bipolar disorder and lithium treatment : etiologies and consequences

Bipolar disorder is a chronic disabling psychiatric disorder marked by episodic disruptive mood swings, accompanied by disturbances in cognition and behavior. Without effective treatment, bipolar disorder can have devastating consequences, including suicide. Lithium has a unique and predominant role in the treatment of bipolar disorder, although the response varies considerably across individuals. Both the causes of bipolar disorder and the mechanism of lithium's therapeutic action remain only partially understood. The present thesis applied genetic epidemiological and pharmacoepidemiological designs to explore the etiologies of bipolar disorder and lithium response, the correlation between bipolar disorder and other mental disorders, and the effect of lithium medication for suicidal behavior in patients.

In Study I, by using a population-based cohort, we extensively quantified the familial aggregation and heritability of bipolar disorder. The precise estimates of familial risks, which increased with genetic relatedness, in conjunction with the high heritability, added to the accumulative evidence for the importance of genetic predisposition in the etiology of bipolar disorder. Furthermore, to understand where bipolar disorder falls among the psychiatric disorders, we examined the familial co-aggregations and phenotypic correlations between them. The shared genetic determinants indicated pleiotropy for genes contributing to bipolar disorder and other psychiatric disorders.

In Study II, we shifted focus to the two main subtypes: bipolar I disorder (BDI) and bipolar II disorder (BDII). Using a similar design for genetically informative data, we found a higher familial clustering within each subtype vs. across the subtypes. Risks for comorbid psychiatric conditions in each subgroup also yielded different patterns. Together with the estimated substantial genetic correlation, the results revealed a distinct but overlapped etiology between the two subtypes of bipolar disorder.

In Study III, we examined the rates of suicide-related events during treatment with lithium and valproate among individuals with bipolar disorder. Using a within-individual study design, the observed rates of suicide-related events were reduced during lithium but not valproate treated periods. The suggestive difference between the two drugs supported the superiority of lithium against suicidal behavior.

In Study IV, we performed genome-wide association studies (GWAS) for lithium response. Subsequent GWAS also tested the subgroup of individuals responding to lithium as cases and compared them with controls without bipolar disorder. No significantly associated genetic loci were identified or validated in both meta-analyses of GWAS. Nevertheless, for the latter, the estimated proportion of variance explained by common genetic variants (“SNP heritability”) is considerable.

In conclusion, our work demonstrates the importance of genetic factors for the origins of bipolar disorder and lithium’s effects. Lithium may serve as a key in both treating and informing the underlying biology of bipolar disorder in future research.

List of scientific papers

I. Song J, Bergen SE, Kuja-Halkola R, Larsson H, Landén M, Lichtenstein P. Bipolar disorder and its relation to major psychiatric disorders: a family-based study in the Swedish population. Bipolar disorders. 2015; 17:184-93.
https://doi.org/10.1111/bdi.12242

II. Song J, Kuja-Halkola R, Sjölander A, Bergen SE, Larsson H, Landén M, Lichtenstein P. A family-based study of bipolar I and bipolar II disorder: co-aggregation and comorbidities. [Manuscript]

III. Song J, Sjölander A, Joas E, Bergen SE, Runeson B, Larsson H, Landén M, Lichtenstein P. Suicidal behavior during lithium and valproate medication: a within-individual eight year prospective study of 50 000 patients with bipolar disorder. [Submitted]

IV. Song J, Bergen SE, Di Florio A, Karlsson R, Charney A, Ruderfer DM, Stahl EA, The International Cohort Collection for Bipolar Disorder, Chambert KD, Moran JL, Gordon-Smith K, Forty L, Green EK, Jones I, Jones L, Scolnick EM, Sklar P, Smoller JW, Lichtenstein P, Hultman C, Craddock N, Landén M. Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder. Mol Psychiatry. [Accepted]
https://doi.org/10.1038/mp.2015.165