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Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li + ) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi + PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li + was positively associated with lithium treatment response in the ConLi + PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li + PGS was positively associated with lithium treatment response in the ConLi + Gen cohort, in both the categorical (P = 9.8 × 10 - 12 decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10 2  = 1.9%) and continuous (P = 6.4 × 10 - 9 , R 2  = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10 - 4 , R 2  = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li + PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment., (© 2023. The Author(s).)

AimSymptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD.MethodDrawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework.ResultsEvidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings.ConclusionsFuture research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.

Circadian dysfunction is a core feature of bipolar disorder and may be due, at least in part, to abnormalities of non-visual photoreception. We critically review the evidence for light hypersensitivity in bipolar disorder and discuss how this may shape future research and clinical innovation, with a focus on a possible novel mechanism of action for lithium. [ABSTRACT FROM AUTHOR]

Background: Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. Methods: Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8-48 (mean 18) years and aged 20-89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea-nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. Results: Overall, 29.5% of subjects experienced at least one low value of eGFR (<60 mL/min/1.73 m), most after ≥15 years of treatment and age > 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m. By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. Limitations: Control data for age-matched subjects not exposed to lithium were lacking. Conclusions: Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age. [ABSTRACT FROM AUTHOR]

Bauer M, Ritter P, Grunze H, Pfennig A. Treatment options for acute depression in bipolar disorder. Bipolar Disord 2012: 14 (Suppl. 2): 37-50. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: The burden of depression represents the most debilitating dimension for the majority of patients with bipolar disorder and dominates the long-term course of the illness. The purpose of this manuscript is to review the evidence base of the available treatment options for bipolar depression within two frequent clinical scenarios. Methods: The evidence is largely based on a systematic literature search and appraisal that was part of the development of the German Guideline for Bipolar Disorders. All relevant randomized controlled trials were critically evaluated. Results: Overall, the number of suitably controlled studies for the treatment of bipolar depression is relatively low. There are two common scenarios. Scenario A, if a patient with bipolar depression is currently not being treated with a mood-stabilizing agent ( de novo depression, first or subsequent episode), then quetiapine or olanzapine are options, or alternatively, carbamazepine and lamotrigine can be considered. Antidepressants are an option for short-term use, but whether they are best administered as monotherapy or in combination with mood-stabilizing agents is still controversial. In practice, most clinicians use antidepressants in combination with an antimanic agent. Scenario B, if a patient is already being treated optimally with a mood-stabilizing agent (good adherence and appropriate dose) such as lithium, lamotrigine is an option. There is no evidence for additional benefit from antidepressants where a patient is already being treated with a mood stabilizer; however, in practice an antidepressant is often trialled. Efficient psychotherapy is an important part of the treatment regimen and should span all phases of the illness. Conclusions: Treatment decisions in bipolar depression involve a range of different pharmacological and non-pharmacological options. Monitoring potential unwanted effects and the appropriateness of treatment can help to effectively balance benefits and risks in individual situations. However, the quality of the assessment and reporting of risks in clinical trials need to be improved to better inform treatment decisions. [ABSTRACT FROM AUTHOR]