Clinical and genetic contributions to medical comorbidity in bipolar disorder: a study using electronic health records-linked biobank data.

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n = 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk.

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder.

There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania.

Antidepressant-Associated Treatment Emergent Mania: A Meta-Analysis to Guide Risk Modeling Pharmacogenomic Targets of Potential Clinical Value.

BACKGROUND: The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression. METHODS: Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model. RESULTS: Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters. CONCLUSION: Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

Clinical characterization of patients with bipolar disorder and a history of asthma: An exploratory study.

INTRODUCTION: Bipolar disorder (BD) and asthma are leading causes of morbidity in the US and frequently co-occur. OBJECTIVES: We evaluated the clinical features and comorbidities of patients with BD and a history of asthma. METHODS: In a cross-sectional analysis from the Mayo Clinic Bipolar Biobank, we explored the clinical characteristics of the BD and an asthma phenotype and fitted a multivariable regression model to identify risk factors for asthma. RESULTS: A total of 721 individuals with BD were included. From these, 140 (19%) had a history of asthma. In a multivariable model only sex and evening chronotype were significant predictors of asthma with the odds ratios and 95% confidence intervals being 1.65 (1.00, 2.72; p=0.05) and 1.99 (1.25, 3.17; p < 0.01), respectively. Individuals with asthma had higher odds of having other medical comorbidities after adjusting for age, sex, and site including hypertension (OR = 2.29 (95% CI 1.42, 3.71); p < 0.01), fibromyalgia (2.29 (1.16, 4.51); p=0.02), obstructive sleep apnea (2.03 (1.18, 3.50); p=0.01), migraine (1.98 (1.31, 3.00); p < 0.01), osteoarthritis (2.08 (1.20, 3.61); p < 0.01), and COPD (2.80 (1.14, 6.84); p=0.02). Finally, individuals currently on lithium were less likely to have a history of asthma (0.48 (0.32, 0.71); p < 0.01). CONCLUSION: A history of asthma is common among patients with BD and is associated with being female and having an evening chronotype, as well as with increased odds of having other medical comorbidities. A lower likelihood of a history of asthma among those currently on lithium is an intriguing finding with potential clinical implications that warrants further study.

Insulin resistance in bipolar disorder: A systematic review of illness course and clinical correlates.

BACKGROUND: Although insulin resistance (IR) and cardiometabolic syndrome are prevalent in patients with bipolar disorder (BD), only a few studies have attempted to precisely assess the degree and clinical impact of IR in BD. METHODS: A comprehensive search was conducted from multiple research databases through May 2022, following a pre-defined protocol (PROSPERO: CRD42022359259). We extracted neuroimaging, cognition, illness course, and treatment response findings from individuals with BD with evidence of IR compared with euglycemic BD individuals. RESULTS: Of 1436 identified articles, 10 reports fulfilling inclusion criteria were included (n = 1183). BD patients with IR displayed worse composite verbal memory scores and worse executive function and exhibited smaller hippocampal volumes along with prefrontal neurochemical alterations compared to euglycemic BD patients. Fixed-effect meta-analysis revealed that BD patients with impaired glucose metabolism (IGM) were more likely to develop a chronic and rapid cycling course when compared with euglycemic BD patients (k = 2, OR = 2.96, 95 % CI 1.69-5.17, OR = 2.88, 95 % CI 1.59-5.21, p < 0.001, respectively), with a trend for significantly lower Global Assessment of Functioning scores (k = 5, MD = -4, 95 % CI -8.23-0.23, p = 0.06). BD patients with IGM displayed a higher rate of poor response to mood stabilizers when compared with euglycemic BD patients (k = 2, OR = 6.74, 95 % CI 1.04-43.54, p = 0.04). LIMITATIONS: Cross-sectional design and small sample sizes of studies included limit the generalizability of results. CONCLUSION: IR is associated with worse clinical outcomes of BD and inadequate treatment response. Implementing strategies to prevent and treat IR in BD is crucial to improve the prognosis of such a difficult-to-treat population.

Pharmacotherapy exposure as a marker of disease complexity in bipolar disorder: Associations with clinical & genetic risk factors.

Individuals with bipolar disorder (BD) require chronic pharmacotherapy, typically including medication switches or polypharmacy due to persisting symptoms or intolerable side effects. Here, we quantified pharmacotherapy exposure (PE) of Mayo Clinic BD Biobank participants using the number of cross-sectional (at enrollment) and lifetime BD-specific medications and medication classes, to understand the relationship between PE and markers of disease severity or treatment failure, psychiatric comorbidities, and polygenic risk scores (PRS) for six major psychiatric disorders. Being female (p < 0.05), older (p < 0.01), having history of suicide attempts (p < 0.0001), and comorbid attention-deficit/hyperactivity disorder (p < 0.05) or generalized anxiety disorder (p < 0.05) were uniformly associated with higher PE. Lifetime exposure to unique medication classes among participants with BD-I was significantly lower than for those with schizoaffective disorder (estimate = -2.1, p < 0.0001) while significantly higher than for those with BD-II (estimate = 0.5, p < 0.01). Further, higher PRS for schizophrenia (SCZ) and anxiety resulted in greater lifetime medication counts (p < 0.01), both driven by antipsychotic (p < 0.001) and anxiolytic use (p < 0.05). Our results provide initial evidence of the utility of PE as a measure of disease complexity or treatment resistance, and that PE may be predicted by higher genetic risk for SCZ and anxiety.

Polygenic prediction of bipolar disorder in a Latin American sample.

To date, bipolar disorder (BD) genetic studies and polygenic risk scores (PRSs) for BD are based primarily on populations of European descent (EUR) and lack representation from other ancestries including Latin American (LAT). Here, we describe a new LAT cohort from the Mayo Clinic Bipolar Biobank (MCBB), a multisite collaboration with recruitment sites in the United States (EUR; 1,443 cases and 777 controls) and Mexico and Chile (LAT; 211 cases and 161 controls) and use the sample to explore the performance of a BD-PRS in a LAT population. Using results from the largest genome-wide association study of BD in EUR individuals, PRSice2 and LDpred2 were used to compute BD-PRSs in the LAT and EUR samples from the MCBB. PRSs explained up to 1.4% (PRSice) and 4% (LDpred2) of the phenotypic variance on the liability scale in the LAT sample compared to 3.8% (PRSice2) and 3.4% (LDpred2) in the EUR samples. Future larger studies should further explore the differential performance of different PRS approaches across ancestries. International multisite studies, such as this one, have the potential to address diversity-related limitations of prior genomic studies and ultimately contribute to the reduction of health disparities.

Antidepressants that increase mitochondrial energetics may elevate risk of treatment-emergent mania.

Preclinical evidence suggests that antidepressants (ADs) may differentially influence mitochondrial energetics. This study was conducted to investigate the relationship between mitochondrial function and illness vulnerability in bipolar disorder (BD), specifically risk of treatment-emergent mania (TEM). Participants with BD already clinically phenotyped as TEM+ (n = 176) or TEM- (n = 516) were further classified whether the TEM associated AD, based on preclinical studies, increased (Mito+, n = 600) or decreased (Mito-, n = 289) mitochondrial electron transport chain (ETC) activity. Comparison of TEM+ rates between Mito+ and Mito- ADs was performed using generalized estimating equations to account for participants exposed to multiple ADs while adjusting for sex, age at time of enrollment into the biobank and BD type (BD-I/schizoaffective vs. BD-II). A total of 692 subjects (62.7% female, 91.4% White, mean age 43.0 ± 14.0 years) including 176 cases (25.3%) of TEM+ and 516 cases (74.7%) of TEM- with previous exposure to Mito+ and/or Mito- antidepressants were identified. Adjusting for age, sex and BD subtype, TEM+ was more frequent with antidepressants that increased (24.7%), versus decreased (13.5%) mitochondrial energetics (OR = 2.21; p = 0.000009). Our preliminary retrospective data suggests there may be merit in reconceptualizing AD classification, not solely based on monoaminergic conventional drug mechanism of action, but additionally based on mitochondrial energetics. Future prospective clinical studies on specific antidepressants and mitochondrial activity are encouraged. Recognizing pharmacogenomic investigation of drug response may extend or overlap to genomics of disease risk, future studies should investigate potential interactions between mitochondrial mechanisms of disease risk and drug response.

The genetics of bipolar disorder with obesity and type 2 diabetes.

BACKGROUND: Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic disorders. Genomic studies may help define if they share genetic liability. This selective review of BD with obesity and T2D will focus on genomic studies, stress their current limitations and guide future steps in developing the field. METHODS: We searched electronic databases (PubMed, Scopus) until December 2021 to identify genome-wide association studies, polygenic risk score analyses, and functional genomics of BD accounting for body mass index (BMI), obesity, or T2D. RESULTS: The first genome-wide association studies (GWAS) of BD accounting for obesity found a promising genome-wide association in an intronic gene variant of TCF7L2 that was further replicated. Polygenic risk scores of obesity and T2D have also been associated with BD, yet, no genetic correlations have been demonstrated. Finally, human-induced stem cell studies of the intronic variant in TCF7L2 show a potential biological impact of the products of this genetic variant in BD risk. LIMITATIONS: The narrative nature of this review. CONCLUSIONS: Findings from BD GWAS accounting for obesity and their functional testing, have prompted potential biological insights. Yet, BD, obesity, and T2D display high phenotypic, genetic, and population-related heterogeneity, limiting our ability to detect genetic associations. Further studies should refine cardiometabolic phenotypes, test gene-environmental interactions and add population diversity.

Quantification of diet quality utilizing the rapid eating assessment for participants-shortened version in bipolar disorder: Implications for prospective depression and cardiometabolic studies.

OBJECTIVES: Recognizing bipolar disorder as a multi-system metabolic condition driven, in part, by binge eating behavior and atypical depressive symptoms, this study aimed to quantify diet quality and evaluate clinical correlates in a bipolar disorder cohort. METHODS: Participants from the Mayo Clinic Bipolar Disorder Biobank (n = 734) completed the Rapid Eating Assessment for Participants - Shortened version (REAP-S) to determine diet quality. The average REAP-S score for a U.S. omnivorous diet is 32 (range 13 to 39) with higher scores indicating healthier diet. Demographic variables were collected in a standardized clinical questionnaire. Depressive symptoms were assessed by the Bipolar Inventory of Symptoms Scale. Cardiometabolic variables were retrieved from the electronic health record. Associations between continuous variables and REAP-S scores (total, 'healthy foods' and 'avoidance of unhealthy foods') were assessed using linear regression. RESULTS: Overall, our sample had a mean REAP-S score of 27.6 (4.9), suggestive of a lower diet quality than the average general population in the US. There was a significant inverse relationship between mean REAP-S lower scores with increased BMI, waist circumference, disordered eating and depression. All these associations were significantly stronger in female participants. LIMITATIONS: EHR cross-sectional data. CONCLUSIONS: Our data suggest unhealthy diet quality in bipolar disorder is associated with depression, obesity and cardiometabolic abnormalities. Additional work is encouraged to prospectively track mood and diet quality to further understand the bidirectional relationship and clarify if dietary interventions can positively impact mood. Further delineating potential sex differences in diet quality and depression may provide greater appreciation of modifiable risk factors for future cardiometabolic burden.

Clinical Phenotype of Tardive Dyskinesia in Bipolar Disorder.

PURPOSE: Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD. MATERIALS AND METHODS: Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis. RESULTS: The prevalence rate of TD was 5.1%. In comparison to the TD- group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics. CONCLUSIONS: This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.

Association of Bipolar Disorder With Major Adverse Cardiovascular Events: A Population-Based Historical Cohort Study.

OBJECTIVE: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors. METHODS: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD). RESULTS: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010). CONCLUSIONS: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes.

Revisiting the bipolar disorder with migraine phenotype: Clinical features and comorbidity.

INTRODUCTION: To evaluate the prevalence and clinical correlates of lifetime migraine among patients with bipolar disorder (BD). METHODS: In a cross-sectional study, we evaluated 721 adults with BD from the Mayo Clinic Bipolar Disorder Biobank and compared clinical correlates of those with and without a lifetime history of migraine. A structured clinical interview (DSM-IV) and a clinician-assessed questionnaire were utilized to establish a BD diagnosis, lifetime history of migraine, and clinical correlates. RESULTS: Two hundred and seven (29%) BD patients had a lifetime history of migraine. BD patients with migraine were younger and more likely to be female as compared to those without migraine (p values <0.01). In a multivariate logistic regression model, younger age (OR=0.98, p<0.01), female sex (OR=2.02, p<0.01), higher shape/weight concern (OR=1.04, p=0.02), greater anxiety disorder comorbidities (OR=1.24, p<0.01), and evening chronotype (OR=1.65, p=0.03) were associated with migraine. In separate regression models for each general medical comorbidity (controlled for age, sex, and site), migraines were significantly associated with fibromyalgia (OR=3.17, p<0.01), psoriasis (OR=2.65, p=0.03), and asthma (OR=2.0, p<0.01). Participants with migraine were receiving ADHD medication (OR=1.53, p=0.05) or compounds associated with weight loss (OR=1.53, p=0.02) at higher rates compared to those without migraine. LIMITATIONS: Study design precludes determination of causality. Migraine subtypes and features were not assessed. CONCLUSIONS: Migraine prevalence is high in BD and is associated with a more severe clinical burden that includes increased comorbidity with pain and inflammatory conditions. Further study of the BD-migraine phenotype may provide insight into common underlying neurobiological mechanisms.

Pharmacogenetics in Psychiatry: Perceived Value and Opinions in a Chilean Sample of Practitioners.

Use of pharmacogenetics (PGx) testing to guide clinical decisions is growing in developed countries. Published guidelines for gene-drug pair analysis are available for prescriptions in psychiatry, but information on their utilization, barriers, and health outcomes in Latin America is limited. As a result, this work aimed at exploring current use, opinions, and perceived obstacles on PGx testing among psychiatrists in Chile, via an online, anonymous survey. Among 123 respondents (5.9% of registered psychiatrists in the country), 16.3% reported ever requesting a PGx test. The vast majority (95%) of tests were ordered by clinicians practicing in the Metropolitan Region of Santiago. Having more than 20 years in practice was positively associated with prior use of PGx (p 0.02, OR 3.74 (1.19-11.80)), while working in the public health system was negatively associated (OR 0.30 (0.10-0.83)). Perceived barriers to local implementation included insufficient evidence of clinical utility, limited clinicians' knowledge on PGx and on test availability, and health systems' issues, such as costs and reimbursement. Despite the recognition of these barriers, 80% of respondents asserted that it is likely that they will incorporate PGx tests in their practice in the next five years. Given these results, we propose next steps to facilitate implementation such as further research in health outcomes and clinical utility of known and novel clinically actionable variants, growth in local sequencing capabilities, education of clinicians, incorporation of clinical decision support tools, and economic evaluations, all in local context.

Body mass index and blood pressure in bipolar patients: Target cardiometabolic markers for clinical practice.

OBJECTIVE: To evaluate the association between cardiometabolic markers and bipolar disorder (BD), examining the impact of sex and cardiometabolic medication use, from a large case-control biorepository of more than 1300 participants. PATIENTS AND METHODS: Recruited from July 2009 through September 2017, cardiometabolic markers were harvested from electronic health records (EHR) of participants (n=661) from the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder and Mayo Clinic Biobank age-sex-matched controls (n=706). Markers were compared between cases and controls using logistic regression, stratified by sex, adjusting for cardiometabolic medications and current smoking status. We studied the effect of psychotropics in case-only analyses. RESULTS: The mean age of the sample was 52.5 ± 11.6 years and 55% were female. BD patients had higher rates of smoking, but lower utilization of lipid-lowering medication compared with controls. After adjustment, BD was associated with obesity [Odds ratio (CI) 1.62 (1.22-2.15)], elevated systolic blood pressure (SBP) [2.18 (1.55-3.06)] and elevated triglycerides [1.58 (1.13-2.2)]. When stratified by sex, obesity [1.8 (1.23-2.66)] and systolic blood pressure [2.32 (1.46-3.7)] were associated with BD females compared to female controls; however, only systolic blood pressure [2.04 (1.23-3.42)] was associated with male bipolars compared to male controls. Psychotropics were marginally associated with mean BMI, abnormal triglycerides, and HbA1c. LIMITATIONS: EHR cross-sectional data CONCLUSION: To our knowledge, this is the largest case controlled study to date to explore the association between cardiometabolic markers and bipolar disorder adjusting for utilization of cardiometabolic medication. Identification of significant, non-laboratory based cardiometabolic markers that are associated with increased risk of major cardiovascular adverse events in patients with bipolar disorder, underscores, both the utility and importance of risk monitoring that can be easily done in community mental health centers.

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

Cytochrome P450 2C19 Poor Metabolizer Phenotype in Treatment Resistant Depression: Treatment and Diagnostic Implications.

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance. Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003-2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.

Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder.

Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke's R2 = 0.021; p = 0.045), BD-I cases without psychosis (R2 = 0.015; p = 0.007), BD-II cases without psychosis (R2 = 0.014; p = 0.017), and controls (R2 = 0.065; p = 2 × 10-13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.

Clinical features of bipolar spectrum with binge eating behaviour.

OBJECTIVE: To determine whether bipolar spectrum disorder with binge eating behavior (BE) is an important clinical sub-phenotype. METHODS: Prevalence rates and correlates of different levels of BE were assessed in 1114 bipolar spectrum patients participating in a genetic biobank. BE and eating disorders (EDs) were assessed with the Eating Disorder Diagnostic Scale (EDDS). Psychiatric illness burden was evaluated with measures of suicidality, psychosis, mood instability, anxiety disorder comorbidity, and substance abuse comorbidity. Medical illness burden was evaluated with body mass index (BMI) and the Cumulative Index Rating Scale (CIRS). RESULTS: Thirty percent of patients had any BE and 27% had BE plus an ED diagnosis. Compared with bipolar spectrum patients without BE, bipolar spectrum patients with BE were younger and more likely to be female; had significantly higher levels of eating psychopathology, suicidality, mood instability, and anxiety disorder comorbidity; had a significantly higher mean BMI and a significantly higher rate of obesity; and had a significantly higher medical illness burden. Bipolar spectrum patients with BE but no ED diagnosis were more similar to bipolar spectrum patients without BE than to those with an ED. Nonetheless, the positive predictive value and specificity of BE predicting an ED was 0.90 and 0.96, respectively. LIMITATIONS: As only two patients had co-occurring anorexia nervosa, these results may not generalize to bipolar spectrum patients with restricting EDs. CONCLUSION: Bipolar spectrum disorder with broadly-defined BE may not be as clinically relevant a sub-phenotype as bipolar spectrum disorder with an ED but may be an adequate proxy for the latter when phenotyping large samples of individuals.

Accumulating evidence for a role of TCF7L2 variants in bipolar disorder with elevated body mass index.

OBJECTIVES: Bipolar 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. METHODS: Using 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. RESULTS: The 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. CONCLUSIONS: The 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.