McElroy, Susan L.

ObjectivesBipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome‐wide association study, we found that BMI modified the association of rs12772424 – a common variant in the gene encoding transcription factor 7‐like 2 (TCF7L2) – with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2–BMI interaction.MethodsUsing a sample of 662 BD cases and 616 controls, we conducted SNP‐level and gene‐level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis.ResultsThe analysis provided independent evidence of an rs12772424–BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2–BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP–BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway.ConclusionsThe current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association.

ObjectivesTo examine the independent effects of sex on the risk of rapid cycling and other indicators of adverse illness course in patients with bipolar I disorder (BP‐I) or bipolar II disorder (BP‐II).MethodsWe analyzed data from the first 1,225 patients enrolled in the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder. Demographic and clinical variables were ascertained using standardized questionnaires; height and weight were assessed to determine body mass index (BMI). Rates of rapid cycling, cycle acceleration, and increased severity of mood episodes over time were compared between women and men overall and within subgroups defined by bipolar disorder subtype (BP‐I or BP‐II). Multiple logistic regression analysis was used to assess the independent effect of sex on the risk of these indicators of adverse illness course.ResultsWomen had significantly higher rates of rapid cycling than men. Overall rates of rapid cycling were higher in patients with BP‐II than BP‐I; and sex differences in the rate of rapid cycling were more pronounced in patients with BP‐II than BP‐I, although the power to detect statistically significant differences was reduced due to the lower sample size of subjects with BP‐II. Female sex was a significant predictor of rapid cycling, cycle acceleration, and increased severity of mood episodes over time after adjusting for age, bipolar disorder subtype, BMI, having any comorbid psychiatric disorder, and current antidepressant use.ConclusionsFemale sex was associated with significantly higher risk of rapid cycling, cycle acceleration, and increased severity of mood episodes over time in a sample of 1,225 patients with bipolar disorders.

ObjectivesBrain‐derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early‐onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association.MethodsDNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early‐onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult‐onset cases at age >19 years). After quality control, 69 TEAM early‐onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early‐onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log‐additive allele effects.ResultsComparison of TEAM cases with controls suggested association of early‐onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early‐onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early‐onset TEAM and Mayo Clinic early‐onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04).ConclusionsThese preliminary analyses of a relatively small sample with early‐onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early‐onset expression of the disorder.

ObjectivesThe aim of the present study was to engage a national advocacy group and local stakeholders for guidance in developing a bipolar disorder biobank through a web‐based survey and a community advisory board.MethodsThe Depression and Bipolar Support Alliance and the Mayo Clinic Bipolar Biobank conducted a national web‐based survey inquiring about interest in participating in a biobank (i.e., giving DNA and clinical information). A community advisory board was convened to guide establishment of the biobank and identify key deliverables from the research project and for the community.ResultsAmong 385 survey respondents, funding source (87%), professional opinion (76%), mental health consumer opinion (79%), and return of research results (91%) were believed to be important for considering study participation. Significantly more patients were willing to participate in a biobank managed by a university or clinic (78.2%) than one managed by government (63.4%) or industry (58.2%; both p < 0.001). The nine‐member community advisory board expressed interest in research to help predict the likelihood of bipolar disorder developing in a child of an affected parent and which medications to avoid. The advisory board endorsed the use of a comprehension questionnaire to evaluate participants' understanding of the study (e.g., longevity of DNA specimens, right to remove samples, accessing medical records) as a means to strengthen the informed consent process.ConclusionsThese national survey and community advisory data support the merit of establishing a biobank to enable studies of disease risk, provided that health records and research results are adequately protected. The goals of earlier diagnosis and individualized treatment of bipolar disorder were endorsed.

ObjectiveExamine the effects of obesity and metabolic syndrome on outcome in bipolar disorder.MethodThe Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6‐month trial comparing lithium‐ and quetiapine‐based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models.ResultsAt baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome.ConclusionObesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium‐ or quetiapine‐based treatment.

ObjectivesTo determine whether clinical features of bipolar disorder, such as history of psychosis, and cardiovascular disease (CVD) risk factors contribute to a higher risk of CVD among patients with bipolar disorder.MethodsThis cross‐sectional study included a sample of 988 patients with bipolar I or bipolar II disorder or schizoaffective bipolar type confirmed by the Structured Clinical Interview for DSM‐IV‐TR disorders (SCID). Medical comorbidity burden was quantified utilizing the Cumulative Illness Severity Rating Scale (CIRS). This 13‐item organ‐based scale includes cardiac disease severity quantification. Confirmed by medical record review, patients who scored 1 (current mild or past significant problem) or higher in the cardiac item were compared by logistic regression to patients who scored 0 (no impairment), adjusting for CVD risk factors that were selected using a backwards stepwise approach or were obtained from the literature.ResultsIn a multivariate model, age [odds ratio (OR) = 3.03, 95% confidence interval (CI): 1.66–5.54, p < 0.0001], hypertension (OR = 2.43, 95% CI: 1.69–3.55, p < 0.0001), and history of psychosis (OR = 1.48, 95% CI: 1.03–2.13, p = 0.03) were associated with CVD. When CVD risk factors from the literature were added to the analysis, age (OR = 3.19, 95% CI: 1.67–6.10, p = 0.0005) and hypertension (OR = 2.46, 95% CI: 1.61–3.76, p < 0.01) remained significant, with psychosis being at the trend level (OR = 1.43, 95% CI: 0.96–2.13, p = 0.08).ConclusionsThe phenotype of psychotic bipolar disorder may reflect higher illness severity with associated cardiac comorbidity. Further studies are encouraged to clarify the effect of the disease burden (i.e., depression), lifestyle, and treatment interventions (i.e., atypical antipsychotics) on this risk association.

Objective: This study examines characteristics of individuals with bipolar disorder who sought psychotherapy versus those who did not. Methods: Bipolar CHOICE was an 11-site comparative effectiveness study of lithium versus quetiapine in symptomatic outpatients ( N = 482) with bipolar disorder. At baseline, participants’ psychotherapy use within the past 3 months, mood, functioning, and overall health were assessed. Logistic regressions were used to test whether psychotherapy users and non-users differed on various demographic and clinical variables at baseline. Mixed-effects regression was used to determine whether psychotherapy groups differed on response to treatment over the 6-month study. Kaplan-Meier plots and log-rank tests were employed to test whether there were any differences in time to recovery (CGI-BP ≤ 2 for at least 8 weeks) between the groups. Results: Thirty one percent of participants reported using psychotherapy services. Psychotherapy users reported greater medication side effect burden than non-users and were more likely to have moderate to high suicide risk and at least one anxiety disorder. Participants not utilizing medications or psychotherapy had greater mania symptom severity, were younger, and less educated than medication only users. Medication only users were more likely to be married than the other participants. Conclusions: These data suggest that a minority of individuals with bipolar disorder attend psychotherapy services, and those that do have greater illness burden.