Differential contributions of circadian clock genes to cell survival in bipolar disorder patient derived neuronal progenitor cells distinguishes lithium responders and non-responders.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past research identified that circadian rhythms in BD patient neurons are associated with lithium response (Li-R) or non-response (Li-NR). However, the underlying cellular mechanisms remain unknown. To study interactions among circadian clock genes and cell survival, and their role in BD and predicting lithium response, we tested selected genes (PER1, BMAL1 and REV-ERBα) and small molecule modulators of ROR/REV-ERB nuclear receptors in models of cell survival using mouse neurons and stem-cell derived neuronal progenitor cells (NPC) from BD patients and controls. In apoptosis assays using staurosporine (STS), lithium was neuroprotective. Knockdown of PER1, BMAL1 and REV-ERBα modified cell survival across models. In NPCs, reduced expression of PER1 and BMAL1 led to more extensive cell death in Li-NR vs. Li-R. Reduced REV-ERBα expression caused more extensive cell death in BD vs. control NPCs, without distinguishing Li-R and Li-NR. In IMHN, The REV-ERB agonist GSK4112 had strong effects on circadian rhythm amplitude, and was neuroprotective in mouse neurons and control NPCs, but not in BD NPCs. Expression of cell survival genes following STS and GSK4112 treatments revealed BD-associated, and Li-R associated differences in expression profiles. We conclude that the neuroprotective response to lithium is similar in NPCs from Li-R and Li-NR. However, knockdown of circadian clock genes or stimulation of REV-ERBs reveal distinct contributions to cell death in BD patient NPCs, some of which distinguish Li-R and Li-NR.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Possible Role of Correlation Coefficients and Network Analysis of Multiple Intracellular Proteins in Blood Cells of Patients with Bipolar Disorder in Studying the Mechanism of Lithium Responsiveness: A Proof-Concept Study.

Background: The mechanism of lithium treatment responsiveness in bipolar disorder (BD) remains unclear. The aim of this study was to explore the utility of correlation coefficients and protein-to-protein interaction (PPI) network analyses of intracellular proteins in monocytes and CD4+ lymphocytes of patients with BD in studying the potential mechanism of lithium treatment responsiveness. Methods: Patients with bipolar I or II disorder who were diagnosed with the MINI for DSM-5 and at any phase of the illness with at least mild symptom severity and received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks were divided into two groups, responders (≥50% improvement in Montgomery-Asberg Depression Rating Scale and/or Young Mania Rating Scale scores from baseline) and non-responders. Twenty-eight intracellular proteins/analytes in CD4+ lymphocytes and monocytes were analyzed with a tyramine-based signal-amplified flow cytometry procedure. Correlation coefficients between analytes at baseline were estimated in both responders and non-responders and before and after lithium treatment in responders. PPI network, subnetwork, and pathway analyses were generated based on fold change/difference in studied proteins/analytes between responders and non-responders. Results: Of the 28 analytes from 12 lithium-responders and 11 lithium-non-responders, there were more significant correlations between analytes in responders than in non-responders at baseline. Of the nine lithium responders with pre- and post-lithium blood samples available, the correlations between most analytes were weakened after lithium treatment with cell-type specific patterns in CD4+ lymphocytes and monocytes. PPI network/subnetwork and pathway analyses showed that lithium response was involved in four pathways, including prolactin, leptin, neurotrophin, and brain-derived neurotrophic factor pathways. Glycogen synthase kinase 3 beta and nuclear factor NF-kappa-B p65 subunit genes were found in all four pathways. Conclusions: Using correlation coefficients, PPI network/subnetwork, and pathway analysis with multiple intracellular proteins appears to be a workable concept for studying the mechanism of lithium responsiveness in BD. Larger sample size studies are necessary to determine its utility.

Estimation of Oral Disease Burden among Older Adults in LTC: A Scoping Review.

Oral health is an essential part of healthy aging and very little data exists around the disease burden for older adults in a long-term care setting. The aim of this scoping review was to estimate the disease burden of dental caries, periodontal disease, and tooth loss among older adults in Long-Term Care (LTC). This scoping review was conducted in accordance with the Joanna Briggs Institute methodology. A detailed strategy was used to conduct a comprehensive search of electronic databases: PubMed, Embase, and Dentistry and Oral Sciences Source (DOSS). The Rayyan AI platform was used to screen abstracts for assessment by one of five co-investigators. Results indicate that only one in three might have a functional dentition upon entry into LTC, and among those who are dentate, most might expect to develop at least one new coronal and one new root caries lesion each year. There is a need to better document the disease experiences of this group to tailor approaches to care that might reduce the avoidable suffering as a result of dental caries and periodontal disease.

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder.

Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.

Demographics and Oral Health Care Utilization for Older Adults.

The population of older adults is projected to increase dramatically as Baby Boomers continue to reach age 65 into 2029. This article discusses key shifts in this demographic, including changes in overall health status and living arrangements, that can aid in defining older adults and their medical needs. It also highlights the changes in dental use patterns and the increase in demand for comprehensive dental services for older adults in recent years. The article focuses on the fact that oral health contributes to overall health and the dental workforce must be prepared to treat older adults in their practices.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Differences in intracellular protein levels in monocytes and CD4+ lymphocytes between bipolar depressed patients and healthy controls: A pilot study with tyramine-based signal-amplified flow cytometry.

BACKGROUND: Molecular biomarkers for bipolar disorder (BD) that distinguish it from other manifestations of depressive symptoms remain unknown. The aim of this study was to determine if a very sensitive tyramine-based signal-amplification technology for flow cytometry (CellPrint™) could facilitate the identification of cell-specific analyte expression profiles of peripheral blood cells for bipolar depression (BPD) versus healthy controls (HCs). METHODS: The diagnosis of psychiatric disorders was ascertained with Mini International Neuropsychiatric Interview for DSM-5. Expression levels for eighteen protein analytes previously shown to be related to bipolar disorder were assessed with CellPrint™ in CD4+ T cells and monocytes of bipolar patients and HCs. Implementation of protein-protein interaction (PPI) network and pathway analysis was subsequently used to identify new analytes and pathways for subsequent interrogations. RESULTS: Fourteen drug-naïve or -free patients with bipolar I or II depression and 17 healthy controls (HCs) were enrolled. The most distinguishable changes in analyte expression based on t-tests included GSK3ß, HMGB1, IRS2, phospho-GSK3αß, phospho-RELA, and TSPO in CD4+ T cells and calmodulin, GSK3ß, IRS2, and phospho-HS1 in monocytes. Subsequent PPI and pathway analysis indicated that prolactin, leptin, BDNF, and interleukin-3 signal pathways were significantly different between bipolar patients and HCs. LIMITATION: The sample size of the study was small and 2 patients were on medications. CONCLUSION: In this pilot study, CellPrint™ was able to detect differences in cell-specific protein levels between BPD patients and HCs. A subsequent study including samples from patients with BPD, major depressive disorder, and HCs is warranted.

Divergent Directionality of Immune Cell-Specific Protein Expression between Bipolar Lithium Responders and Non-Responders Revealed by Enhanced Flow Cytometry.

Background and Objectives: There is no biomarker to predict lithium response. This study used CellPrint™ enhanced flow cytometry to study 28 proteins representing a spectrum of cellular pathways in monocytes and CD4+ lymphocytes before and after lithium treatment in patients with bipolar disorder (BD). Materials and Methods: Symptomatic patients with BD type I or II received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks. Patients were assessed with standard rating scales and divided into two groups, responders (≥50% improvement from baseline) and non-responders. Twenty-eight intracellular proteins in CD4+ lymphocytes and monocytes were analyzed with CellPrint™, an enhanced flow cytometry procedure. Data were analyzed for differences in protein expression levels. Results: The intent-to-treat sample included 13 lithium-responders (12 blood samples before treatment and 9 after treatment) and 11 lithium-non-responders (11 blood samples before treatment and 4 after treatment). No significant differences in expression between the groups was observed prior to lithium treatment. After treatment, the majority of analytes increased expression in responders and decreased expression in non-responders. Significant increases were seen for PDEB4 and NR3C1 in responders. A significant decrease was seen for NR3C1 in non-responders. Conclusions: Lithium induced divergent directionality of protein expression depending on the whether the patient was a responder or non-responder, elucidating molecular characteristics of lithium responsiveness. A subsequent study with a larger sample size is warranted.

Current oral health services and the divergent needs of the baby boom cohorts.

The two cohorts of Baby Boomers, the Early (born between 1945 and 1955) and the Late (born between 1956 and 1964), have some subtle yet distinct differences when it comes to their oral health and oral health related behaviors. Unlike their predecessors, the Baby Boomer cohorts are retaining more teeth, as there is a sharp fall in edentulous rates in this population. The oral health care community is now facing unparalleled challenges in providing and maintaining the oral health of this unique cohort who are keeping their teeth longer, have multiple comorbidities, and are living longer than previous generations. This paper draws from the latest studies, scientific data and research to describe a realistic picture of the oral health services available to and utilized by the Baby Boomers. The factors affecting utilization, their rising needs, demands, expectations, and areas where improvement is needed for the Baby Boomer are also reported here.

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes.

OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. RESULTS: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder.

BACKGROUND: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. METHODS: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). RESULTS: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. CONCLUSION: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

Protein Biomarkers in Monocytes and CD4+ Lymphocytes for Predicting Lithium Treatment Response of Bipolar Disorder: a Feasibility Study with Tyramine-Based Signal-Amplified Flow Cytometry.

Purpose: To determine if enhanced flow cytometry (CellPrint™) can identify intracellular proteins of lithium responsiveness in monocytes and CD4+ lymphocytes from patients with bipolar disorder. Methods: Eligible bipolar I or II patients were openly treated with lithium for 16-weeks. Baseline levels of Bcl2, BDNF, calmodulin, Fyn, phospho-Fyn/phospho-Yes, GSK3ß, phospho-GSK3αß, HMGB1, iNOS, IRS2, mTor, NLPR3, PGM1, PKA C-α, PPAR-γ, phospho-RelA, and TPH1 in monocytes and CD4+ lymphocytes of lithium responders and non-responders were measured with CellPrint™. Their utility of discriminating responders from non-responders was explored. Protein-protein network and pathway enrichment analyses were conducted. Results: Of the 24 intent-to-treat patients, 12 patients completed the 16-week study. Eleven of 13 responders and 8 of 11 non-responders were available for this analysis. The levels of the majority of analytes in lithium responders were lower than non-responders in both cell types, but only the level of GSK3ß in monocytes was significantly different (p = 0.034). The combination of GSK3ß and phospho-GSK3αß levels in monocytes correctly classified 11/11 responders and 5/8 non-responders. Combination of GSK3ß, phospho-RelA, TPH1 and PGM1 correctly classified 10/11 responders and 6/7 non-responders, both with a likelihood of ≥ 85%. Prolactin, leptin, BDNF, neurotrophin, and epidermal growth factor/epidermal growth factor receptor signaling pathways are involved in the lithium treatment response. GSK3ß and RelA genes are involved in 4 of 5 these pathways. Conclusion: CellPrint™ flow cytometry was able to detect differences in multiple proteins in monocytes and CD4+ lymphocytes between lithium responders and non-responders. A large study is warranted to confirm or refute these findings.

Cingulum bundle connectivity in treatment-refractory compared to treatment-responsive patients with bipolar disorder and healthy controls: a tractography and surgical targeting analysis.

OBJECTIVE: The clinical response of patients with bipolar disorder to medical treatment is variable. A better understanding of the underlying neural circuitry involved in bipolar treatment responsivity subtypes may provide insight into treatment resistance and aid in identifying an effective surgical target for deep brain stimulation (DBS) specific to the disorder. Despite considerable imaging research related to the disease, a paucity of comparative imaging analyses of treatment responsiveness exists. There are also no DBS targets designed expressly for patients with bipolar disorder. Therefore, the authors analyzed cingulum bundle axonal connectivity in relation to cortico-striatal-thalamo-cortical (CSTC) loops implicated in bipolar disorder across subjects who are responsive to treatment (RSP) and those who are refractory to therapy (REF), compared to healthy controls (HCs). METHODS: Twenty-five subjects with bipolar disorder (13 RSP and 12 REF), diagnosed using the Mini International Neuropsychiatric Interview and classified with standardized rating scales, and 14 HCs underwent MRI with diffusion sequences for probabilistic diffusion-weighted tractography analysis. Image processing and tractography were performed using MRTrix. Region of interest (ROI) masks were created manually for 10 anterior cingulum bundle subregions, including surgical targets previously evaluated for the treatment of bipolar disorder (cingulotomy and subgenual cingulate DBS targets). Cortical and subcortical ROIs of brain areas thought to be associated with bipolar disorder and described in animal tract-tracing models were created via FreeSurfer. The number of axonal projections from the cingulum bundle subregion ROIs to cortical/subcortical ROIs for each group was compared. RESULTS: Significant differences were found across groups involving cingulum bundle and CSTC loops. Subjects in the RSP group had increased connections from rostral cingulum bundle to medial orbitofrontal cortex, which is part of the limbic CSTC loop, whereas subjects in the REF group had increased connectivity from rostral cingulum bundle to thalamus. Additionally, compared to HCs, both RSP and REF subjects had decreased cingulum bundle dorsal connectivity (dorsal anterior/posterior cingulate, dorsomedial/lateral frontal cortex) and increased cingulum bundle ventral connectivity (subgenual cingulate, frontal pole, lateral orbitofrontal cortex) involving limbic and associative CSTC loops. CONCLUSIONS: Findings demonstrate that bipolar treatment responsivity may be associated with significant differences in cingulum bundle connectivity in relation to CSTC loops, which may help identify a surgical target for bipolar disorder treatment via DBS in the future.

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information.

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.