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.
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.
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.
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.
The narrative nature of this review.
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.
•In this study, we evaluated the association between MDD and several potential risk factors, with a focus on current and past abuse experiences. For this purpose, a large (n = 1068) representative ...sample of medical students from each academic year during exam season was evaluated.•We present two main findings: (1) depressive symptom severity correlates with perceived academic stress levels on each academic year, and (2) current emotional abuse, personal and family history of depression, and perceived academic stress were significantly associated with an increased risk of current MDD among medical students.•We discuss on the implications of our findings for implementing preventive actions, early detection and prompt treatment of students with an elevated risk to suffer MDD throughout their medical career.
Major depressive disorder (MDD) is highly prevalent among medical students (MS). Abuse experiences, as well as stress, are among the factors associated with MDD. However, their association with MDD in MS has been scarcely addressed.
A cross-sectional study design was used to evaluate the association between MDD and possible risk factors, focusing on current and past abuse experiences inside and outside the academic setting in a large representative MS sample (n = 1,068) using self-report instruments to assess MDD (PHQ-9) and perceived academic stress levels during exam season.
Depressive symptom severity directly correlates with levels of perceived academic stress. The prevalence of MDD was 16.2%. A history of emotional abuse during childhood or adolescence, as well as most types of current abuse were associated with MDD. Multiple logistic regression analysis showed that current emotional abuse outside school had the strongest association with MDD in MS, followed by a personal history of depression and suicide attempt, a family history of depression, and perceived academic stress levels.
Cross-sectional design, participants represent a specific population, and other variables that could be associated with MDD: comorbid psychiatric disorders, current antidepressant treatment and protective factors (resilience and health-promoting coping strategies) were not evaluated.
MDD is strongly associated with several risk factors that include most types of current and past abuse experiences. Timely identification of individuals at-risk will be critical to establish preventive strategies to limit the impact of MDD in MS and offer prompt therapeutic alternatives when needed.
Abstract
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;
I
2
= 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.
•Bipolar disorder associations: obesity, elevated blood pressure and triglycerides.•Results remained after controlling for cardiometabolic medication use and smoking.•Obesity and systolic blood ...pressure were associated with female bipolars vs controls.•Cardiometabolic medications in bipolar patients were under-prescribed.
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.
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.
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.
EHR cross-sectional data
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.
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.
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.
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.
EHR cross-sectional data.
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.
•Patients with bipolar disorder have lower diet quality than the general population.•Unhealthy diet in bipolar disorder is associated with depression and obesity.•Women with poor diet were more liable than men to have obesity and severe depression.
•Almost one third (29%) of patients with BD have experienced migraine headaches.•Migraine is associated with evening chronotype and anxiety disorders.•A younger age and female sex are associated with ...migraine.•Migraine is associated with fibromyalgia, psoriasis, and asthma.•Migraine was not associated with BD subtype, onset, eating behavior, or suicidality.
To evaluate the prevalence and clinical correlates of lifetime migraine among patients with bipolar disorder (BD).
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.
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.
Study design precludes determination of causality. Migraine subtypes and features were not assessed.
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.
