Clinical, Biological and Genetic Predictors of Lithium Treatment Response (original) (raw)
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Neuropsychobiology, 2010
For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for
Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics
Molecular psychiatry, 2015
After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by the absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signaling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na(+)-K(+) ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need...
Pharmacogenetics of lithium response in bipolar disorder
Pharmacogenomics, 2010
Bipolar disorder (BD) is a serious mental illness with well-established, but poorly characterized genetic risk. Lithium is among the best proven mood stabilizer therapies for BD, but treatment responses vary considerably. Based upon these and other findings, it has been suggested that lithium-responsive BD may be a genetically distinct phenotype within the mood disorder spectrum. This assertion has practical implications both for the treatment of BD and for understanding the neurobiological basis of the illness: genetic variation within lithium-sensitive signaling pathways may confer preferential treatment response, and the involved genes may underlie BD in some individuals. Presently, the mechanism of lithium is reviewed with an emphasis on gene-expression changes in response to lithium. Within this context, findings from genetic-association studies designed to identify lithium response genes in BD patients are evaluated. Finally, a framework is proposed by which future pharmacogen...
Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium
2016
Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the ''Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder'' scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (k)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated firstround vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (k = 0.66 and k = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC 1 = 0.71 and ICC 2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
PloS one, 2013
The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores ava...
Lancet (London, England), 2016
Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for associa...
Clinical factors associated with lithium response in bipolar disorders
The Australian and New Zealand journal of psychiatry, 2016
Bipolar disorder is a common chronic illness characterized by high levels of morbidity and all-cause mortality. Lithium is one of the gold standard mood stabilizer treatments, but the identification of good, partial and non-responders in clinical settings is inconsistent. We used an established rating scale (the Alda scale) to classify the degree of lithium response (good response, partial response, non-response) in a large, multicentre clinically representative sample of well-characterized cases of bipolar disorders I and II. Next, we examined previously reported clinical predictors of response to determine which factors significantly differentiated between the three response groups. Of 754 cases, 300 received lithium, for at least 6 months, as a treatment for bipolar disorder (40%). Of these cases, 17% were classified as good response, 52% as partial response and 31% as non-response. Lifetime history of mixed episodes (p = 0.017) and alcohol use disorders (p = 0.015) both occurred...
International Journal of Bipolar Disorders
Background Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. Structure The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including o...