Risk factors, prevention and treatment of weight gain associated with the use of antidepressants and antipsychotics: a state-of-the-art clinical review.

INTRODUCTION: People with severe mental illness have poor cardiometabolic health. Commonly used antidepressants and antipsychotics frequently lead to weight gain, which may further contribute to adverse cardiovascular outcomes. AREAS COVERED: We searched MEDLINE up to April 2023 for umbrella reviews, (network-)meta-analyses, trials and cohort studies on risk factors, prevention and treatment strategies of weight gain associated with antidepressants/antipsychotics. We developed 10 clinical recommendations. EXPERT OPINION: To prevent, manage, and treat antidepressant/antipsychotic-related weight gain, we recommend i) assessing risk factors for obesity before treatment, ii) monitoring metabolic health at baseline and regularly during follow-up, iii) offering lifestyle interventions including regular exercise and healthy diet based on patient preference to optimize motivation, iv) considering first-line psychotherapy for mild-moderate depression and anxiety disorders, v) choosing medications based on medications' and patient's weight gain risk, vi) choosing medications based on acute vs long-term treatment, vii) using effective, tolerated medications, viii) switching to less weight-inducing antipsychotics/antidepressants where possible, ix) using early weight gain as a predictor of further weight gain to inform the timing of intervention/switch options, and x) considering adding metformin or glucagon-like peptide-1 receptor agonists, or topiramate (second-line due to potential adverse cognitive effects) to antipsychotics, or aripiprazole to clozapine or olanzapine.

Prediction of medical admissions after psychiatric inpatient hospitalization in bipolar disorder: a retrospective cohort study.

Objective: Bipolar Disorder (BD) is a severe mental illness associated with high rates of general medical comorbidity, reduced life expectancy, and premature mortality. Although BD has been associated with high medical hospitalization, the factors that contribute to this risk remain largely unexplored. We used baseline medical and psychiatric records to develop a supervised machine learning model to predict general medical admissions after discharge from psychiatric hospitalization. Methods: In this retrospective three-year cohort study of 71 patients diagnosed with BD (mean age=52.19 years, females=56.33%), lasso regression models combining medical and psychiatric records, as well as those using them separately, were fitted and their predictive power was estimated using a leave-one-out cross-validation procedure. Results: The proportion of medical admissions in patients with BD was higher compared with age- and sex-matched hospitalizations in the same region (25.4% vs. 8.48%). The lasso model fairly accurately predicted the outcome (area under the curve [AUC]=69.5%, 95%C.I.=55-84.1; sensitivity=61.1%, specificity=75.5%, balanced accuracy=68.3%). Notably, pre-existing cardiovascular, neurological, or osteomuscular diseases collectively accounted for more than 90% of the influence on the model. The accuracy of the model based on medical records was slightly inferior (AUC=68.7%, 95%C.I. = 54.6-82.9), while that of the model based on psychiatric records only was below chance (AUC=61.8%, 95%C.I.=46.2-77.4). Conclusion: Our findings support the need to monitor medical comorbidities during clinical decision-making to tailor and implement effective preventive measures in people with BD. Further research with larger sample sizes and prospective cohorts is warranted to replicate these findings and validate the predictive model.

Association between exposure to antidepressants and stimulants and age at onset of mania or psychosis: A retrospective population-based cohort study.

This study investigated the impact of prior antidepressant and stimulant exposure on the age at onset (AAO) of first episode mania (FEM) or psychosis (FEP). Patients with FEP and FEM born after 1985 in Olmsted County, Minnesota, were identified using the Rochester Epidemiology Project. Duration and peak dose of antidepressant and stimulant exposure were quantified by review of the electronic health record. Peak doses were converted to defined daily dose (DDD), and cumulative exposure was calculated as DDD multiplied by treatment duration. Linear models were used to assess relationships between AAO with any exposures, and cumulative antidepressant and stimulant exposures. A total of 190 FEM/FEP patients (mean AAO=20.8 ± 3.7 years) were included. There was no significant difference in AAO with vs. without exposure to antidepressants or stimulants. Cumulative antidepressant exposure correlated with a later AAO in overall sample (r = 0.28, p < 0.001), and in FEP (r = 0.33, p < 0.001). No significant correlation emerged between cumulative stimulant exposure and AAO. Multivariable modeling confirmed that cumulative antidepressant exposure (Estimate=2.42, 95 %CI=1.66-3.18, p < 0.001), but not cumulative stimulant exposure (Estimate=-0.04, 95 %CI=-1.10-1.02, p = 0.94), was associated with later AAO. Antidepressant and stimulant exposures were not associated with earlier AAO. However, cumulative antidepressant exposure was associated with later AAO. Limitations include retrospective design and relatively small sample size. Our findings may inform adolescent treatment recommendations when assessing risk for psychotropic-related adverse events. Further risk modeling investigations of antidepressants and stimulants with larger sample sizes are needed to explore the role of antidepressant and stimulant exposure in the trajectory leading to FEM/FEP.

Antidepressant-associated diagnostic change from major depressive to bipolar disorder.

BACKGROUND: Anticipating diagnostic change from major depressive (MDD) to bipolar disorder (BD) can support better prognosis and treatment, especially of depression but is challenging and reported research results are inconsistent. We therefore assessed clinical characteristics associated with diagnostic change from MDD to BD with antidepressant treatments. METHODS: We compared characteristics of 3212 initially MDD patients who became (hypo)manic during antidepressant treatment to those with stable MDD diagnoses as well as with cases of stable, spontaneous BD, using standard bivariate and multivariate statistics. RESULTS: Among MDD patients, 6.69% [CI: 5.85-7.61] changed to BD, mostly type II (BD2, 76.7%). BD-converters had higher rates of familial mood disorders (74.1% vs. 57.1%) or BD (33.7% vs. 21.0%) and 2.8-years younger onset than stable MDD patients. They also had more prior depressive recurrences/year, years-of-illness, mood-stabilizer treatment, divorces, fewer children, more suicide attempts and drug-abuse, and higher intake cyclothymia, YMRS and MDQ scores. Predictors independently associated with diagnostic conversion were: more familial BD, depressions/year, unemployment, cyclothymic temperament, suicidal ideation or acts, and fewer children. BD-converters vs. spontaneous BD cases had significantly more suicide attempts, BD2 diagnoses, and affected relatives. Converting to vs. spontaneous BD1 was associated with more ADHD, more suicidal ideation or behavior, MDI course, and younger onset; converting to vs. spontaneous BD2 had more episodes/year, unemployment, ADHD, substance abuse, suicidal ideation or attempts, and more relatives with BD. CONCLUSIONS: Few (6.69%) initially MDD subjects converted to BD, most (76.7%) to BD2. Independent predictive associations with diagnostic change included: familial BD, more depressions/year, unemployment, cyclothymic temperament, suicidal behavior and fewer children. Notably, several characteristics were stronger among those changing to BD during antidepressant treatment vs. others with spontaneous BD.

The functional connectivity of the right superior temporal gyrus is associated with psychological risk and resilience factors for suicidality.

INTRODUCTION: Suicide attempters show increased activation in the right superior temporal gyrus (rSTG). Here, we investigated the rSTG functional connectivity (FC) to identify a functional network involved in suicidality and its associations with psychological suicidality risk and resilience factors. METHODS: The resting state functional magnetic resonance imaging data of 151 healthy individuals from the Human Connectome Project Young Adult database were used to explore the FC of the rSTG with itself and with the rest of the brain. The correlation between the rSTG FC and loneliness and purpose in life scores was assessed with the NIH Toolbox. The effect of sex was also investigated. RESULTS: The rSTG had a positive FC with bilateral cortical and subcortical regions, including frontal, temporal, parietal, occipital, limbic, and cerebellar regions, and a negative FC with the medulla oblongata. The FC of the rSTG with itself and with the left central operculum were associated with loneliness scores. The within rSTG FC was also negatively correlated with purpose in life scores, although at a trend level. We did not find any effect of sex on FC and its associations with psychological factors. LIMITATIONS: The cross-sectional design, the limited age range, and the lack of measures of suicidality limit the generalizability of our findings. CONCLUSIONS: The rSTG functional network is associated with loneliness and purpose in life. Together with the existing literature on suicide, this supports the idea that the neural activity of rSTG may contribute to suicidality by modulating risk and resilience factors associated with suicidality.

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.

Current Status and Treatment of Rapid Cycling Bipolar Disorder.

BACKGROUND: Rapid cycling (RC) at least 4 recurrent episodes per year in bipolar disorder (BD) has been recognized since the 1970s. We now comment on our recent review of the topic and extensive RC analysis in a large clinical cohort, emphasizing therapeutics research. COMMENTS: Prevalence of RC-BD averages 36% for any year versus 22% in the preceding year. Rapid cycling is not a consistent feature over many years, although average long-term, annual recurrence rates are greater in RC-BD patients. Risk of RC may be somewhat greater among women and with older ages. It is also associated with cyclothymic temperament, prominent depression, and mood-switching with antidepressant treatment and is associated with increased suicidal risk. Treatment of individual episodes in RC-BD and effective long-term prevention remain inadequately studied, although antidepressant treatment can worsen RC. Some research supports treatment with aripiprazole, lamotrigine, and lithium, and interest in second-generation antipsychotics is emerging. All such options are used in various inadequately evaluated combinations. CONCLUSIONS: Rapid cycling is prevalent among BD patients but seems to vary in risk over time without evidence of progressive worsening. Treatment of acute episodes in RC-BD patients and effective long-term preventive management require much more intensive investigation.

Whole-brain structural and functional neuroimaging of individuals who attempted suicide and people who did not: A systematic review and exploratory coordinate-based meta-analysis.

Suicide is the cause of death of approximately 800,000 people a year. Despite the relevance of this behaviour, risk assessment tools rely on clinician experience and subjective ratings. Given that previous suicide attempts are the single strongest predictors of future attempts, we designed a systematic review and coordinate-based meta-analysis to demonstrate whether neuroimaging features can help distinguish individuals who attempted suicide from subjects who did not. Out of 5,659 publications from PubMed, Scopus, and Web of Science, we summarised 102 experiments and meta-analysed 23 of them. A cluster in the right superior temporal gyrus, a region implicated in emotional processing, might be functionally hyperactive in individuals who attempted suicide. No statistically significant differences in brain morphometry were evidenced. Furthermore, we used JuSpace to show that this cluster is enriched in 5-HT1A heteroreceptors in the general population. This exploratory meta-analysis provides a putative neural substrate linked to previous suicide attempts. Heterogeneity in the analytical techniques and weak or absent power analysis of the studies included in this review currently limit the applicability of the findings, the replication of which should be prioritised.

Network dysfunction of sadness facial expression processing and morphometry in euthymic bipolar disorder.

Facial emotion recognition (FER), including sadness, is altered in bipolar disorder (BD). However, the relationship between this impairment and the brain structure in BD is relatively unexplored. Furthermore, its association with clinical variables and with the subtypes of BD remains to be clarified. Twenty euthymic patients with BD type I (BD-I), 28 BD type II (BD-II), and 45 healthy controls completed a FER test and a 3D-T1-weighted magnetic resonance imaging. Gray matter volume (GMV) of the cortico-limbic regions implicated in emotional processing was estimated and their relationship with FER performance was investigated using network analysis. Patients with BD-I had worse total and sadness-related FER performance relative to the other groups. Total FER performance was significantly negatively associated with illness duration and positively associated with global functioning in patients with BD-I. Sadness-related FER performance was also significantly negatively associated with the number of previous manic episodes. Network analysis showed a reduced association of the GMV of the frontal-insular-occipital areas in patients with BD-I, with a greater edge strength between sadness-related FER performance and amygdala GMV relative to controls. Our results suggest that FER performance, particularly for facial sadness, may be distinctively impaired in patients with BD-I. The pattern of reduced interrelationship in the frontal-insular-occipital regions and a stronger positive relationship between facial sadness recognition and the amygdala GMV in BD may reflect altered cortical modulation of limbic structures that ultimately predisposes to emotional dysregulation. Future longitudinal studies investigating the effect of mood state on FER performance in BD are warranted.

Factors associated with suicide attempts in the antecedent illness trajectory of bipolar disorder and schizophrenia.

BACKGROUND: Factors associated with suicide attempts during the antecedent illness trajectory of bipolar disorder (BD) and schizophrenia (SZ) are poorly understood. METHODS: Utilizing the Rochester Epidemiology Project, individuals born after 1985 in Olmsted County, MN, presented with first episode mania (FEM) or psychosis (FEP), subsequently diagnosed with BD or SZ were identified. Patient demographics, suicidal ideation with plan, self-harm, suicide attempts, psychiatric hospitalizations, substance use, and childhood adversities were quantified using the electronic health record. Analyses pooled BD and SZ groups with a transdiagnostic approach given the two diseases were not yet differentiated. Factors associated with suicide attempts were examined using bivariate methods and multivariable logistic regression modeling. RESULTS: A total of 205 individuals with FEM or FEP (BD = 74, SZ = 131) were included. Suicide attempts were identified in 39 (19%) patients. Those with suicide attempts during antecedent illness trajectory were more likely to be female, victims of domestic violence or bullying behavior, and have higher rates of psychiatric hospitalizations, suicidal ideation with plan and/or self-harm, as well as alcohol, drug, and nicotine use before FEM/FEP onset. Based on multivariable logistic regression, three factors remained independently associated with suicidal attempts: psychiatric hospitalization (OR = 5.84, 95% CI 2.09-16.33, p < 0.001), self-harm (OR = 3.46, 95% CI 1.29-9.30, p = 0.014), and nicotine use (OR = 3.02, 95% CI 1.17-7.76, p = 0.022). CONCLUSION: Suicidal attempts were prevalent during the antecedents of BD and SZ and were associated with several risk factors before FEM/FEP. Their clinical recognition could contribute to improve early prediction and prevention of suicide during the antecedent illness trajectory of BD and SZ.

An Update on the Efficacy of Single and Serial Intravenous Ketamine Infusions and Esketamine for Bipolar Depression: A Systematic Review and Meta-Analysis.

Ketamine has shown rapid antidepressant and anti-suicidal effects in treatment-resistant depression (TRD) with single and serial intravenous (IV) infusions, but the effectiveness for depressive episodes of bipolar disorder is less clear. We conducted an updated systematic review and meta-analysis to appraise the current evidence on the efficacy and tolerability of ketamine/esketamine in bipolar depression. A search was conducted to identify randomized controlled trials (RCTs) and non-randomized studies examining single or multiple infusions of ketamine or esketamine treatments. A total of 2657 articles were screened; 11 studies were included in the systematic review of which 7 studies were included in the meta-analysis (five non-randomized, N = 159; two RCTs, N = 33) with a mean age of 42.58 ± 13.1 years and 54.5% females. Pooled analysis from two RCTs showed a significant improvement in depression symptoms measured with MADRS after receiving a single infusion of ketamine (1-day WMD = -11.07; and 2 days WMD = -12.03). Non-randomized studies showed significant response (53%, p < 0.001) and remission rates (38%, p < 0.001) at the study endpoint. The response (54% vs. 55%) and remission (30% vs. 40%) rates for single versus serial ketamine infusion studies were similar. The affective switch rate in the included studies approximated 2.4%. Esketamine data for bipolar depression are limited, based on non-randomized, small sample-sized studies. Further studies with larger sample sizes are required to strengthen the evidence.

Early sexual or physical abuse in female and male mood disorder patients.

Early abuse has been associated with psychiatric morbidity but comparisons of bipolar (BD) and major depressive (MDD) disorder subjects with versus without early sexual or physical abuse are rare. Patients (n = 684) diagnosed with a DSM-5-TR major mood disorder were evaluated and followed for several years at mood disorder centers to compare details of history and clinical status in participants with versus without early sexual or physical abuse. Early history of sexual (16.2%) or physical abuse (11.9%) was prevalent; 5.15% reported both. Both types of abuse were much more prevalent with BD than MDD. Sexual abuse was associated with younger illness-onset and somewhat younger menarche in females; both abuse-types were associated with familial mood disorders, especially BD. Prospective, long-term illness episode-frequency, depressions or [hypo]manias/year and %-time [hypo]manic all were greater following sexual abuse but morbidity measures did not differ following physical abuse. Prevalence of suicidal behavior ranked: double (48.5%) > physical (32.1%) > sexual (30.3%) abuse, and with BD > MDD (OR = 2.31). Recall bias and not using psychometric instruments to define abuse severity or type may limit interpretation of findings. Early sexual (more than physical) abuse, led to greater morbidity and both abuses were strongly associated with familial mood disorders and greater suicidal risk, especially with double-abuse and BD diagnosis. We support a bilateral relationship between abuse and diagnosis of BD: abuse may facilitate early appearance of BD but also may result from the actions of abusive BD family members.

Racial differences in pathways to care preceding first episode mania or psychosis: a historical cohort prodromal study.

Background: There is evidence suggesting racial disparities in diagnosis and treatment in bipolar disorder (BD) and schizophrenia (SZ). The purpose of this study is to compare psychiatric diagnoses and psychotropic use preceding a first episode of mania (FEM) or psychosis (FEP) in racially diverse patients. Methods: Using a comprehensive medical records linkage system (Rochester Epidemiology Project, REP), we retrospectively identified individuals diagnosed with BD or SZ and a documented first episode of mania or psychosis. Illness trajectory before FEP/FEM were characterized as the time from first visit for a mental health complaint to incident case. Pathways to care and clinical events preceding FEP/FEM were compared based on subsequent incident case diagnosis (BD or SZ) and self-reported race (White vs. non-White). Results: A total of 205 (FEM = 74; FEP = 131) incident cases were identified in the REP. Duration of psychiatric antecedents was significantly shorter in non-White patients, compared to White patients (2.2 ± 4.3 vs. 7.4 ± 6.6 years; p < 0.001) with an older age at time of first visit for a mental health complaint (15.7 ± 6.3 vs. 11.1 ± 6.0 years; p = 0.005). There were no significant differences by race in FEM pathway to care or age of first seeking mental health. Overall non-White patients had lower rates of psychotropic use. Conclusion: These data are unable to ascertain reasons for shorter duration of psychiatric antecedents and later age of seeking care, and more broadly first age of initial symptom presentation. If symptoms are confirmed to be earlier than first time seeking care in both groups, it would be important to identify barriers that racial minorities face to access timely psychiatric care and optimize early intervention strategies.

Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies.

OBJECTIVE: To systematically assess credibility and certainty of associations between cannabis, cannabinoids, and cannabis based medicines and human health, from observational studies and randomised controlled trials (RCTs). DESIGN: Umbrella review. DATA SOURCES: PubMed, PsychInfo, Embase, up to 9 February 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews with meta-analyses of observational studies and RCTs that have reported on the efficacy and safety of cannabis, cannabinoids, or cannabis based medicines were included. Credibility was graded according to convincing, highly suggestive, suggestive, weak, or not significant (observational evidence), and by GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (RCTs). Quality was assessed with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). Sensitivity analyses were conducted. RESULTS: 101 meta-analyses were included (observational=50, RCTs=51) (AMSTAR 2 high 33, moderate 31, low 32, or critically low 5). From RCTs supported by high to moderate certainty, cannabis based medicines increased adverse events related to the central nervous system (equivalent odds ratio 2.84 (95% confidence interval 2.16 to 3.73)), psychological effects (3.07 (1.79 to 5.26)), and vision (3.00 (1.79 to 5.03)) in people with mixed conditions (GRADE=high), improved nausea/vomit, pain, spasticity, but increased psychiatric, gastrointestinal adverse events, and somnolence among others (GRADE=moderate). Cannabidiol improved 50% reduction of seizures (0.59 (0.38 to 0.92)) and seizure events (0.59 (0.36 to 0.96)) (GRADE=high), but increased pneumonia, gastrointestinal adverse events, and somnolence (GRADE=moderate). For chronic pain, cannabis based medicines or cannabinoids reduced pain by 30% (0.59 (0.37 to 0.93), GRADE=high), across different conditions (n=7), but increased psychological distress. For epilepsy, cannabidiol increased risk of diarrhoea (2.25 (1.33 to 3.81)), had no effect on sleep disruption (GRADE=high), reduced seizures across different populations and measures (n=7), improved global impression (n=2), quality of life, and increased risk of somnolence (GRADE=moderate). In the general population, cannabis worsened positive psychotic symptoms (5.21 (3.36 to 8.01)) and total psychiatric symptoms (7.49 (5.31 to 10.42)) (GRADE=high), negative psychotic symptoms, and cognition (n=11) (GRADE=moderate). In healthy people, cannabinoids improved pain threshold (0.74 (0.59 to 0.91)), unpleasantness (0.60 (0.41 to 0.88)) (GRADE=high). For inflammatory bowel disease, cannabinoids improved quality of life (0.34 (0.22 to 0.53) (GRADE=high). For multiple sclerosis, cannabinoids improved spasticity, pain, but increased risk of dizziness, dry mouth, nausea, somnolence (GRADE=moderate). For cancer, cannabinoids improved sleep disruption, but had gastrointestinal adverse events (n=2) (GRADE=moderate). Cannabis based medicines, cannabis, and cannabinoids resulted in poor tolerability across various conditions (GRADE=moderate). Evidence was convincing from observational studies (main and sensitivity analyses) in pregnant women, small for gestational age (1.61 (1.41 to 1.83)), low birth weight (1.43 (1.27 to 1.62)); in drivers, car crash (1.27 (1.21 to 1.34)); and in the general population, psychosis (1.71 (1.47 to 2.00)). Harmful effects were noted for additional neonatal outcomes, outcomes related to car crash, outcomes in the general population including psychotic symptoms, suicide attempt, depression, and mania, and impaired cognition in healthy cannabis users (all suggestive to highly suggestive). CONCLUSIONS: Convincing or converging evidence supports avoidance of cannabis during adolescence and early adulthood, in people prone to or with mental health disorders, in pregnancy and before and while driving. Cannabidiol is effective in people with epilepsy. Cannabis based medicines are effective in people with multiple sclerosis, chronic pain, inflammatory bowel disease, and in palliative medicine but not without adverse events. STUDY REGISTRATION: PROSPERO CRD42018093045. FUNDING: None.

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.

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.

Suicidal risk and protective factors in major affective disorders: A prospective cohort study of 4307 participants.

BACKGROUND: Suicidal behavior is strongly associated with major affective disorders, but there is a need to quantify and compare specific risk and protective factors in bipolar disorder (BD) and major depressive disorder (MDD). METHODS: In 4307 extensively evaluated major affective-disorder participants with BD (n = 1425) or MDD (n = 2882) diagnosed by current international criteria, we compared characteristics among those with versus without suicidal acts from illness-onset through 8.24 years of follow-up. RESULTS: Suicidal acts were identified in 11.4 % of participants; 25.9 % were violent and 6.92 % (0.79 % of all participants) were fatal. Associated risk factors included: diagnosis (BD > MDD), manic/psychotic features in first-episodes, family history of suicide or BD, separation/divorce, early abuse, young at illness-onset, female sex with BD, substance abuse, higher irritable, cyclothymic or dysthymic temperament ratings, greater long-term morbidity, and lower intake functional ratings. Protective factors included marriage, co-occurring anxiety disorder, higher ratings of hyperthymic temperament and depressive first episodes. Based on multivariable logistic regression, five factors remained significantly and independently associated with suicidal acts: BD diagnosis, more time depressed during prospective follow-up, younger at onset, lower functional status at intake, and women > men with BD. LIMITATIONS: Reported findings may or may not apply consistently in other cultures and locations. CONCLUSIONS: Suicidal acts including violent acts and suicides were more prevalent with BD than MDD. Of identified risk (n = 31) and protective factors (n = 4), several differed with diagnosis. Their clinical recognition should contribute to improved prediction and prevention of suicide in major affective disorders.

Characteristics of rapid cycling in 1261 bipolar disorder patients.

BACKGROUND: Rapid-cycling (RC; ≥ 4 episodes/year) in bipolar disorder (BD) has been recognized since the 1970s and associated with inferior treatment response. However, associations of single years of RC with overall cycling rate, long-term morbidity, and diagnostic subtypes are not clear. RESULTS: We compared descriptive and clinical characteristics in 1261 BD patients with/without RC, based on history and prospective follow-up for several years. RC in any previous year was identified in 9.36% of BD subjects (3.74% in BD1, 15.2% BD2), and somewhat more among women than men. RC-BD subjects had 3.21-fold greater average prospective annual rates of recurrence but not hospitalizations, had less difference in %-time-ill, received more mood-stabilizing treatments, and had greater suicidal risk, lacked familial psychiatric illnesses, had more cyclothymic temperament, were more likely to be married, had more siblings and children, experienced early sexual abuse, but were less likely to abuse drugs (not alcohol) or smoke. In multivariable regression modeling, older age, mood-switching with antidepressants, and BD2 > BD1 diagnosis, as well as more episodes/year were independently associated with RC. Notably, prospective mean recurrence rates were below 4/year in 79.5% of previously RC patients, and below 2/year in 48.1%. CONCLUSIONS: Lifetime risk of RC in BD was 9.36%, more likely in women, with older age, and in BD2 > BD1. With RC, recurrence rates were much higher, especially for depression with less effect on %-time ill, suggesting shorter episodes. Variable associations with unfavorable outcomes and prospective recurrence rates well below 4/year in most previously RC patients indicate that RC was not a sustained characteristic and probably was associated with use of antidepressants.

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.