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.

Real-World Clinical Practice Among Patients With Bipolar Disorder and Chronic Kidney Disease on Long-term Lithium Therapy.

PURPOSE: Long-term lithium therapy (LTLT) has been associated with chronic kidney disease (CKD). We investigated changes in clinical characteristics, pharmacotherapeutic treatments for medical/psychiatric disorders, and outcomes among patients with bipolar disorder (BD) and CKD on LTLT in a 2-year mirror-image study design. METHODS: Adult BD patients on LTLT for ≥1 year who enrolled in the Mayo Clinic Bipolar Disorder Biobank and developed CKD (stage 3) were included, and our study was approved by the Mayo Clinic Institutional Review Board. The primary outcome was the time to the first mood episode after CKD diagnosis among the lithium (Li) continuers and discontinuers. Cox proportional hazards models were used to estimate the time to the first mood episode. We tested for differences in other medication changes between the Li continuers and discontinuers group using Mantel-Haenszel χ2 tests (linear associations). RESULTS: Of 38 BD patients who developed CKD, 18 (47%) discontinued Li, and the remainder continued (n = 20). The median age of the cohort was 56 years (interquartile range [IQR], 48-67 years), 63.2% were female, and 97.4% were White. As compared with continuers, discontinuers had more psychotropic medication trials (6 [IQR, 4-6] vs 3 [IQR, 2-5], P = 0.02), a higher rate of 1 or more mood episodes (61% vs 10%, P = 0.002), and a higher risk of a mood episode after CKD diagnoses (Hazard Ratio, 8.38; 95% confidence interval, 1.85-38.0 [log-rank P = 0.001]]. CONCLUSIONS: Bipolar disorder patients on LTLT who discontinued Li had a higher risk for relapse and a shorter time to the first mood episode, suggesting a need for more thorough discussion before Li discontinuation after the CKD diagnosis.

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 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 Optimal Lamotrigine Serum Levels and Therapeutic Efficacy in Mood Disorders: A Systematic Review.

PURPOSE: The aim of the study was to appraise the current evidence on the optimal serum level for lamotrigine (LAM) in the treatment of mood disorders (major depressive disorder, bipolar disorder). METHODS: Major databases were searched for randomized controlled trials, open-label trials, and observational studies reporting serum LAM levels in adult patients treated with LAM for mood disorders. RESULTS: A total of 814 abstracts were screened and 24 articles were selected for full-text review. Seven studies (226 bipolar disorder and 17 major depressive disorder patients) including 1 randomized controlled trial (n = 43), 3 prospective (n = 53), and 3 retrospective (n = 147) studies met the study criteria with a study duration range from 6 to 96 weeks. Lamotrigine daily dosage varied from 25 to 425 mg/d among the studies. Studies reported inconsistent findings between LAM concentration and efficacy. Three studies did not identify a relationship between LAM levels and a significant improvement in mood symptoms. Two studies (n = 99) reported higher response rates with LAM serum levels of greater than 3.25 µg/mL and 1 study (n = 25) reported a wide therapeutic window of 5 to 11 µg/mL. Overall, LAM was well tolerated with no major significant adverse effects. CONCLUSIONS: Most studies showed a minimum LAM threshold level of 3 µg/mL in patients with mood disorders; however, the data are inconsistent regarding the therapeutic range for LAM. Based on the pooled data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM serum levels for mood improvement. Further studies including larger sample sizes are required to address this relevant clinical question.

Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: A meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of the dopaminergic-enhancing agent modafinil/armodafinil (MoArm) as adjunctive treatment for bipolar depression. METHODS: A comprehensive search of major electronic databases was conducted to identify randomized controlled trials (RCTs) of adjunctive MoArm that included patients with bipolar I (BP-I) or bipolar II (BP-II) depression. Data for response/remission and all-cause discontinuation were analyzed. Effect size was summarized by relative risk (RR) using a random effect model. RESULTS: Of 58 studies, five RCTs (N = 795 drug, N = 792 placebo) met inclusion criteria. Four armodafinil studies included only BP-I patients and one modafinil study included both bipolar subtypes with limited heterogeneity (I2  = 34%, P = .19; I2  = 18%, P = .30). Compared to placebo, augmentation with MoArm was associated with significantly greater rates of treatment response (RR, 1.18; 95% CI, 1.01-1.37; P = .03) and remission (RR, 1.38; 95% CI, 1.10-1.73; P = .005). All-cause discontinuation was not different than placebo (RR, 1.08; 95% CI, 0.89-1.30; P = .45) with no evidence of increased risk of mood switch or suicide attempts with MoArm (RR, 0.99; 95% CI, 0.39-2.5; P = .98; RR, 1.02; 95% CI, 0.37-2.85; P = .97). CONCLUSION: This narrower scope meta-analysis of one drug for one disease suggests that adjunctive MoArm may represent a novel therapeutic intervention. Further studies delineating the subtypes of bipolar depression responsive to these novel dopaminergic-enhancing agents are encouraged.

Type 1 equilibrative nucleoside transporter (ENT1) regulates sex-specific ethanol drinking during disruption of circadian rhythms.

Disruptions in circadian rhythms are risk factors for excessive alcohol drinking. The ethanol-sensitive adenosine equilibrative nucleoside transporter type 1 (ENT1, slc29a1) regulates ethanol-related behaviors, sleep, and entrainment of circadian rhythms. However, the mechanism underlying the increased ethanol consumption in ENT1 knockout (KO) mice in constant light (LL) and whether there are sex differences in ethanol consumption in ENT1 mice are less studied. Here, we investigated the effects of loss of ENT1, LL, and sex on ethanol drinking using two-bottle choice. In addition, we monitored the locomotor activity rhythms. We found that LL increased ethanol drinking and reduced accumbal ENT1 expression and adenosine levels in male but not female mice, compared with control mice. Interestingly, only LL-exposed male, not female, ENT1 KO mice exhibited higher ethanol drinking and a longer circadian period with a higher amplitude compared with wild-type (WT) mice. Furthermore, viral-mediated rescue of ENT1 expression in the NAc of ENT1 KO mice reduced ethanol drinking, demonstrating a possible causal link between ENT1 expression and ethanol drinking in males. Together, our findings indicate that deficiency of ENT1 expression contributes to excessive ethanol drinking in a sex-dependent manner.

The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review.

Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current antidepressant medications are suboptimal, as most MDD patients fail to achieve complete remission from symptoms. At present, clinicians are unable to predict which antidepressant is most effective for a particular patient, exposing patients to multiple medication trials and side effects. Since MDD's etiology includes interactions between genes and environment, the epigenome is of interest for predictive utility and treatment monitoring. Epigenetic mechanisms of antidepressant medications are incompletely understood. Differences in epigenetic profiles may impact treatment response. A systematic literature search yielded 24 studies reporting the interaction between antidepressants and eight genes (BDNF, MAOA, SLC6A2, SLC6A4, HTR1A, HTR1B, IL6, IL11) and whole genome methylation. Methylation of certain sites within BDNF, SLC6A4, HTR1A, HTR1B, IL11, and the whole genome was predictive of antidepressant response. Comparing DNA methylation in patients during depressive episodes, during treatment, in remission, and after antidepressant cessation would help clarify the influence of antidepressant medications on DNA methylation. Individuals' unique methylation profiles may be used clinically for personalization of antidepressant choice in the future.

Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder.

OBJECTIVES: Brain-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. METHODS: DNA 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. RESULTS: Comparison 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). CONCLUSIONS: These 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.

Sex differences in effectiveness and adverse effects of mood stabilizers and antipsychotics: A systematic review.

BACKGROUND: Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically. METHODS: We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk. RESULTS: Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies. LIMITATIONS: Substantial heterogeneity among the studies precluded performing a meta-analysis. CONCLUSION: Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention.

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.

DNA methylation/demethylation network expression in psychotic patients with a history of alcohol abuse.

BACKGROUND: Recent studies suggest that protracted and excessive alcohol use induces an epigenetic dysregulation in human and rodent brains. We recently reported that DNA methylation dynamics are altered in brains of psychotic (PS) patients, including schizophrenia and bipolar disorder patients. Because PS patients are often comorbid with chronic alcohol abuse, we examined whether the altered expression of multiple members of the DNA methylation/demethylation network observed in postmortem brains of PS patients was modified in PS patients with a history of chronic alcohol abuse. METHODS: DNA-methyltransferase-1 (DNMT1) mRNA-positive neurons were counted in situ in prefrontal cortex samples obtained from the Harvard Brain Tissue Resource Center, Belmont, MA. 10-11-translocation (TETs 1, 2, 3), apolipoprotein B editing complex enzyme (APOBEC-3C), growth and DNA-damage-inducible protein 45ß (GADD45ß), and methyl-binding domain protein-4 (MBD4) mRNAs were measured by quantitative real-time polymerase chain reaction in inferior parietal cortical lobule samples obtained from the Stanley Foundation Neuropathology Consortium, Bethesda, MD. RESULTS: We observed an increase in DNMT1 mRNA-positive neurons in PS patients compared with non-PS subjects. In addition, there was a pronounced decrease in APOBEC-3C and a pronounced increase in GADD45ß and TET1 mRNAs in PS patients with no history of alcohol abuse. In PS patients with a history of chronic alcohol abuse, the numbers of DNMT1-positive neurons were not increased significantly. Furthermore, the decrease in APOBEC-3C mRNA was less pronounced, while the increase in TET1 mRNA had a tendency to be potentiated in those PS patients that were chronic alcohol abusers. GADD45ß and MBD4 mRNAs were not influenced by alcohol abuse. The effect of chronic alcohol abuse on DNA methylation/demethylation network enzymes cannot be attributed to confounding demographic variables or to the type and dose of medication used. CONCLUSIONS: Based on these results, we hypothesize that PS patients may abuse alcohol as a potential attempt at self-medication to normalize altered DNA methylation/demethylation network pathways. However, before accepting this conclusion, we need to study alterations in the DNA methylation/demethylation pathways and the DNA methylation dynamics in a substantial number of alcoholic PS and non-PS patients. Additional investigation may also be necessary to determine whether the altered DNA methylation dynamics are direct or the consequence of an indirect interaction of alcohol with the neuropathogenetic mechanisms underlying psychosis.

Prevalence and outcomes of rapid cycling bipolar disorder: Mixed method systematic meta-review.

Rapid-cycling in bipolar disorder (RC-BD) is associated with greater illness morbidity and inferior treatment response but many aspects remain unclear, prompting this systematic review of its definitions, prevalence, and clinical characteristics. We searched multiple literature databases through April 2022 for systematic reviews or meta-analyses on RC-BD and extracted associated definitions, prevalence, risk-factors, and clinical outcomes. We assessed study quality (NIH Quality Assessment Tool) and levels of evidence (Oxford criteria). Of 146 identified reviews, 22 fulfilling selection criteria were included, yielding 30 studies involving 13,698 BD patients, of whom 3777 (27.6% [CI: 26.8-28.3]) were considered RC-BD, as defined in 14 reports by ≥4 recurrences/year within the past 12 months or in any year, without considering responsiveness to treatment. Random-effects meta-analytically pooled one-year prevalence was 22.3% [CI: 14.4-32.9] in 12 reports and lifetime prevalence was 35.5% [27.6-44.3] in 18 heterogenous reports. Meta-regression indicated greater lifetime prevalence of RC-BD among women than men (p=0.003). Association of RC-BD with suicide attempts, and unsatisfactory response to mood-stabilizers was supported by strong evidence (Level 1); associations with childhood maltreatment, mixed-features, female sex, and type-II BD had moderate evidence (Level 2). Other factors: genetic predisposition, metabolic disturbances or hypothyroidism, antidepressant exposure, predominant depressive polarity (Level 3), along with greater illness duration and immune-inflammatory dysfunction (Level 4) require further study. RC-BD was consistently recognized as having high prevalence (22.3%-35.5% of BD cases) and inferior treatment response. Identified associated factors can inform clinical practice. Long-term illness-course, metabolic factors, and optimal treatment require further investigation.

The Association Between Thyroid Stimulating Hormone and Depression: A Historical Cohort Study.

OBJECTIVE: To investigate the association between thyroid-stimulating hormone (TSH) and clinically relevant depression (CRD) in a population-based study. PATIENTS AND METHODS: Adult patients (≥18 years of age) who received care at Mayo Clinic in Rochester, Minnesota, and completed a TSH and Patient Health Questionnaire - 9 (PHQ-9) within 6 months of each other, between July 8, 2017, and August 31, 2021, were included. Demographics, medical comorbidities, thyroid function laboratory data, psychotropic medications, presence of primary thyroid disorder, thyroid hormone replacement (T4 and/or T3), and mood disorder diagnoses (using International Classification of Diseases, 10th version, Clinical Modifications codes) were extracted electronically. The primary outcome, CRD, was defined as a PHQ-9 score greater than or equal to 10. Logistic regression analysis was conducted to assess the association between TSH categories (low ≤0.3 mIU/L; normal >0.3-4.2 mIU/L; high >4.2 mIU/L) and CRD. RESULTS: The cohort included 29,034 patients, mean age 51.4 years, 65% females, 89.9% White, and a mean body mass index of 29.9 kg/m2. The mean ± standard deviation for TSH was 3.0±8.5 mIU/L, and the mean PHQ-9 score was 6.3±6.2. After adjustment, the odds of CRD were significantly higher among the low TSH category (odds ratio, 1.37; 95% CI, 1.18-1.57; P<.001) compared with the normal TSH category, especially in people 70 years of age or younger compared with people older than 70 years of age. Subgroup analysis did not show an increase in odds of CRD among patients with subclinical/overt hypothyroidism/hyperthyroidism (after adjustment). CONCLUSION: In this large population-based cross-sectional study, we report that low TSH was associated with higher odds of depression. Future longitudinal cohort studies are needed to investigate the relationship between thyroid dysfunction and depression as well as sex differences.

Cardiometabolic and endocrine comorbidities in women with bipolar disorder: A systematic review.

INTRODUCTION: Bipolar Disorder (BD) is known to be equally distributed among males and females. The well-documented increased risk of medical comorbidities in patients with BD, in comparison to BD patients without medical comorbidities, shows a negative impact on the course of illness. There is some evidence suggesting that women with BD have higher psychiatric and medical comorbidities in comparison to men with BD, however there is no evidence in comparison to women without BD or other major psychiatric illness. These comorbidities, along with various psychosocial factors, are known to affect the course of BD. METHODS: We aimed to systematically review the literature on cardiovascular, metabolic and endocrine comorbidities in women with BD in comparison to men with BD and control women. A comprehensive search of electronic databases including PubMed, PsycINFO, Embase, and SCOPUS was conducted, and a total of 61 identified studies were included in this review. RESULTS: Women with BD had higher rates of cardiovascular risk factors/mortality, diabetes mellitus II and thyroid disorders compared to women in the general population. In comparison to men with BD, women with BD had comparable cardiovascular risk but higher prevalence of metabolic and thyroid disorders. LIMITATIONS: Gender specific data was limited in multiple studies. CONCLUSIONS: Results present a need for gender-specific screening and interventions for various medical comorbidities in patients with BD.

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.

Short Term Second-Generation Antidepressant Monotherapy in Acute Depressive Episodes of Bipolar II Disorder: A Systematic Review and Meta-Analysis.

Purpose: Bipolar II disorder (BD-II) has limited evidence-based treatment guidelines. The aim of this systematic review and meta-analysis was to estimate the efficacy and safety of second-generation antidepressant (SGAD) monotherapy in acute BD-II depression. Methods: A literature search was conducted from the database inception through March 2021. Only randomized controlled trials (RCTs) were included. Outcome measures included: response rates, treatment-emergent affective switch (TEAS) rates, discontinuation due to side-effects, and all-cause discontinuation. Risk ratio (RR) was calculated using the Mantel-Haenszel random effects model. Results: 3301 studies were screened, and 15 articles were selected for full-text review. Five studies met the inclusion criteria: Four double-blind RCTs (n = 533) and one open-label RCT (n = 83) were included. Two double-blind RCTs [n = 223, SGAD = 110 (venlafaxine = 65, sertraline = 45), lithium/control = 113] were included for meta-analysis. The response rate for SGAD monotherapy compared to lithium monotherapy were similar (RR = 1.44, 95% CI 0.78, 2.66). The TEAS rate for SGAD monotherapy was not significantly different from lithium monotherapy (p = 0.76). The discontinuation rate due to side-effects for SGAD monotherapy was significantly lower than lithium monotherapy with a RR = 0.32, 95% CI 0.11, 0.96, p = 0.04 but all-cause discontinuation rates were similar in both groups. Conclusions: Limited data suggests short-term efficacy of venlafaxine and sertraline monotherapy in patients with acute BD-II depression with good side effect tolerability and without significantly increased switch rate. There is an urgent need for RCTs investigating the role of SGAD monotherapy in short and long-term among patients with BD-II.