Lithium In Bipolar Disorder Research Articles

Lithium carbonate-induced confusional state in patients with bipolar disorder: identification of case reports and review of the evidence

Objective: Lithium carbonate is a mood stabilizer used in the treatment of bipolar disorder. However, its narrow therapeutic index (normal = 0.6-1.2 mmol/L) predisposes patients to toxic effects. This study aimed to identify case reports and review the evidence on the frequency, mechanism, risk factors and guidelines associated with a lithium-induced confusional state in patients with bipolar disorder. Methods: All Databases from the National Center for Biotechnology Information (NCBI) were used to search for lithium AND “confusional state” AND “case report” published in English between 2015 and 2020. This search engine was also used to search for lithium AND “confusional state” AND frequency OR mechanism OR “risk factor” OR guideline published in English. Results: Case reports showed (1) all patients were treated with lithium for bipolar disorder and hospitalized for a confusional state, (2) most patients took concomitant therapies and recovered after lithium withdrawal, (3) some patients were female and old-aged (65+ years old), and (4) no ethnicities, causality assessments and dose patterns were reported. Other scientific literature showed (1) frequencies of a lithium-induced confusional state varied from very common (>10%) to rare (<0.01%), (2) inhibition of inositol phosphate-phosphatase (IMPase) and glycogen synthase kinase-3 (GSK3) might result in a lithium-induced confusional state, (3) ageing, diseases and concomitant therapies increased the risk of a lithium-induced confusional state, and (4) patients should complete lab tests and diagnostic procedures to monitor and/or prevent a lithium-induced confusional state. Conclusion: Case reports and other scientific literature elucidated the relationship between lithium and a confusional state.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Use of Lithium in Bipolar Disorder is Shockingly Low: The Need for a Re-evaluation

Bipolar disorder often starts on childhood or adolescence but is too often poorly recognized and treated leading to the evolution of an illness with considerable disability. While lithium is widely recognized a first line treatment option its use is declining in comparison to other less effective agents. Here we review the major assets of lithium a drug that can prevent many aspects of illness progression as a function of increased numbers of episodes experienced. More episodes are related to faster and more severe recurrences cognitive deficits, and treatment refractoriness. Many of the side effects of lithium, such as renal dysfunction, are based on earlier and uncontrolled literature and are over emphasized. Given lithium's unique therapeutic profile, a re-evaluation of its under-utilization is definitely indicated.

W34. DNA METHYLATION, GENE EXPRESSION, AND RESPONSE TO LITHIUM IN BIPOLAR DISORDER: A STUDY FROM IPS CELLS DERIVED INTO NEURONS

W34. DNA METHYLATION, GENE EXPRESSION, AND RESPONSE TO LITHIUM IN BIPOLAR DISORDER: A STUDY FROM IPS CELLS DERIVED INTO NEURONS

Spectrophotometric Measurement of Lithium in Human Saliva Using the Chromogenic Reagent Thorin

The feasibility of using the chromogenic dye Thorin to spectrophotometrically measure lithium concentration in human saliva was explored. Absorbance wavelength maximum of the Li-Thorin complex was found to be 480 nm. Absorbance at 480 nm was obtained for saliva calibration standards containing 0.00–5.29 mEq/L of lithium. A least-squares fit produced a regression equation y = 0.128x + 1.449, R = 0.997. This was used to predict lithium concentrations in both artificially prepared lithium/saliva test solutions and in hospitalized patients treated with lithium. Results agree well with atomic absorption spectroscopy. Using a reagent blank with an equivalent amount of saliva as the test samples eliminated protein and electrolyte absorbance interference. This study supports the continued exploration of this method as a non-invasive point-of-care testing approach for monitoring saliva lithium in bipolar disorder.

The immunomodulatory effect of lithium as a mechanism of action in bipolar disorder.

Bipolar disorder (BD) is a chronic mental disorder characterized by recurrent episodes of mania and depression alternating with periods of euthymia. Although environmental and genetic factors have been described, their pathogenesis is not fully understood. Much evidence suggests a role for inflammatory mediators and immune dysregulation in the development of BD. The first-line treatment in BD are mood-stabilizing agents, one of which is lithium (Li) salts. The Li mechanism of action is not fully understood, but it has been proposed that its robust immunomodulatory properties might be one of the mechanisms responsible for its effectiveness. In this article, the authors present the current knowledge about immune system changes accompanying BD, as well as the immunomodulatory effect of lithium. The results of studies describing connections between immune system changes and lithium effectiveness are often incoherent. Further research is needed to understand the connection between immune system modulation and the therapeutic action of lithium in BD.

Basic quality indicators for clinical care of patients with major depression, schizophrenia, and bipolar disorder

ObjectiveTo identify a set of indicators to monitor the quality of care for patients with major depression, schizophrenia, or bipolar disorder. MethodsA group of 10 experts selected the most automatically applicable indicators from a total of 98 identified in a previous study. Five online sessions and 5 discussion meetings were performed to select the indicators that met theoretical feasibility criteria automatically. Subsequently, feasibility was tested in a pilot study conducted in two hospitals of the Spanish Health Service. ResultsAfter evaluating its measurement possibilities in the Spanish Health Service, and the fulfillment of all the quality premises defined, 16 indicators were selected. Three were indicators of major depression, 5 of schizophrenia, 3 of bipolar disorder, and 5 indicators common to all three pathologies. They included measures related to patient safety, maintenance and follow-up of treatment, therapeutic adherence, and adequacy of hospital admissions. After the pilot study, 5 indicators demonstrated potential in the automatic generation of results, with 3 of them related to treatments (clozapine in schizophrenia, lithium for bipolar disorder, and valproate in women of childbearing age). ConclusionsIndicators support the monitoring of the quality of treatment of patients with major depression, schizophrenia, or bipolar disorder. Based on this proposal, each care setting can draw up a balanced scorecard adjusted to its priorities and care objectives, which will allow for comparison between centers.

Clinicians’ preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders around the world: a survey from the ISBD Lithium task force

BackgroundLithium has long been considered the gold-standard pharmacological treatment for the maintenance treatment of bipolar disorders (BD) which is supported by a wide body of evidence. Prior research has shown a steady decline in lithium prescriptions during the last two decades. We aim to identify potential factors explaining this decline across the world with an anonymous worldwide survey developed by the International Society for Bipolar Disorders (ISBD) Task Force “Role of Lithium in Bipolar Disorders” and distributed by diverse academic and professional international channels.ResultsA total of 886 responses were received of which 606 completed the entire questionnaire while 206 completed it partially. Respondents were from 43 different countries comprising all continents. Lithium was the most preferred treatment option for the maintenance of BD patients (59%). The most relevant clinical circumstances in which lithium was the preferred option were in patients with BD I (53%), a family history of response (18%), and a prior response during acute treatment (17%). In contrast, Lithium was not the preferred option in case of patients´ negative beliefs and/or attitudes towards lithium (13%), acute side-effects or tolerability problems (10%) and intoxication risk (8%). Clinicians were less likely to prefer lithium as a first option in BD maintenance phase when practising in developing economy countries [X2 (1, N = 430) = 9465, p = 0.002) ] and private sectors [X2 (1, N = 434) = 8191, p = 0.004)].ConclusionsClinicians’ preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders appear to be affected by both the patients’ beliefs and the professional contexts where clinicians provide their services. More research involving patients is needed for identifying their attitudes toward lithium and factors affecting its use, particularly in developing economies.

Effect of Regulated Add-on Sodium Chloride Intake on Stabilization of Serum Lithium Concentration in Bipolar Disorder: A Randomized Controlled Trial

IntroductionThe therapeutic use of lithium in bipolar disorder is often restricted due to its narrow therapeutic window and adverse drug reactions. Lithium-induced early renal dysfunction is clinically important as it may lead to sodium depletion due to natriuresis leading to lithium retention and lithium toxicity. This is most often seen in the initial phases of therapy, and psychiatrists struggle titrating the dose of lithium and stabilizing the serum lithium level.ObjectivesThe present study was conducted to evaluate the effect of add-on sodium chloride on serum lithium levels in bipolar disorder.MethodsThe present randomized controlled trial (NCT04222816) was conducted in 60 patients with type I bipolar disorder who were randomized into the control group who received lithium carbonate with the advice not to take additional salt (at the table) and the test group who received sachets of sodium chloride (1 g/d) as an add-on to lithium carbonate and were advised to restrict their additional salt intake (at the table) to 1 g/d. After baseline assessments, all patients were followed up at 4 weeks, 8 weeks, and 12 weeks when serum lithium, sodium and potassium were estimated. Serum creatinine and aldosterone were repeated at 12 weeks.ResultsIn the test group, the fluctuation rate in serum lithium (26.7%) was significantly (p=0.01) lower than in the control group (63.3%). There was a significant difference in serum lithium in the control group at different time points; however, the changes were not significant in the test group. There was a significant difference in serum lithium between the groups at 8 and 12 weeks of follow-up. There were no significant differences in the change in serum sodium, potassium, creatinine, aldosterone, creatinine clearance, and blood pressure within the group and between the groups. A significant positive correlation was found between serum lithium and aldosterone at baseline.ConclusionsIntake of add-on sodium chloride (1 gm/day) may reduce the fluctuations in serum lithium during the maintenance phase of lithium therapy in type I bipolar disorder.Disclosure of InterestNone Declared

Lithium for bipolar disorder: Which patients will respond?

Lithium for bipolar disorder: Which patients will respond?

Risk factors for early recurrence after discontinuing lithium in bipolar disorder.

Time to a new episode of bipolar disorder (BD) is shorter after discontinuing lithium rapidly. We now address this and other factors associated with the risk of early illness after discontinuing lithium. We compared factors for association with recurrences of BD within 12months of discontinuing long-term lithium treatment, using bivariate and multivariable analyses, as well as survival analysis to evaluate latency to new episodes versus rate of lithium-discontinuation and prior treatment duration. Among 227 BD subjects who received lithium for 4.47 [CI: 3.89-5.04] years and then discontinued, rapid treatment-discontinuation, and stopping for medical reasons were strongly associated with new illness-episodes within 12months, as were diagnosis (BD-I > BD-II), greater morbidity during lithium-treatment, and less education, but neither longer treatment nor serum lithium concentrations. Discontinuation rate was strongly associated with shorter median latency to a new episode (rapid: 3.50; gradual [≥2 weeks]: 10.6 months), even with very early recurrences excluded to avoid potential contributions of emerging illness to treatment-discontinuation. Early recurrence was not associated with treatment-duration of ≥2 or ≥5 years or less. In multivariable logistic regression, rapid discontinuation, stopping for medical reasons, and BD-I diagnosis remained significantly, independently associated with early illness after lithium-discontinuation, with no effect of treatment duration. Early recurrence risk was again much greater after rapid discontinuation of lithium and discontinuing for medical reasons, somewhat greater with BD-I than BD-II, and following greater morbidity during lithium-treatment, but not related to dose or duration of preceding treatment exposure.

Dynamic insulin-stimulated mTOR/GSK3 signaling in peripheral immune cells: Preliminary evidence for an association with lithium response in bipolar disorder.

A key mechanism of lithium is the inhibition of glycogen synthase kinase-3β (GSK3β) and activation of mammalian target of rapamycin (mTOR), two contributors to insulin signaling. We explored the relationship between these markers and clinical response to lithium in bipolar disorder (BD). Thirty-four subjects with BD who had been taking lithium for ≥2years and had a maintenance lithium Alda score defined as either high (≥7; n=20) or low (≤2; n=14) were included in the study. Baseline protein expression of GSK3β and mTOR (total and phosphorylated (p)) was obtained from a buffy coat. Peripheral blood mononuclear cells (PBMCs) from a subset of each group (n=11) were stimulated with insulin (10µg) and change in protein expression was determined using Western blot. In buffy coat samples, significantly higher levels of pmTOR were present in subjects with an Alda score ≤2 (lithium non-responsive), relative to those with scores ≥7 (lithium-responsive). No differences were observed for pGSK3β. In contrast, functional PBMC responses to 5min of insulin stimulation demonstrated robust increases in pGSK3β (87.05±43.41%) and pmTOR (105.7±66.48%) in the lithium responsive group only. This contrasted observed decreases in pGSK3β (34.08±16.12%) and pmTOR (37.84±14.39%) 5mins post-insulin in non-responders. Dynamic increases in pmTOR and pGSK3β post-insulin stimulation may reflect an immunometabolic state that facilitates lithium response. Further prospective analyses are needed to replicate and extend these preliminary findings and further investigate the role of insulin signaling in lithium response in BD.

Therapeutic lithium alters polar head-group region of lipid bilayer and prevents lipid peroxidation in forebrain cortex of sleep-deprived rats

Lithium is regarded as a unique therapeutic agent for the management of bipolar disorder (BD). In efforts to explain the favourable effects of lithium in BD, a wide range of mechanisms was suggested. Among those, the effect of clinically relevant concentrations of lithium on the plasma membrane was extensively studied. However, the biophysical properties of brain membranes isolated from experimental animals exposed to acute, short-term and chronic lithium have not been performed to-date. In this study, we compared the biophysical parameters and level of lipid peroxidation in membranes isolated from forebrain cortex (FBC) of therapeutic lithium-treated and/or sleep-deprived rats. Lithium interaction with FBC membranes was characterized by appropriate fluorescent probes. DPH (1,6-diphenyl-1,3,5-hexatriene) and TMA-DPH (1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulphonate) were used for characterization of the hydrophobic lipid core and Laurdan (6-dodecanoyl-2-dimethylaminonaphthalene) for the membrane-water interface. Lipid peroxidation was determined by immunoblot analysis of 4-HNE-(4-hydroxynonenal)-protein adducts. The organization of polar head-group region of FBC membranes, measured by Laurdan generalized polarization, was substantially altered by sleep deprivation and augmented by lithium treatment. Hydrophobic membrane interior characterized by steady-state anisotropy of DPH and TMA-DPH fluorescence was unchanged. Chronic lithium had a protective effect against peroxidative damage of membrane lipids in FBC. In summary, lithium administration at a therapeutic level and/or sleep deprivation as an animal model of mania resulted in changes in rat FBC membrane properties.

Prediction of individuals at high risk of chronic kidney disease during treatment with lithium for bipolar disorder

BackgroundLithium is the most effective treatment in bipolar disorder. Its use is limited by concerns about risk of chronic kidney disease (CKD). We aimed to develop a model to predict risk of CKD following lithium treatment initiation, by identifying individuals with a high-risk trajectory of kidney function.MethodsWe used United Kingdom Clinical Practice Research Datalink (CPRD) electronic health records (EHRs) from 2000 to 2018. CPRD Aurum for prediction model development and CPRD Gold for external validation. We used elastic net regularised regression to generate a prediction model from potential features. We performed discrimination and calibration assessments in an external validation data set.We included all patients aged ≥ 16 with bipolar disorder prescribed lithium. To be included patients had to have ≥ 1 year of follow-up before lithium initiation, ≥ 3 estimated glomerular filtration rate (eGFR) measures after lithium initiation (to be able to determine a trajectory) and a normal (≥ 60 mL/min/1.73 m2) eGFR at lithium initiation (baseline). In the Aurum development cohort, 1609 fulfilled these criteria. The Gold external validation cohort included 934 patients.We included 44 potential baseline features in the prediction model, including sociodemographic, mental and physical health and drug treatment characteristics. We compared a full model with the 3-variable 5-year kidney failure risk equation (KFRE) and a 3-variable elastic net model.We used group-based trajectory modelling to identify latent trajectory groups for eGFR. We were interested in the group with deteriorating kidney function (the high-risk group).ResultsThe high risk of deteriorating eGFR group included 191 (11.87%) of the Aurum cohort and 137 (14.67%) of the Gold cohort. Of these, 168 (87.96%) and 117 (85.40%) respectively developed CKD 3a or more severe during follow-up. The model, developed in Aurum, had a ROC area of 0.879 (95%CI 0.853–0.904) in the Gold external validation data set. At the empirical optimal cut-point defined in the development dataset, the model had a sensitivity of 0.91 (95%CI 0.84–0.97) and a specificity of 0.74 (95% CI 0.67–0.82). However, a 3-variable elastic net model (including only age, sex and baseline eGFR) performed similarly well (ROC area 0.888; 95%CI 0.864–0.912), as did the KFRE (ROC area 0.870; 95%CI 0.841–0.898).ConclusionsIndividuals at high risk of a poor eGFR trajectory can be identified before initiation of lithium treatment by a simple equation including age, sex and baseline eGFR. Risk was increased in individuals who were younger at commencement of lithium, female and had a lower baseline eGFR. We did not identify strong predicters of eGFR decline specific to lithium-treated patients. Notably, lithium duration and toxicity were not associated with high-risk trajectory.

In vivo hippocampal subfield volumes in bipolar disorder—A mega‐analysis from The Enhancing Neuro Imaging Genetics through Meta‐Analysis Bipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

Neurocognitive functioning improves with lithium for bipolar disorder

The Brown University Psychopharmacology UpdateVolume 31, Issue 10 p. 8-8 Research Roundup Neurocognitive functioning improves with lithium for bipolar disorder First published: 31 August 2020 https://doi.org/10.1002/pu.30636Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume31, Issue10October 2020Pages 8-8 RelatedInformation

Predicted Cellular and Molecular Actions of Lithium in the Treatment of Bipolar Disorder: An In Silico Study.

Lithium remains the first-line treatment for bipolar disorder (BD), but patients respond to it variably. While a myriad of studies have attributed many genes and signaling pathways to lithium responsiveness, a comprehensive study with an integrated conclusion is still lacking. We aim to present an integrated mechanism for the therapeutic actions of lithium in BD. First, a list of lithium responsiveness-associated genes (LRAGs) was collected by searching in the literature. Thereafter, gene set enrichment analysis together with gene-gene interaction network analysis was performed, in order to find the cellular and molecular events related to the LRAGs. Gene set enrichment analyses showed that the chromosomal regions 3p26, 4p21, 5q34 and 7p13 could be novel associated loci for lithium responsiveness in BD. Also, expression pattern analysis of the LRAGs showed their enrichment in adulthood stages and different cell lineages of brain, blood and immune system. Most of the LRAGs exhibited enriched expression in central parts of human brain, suggesting major contribution of these parts in lithium responsiveness. Beside the prediction of several biological processes and signaling pathways related to lithium responsiveness, an interaction network between these processes was constructed that was found to be regulated by a set of microRNAs. Proteins of the network were mainly classified as transcription factors and kinases, which also highlighted the crucial role of glycogen synthase kinase 3β (GSK3β) in lithium responsiveness. The predicted cellular and molecular events in this study could be considered as mechanisms and also determinants of lithium responsiveness in BD.

An Adolescent Female with Bipolar Disorder Presenting with Lithium-Induced Hyperthyroidism

Lithium therapy has been associated with several endocrine disorders including thyroid dysfunction, diabetes insipidus, and hyperparathyroidism. While its suppressive effect on thyroid function is well known, it is very rare to observe lithium-induced hyperthyroidism especially in the pediatric population. Here, we describe a case of lithium-induced hyperthyroidism in an adolescent female with bipolar disorder. The patient is a 17-year-old female who was treated with lithium for bipolar disorder and presented with symptoms and laboratory findings consistent with hyperthyroidism. Since thyroid autoantibodies were negative, thyroid dysfunction was attributed to lithium toxicity. Indeed, her clinical and biochemical hyperthyroid state resolved after stopping lithium therapy. Lithium-associated hyperthyroidism can occur in the pediatric population. We propose close monitoring of thyroid hormone levels in children on lithium therapy.

Risk of dementia in bipolar disorder and the interplay of lithium: a systematic review and meta-analyses.

To assess whether bipolar disorder (BD) increases the rate of dementia and whether lithium is related to a lower risk of dementia in BD. A total of 10 studies (6859 BD; 487966 controls) were included in the meta-analysis to test whether BD is a risk factor for dementia. In addition, five studies (6483 lithium; 43496 non-lithium) were included in the meta-analysis about the potential protective effect of lithium in BD. BD increases the risk of dementia (odds ratio (OR): 2.96 [95% CI: 2.09-4.18], P<0.001), andtreatment with lithium decreases the risk of dementia in BD (OR: 0.51 [95% CI: 0.36-0.72], P<0.0001). In addition, secondary findings from our systematic review showed that the risk of progression to dementia is higher in BD than in major depressive disorder (MDD). Moreover, the number of mood episodes predicted the development of dementia in BD. Individuals with BD are at higher risk of dementia than both the general population or those with MDD. Lithium appears to reduce the risk of developing dementia in BD.

SU81 - COMPREHENSIVE EVALUATION OF ENRICHMENT FOR CIRCADIAN CLOCK GENE SETS IN PSYCHIATRIC TRAITS: SPECIFIC ENRICHMENT IN CLINICAL RESPONSE TO LITHIUM

Background A disrupted circadian clock has been linked to the risk of several neuropsychiatric disorders. Likewise, circadian rhythms have been suggested as mediators of the mechanism of action of lithium in bipolar disorder. Nonetheless the relationship between the ‘clock genes’ that regulate circadian rhythms and lithium treatment response is not completely understood. To our knowledge there has not been a systematic pathway / enrichment analysis of clock genes in the context of psychiatric traits, in general, and of clinical response to lithium, in particular. The objective of this study was to perform formal gene set enrichment analyses for circadian clock genes, using publicly available GWAS summary statistics from several psychiatric disorders, as well as the results from The International Consortium on Lithium Genetics (ConLiGen) GWAS (Hou et al., 2016). Methods Based on previous literature (Pizarro et al., 2013; Chen et al., 2016) and available resources (e.g. http://circadb.hogeneschlab.org/) curated gene sets related to circadian control were generated. These sets can be divided in three categories: clock modulator (upstream) genes, core clock genes and clock controlled (downstream) genes. GWAS summary statistics from schizophrenia, bipolar disorder, major depressive disorder, ADHD, autism, Alzheimer's disease and continuous/dichotomous lithium response were used as reference. Gene set enrichment analyses were carried out using both INRICH and MAGMA. Results Gene set enrichment analyses using INRICH and MAGMA reported a significant enrichment of a set of 19 genes that constitute the ‘core clock’ in the dichotomous lithium response phenotype (INRICH: empirical P=0.001; corrected P=0.008; MAGMA: competitive P=0.005; corrected P=0.0336). None of the circadian gene sets showed a significant enrichment in any of the other psychiatric traits included in this study (all corrected P>0.05). 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. The specificity of these results suggests that the participation of circadian rhythms is especially relevant in the modulation of lithium response rather than in the overall risk of mental illness. A better understanding of potential links between circadian mechanisms, genetic risk factors, and the lithium treatment response may open new avenues into the clinical management of bipolar disorder.