Lithium Response In Bipolar Disorder Research Articles

Evaluation of 2D:4D digit ratio in bipolar 1 disorder patients and its relationship with treatment response

BackgroundThe role of sex steroids in bipolar disorder (BD) has been demonstrated in adults. We aimed to evaluate the 2D:4D ratio, which indirectly reflects prenatal sex steroids, in BD. Another purpose of this study was to determine the relationship between clinical features, especially lithium response, and digit ratio. MethodsThe study included 74 patients with bipolar 1 disorder and 74 healthy individuals matched according to age, gender, and educational status. The digit ratio was calculated by dividing the index finger (2D) length by the ring finger (4D) length in both hands. A lithium response scale was used to evaluate the lithium response history. ResultsThere was no difference in 2D:4D ratio between the patients and controls in either right or left hands. The digit ratio was not different between groups with and without suicide attempts. The 2D:4D ratio in the patient group was lower in individuals unresponsive to lithium therapy than in partial and good responders for both right and left hands. DiscussionAccording to the results of our study, the 2D:4D ratio in the BD group was not different from healthy controls but was lower in patients unresponsive to lithium. In this respect, the 2D:4D ratio can be considered as a biomarker for lithium response in BD. In large-sample studies, the 2D:4D ratio should be investigated for pathophysiology and treatment response of BD.

P.305 Convergent sequencing and microarray data analyses suggest the involvement of miRNAs and target mRNAs in lithium response in bipolar disorder

The immunogenicity benefit of inactivated influenza vaccine (IIV) adjuvanted by squalene over non-adjuvanted aqueous IIV was explored in a meta-analysis involving 49 randomised trials published between 1999 and 2017, and 22,470 eligible persons of all age classes. Most vaccines contained 15 μg viral haemagglutinin per strain. Adjuvanted IIV mostly contained 9.75 mg squalene per dose. Homologous pre- and post-vaccination geometric mean titres (GMTs) of haemagglutination-inhibition (HI) antibody were recorded for 290 single influenza (sub-)type arms. The adjuvant effect was expressed as the ratio of post-vaccination GMTs between squalene-IIV and aqueous IIV (GMTR, 145 estimates). GMTRs > 1.0 favoured squalene-IIV over aqueous IIV. For all influenza (sub-)types, the adjuvant effect proved negatively associated with pre-vaccination GMT and mean age. The adjuvant effect appeared most pronounced in young children (mean age < 2.5 years) showing an average GMTR of 3.7 (95% CI: 2.5 to 5.5). With increasing age, GMTR values gradually decreased towards 1.4 (95% CI: 1.0 to 1.9) in older adults. Heterologous antibody titrations simulating mismatch between vaccine and circulating virus (30 GMTR estimates) again showed a larger adjuvant effect at young age. GMT values and their variances were converted to antibody-predicted protection rates using an evidence-based clinical protection curve. The adjuvant effect was expressed as the protection rate differences, which showed similar age patterns as corresponding GMTR values. However for influenza B, the adjuvant effect lasted longer than for influenza A, possibly due to a generally later influenza B virus exposure. Collectively, this meta-analysis indicates the highest benefit of squalene-IIV over aqueous IIV in young children and decreasing benefit with progressing age. This trend is similar for seasonal influenza (sub-)types and the 2009 pandemic strain, by both homologous and heterologous titration. The impact of pre-seasonal immunity on vaccine effectiveness, and its implications for age-specific vaccination recommendations, are discussed.

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder.

Lithium is the mainstay in the maintenance of bipolar disorder (BD) and the most efficacious pharmacological treatment in suicide prevention. Nevertheless, its use is hampered by a high interindividual variability and important side effects. Genetic and epigenetic factors have been suggested to modulate lithium response, but findings so far have not allowed identifying molecular targets with predictive value. In this study we used next generation sequencing to measure genome-wide miRNA expression in lymphoblastoid cell lines from BD patients excellent responders (ER, n = 12) and non-responders (NR, n = 12) to lithium. These data were integrated with microarray genome-wide expression data to identify pairs of miRNA/mRNA inversely and significantly correlated. Significant pairs were prioritized based on strength of association and in-silico miRNA target prediction analyses to select candidates for validation with qRT-PCR. Thirty-one miRNAs were differentially expressed in ER vs. NR and inversely correlated with 418 genes differentially expressed between the two groups. A total of 331 of these correlations were also predicted by in-silico algorithms. miR-320a and miR-155-3p, as well as three of their targeted genes (CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regulator of G Protein Signaling 16) for miR-320, SP4 (Sp4 Transcription Factor) for miR-155-3p) were validated. These miRNAs and mRNAs were previously implicated in psychiatric disorders (miR-320a and SP4), key processes of the central nervous system (CAPNS1, RGS16, SP4) or pathways involved in mental illnesses (miR-155-3p). Using an integrated approach, we identified miRNAs and their targeted genes potentially involved in lithium response in BD.

A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder.

ObjectiveTo determine clinical predictors of lithium response in bipolar disorder.MethodsSystematic review of studies examining clinical predictors of lithium response was conducted. Meta‐analyses were performed when ≥2 studies examined the same potential predictor.ResultsA total of 71 studies, including over 12 000 patients, identified six predictors of good response: mania‐depression‐interval sequence [odds ratio (OR): 4.27; 95% CI: 2.61, 6.97; P < 0.001], absence of rapid cycling (OR for rapid cycling: 0.30; 95% CI: 0.17, 0.53; P < 0.001), absence of psychotic symptoms (OR for psychotic symptoms: 0.52; 95% CI: 0.34, 0.79; P = 0.002), family history of bipolar disorder (OR: 1.61; 95% CI: 1.03, 2.52; P = 0.036), shorter prelithium illness duration [standardised mean difference (SMD): −0.26; 95% CI: −0.41, −0.12; P < 0.001] and later age of onset (SMD: 0.17; 95% CI: 0.02, 0.36; P = 0.029). Additionally, higher body mass index was associated with poor response in two studies (SMD: −0.61; 95% CI: −0.90, −0.32; P < 0.001). There was weak evidence for number of episodes prior to lithium treatment (SMD: −0.42; 95% CI: −0.84, −0.01; P = 0.046), number of hospitalisations before lithium (SMD: −0.40; 95% CI: −0.81, 0.01; P = 0.055) and family history of lithium response (OR: 10.28; 95% CI: 0.66, 161.26; P = 0.097).ConclusionsThe relative importance of these clinical characteristics should be interpreted with caution because of potential biases and confounding.

A pilot fMRI study of lithium response in bipolar disorder

A pilot fMRI study of lithium response in bipolar disorder

Study of 45 candidate genes suggests CACNG2 may be associated with lithium response in bipolar disorder

BackgroundBipolar disorder is a neuropsychiatric disorder that is characterized by fluctuations between manic and depressive phases. Lithium is the original and best mood stabilizing treatment for bipolar disorder. While its mechanism is not well understood, it is believed to have a strong genetic component, as several studies suggest that lithium responsiveness, in bipolar disorder, is heritable. In this study we aimed to identify genetic variants that are associated with lithium responsiveness in bipolar disorder. MethodsHere we present two cohorts; a retrospective cohort in which patients were surveyed about their response to lithium, and a prospective cohort, in which patients were placed on a lithium monotherapy and monitored for their response to lithium. In both cohorts, patients were stratified into two categories in terms of lithium response; good responders and poor responders. 45 genes were selected based on previous associations with lithium pathways or bipolar disorder and 684 SNPs within these genes were selected to test for association with lithium response. ResultsWhile no single SNP was significant after correcting for multiple comparisons, there were several that were nominally significant (p < 0.05). Of these nominally significant SNPs, the most highly significant SNP in both the prospective and retrospective cohorts were found to be in CACNG2, or Stargazin. The second best association with lithium response was several SNPs in NRG1, a gene that has previously been associated with schizophrenia. ConclusionsEvidence for the association of lithium response with SNPs in CACNG2 is consistent with previous findings that have identified CACNG2 as associated with both bipolar disorder and lithium responsiveness.

Research Experience In Psychiatric Genetics In Colombia: Ongoing Studies

BackgroundThe “Paisa Population” is a genetically and culturally homogeneous population of Colombia which has been focus of genetics studies in neuropsychiatric disorders in the last decade. This population is highly affected by major mental disorders, especially Bipolar Disorder. Several studies have been performed trying to understand the genetic basis underlying the disease by evaluating extended pedigrees. Also, the first pharmacogenetic study in this special population is being carried out with the aim to identify genetic variants associated with lithium response in the treatment of bipolar disorder. MethodsHere we will show the ongoing projects on psychiatric genetics in the Paisa Population in both genetics of severe mental illness and pharmacogenetics of lithium response in Bipolar Disorder. ResultsWe will discuss the importance of genetic studies in a genetically isolated and how this potentially more homogeneous population may help to detect common and rare genetic variants underpinning severe mental illness and traits like lithium response. ConclusionsGenetics studies in isolated populations represent an important strategy in the mapping and understanding of genetic basis of complex disorders as bipolar disorder and other mental illnesses. We will show and discuss the ongoing psychiatric genetics studies in the Paisa Population from Colombia.

S.15.02 Non-genetic predictors of lithium response in bipolar disorder

Numerous studies have been published describing the effect of various probiotics (PRO) on behaviours related to psychiatric disease. We have previously shown a robust antidepressant-like effect of PRO in rats, but over time, the treatment effect seems to vary significantly between different sets of rats from the same commercial vendor. Therefore, we hypothesised that the antidepressant-like response may be modulated by the cohabiting gut microbiota.The aims of the present study were (1) to investigate any differences in the gut microbiota composition between responders (Resp) and non-responders (Non-resp) to PRO with regards to depressive-like behaviour, and (2) to evaluate the effects of PRO on the microbiota composition.Two sets of 20 male Sprague-Dawley rats each were treated with multi-species PRO (nine Bifidobacterium, Lactococcus and Lactobacillus species) for eight weeks and subjected to a behavioural assessment. Faecal samples were collected for 16 s rRNA (VR4) gene amplicon sequencing (Illumina MiSeq).As previously reported, PRO-treated Resp animals showed a marked decrease in depressive-like behaviour, whereas no such response was seen in Non-resp. We observed profound differences in the gut microbiota composition between the two sets of rats, and the relative faecal abundance of the genera that comprised PRO was higher in Resp than in Non-resp although treated with the same dose of PRO. Particularly, the relative abundance of the Lactobacillus genus was not increased in PRO-treated Non-resp animals.In conclusion, the cohabiting microbiota and the faecal abundance of PRO may modulate the antidepressant-like effect of PRO in rats.

Convergent analysis of genome-wide genotyping and transcriptomic data suggests association of zinc finger genes with lithium response in bipolar disorder.

Lithium is the mainstay treatment in bipolar disorder (BD) for its effectiveness in the acute phases of illness and in prevention of recurrences. Lithium's mechanism of action is complex, and while it modulates the function of hundreds of molecular targets, most of these effects could be unspecific and not relevant for its clinical efficacy. In this study, we applied an integrated analytical approach using genome-wide expression and genotyping data from BD patients to identify lithium-responsive genes that may serve as biomarkers of its efficacy. To this purpose, we tested the effect of treatment with lithium chloride 1 mM on the transcriptome of lymphoblasts from 10 lithium responders (LR) and 10 nonresponders (NR) patients and identified genes significantly influenced by the treatment exclusively in LR. These findings were integrated with gene-based analysis on genome-wide genotyping data from an extended sample of 205 BD patients characterized for lithium response. The expression of 29 genes was significantly changed by lithium exclusively in LR. Gene-based analysis showed that two of these genes, zinc finger protein 429 (ZNF429) and zinc finger protein 493 (ZNF493), were also significantly associated with lithium response. Validation with quantitative real-time polymerase chain reaction confirmed the lithium-induced downregulation of ZNF493 in LR (p = .036). Using convergent analyses of genome-wide expression and genotyping data, we identified ZNF493 as a potential lithium-responsive target that may be involved in modulating lithium efficacy in BD. To our knowledge, this is the first evidence supporting the involvement of zinc finger proteins in lithium response.

Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Genetics of Lithium Response in Bipolar Disorder.

Lithium remains the best-established long-term treatment for bipolar disorder because of its efficacy in maintaining periods of remission and reducing the risk of suicide. Not all patients successfully respond to lithium treatment, and the individual response, including the occurrence of side effects, is highly variable and not easy to predict. The genetic basis of lithium response is supported by the fact that the response clusters in families. Likewise, recent high-throughput genomic analyses have shed light on its genetic architecture. This nonsystematic review summarizes the main results obtained in genetic association studies using lithium response as target trait. These studies suggest that several genetic loci might modulate the way a patient responds to lithium maintenance treatment. Further studies to fully characterize the genetic architecture of lithium response are warranted. The identification of genetic factors associated with lithium response will be important for (1) better understanding of lithium's mode of action and (2) development of a predictive model for optimization of long-term treatment of bipolar disorder.

RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium’s clinical efficacy

Objectives: Lithium remains the oldest and most effective treatment for mood stabilisation in bipolar disorder (BD), even though at least half of patients are only partially responsive or do not respond. This study aimed to identify biomarkers associated with lithium response in BD, based on comparing RNA sequencing information derived from lymphoblastoid cell lines (LCLs) of lithium-responsive (LR) versus lithium non-responsive (LNR) BD patients, to assess gene expression variations that might bear on treatment outcome.Methods: RNA sequencing was carried out on 24 LCLs from female BD patients (12 LR and 12 LNR) followed by qPCR validation in two additional independent cohorts (41 and 17 BD patients, respectively).Results: Fifty-six genes showed nominal differential expression comparing LR and LNR (FC ≥ |1.3|, P ≤ 0.01). The differential expression of HDGFRP3 and ID2 was validated by qPCR in the independent cohorts.Conclusions: We observed higher expression levels of HDGFRP3 and ID2 in BD patients who favourably respond to lithium. Both of these genes are involved in neurogenesis, and HDGFRP3 has been suggested to be a neurotrophic factor. Additional studies in larger BD cohorts are needed to confirm the potential of HDGFRP3 and ID2 expression levels in blood cells as tentative favourable lithium response biomarkers.

704. Circadian Clock Genes and Lithium Response in Bipolar Disorder

Circadian rhythm abnormalities are a central clinical feature of bipolar disorder (BD), affecting rhythms in sleep and activity. The mood stabilizer lithium corrects circadian rhythm abnormalities in bipolar disorder and changes the expression of “clock genes” that direct rhythms. However, the role of clock genes in bipolar disorder is unknown, and it is unclear if lithium’s effects on rhythms are relevant to treatment outcomes.

Lithium response in bipolar disorder: No difference in GADL1 gene expression between cell lines from excellent-responders and non-responders

Previous association studies have shown mixed results between glutamic acid decarboxylase like-1 (GADL1) gene polymorphism and prophylactic lithium response in bipolar disorder (BD) patients. In the present study, GADL1 gene expression was investigated in regard to lithium response, using Alda scale, in lymphoblastoid cells (LCLs) of 36 Caucasian BD patients. No difference in GADL1 expression was observed among LCLs from excellent-responders, non-responders or controls. Furthermore, lithium did not induce significant changes in GADL1 expression levels after 4 or 8 days. These results did not support an association of GADL1 expression in the determination of a lithium response in BD patients.

Brain oscillations in bipolar disorder and lithium-induced changes.

Electroencephalography (EEG) studies in patients with bipolar disorder have revealed lower amplitudes in brain oscillations. The aim of this review is to describe lithium-induced EEG changes in bipolar disorder and to discuss potential underlying factors. A literature survey about lithium-induced EEG changes in bipolar disorder was performed. Lithium consistently enhances magnitudes of brain oscillations in slow frequencies (delta and theta) in both resting-state EEG studies as well as event-related oscillations studies. Enhancement of magnitudes of beta oscillations is specific to event-related oscillations. Correlation between serum lithium levels and brain oscillations has been reported. Lithium-induced changes in brain oscillations might correspond to lithium-induced alterations in neurotransmitters, signaling cascades, plasticity, brain structure, or biophysical properties of lithium. Therefore, lithium-induced changes in brain oscillations could be promising biomarkers to assess the molecular mechanisms leading to variability in efficacy. Since the variability of lithium response in bipolar disorder is due to the genetic differences in the mechanisms involving lithium, it would be highly promising to assess the lithium-induced EEG changes as biomarkers in genetic studies.

Epigenomic mapping and effect sizes of noncoding variants associated with psychotropic drug response.

To provide insight into potential regulatory mechanisms of gene expression underlying addiction, analgesia, psychotropic drug response and adverse drug events, genome-wide association studies searching for variants associated with these phenotypes has been undertaken with limited success. We undertook analysis of these results with the aim of applying epigenetic knowledge to aid variant discovery and interpretation. We applied conditional imputation to results from 26 genome-wide association studies and three candidate gene-association studies. The analysis workflow included data from chromatin conformation capture, chromatin state annotation, DNase I hypersensitivity, hypomethylation, anatomical localization and biochronicity. We also made use of chromatin state data from the epigenome roadmap, transcription factor-binding data, spatial maps from published Hi-C datasets and 'guilt by association' methods. We identified 31 pharmacoepigenomic SNPs from a total of 2024 variants in linkage disequilibrium with lead SNPs, of which only 6% were coding variants. Interrogation of chromatin state using our workflow and the epigenome roadmap showed agreement on 34 of 35 tissue assignments to regulatory elements including enhancers and promoters. Loop boundary domains were inferred by association with CTCF (CCCTC-binding factor) and cohesin, suggesting proximity to topologically associating domain boundaries and enhancer clusters. Spatial interactions between enhancer-promoter pairs detected both known and previously unknown mechanisms. Addiction and analgesia SNPs were common in relevant populations and exhibited large effect sizes, whereas a SNP located in the promoter of the SLC1A2 gene exhibited a moderate effect size for lithium response in bipolar disorder in patients of European ancestry. SNPs associated with drug-induced organ injury were rare but exhibited the largest effect sizes, consistent with the published literature. This work demonstrates that an in silico bioinformatics-based approach using integrative analysis of a diversity of molecular and morphological data types can discover pharmacoepigenomic variants that are suitable candidates for further validation in cell lines, animal models and human clinical trials.

A glutamatergic network mediates lithium response in bipolar disorder as defined by epigenome pathway analysis.

A regulatory network in the human brain mediating lithium response in bipolar patients was revealed by analysis of functional SNPs from genome-wide association studies (GWAS) and published gene association studies, followed by epigenome mapping. An initial set of 23,312 SNPs in linkage disequilibrium with lead SNPs, and sub-threshold GWAS SNPs rescued by pathway analysis, were studied in the same populations. These were assessed using our workflow and annotation by the epigenome roadmap consortium. Twenty-seven percent of 802 SNPs that were associated with lithium response (13 published studies gene association studies and two GWAS) were shared in common with 1281 SNPs from 18 GWAS examining psychiatric disorders and adverse events associated with lithium treatment. Nineteen SNPs were annotated as active regulatory elements such as enhancers and promoters in a tissue-specific manner. They were located within noncoding regions of ten genes: ANK3, ARNTL, CACNA1C, CACNG2, CDKN1A, CREB1, GRIA2, GSK3B, NR1D1 and SLC1A2. Following gene set enrichment and pathway analysis, these genes were found to be significantly associated (p = 10(-27); Fisher exact test) with an AMPA2 glutamate receptor network in human brain. Our workflow results showed concordance with annotation of regulatory elements from the epigenome roadmap. Analysis of cognate mRNA and enhancer RNA exhibited patterns consistent with an integrated pathway in human brain. This pharmacoepigenomic regulatory pathway is located in the same brain regions that exhibit tissue volume loss in bipolar disorder. Although in silico analysis requires biological validation, the approach provides value for identification of candidate variants that may be used in pharmacogenomic testing to identify bipolar patients likely to respond to lithium.

Novel integrative genomic tool for interrogating lithium response in bipolar disorder.

We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery.

Factors associated with lithium efficacy in bipolar disorder.

About one-third of lithium-treated, bipolar patients are excellent lithium responders; that is, lithium monotherapy totally prevents further episodes of bipolar disorder for ten years and more. These patients are clinically characterized by an episodic clinical course with complete remission, a bipolar family history, low psychiatric comorbidity, mania-depression episode sequences, a moderate number of episodes, and a low number of hospitalizations in the pre-lithium period. Recently, it has been found that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis. Lithium exerts a neuroprotective effect, in which increased expression of brain-derived neurotrophic factor (BDNF) and inhibition of the glycogen synthase kinase-3 (GSK-3) play an important role. The response to lithium has been connected with the genotype of the BDNF gene and serum BDNF levels. A better response to lithium is connected with the Met allele of the BDNF Val/Met polymorphism, as is a hyperthymic temperament. Excellent lithium responders have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. The preservation of cognitive functions in long-term lithium-treated patients may be connected with the stimulation of the BDNF system, with the resulting prevention of affective episodes exerting deleterious cognitive effects, and possibly also with lithium's antiviral effects. A number of candidate genes that are related to neurotransmitters, intracellular signaling, neuroprotection, circadian rhythms, and other pathogenic mechanisms of bipolar disorder were found to be associated with the lithium prophylactic response. The Consortium on Lithium Genetics (ConLiGen) has recently performed the first genome-wide association study on the lithium response in bipolar disorder.

Response to Lithium in Bipolar Disorder: Clinical and Genetic Findings

The use of lithium is a cornerstone for preventing recurrences in bipolar disorder (BD). The response of patients with bipolar disorder to lithium has different levels of magnitude. About one-third of lithium-treated patients are excellent lithium responders (ELR), showing total prevention of the episodes. A number of clinical characteristics were delineated in patients with favorable response to lithium as regards to clinical course, family history of mood disorders, and psychiatric comorbidity. We have also demonstrated that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis. A degree of prevention against manic and depressive episodes has been regarded as an endophenotype for pharmacogenetic studies. The majority of data have been gathered from so-called "candidate" gene studies. The candidates were selected on the basis of neurobiology of bipolar disorder and mechanisms of lithium action including, among others, neurotransmission, intracellular signaling, neuroprotection or circadian rhythms. We demonstrated that response to lithium has been connected with the genotype of BDNF gene and serum BDNF levels and have shown that ELR have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. A number of genome-wide association studies (GWAS) of BD have been also performed in recent years, some of which also focused on lithium response. The Consortium on Lithium Genetics (ConLiGen) has established the large sample for performing the genome-wide association study (GWAS) of lithium response in BD, and the first results have already been published.