Lithium Treatment Response Research Articles

557. Pharmacogenetic Association of Lithium Treatment Response with Bcl2 Polymorphism in Bipolar Disorder

557. Pharmacogenetic Association of Lithium Treatment Response with Bcl2 Polymorphism in Bipolar Disorder

261. Assessing Pretreatment Multimodal Neuroimaging Markers of Lithium Treatment Response in Bipolar Depression

261. Assessing Pretreatment Multimodal Neuroimaging Markers of Lithium Treatment Response in Bipolar Depression

M23 - Enrichment of Genetic Variants Associated With Clinical Response To Lithium In Circadian Clock System Gene Sets

Background A connection between the mechanism of action of lithium in bipolar disorder and circadian rhythms has been suggested. Nonetheless the relationship between the “clock genes“ that regulate circadian rhythms and lithium treatment response is not completely understood. Some studies, based on candidate-gene approaches have attempted to find the association of specific genes in the clock system with treatment response. However, to our knowledge there has not been a systematic pathway / enrichment analysis of clock genes in the context of the clinical response to lithium in bipolar disorder. The objective of this study is to perform a gene-based analyses and formal gene set enrichment analyses based on circadian clock system genes, using the currently available summary statistics from The International Consortium on Lithium Genetics (ConLiGen) GWAS. Methods Based on previous literature ( Pizarro et al., 2013 , Chen et al., 2016 ) and available resources (e.g. http://circadb.hogeneschlab.org/) we have generated curated gene sets related to circadian control that are grouped as ‘clock modulator (upstream) genes’, ‘core clock genes’ and ‘clock controlled (downstream) genes’. Summary statistics derived from the ConLiGen GWAS on continuous/dichotomous lithium response were used as reference. For gene-set enrichment, analyses involved the use of two softwares in order to cross-validate the results: INRICH and MAGMA, the later being also used for gene-based analyses. Results None of the significant associations obtained in gene-based analyses survived multiple testing correction. However gene-set enrichment analyses using INRICH and MAGMA reported a significant enrichment of a set of core clock genes with respect to the dichotomous lithium response phenotype (INRICH: corrected P=0.008; MAGMA: competitive P=0.005). No enrichment was observed using the continuous lithium response as target phenotype. Discussion Our results suggest the involvement of those genes that constitute the core clock machinery in the determination of the clinical response to lithium in bipolar disorder patients. Enrichment analyses based on other methods and other psychiatric phenotypes are ongoing in order to i) further validate these findings and ii) evaluate their specificity.

Evaluation of The Association Between Lithium Treatment and GSK3ß Polymorphism in Bipolar Disorder Patients

There is a lack of evidence regarding clinical predictors for the treatment response to lithium, which is the main stay treatment option for bipolar disorder. Studies that examined the mechanistic action of lithium revealed that glycogen synthase kinase 3β (GSK-3β) enzymeinhibition was important in regard to treatment responses. Based on this background, we aimed to investigate the association between responses to lithium treatment and five different polymorphisms of GSK-3β. Lithium treatment response scale (LTRS) scores for 100 patients diagnosed with bipolar disorders type I were calculated according to the hospital records. Blood samples were collected and genomic DNA was obtained using the MagNA Pure Compact automatic isolation method. The GSK-3β: rs17183904, rs17183897, rs34009575, rs34002644, and rs17183890 polymorphisms were analyzed by real time PCR. In this cohort, the mean age of patients was 41.1±10.3 years, the mean age of disease onset was 24.5±8.2, and the mean LTRS score was 4.9±1.8. There was no statistically significant difference for LTRS scores between groups in terms of gender, marital status, level of education, and the type of first episode. LTRS was significantly higher in only the patients harbouring GSK-3β rs17183890 AG genotype (p=0.008, t:2.71). Interestingly, no differences were found for the remaining polymorphisms. The specific GSK-3β polymorphism that associated with lithium-response in our study may help to predict lithium responses and to develop individualized treatment. We presume that our pharmacogenomic findings may also provide important contributions to the clinical practice in regard to future evaluation of the treatment adherence and side effects. To obtain these goals, further genome-wide scanning studies conducted on larger sample cohorts are required.

Pharmacogenomics of Mood Disorders

Overall Abstract Single gene and GWAS analyses of pharmacological treatment response in depression and bipolar disorder have had varying success in identifying functionally relevant genes associated with pharmacological treatment response such as response to SSRI in depression and lithium in bipolar disorder. Hence, the need to better understand the complex genetic underpinnings of pharmacoresponse may include methodologies such as RNA-seq and microarray analyses. Such approaches contribute to a more in in-depth functional characterization of risk loci related to treatment response and to characterize the genetic underpinnings of both adverse events (e.g. induction of mania by antidepressants) and of medical comorbidity contributing to poor treatment response. In addition, gene expression profile and eQTLs can assist an improved understanding of the functional genomics of mood disorders. Specifically, recent large-scale GWAS meta-analyses (ConLiGen) have implicated multiple novel loci, two of which met the threshold for genome-wide significance: GADL1 (Chen et al., 2014) and an intergenic locus on chromosome 21 (Hou et al., 2016). The functional implications of the related genes remain to be described. In a first presentation, results will be presented from whole blood RNA-seq-data in a subsample of ConLiGen to validate and characterize these associations with clinical lithium treatment response and how these loci impact gene function and lithium response (David Stacey). Addressing the need to investigate the genetic underpinning of a broader range of treatment outcomes and adverse events, the genetic contribution of a potential induction of mania by antidepressants will be discussed in a second presentation, that shows results from a GWAS of antidepressant-induced mania (Joanna Biernacka). Among other factors, the co-morbidity of depression with other psychiatric and cardiometabolic disorders may negatively influence antidepressants treatment outcome. Moreover, response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect. Hence, use of polygenic scores (PGS) could be a better alternative to estimate the overall effect of genetic factors on treatment response and assess the importance of co-morbidities and related phenotypes. To investigate this further, we evaluated whether PGS derived from 25 recognized comorbid cardiometabolic and psychiatric disorders, personality traits and educational attainment predict treatment outcome to SSRIs in major depressive disorder using the ISPC data (Bernhard Baune). Previous studies aiming to identify the transcriptome signature of depression are inconsistent with low replicability at the single gene level in both brain and peripheral tissues. In a fourth presentation, results from analyses of whole blood transcriptomes of 521 elderly people from the general population (The Sydney Memory and Age Study, MAS, Sydney) are shown to describe molecular networks involved in geriatric depression. Functional characterisation of two out of 29 modules of the co-expression network indicated that abnormalities in structural constituents of ribosome may be involved in the pathophysiology of geriatric depression. In addition, results of pathway analyses using Ingenuity Pathway Analysis software will be shown (Liliana Ciobanu).

P.2.d.030 - Temperament characteristics of bipolar patients on lithium therapy and relationship with lithium treatment response

P.2.d.030 - Temperament characteristics of bipolar patients on lithium therapy and relationship with lithium treatment response

Therapeutic Mechanisms of Lithium in Bipolar Disorder: Recent Advances and Current Understanding.

Lithium is the most effective and well established treatment for bipolar disorder, and it has a broad array of effects within cellular pathways. However, the specific processes through which therapeutic effects occur and are maintained in bipolar disorder remain unclear. This paper provides a timely update to an authoritative review of pertinent findings that was published in CNS Drugs in 2013. A literature search was conducted using the Scopus database, and was limited by year (from 2012). There has been a resurgence of interest in lithium therapy mechanisms, perhaps driven by technical advancements in recent years that permit the examination of cellular mechanisms underpinning the effects of lithium-along with the reuptake of lithium in clinical practice. Recent research has further cemented glycogen synthase kinase 3β (GSK3β) inhibition as a key mechanism, and the inter-associations between GSK3β-mediated neuroprotective, anti-oxidative and neurotransmission mechanisms have been further elucidated. In addition to highly illustrative cellular research, studies examining higher-order biological systems, such as circadian rhythms, as well as employing innovative animal and human models, have increased our understanding of how lithium-induced changes at the cellular level possibly translate to changes at behavioural and clinical levels. Neural circuitry research is yet to identify clear mechanisms of change in bipolar disorder in response to treatment with lithium, but important structural findings have demonstrated links to the modulation of cellular mechanisms, and peripheral marker and pharmacogenetic studies are showing promising findings that will likely inform the exploration for predictors of lithium treatment response. With a deeper understanding of lithium's therapeutic mechanisms-from the cellular to clinical levels of investigation-comes the opportunity to develop predictive models of lithium treatment response and identify novel drug targets, and recent findings have provided important leads towards these goals.

GADL1 variant and medication adherence in predicting response to lithium maintenance treatment in bipolar I disorder.

BackgroundGenetic variants and medication adherence have been identified to be the main factors contributing to lithium treatment response in bipolar disorders.AimsTo simultaneously examine effects of variant glutamate decarboxylase-like protein 1 (GADL1) and medication adherence on response to lithium maintenance treatment in Han Chinese patients with bipolar I (BPI) disorder.MethodFrequencies of manic and depressive episodes between carriers and non-carriers of the effective GADL1 rs17026688 T allele during the cumulative periods of off-lithium, poor adherence to lithium treatment and good adherence to lithium treatment were compared in Han Chinese patients with BPI disorder (n=215).ResultsGADL1 rs17026688 T carriers had significantly lower frequencies of recurrent affective episodes than non-T carriers during the cumulative period of good adherence, but not during those of poor adherence.ConclusionsGADL1 rs17026688 and medication adherence jointly predict response to lithium maintenance treatment in Han Chinese BPI patients.Declaration of interestNone.Copyright and usage© The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Olfactory Neurons Obtained through Nasal Biopsy Combined with Laser-Capture Microdissection: A Potential Approach to Study Treatment Response in Mental Disorders

Bipolar disorder (BD) is a severe neuropsychiatric disorder with poorly understood pathophysiology and typically treated with the mood stabilizer, lithium carbonate. Animal studies as well as human genetic studies indicate that lithium affects molecular targets that are involved in neuronal growth, survival and maturation, and notably molecules involved in Wnt signaling. Given the ethical challenge to obtaining brain biopsies for investigating dynamic molecular changes associated with lithium-response in the central nervous system (CNS), one may consider the use of neurons obtained from olfactory tissues to achieve this goal.The olfactory epithelium contains olfactory receptor neurons at different stages of development and glial-like supporting cells. This provides a unique opportunity to study dynamic changes in the CNS of patients with neuropsychiatric diseases, using olfactory tissue safely obtained from nasal biopsies. To overcome the drawback posed by substantial contamination of biopsied olfactory tissue with non-neuronal cells, a novel approach to obtain enriched neuronal cell populations was developed by combining nasal biopsies with laser-capture microdissection. In this study, a system for investigating treatment-associated dynamic molecular changes in neuronal tissue was developed and validated, using a small pilot sample of BD patients recruited for the study of the molecular mechanisms of lithium treatment response.

Olfactory neurons obtained through nasal biopsy combined with laser-capture microdissection: a potential approach to study treatment response in mental disorders.

Bipolar disorder (BD) is a severe neuropsychiatric disorder with poorly understood pathophysiology and typically treated with the mood stabilizer, lithium carbonate. Animal studies as well as human genetic studies indicate that lithium affects molecular targets that are involved in neuronal growth, survival and maturation, and notably molecules involved in Wnt signaling. Given the ethical challenge to obtaining brain biopsies for investigating dynamic molecular changes associated with lithium-response in the central nervous system (CNS), one may consider the use of neurons obtained from olfactory tissues to achieve this goal.The olfactory epithelium contains olfactory receptor neurons at different stages of development and glial-like supporting cells. This provides a unique opportunity to study dynamic changes in the CNS of patients with neuropsychiatric diseases, using olfactory tissue safely obtained from nasal biopsies. To overcome the drawback posed by substantial contamination of biopsied olfactory tissue with non-neuronal cells, a novel approach to obtain enriched neuronal cell populations was developed by combining nasal biopsies with laser-capture microdissection. In this study, a system for investigating treatment-associated dynamic molecular changes in neuronal tissue was developed and validated, using a small pilot sample of BD patients recruited for the study of the molecular mechanisms of lithium treatment response.

P.2.d.021 Lithium monotherapy versus lithium and valproate in manic and mixed states: correlation between serum lithium levels and treatment response

P.2.d.021 Lithium monotherapy versus lithium and valproate in manic and mixed states: correlation between serum lithium levels and treatment response

Pharmacogenetics of Lithium Response in Bipolar Disorder

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 pharmacogenetic studies can incorporate advances in genetics, molecular biology and bioinformatics in a pathway-based approach to predicting lithium treatment response.

Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder

Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder.

Possible relationship between mitochondrial DNA polymorphisms and lithium response in bipolar disorder.

Although many investigators have been searching for genetic markers to predict lithium response in bipolar disorders, no genetic predictor has been established yet. We previously reported the association of mitochondrial DNA (mtDNA) 5178 and 10398 polymorphisms with bipolar disorder. The objective of this study is to clarify whether these mtDNA polymorphisms can predict response to maintenance lithium treatment in bipolar patients. We examined these polymorphisms and some clinical variables in 54 bipolar patients. A logistic regression analysis was performed and revealed that patients carrying the 10398A polymorphism showed a significantly better response to lithium (p=0.03). Some clinical variables such as sex, age at onset, and rapid cycling also showed a significant association with lithium response in univariate analysis (chi2 test, p&0.05). Our findings suggest that the mtDNA 10398 polymorphism might be related to maintenance lithium treatment response.

Lithium treatment response in bipolar affective disorder coexisting with multiple sclerosis: A case report

Lithium treatment response in bipolar affective disorder coexisting with multiple sclerosis: A case report

ECT in medication resistant schizoaffective disorder

For the clinician, schizoaffective patients are a formidable challenge. They are usually the most disturbed, agitated, and difficult to control on the ward. Because they are often young, retain affect (though it may be bizarre) and may have functioned relatively well between episodes and/or prior to hospitalization, ECT is often considered a last resort or may not be given at all. This is unfortunate given the excellent response to ECT and Tsuang's 3 finding that schizoaffective patients not treated with ECT had higher suicide and mortality rates compared with those who had received ECT. The present study and review concludes that: (1) ECT is a very effective acute treatment in schizoaffective disorder; (2) whether called schizoaffective or affective disorder with psychosis there appears to be a subgroup of young patients with prominent confusion and lack of response to medications for whom ECT is particularly effective; (3) lithium should be considered as a prophylactic treatment with these patients; and (4) patients with schizoaffective disorder (as described) should be considered as a separate group in future ECT and/or lithium treatment response studies.