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.

Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition.

The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-CoV, and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors, including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR-tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35-0.74], P = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type-dependent manner. Targeting GSK-3 may therefore provide an approach to treat COVID-19 and future coronavirus outbreaks.

Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies.

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

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.

Suicidality and Alcohol Use as Predictors of Future Suicidal Behavior in College Students.

AIMS: There has been a marked increase in suicide fatalities among college-age students in recent years. Moreover, heavy alcohol use, a well-known risk factor for suicide, is present on most campuses. Yet, no prospective studies have examined alcohol use patterns among college students as predictors of suicidal behaviors. METHODS: Online of 40,335 students at four universities took place at the beginning of four academic years, 2015-2018. Of these, 2296 met criteria for an increased risk of suicidal behavior and completed 1- and/or 6-month follow-up evaluation(s). Baseline assessments included the Alcohol Use Disorders Identification Test to quantify alcohol consumption and resulting problems, and measures of depression, suicidal ideation and suicidal behavior. RESULTS: Suicide attempts during follow-up were reported by 35 (1.5%) of high-risk students. Regression analyses indicated that baseline severity of alcohol use consequences, but not amount of alcohol consumption, was associated with greater odds of a follow-up suicide attempt after controlling for baseline suicidal ideation, functional impairment and history of suicide attempts. CONCLUSIONS: Among college students at elevated risk for suicide, the severity of alcohol-related consequences was a significant predictor of future suicide attempts. Alcohol consumption was not a significant predictor, suggesting that the amount students drink is less of a concern for suicidal behavior than are the problems (e.g. failing to meet expectations, experiencing blackouts) associated with drinking.

Characterisation of age and polarity at onset in bipolar disorder.

BACKGROUND: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (ß = -0.34 years, s.e. = 0.08), major depression (ß = -0.34 years, s.e. = 0.08), schizophrenia (ß = -0.39 years, s.e. = 0.08), and educational attainment (ß = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. CONCLUSIONS: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Predictors of depressive symptom trajectories in a prospective follow-up of late adolescents.

BACKGROUND: Group-based trajectory modeling holds promise for the study of prognostic indicators in the mood disorders because the courses that the individuals with these disorders follow are so highly variable. However, trajectory analyses of major depressive disorder have so far not included some of the more robust predictors of mood disorder outcome, nor have they described interactions between these predictors. METHODS: A group of 186 individuals aged 15-20 years with past or current depressive symptoms, who had recently begun taking a serotonin reuptake inhibitors antidepressant, underwent extensive baseline evaluations and were then followed for up to 2 years. Trajectory analyses used weekly ratings of depressive symptoms and the resulting groups were compared by the risk factors of sex, psychiatric comorbidity, negative emotionality, and childhood adversity. RESULTS: A three-group solution provided the best statistical fit to the 2-year symptom trajectory. Negative emotionality and childhood adversity, though correlated, independently predicted membership in higher-morbidity groups. Female sex and comorbidity with generalized anxiety disorder (GAD) were also significantly more likely in the trajectory groups with higher symptom levels. However, the presence of GAD, rather than female sex, was the most important determinant of group membership. Negative emotionality was predictive of group membership only among women. CONCLUSIONS: Trajectory analyses indicated that week-to-week variations in depressive symptoms across individuals could best be condensed into low, remitting and persistent symptom patterns. Female sex, anxiety symptoms, negative emotionality and childhood adversity were each independently associated with trajectories of higher morbidity but negative emotionality may be prognostically important only among women.

Impact, Diagnosis, Phenomenology, and Biology.

This section provides summaries of the epidemiology, phenomenology, nosology, and the suspected biological substrates of the depressive disorders. It particularly emphasizes the historical evolution of the pertinent diagnostic constructs and the prognostic import both of the various diagnostic groupings and of the individual symptoms and symptom clusters.

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.

Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.

Mixed state and suicide: Is the effect of mixed state on suicidal behavior more than the sum of its parts?

OBJECTIVE: To assess whether suicidal behavior during mixed states exceeds that expected from the manic or depressive components alone. METHODS: This study included 429 participants with bipolar disorder from the National Institute of Mental Health Collaborative Depression Study (CDS). Mood and suicidal behavior were captured using the Longitudinal Interval Follow-up Evaluation and the Schedule of Affective Disorders and Schizophrenia. Suicidal behavior during each mood state, relative to euthymia, was analyzed using Cox regression to allow for repeated events, with a frailty term to account for intra-participant correlation. Mixed states were modeled as a depression-by-mania interaction. RESULTS: Individuals with a history of mixed states were at higher risk of suicidal behavior and spent more time depressed, compared to subjects with no such history. In bipolar I disorder, risk increased during episodes of mania (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.28-2.99, P = .0019) and depression (HR: 5.49, 95% CI: 4.01-7.51, P < .0001) and there was a less than additive effect of mixed states. In bipolar II disorder, risk was increased during episodes of depression (HR: 3.66, 95% CI: 2.51-5.35, P < .0001) and there was no excess risk during mixed states beyond that attributable to the depressed component. Most of the excess risk (71%) among those with a history of mixed states was attributable to a depression predominant course of illness. CONCLUSIONS: Individuals with mixed states are at high risk of suicidal behavior, largely due to more time spent depressed. Clinicians should aggressively treat depression to mitigate suicide risk for patients with or without mixed states.

Hippocampal subfield volumes in short- and long-term lithium-treated patients with bipolar I disorder.

OBJECTIVES: Patients diagnosed with bipolar disorder (BP) may experience hippocampal atrophy. Lithium exposure has been associated with increased hippocampal volumes. However, its effects on hippocampal subfields remain to be clarified. METHODS: We investigated the effects of short- and long-term lithium exposure on the hippocampus and its subfields in patients affected by bipolar I disorder (BP-I). Hippocampal subfields and total hippocampal volumes were measured in 60 subjects divided into four groups: 15 patients with BP-I who were never exposed to lithium [no-exposure group (NE)], 15 patients with BP-I exposed to lithium for < 24 months [short-exposure group (SE)], 15 patients with BP-I exposed to lithium for > 24 months [long-exposure group (LE)], and 15 healthy control subjects (HC). RESULTS: The SE and NE groups showed smaller total hippocampal volumes and smaller bilateral cornu ammonis CA2-3, CA4-dentate gyrus (DG), presubiculum, and subiculum volumes compared with HC. The LE group showed larger total hippocampal volumes and bilateral CA2-3, left CA4-DG, left presubiculum, and right subiculum volumes compared with the NE group, and larger volumes of the right CA2-3, left CA4-DG, left presubiculum, and right subiculum compared with the SE group. No differences were found between the LE group and HC or between the SE and NE groups. CONCLUSIONS: Long-term, but not short-term, exposure to lithium treatment may exert neuroprotective effects on specific hippocampal subfields linked to disease progression.

The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.

BACKGROUND: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. METHODS/DESIGN: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. DISCUSSION: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.

Age at onset of DSM-IV pathological gambling in a non-treatment sample: Early- versus later-onset.

BACKGROUND: Pathological gambling (PG) is a prevalent and impairing public health problem. In this study we assessed age at onset in men and women with PG and compared the demographic and clinical picture of early- vs. later-onset individuals. We also compared age at onset in PG subjects and their first-degree relatives with PG. METHOD: Subjects with DSM-IV PG were recruited during the conduct of two non-treatment clinical studies. Subjects were evaluated with structured interviews and validated questionnaires. Early-onset was defined as PG starting prior to age 33years. RESULTS: Age at onset of PG in the 255 subjects ranged from 8 to 80years with a mean (SD) of 34.0 (15.3) years. Men had an earlier onset than women. 84% of all subjects with PG had developed the disorder by age 50years. Early-onset subjects were more likely to be male, to prefer action games, and to have substance use disorders, antisocial personality disorder, attention deficit/hyperactivity disorder, trait impulsiveness, and social anxiety disorder. Later-onset was more common in women and was associated with a preference for slots and a history of sexual abuse. CONCLUSIONS: Age at onset of PG is bimodal and differs for men and women. Early-onset PG and later-onset PG have important demographic and clinical differences. The implications of the findings are discussed.

Personality Disorders, Impulsiveness, and Novelty Seeking in Persons with DSM-IV Pathological Gambling and Their First-Degree Relatives.

This study investigates the presence of personality disorders, impulsiveness, and novelty seeking in probands with DSM-IV pathological gambling (PG), controls, and their respective first-degree relatives using a blind family study methodology. Ninety-three probands with DSM-IV PG, 91 controls, and their 395 first-degree relatives were evaluated for the presence of personality disorder with the Structured Interview for DSM-IV Personality. Impulsiveness was assessed with the Barratt Impulsiveness Scale (BIS). Novelty seeking was evaluated using questions from Cloninger's Temperament and Character Inventory. Results were analyzed using logistic regression by the method of generalized estimating equations to account for within family correlations. PG probands had a significantly higher prevalence of personality disorders than controls (41 vs. 7 %, OR = 9.0, P < 0.001), along with higher levels of impulsiveness and novelty seeking. PG probands with a personality disorder had more severe gambling symptoms; earlier age at PG onset; more suicide attempts; greater psychiatric comorbidity; and a greater family history of psychiatric illness than PG probands without a personality disorder. PG relatives had a significantly higher prevalence of personality disorder than relatives of controls (24 vs. 9%, OR = 3.2, P < 0.001) and higher levels of impulsiveness. Risk for PG in relatives is associated with the presence of personality disorder and increases along with rising BIS Non-Planning and Total scale scores. Personality disorders, impulsiveness, and novelty seeking are common in people with PG and their first-degree relatives. The presence of a personality disorder appears to be a marker of PG severity and earlier age of onset. Risk for PG in relatives is associated with the presence of personality disorder and trait impulsiveness. These findings suggest that personality disorder and impulsiveness may contribute to a familial diathesis for PG.

A mega-analysis of genome-wide association studies for major depressive disorder.

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Vascular mortality in participants of a bipolar genomics study.

BACKGROUND: In prior work, we identified a relationship between symptom burden and vascular outcomes in bipolar disorder. OBJECTIVE: We sought to replicate these findings using a readily accessible measure of mood disorder chronicity and vascular mortality. METHODS: We conducted a mortality assessment using the National Death Index for 1716 participants with bipolar I disorder from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium. We assessed the relationship between the duration of the most severe depressive and manic episodes and time to vascular mortality (cardiovascular or cerebrovascular) using Cox proportional hazards models, adjusting for potentially confounding variables. RESULTS: Mortality was assessed a mean for 7 years following study intake, at which time 58 participants died, 18 of vascular causes. These participants had depression for much longer than their counterparts did (Wilcoxon rank sum Z = 2.30, p = 0.02) and the duration of the longest depressive episode in years was significantly associated with time to vascular mortality in models (hazard ratio = 1.16, 95% confidence interval: 1.02-1.33, p = 0.02), which controlled for age, gender, vascular disease equivalents, and vascular disease risk factors. The duration of longest mania was not related to vascular mortality. CONCLUSION: The duration of the most severe depression is independently predictive of vascular mortality, lending further support to the idea that mood disorders hasten vascular mortality in a dose-dependent fashion. Further study of the relevant mechanisms by which mood disorders may hasten vascular disease and of integrated treatments for mood and cardiovascular risk factors is warranted.

Omega-3 fatty acid biomarkers and subsequent depressive symptoms.

OBJECTIVE: We sought to determine the relationship between the omega-3 fatty acid content of red blood cell membranes (RBC), in particular docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and baseline and new-onset depressive symptoms in post-menopausal women. We secondarily sought to characterize the association between dietary omega-3 fatty acid intake and depressive symptomatology. METHODS: Study participants included 7086 members of the Women's Health Initiative Memory Study (aged 63-81 years) who had an assessment of RBC omega-3 fatty acid concentrations at the baseline screening visit. Depressive symptoms at baseline and follow-up were characterized using the Burnam eight-item scale for depressive disorders (Center for Epidemiologic Studies Depression Scale/Diagnostic Interview Schedule short form) and secondarily additionally inferred by antidepressant medication use. RESULTS: In multivariable-adjusted models, our primary exposure, RBC DHA + EPA, was not related to depressive symptoms by any measure at baseline or follow-up, nor were RBC total omega-3, DHA, or EPA (all p > 0.2). In contrast, dietary intake of omega-3 was positively associated with depressive symptoms at baseline (adjusted odds ratio 1.082, 95% confidence interval 1.004-1.166; p = 0.04 for dietary DHA + EPA and Burnam score ≥0.06), although this generally did not persist at follow-up. CONCLUSION: No relationship between RBC omega-3 levels and subsequent depressive symptoms was evident, and associations between dietary omega-3 and depressive symptoms were variable. Biomarkers of omega-3 status do not appear to be related to risk of new depression in post-menopausal women.

Seasonal variation of depressive symptoms in unipolar major depressive disorder.

OBJECTIVES: Retrospective and cross-sectional studies of seasonal variation of depressive symptoms in unipolar major depression have yielded conflicting results. We examined seasonal variation of mood symptoms in a long-term prospective cohort - the Collaborative Depression Study (CDS). METHODS: The sample included 298 CDS participants from five academic centers with a prospectively derived diagnosis of unipolar major depression who were followed for at least ten years of annual or semi-annual assessments. Generalized linear mixed models were utilized to investigate the presence of seasonal patterns. In a subset of 271 participants followed for at least 20 years, the stability of a winter depressive pattern was assessed across the first two decades of follow-up. RESULTS: A small increase in proportion of time depressed was found in the months surrounding the winter solstice, although the greatest symptom burden was seen in December through April with a peak in March. The relative burden of winter depressive symptoms in the first decade demonstrated no relationship to that of the second decade. The onset of new episodes was highest October through January, peaking in January. CONCLUSIONS: There exists a small but statistically significant peak in depressive symptoms from the month of the winter solstice to the month of the spring equinox. However, the predominance of winter depressive symptoms did not appear stable over the long-term course of illness.