A Novel Unsupervised Machine Learning Approach to Assess Postural Dynamics in Euthymic Bipolar Disorder.

Bipolar disorder (BD) is a mood disorder with different phases alternating between euthymia, manic or hypomanic episodes, and depressive episodes. While motor abnormalities are commonly seen during depressive or manic episodes, not much attention has been paid to postural abnormalities during periods of euthymia and their association with illness burden. We collected 24-hour posture data in 32 euthymic participants diagnosed with BD using a shirt-based wearable. We extracted a set of nine time-domain features, and performed unsupervised participant clustering. We investigated the association between posture variables and 12 clinical characteristics of illness burden. Based on their postural dynamics during the daytime, evening, or nighttime, participants clustered in three clusters. Higher illness burden was associated with lower postural variability, in particular during daytime. Participants who exhibited a mostly upright sitting/standing posture during the night with frequent nighttime postural transitions had the highest number of lifetime depressive episodes. Euthymic participants with BD exhibit postural abnormalities that are associated with illness burden, especially with the number of depressive episodes. Our results contribute to understanding the role of illness burden on posture changes and sleep consolidation in periods of euthymia.

Not missing at random: Missing data are associated with clinical status and trajectories in an electronic monitoring longitudinal study of bipolar disorder.

There is limited information on the association between participants' clinical status or trajectories and missing data in electronic monitoring studies of bipolar disorder (BD). We collected self-ratings scales and sensor data in 145 adults with BD. Using a new metric, Missing Data Ratio (MDR), we assessed missing self-rating data and sensor data monitoring activity and sleep. Missing data were lowest for participants in the midst of a depressive episode, intermediate for participants with subsyndromal symptoms, and highest for participants who were euthymic. Over a mean ± SD follow-up of 246 ± 181 days, missing data remained unchanged for participants whose clinical status did not change throughout the study (i.e., those who entered the study in a depressive episode and did not improve, or those who entered the study euthymic and remained euthymic). Conversely, when participants' clinical status changed during the study (e.g., those who entered the study euthymic and experienced the occurrence of a depressive episode), missing data for self-rating scales increased, but not for sensor data. Overall missing data were associated with participants' clinical status and its changes, suggesting that these are not missing at random.

The Use of Text Messaging as an Adjunct to Internet-Based Cognitive Behavioral Therapy for Major Depressive Disorder in Youth: Secondary Analysis.

BACKGROUND: As an established treatment for major depressive disorder (MDD), cognitive behavioral therapy (CBT) is now implemented and assessed in internet-based formats that, when combined with smartphone apps, enable secure text messaging. As an adjunct to such internet-based CBT (ICBT) approaches, text messaging has been associated with increased adherence and therapeutic alliance. OBJECTIVE: This study analyzed data from the intervention arm of a randomized control trial evaluating 24-week ICBT for MDD (intervention arm) against standard-care psychiatry (waitlist control). The aim of this secondary analysis was to assess MDD symptom improvement in relation to the frequency and content of text messages sent by ICBT participants to Navigator-Coaches during randomized control trial participation. Higher text frequency in general and in 3 conceptual categories (appreciating alliance, alliance building disclosures, and agreement confirmation) was hypothesized to predict larger MDD symptom improvement. METHODS: Participants were young adults (18-30 years) from the Centre for Addiction and Mental Health. The frequencies of categorized texts from 20 ICBT completers were analyzed with respect to MDD symptom improvement using linear regression models. Texts were coded by 2 independent coders and categorized using content analysis. MDD symptoms were measured using the Beck Depression Inventory-II (BDI-II). RESULTS: Participants sent an average of 136 text messages. Analyses indicated that BDI-II improvement was negatively associated with text messaging frequency in general (ß=-0.029, 95% CI -0.11 to 0.048) and in each of the 3 categories: appreciating alliance (ß=-0.096, 95% CI -0.80 to 0.61), alliance building disclosures (ß=-0.098, 95% CI -0.28 to 0.084), and agreement confirmation (ß=-0.076, 95% CI -0.40 to 0.25). Altogether, the effect of text messaging on BDI-II improvement was uniformly negative across statistical models. More text messaging appeared associated with less MDD symptom improvement. CONCLUSIONS: The hypothesized positive associations between conceptually categorized text messages and MDD symptom improvement were not supported in this study. Instead, more text messaging appeared to indicate less treatment benefit. Future studies with larger samples are needed to discern the optimal use of text messaging in ICBT approaches using adjunctive modes of communication. TRIAL REGISTRATION: Clinical Trials.gov NCT03406052; https://www.clinicaltrials.gov/ct2/show/NCT03406052.

Impact of DNA ligase 1 and IIIα interactions with APE1 and polß on the efficiency of base excision repair pathway at the downstream steps.

Base excision repair (BER) requires a tight coordination between the repair enzymes through protein-protein interactions and involves gap filling by DNA polymerase (pol) ß and subsequent nick sealing by DNA ligase (LIG) 1 or LIGIIIα at the downstream steps. Apurinic/apyrimidinic-endonuclease 1 (APE1), by its exonuclease activity, proofreads 3' mismatches incorporated by polß during BER. We previously reported that the interruptions in the functional interplay between polß and the BER ligases result in faulty repair events. Yet, how the protein interactions of LIG1 and LIGIIIα could affect the repair pathway coordination during nick sealing at the final steps remains unknown. Here, we demonstrate that LIGIIIα interacts more tightly with polß and APE1 than LIG1, and the N-terminal noncatalytic region of LIG1 as well as the catalytic core and BRCT domain of LIGIIIα mediate interactions with both proteins. Our results demonstrated less efficient nick sealing of polß nucleotide insertion products in the absence of LIGIIIα zinc-finger domain and LIG1 N-terminal region. Furthermore, we showed a coordination between APE1 and LIG1/LIGIIIα during the removal of 3' mismatches from the nick repair intermediate on which both BER ligases can seal noncanonical ends or gap repair intermediate leading to products of single deletion mutagenesis. Overall results demonstrate the importance of functional coordination from gap filling by polß coupled to nick sealing by LIG1/LIGIIIα in the presence of proofreading by APE1, which is mainly governed by protein-protein interactions and protein-DNA intermediate communications, to maintain repair efficiency at the downstream steps of the BER pathway.

Elevated senescence-associated secretory phenotype index in late-life bipolar disorder.

BACKGROUND: The senescence-associated secretory phenotype (SASP) is a biomarker index based on the profile of 22 blood proteins associated with cellular senescence. The SASP index has not been assessed in older patients with bipolar disorder (BD). We hypothesized that older adults with BD will have elevated cellular senescence burden as measured by the SASP index. METHODS: We measured the 22 SASP proteins to calculate the SASP index in 38 older patients with BD and 34 non-psychiatric comparison individuals (HC). RESULTS: The SASP index scores were significantly higher in BD than HC after controlling for age, sex, psychopathology, and physical health (F(1,8) = 5.37, p = 0.024, η2 = 0.08). SASP index scores were also associated with higher age, more severe depressive symptoms, and physical illness burden (p < 0.05) in the whole sample. LIMITATION: Cross-sectional study and small sample size. CONCLUSION: This is the first report of increased SASP index scores in older adults with BD. Our results suggest that dysregulation of age-related biological processes may contribute to more severe depressive symptoms and worse physical health in older adults with BD.

Prescribed psychostimulants and other pro-cognitive medications in bipolar disorder: A systematic review and meta-analysis of recurrence of manic symptoms.

OBJECTIVES: Clinicians are often hesitant to prescribe psychostimulants in bipolar disorder (BD) due to concerns of inducing (hypo)mania, despite limited published evidence on associations between prescribed psychostimulant use and recurrence of mood episodes in BD. The current systematic review and meta-analysis evaluated the emergence of (hypo)manic symptoms in patients with BD receiving prescribed psychostimulants or other pro-cognitive medications in euthymic or depressive states. METHODS: A systematic search was performed of MEDLINE, Embase, and PsychINFO from inception to April 5, 2023 and search of Clinicaltrials.gov and Clinicaltrialsregister.eu for unpublished data. References of included studies were hand-searched. Randomized trials and prospective longitudinal studies that evaluated psychostimulants and non-stimulant medications recommended for the treatment of ADHD by the Canadian ADHD practice guidelines were included. The review was reported in line with PRISMA guidelines and was preregistered on PROSPERO (CRD42022358588). RESULTS: After screening 414 unique records, we included 27 studies, of which five reported data that was quantitatively synthesized (n = 1653). The use of psychostimulants in BD was not associated with increased scores on the Young Mania Rating Scale in patients who were in a euthymic or depressed state (SMD IV -0.17; 95% CI, -0.40 to 0.06) compared to placebo. There was a high degree of study-level heterogeneity (I2 = 80%). A qualitative synthesis of studies revealed a limited risk of medication-induced manic symptoms. CONCLUSIONS: Our review provides preliminary evidence to suggest psychostimulants and non-stimulant ADHD medications have a limited risk of precipitating (hypo)mania symptoms. More extensive studies evaluating the safety and efficacy of these medications are warranted.

A History of Suicide Attempt Is Associated with Increased Sympathetic Activation in Bipolar Disorder.

OBJECTIVE: Suicide risk in bipolar disorder (BD) is estimated to be up to 20 times higher than in the general population. While there is a large body of evidence suggesting that increased sympathetic activation is associated with disease and death, there is a paucity of research on the role of autonomic nervous system (ANS) dysfunction in patients with BD who have attempted suicide. METHODS: Fifty-three participants with BD used a wearable device to assess the association between history of suicide attempt, current suicidal ideation, and ANS dysfunction, including measures of heart rate variability (HRV) and respiratory rate. Data were analyzed in a series of unadjusted and adjusted bivariate models of association controlling for relevant variables. RESULTS: A history of suicide attempts was significantly associated with an increase in respiratory rate (p < 0.01). These results remained significant after adjusting for age, BMI, and current mood state. There was no association between current suicidal ideation and heart rate or respiratory rate. In the frequency domain, HRV parameters suggest reduced parasympathetic (i.e., vagal) activity in participants with a history of suicide attempts and in those with current suicidality, suggesting changes in sympathicovagal balance in BD. CONCLUSIONS: Our results suggest that changes in the ANS in patients with BD and a history of suicide attempt are not restricted to pure vagally mediated HRV parameters, but rather signal a general ANS dysregulation. This ANS imbalance may be contributing to illness burden and cardiovascular disease. Further research on the relationship between ANS and suicidality in BD is needed.

Challenges in defining treatment-resistant mania in adults: A systematic review.

OBJECTIVES: To review the definitions of treatment-resistant mania (TRM) in the literature and propose criteria for an operationalized definition. METHODS: A systematic search of five databases (MEDLINE, EMBASE, PsychInfo, Cochrane Central, and CINAHL) and data extraction of eligible articles. RESULTS: In total, 47 articles addressing the concept of TRM were included, comprising 16 case reports, 11 case series, 3 randomized clinical trials, 8 open-label clinical trials, 1 experimental study, 7 narrative reviews, and 1 systematic review. While reviews discussed several challenges in defining TRM, definitions varied substantially based on different criteria for severity of mania, duration of mania, and use of specific therapeutic agents with minimal dosages and duration of treatment. Only a handful of the reviewed articles operationalized these criteria. CONCLUSION: While the concept of TRM has been discussed in the literature for over three decades, we could not find an agreed-upon operationalized definition based on specific criteria. We propose and discuss a possible definition that could be used by clinicians to guide their practice and by researchers to assess the prevalence of TRM and develop and test interventions targeting TRM.

Impact of polß/XRCC1 Interaction Variants on the Efficiency of Nick Sealing by DNA Ligase IIIα in the Base Excision Repair Pathway.

Base excision repair (BER) requires a coordination from gap filling by DNA polymerase (pol) ß to subsequent nick sealing by DNA ligase (LIG) IIIα at downstream steps of the repair pathway. X-ray cross-complementing protein 1 (XRCC1), a non-enzymatic scaffolding protein, forms repair complexes with polß and LIGIIIα. Yet, the impact of the polß mutations that affect XRCC1 interaction and protein stability on the repair pathway coordination during nick sealing by LIGIIIα remains unknown. Our results show that the polß colon cancer-associated variant T304 exhibits a reduced interaction with XRCC1 and the mutations in the interaction interface of V303 loop (L301R/V303R/V306R) and at the lysine residues (K206A/K244A) that prevent ubiquitin-mediated degradation of the protein exhibit a diminished repair protein complex formation with XRCC1. Furthermore, we demonstrate no significant effect on gap and nick DNA binding affinity of wild-type polß by these mutations. Finally, our results reveal that XRCC1 leads to an efficient channeling of nick repair products after nucleotide incorporation by polß variants to LIGIIIα, which is compromised by the L301R/V303R/V306R and K206A/K244A mutations. Overall, our findings provide insight into how the mutations in the polß/XRCC1 interface and the regions affecting protein stability could dictate accurate BER pathway coordination at the downstream steps involving nick sealing by LIGIIIα.

The Role of Daily Steps in the Treatment of Major Depressive Disorder: Secondary Analysis of a Randomized Controlled Trial of a 6-Month Internet-Based, Mindfulness-Based Cognitive Behavioral Therapy Intervention for Youth.

BACKGROUND: Current evidence supports physical activity (PA) as an adjunctive treatment for major depressive disorder (MDD). Few studies, however, have examined the relationship between objectively measured PA and MDD treatment outcomes using prospective data. OBJECTIVE: This study is a secondary analysis of data from a 24-week internet-based, mindfulness-based cognitive behavioral therapy program for MDD. The purpose of this analysis was twofold: (1) to examine average daily step counts in relation to MDD symptom improvement, and whether pain moderated this relationship; and (2) to examine whether changes in step activity (ie, step trajectories) during treatment were associated with baseline symptoms and symptom improvement. METHODS: Patients from the Centre for Addiction and Mental Health were part of a randomized controlled trial evaluating the effects of internet-based, mindfulness-based cognitive behavioral therapy for young adults (aged 18-30 years old) with MDD. Data from 20 participants who had completed the intervention were analyzed. PA, in the form of objectively measured steps, was measured using the Fitbit-HR Charge 2 (Fitbit Inc), and self-reported depression severity was measured with the Beck Depression Inventory-II (BDI-II). Linear regression analysis was used to test PA's relationship with depression improvement and the moderating effect of pain severity and pain interference. Growth curve and multivariable regression models were used to test longitudinal associations. RESULTS: Participants walked an average of 8269 steps per day, and each additional +1000-step difference between participants was significantly associated with a 2.66-point greater improvement (reduction) in BDI-II, controlling for anxiety, pain interference, and adherence to Fitbit monitoring (P=.02). Pain severity appeared to moderate (reduce) the positive effect of average daily steps on BDI-II improvement (P=.03). Higher baseline depression and anxiety symptoms predicted less positive step trajectories throughout treatment (Ps≤.001), and more positive step trajectories early in the trial predicted greater MDD improvement at the end of the trial (Ps<.04). However, step trajectories across the full duration of the trial did not significantly predict MDD improvement (Ps=.40). CONCLUSIONS: This study used objective measurements to demonstrate positive associations between PA and depression improvement in the context of cognitive behavioral treatment. Pain appeared to moderate this relationship, and baseline symptoms of anxiety and depression predicted PA trajectories. The findings inform future interventions for major depression. Future research with larger samples should consider additional moderators of PA-related treatment success and the extent to which outcomes are related to PA change in multimodal interventions. TRIAL REGISTRATION: Clinical Trials.gov NCT03406052; https://www.clinicaltrials.gov/ct2/show/NCT03406052. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/11591.

Protocol for a systematic review and meta-analysis of coordinate-based network mapping of brain structure in bipolar disorder across the lifespan.

BACKGROUND: Studies about brain structure in bipolar disorder have reported conflicting findings. These findings may be explained by the high degree of heterogeneity within bipolar disorder, especially if structural differences are mapped to single brain regions rather than networks. AIMS: We aim to complete a systematic review and meta-analysis to identify brain networks underlying structural abnormalities observed on T1-weighted magnetic resonance imaging scans in bipolar disorder across the lifespan. We also aim to explore how these brain networks are affected by sociodemographic and clinical heterogeneity in bipolar disorder. METHOD: We will include case-control studies that focus on whole-brain analyses of structural differences between participants of any age with a standardised diagnosis of bipolar disorder and controls. The electronic databases Medline, PsycINFO and Web of Science will be searched. We will complete an activation likelihood estimation analysis and a novel coordinate-based network mapping approach to identify specific brain regions and brain circuits affected in bipolar disorder or relevant subgroups. Meta-regressions will examine the effect of sociodemographic and clinical variables on identified brain circuits. CONCLUSIONS: Findings from this systematic review and meta-analysis will enhance understanding of the pathophysiology of bipolar disorder. The results will identify brain circuitry implicated in bipolar disorder, and how they may relate to relevant sociodemographic and clinical variables across the lifespan.

Effect of a pescetarian and vegan diet on fatty acid composition in blood and spermatozoa in young healthy men.

INTRODUCTION: There is a growing interest in vegetarian and vegan diets, but both can potentially affect tissue fatty acids (FA) composition. We aimed to evaluate the effect of vegetarian diets on plasma, erythrocytes, and sperm n-3 polyunsaturated fatty acids (n-3 PUFA) status in healthy young men. METHODS: Four groups were studied: i) men consuming a regular omnivore diet (OMV-1, n = 35); ii) men consuming an omnivore diet but excluding fish and seafood (OMV-2, n = 34); iii) men consuming a pescetarian diet (including dairy, eggs, fish, and seafood) (PESC, n = 36); and iv) men following a strict vegan diet (VEG, n = 35). Participants in each group should follow their diet for at least the previous 12 months. Diet evaluation used a structured validated food frequency questionnaire. FA composition was measured in plasma, erythrocyte phospho-lipids, and spermatozoa by gas-liquid chromatography, expressed as a mole percentage of the total FA content. RESULTS: Main findings showed higher alpha-linolenic fatty acid (ALA) and total n-3 PUFA dietary intake in the VEG group. In plasma, arachidonic and eicosapentaenoic acids were higher in OMV and PESC groups, whereas docosahexaenoic acid (DHA) level was lower in VEG. Higher ALA, but reduced DHA and total n-3 PUFA levels were found in erythrocytes and spermatozoa in the VEG group. CONCLUSION: Higher dietary ALA intake was found in pescetarians and vegan men. However, the higher ALA intake was not reflected in higher DHA content in the evaluated tissues. PUFA assessment, with particular emphasis in DHA, are necessary to improve PUFA status in vegan men.

Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial.

BACKGROUND: Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone. AIMS: To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone). METHOD: In a 4-week, three-arm, 'double dummy' trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure. RESULTS: This trial will advance the understanding of psilocybin's mechanism of antidepressant action. CONCLUSIONS: This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.

Associations between peripheral inflammation and clinical phenotypes of bipolar depression in a lower-middle income country.

OBJECTIVE: There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan. METHODS: The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or < 3 mg/L and log10CRP) and clinical and demographic features of interest and symptoms of depression. Baseline clinical trial data was used to extract clinical and demographic features and symptoms of depression were assessed using the 24-item Hamilton Depression Rating Scale. RESULTS: The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation. CONCLUSIONS: Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.

Predictors of adherence to electronic self-monitoring in patients with bipolar disorder: a contactless study using Growth Mixture Models.

BACKGROUND: Several studies have reported on the feasibility of electronic (e-)monitoring using computers or smartphones in patients with mental disorders, including bipolar disorder (BD). While studies on e-monitoring have examined the role of demographic factors, such as age, gender, or socioeconomic status and use of health apps, to our knowledge, no study has examined clinical characteristics that might impact adherence with e-monitoring in patients with BD. We analyzed adherence to e-monitoring in patients with BD who participated in an ongoing e-monitoring study and evaluated whether demographic and clinical factors would predict adherence. METHODS: Eighty-seven participants with BD in different phases of the illness were included. Patterns of adherence for wearable use, daily and weekly self-rating scales over 15 months were analyzed to identify adherence trajectories using growth mixture models (GMM). Multinomial logistic regression models were fitted to compute the effects of predictors on GMM classes. RESULTS: Overall adherence rates were 79.5% for the wearable; 78.5% for weekly self-ratings; and 74.6% for daily self-ratings. GMM identified three latent class subgroups: participants with (i) perfect; (ii) good; and (iii) poor adherence. On average, 34.4% of participants showed "perfect" adherence; 37.1% showed "good" adherence; and 28.2% showed poor adherence to all three measures. Women, participants with a history of suicide attempt, and those with a history of inpatient admission were more likely to belong to the group with perfect adherence. CONCLUSIONS: Participants with higher illness burden (e.g., history of admission to hospital, history of suicide attempts) have higher adherence rates to e-monitoring. They might see e-monitoring as a tool for better documenting symptom change and better managing their illness, thus motivating their engagement.

A systematic review on the effectiveness of dialectical behavior therapy for improving mood symptoms in bipolar disorders.

BACKGROUND: Evidence-based psychotherapies available to treat patients with bipolar disorders (BD) are limited. Dialectical behavior therapy (DBT) may target several common symptoms of BD. We conducted a systematic review on the efficacy of DBT for mood symptoms in patients with BD. The systematic search used key words related to DBT and BD in Medline, Embase, PsycInfo, CINAHL, and Cochrane Library databases from 1980 to April 1st, 2022. We included studies that enrolled patients with a BD I or II diagnosis (DSM or ICD), age 12 and older who received a DBT-based intervention. Studies reviewed were clinical trials including observational studies that reported at least one outcome related to BD mood symptoms or severity. We did not exclude based upon psychiatric or physical co-morbidity. RESULTS: We screened 848 abstracts and reviewed 28 full texts; 10 publications with 11 studies met our pre-determined eligibility criteria. All but one were feasibility pilot studies and most included participants in all mood states except for mania. The studies provided preliminary evidence suggesting these interventions may be effective for improving several core symptoms of BD. Overall, all the studies consistently supported that DBT-based interventions are feasible and acceptable for patients with BD. CONCLUSION: DBT may be an effective treatment for BD; however, the confidence in this conclusion is limited by the small sample sizes, heterogeneity, and high risk of bias in all published trials. Larger well-designed RCTs are now required to establish the effectiveness of DBT in BD.

A cross-sectional study of cognitive performance in bipolar disorder across the lifespan: the cog-BD project.

BACKGROUND: Neuroprogressive models of the trajectory of cognitive dysfunction in patients with bipolar disorder (BD) have been proposed. However, few studies have explored the relationships among clinical characteristics of BD, cognitive dysfunction, and aging. METHODS: We conducted a cross-sectional analysis in euthymic participants with the MATRICS Cognitive Consensus Battery, the Trail Making Test B, the Stroop Test, and the Wechsler Test of Adult Reading. Age- and gender-equated control participants without a mental disorder ['Healthy Controls' - HC)] were assessed similarly. We compared cognitive performance both globally and in seven domains in four groups: younger BD (age ⩽49 years; n = 70), older BD (age ⩾50 years; n = 48), younger HC (n = 153), and older HC (n = 44). We also compared the BD and HC groups using age as a continuous measure. We controlled for relevant covariates and applied a Bonferroni correction. RESULTS: Our results support both an early impairment ('early hit') model and an accelerated aging model: impairment in attention/vigilance, processing speed, and executive function/working memory were congruent with the accelerated aging hypothesis whereas impairment in verbal memory was congruent with an early impairment model. BD and HC participants exhibited similar age-related decline in reasoning/problem solving and visuospatial memory. There were no age- or diagnosis-related differences in social cognition. CONCLUSION: Our findings support that different cognitive domains are affected differently by BD and aging. Longitudinal studies are needed to explore trajectories of cognitive performance in BD across the lifespan.

A critical evaluation of dynamical systems models of bipolar disorder.

Bipolar disorder (BD) is a mood disorder involving recurring (hypo)manic and depressive episodes. The inherently temporal nature of BD has inspired its conceptualization using dynamical systems theory, which is a mathematical framework for understanding systems that evolve over time. In this paper, we provide a critical review of the dynamical systems models of BD. Owing to the heterogeneity of methodological and experimental designs in computational modeling, we designed a structured approach that parallels the appraisal of animal models by their face, predictive, and construct validity. This tool, the validity appraisal guide for computational models (VAG-CM), is not an absolute measure of validity, but rather a guide for a more objective appraisal of models in this review. We identified 26 studies published before November 18, 2021 that proposed generative dynamical systems models of time-varying signals in BD. Two raters independently applied the VAG-CM to the included studies, obtaining a mean Cohen's κ of 0.55 (95% CI [0.45, 0.64]) prior to establishing consensus ratings. Consensus VAG-CM ratings revealed three model/study clusters: data-driven models with face validity, theory-driven models with predictive validity, and theory-driven models lacking all forms of validity. We conclude that future modeling studies should employ a hybrid approach that first operationalizes BD features of interest using empirical data to achieve face validity, followed by explanations of those features using generative models with components that are homologous to physiological or psychological systems involved in BD, to achieve construct validity. Such models would be best developed alongside long-term prospective cohort studies involving a collection of multimodal time-series data. We also encourage future studies to extend, modify, and evaluate the VAG-CM approach for a wider breadth of computational modeling studies and psychiatric disorders.

Sex-specific associations between lifetime diagnosis of bipolar disorder and cardiovascular disease: A cross-sectional analysis of 257,673 participants from the UK Biobank.

BACKGROUND: Sex is seldom considered as a potential moderator of the impact of bipolar disorder (BD) on cardiovascular disease (CVD) risk. We aimed to characterize the sex-specific association of CVD and BD using data from the UK Biobank. METHODS: In a cross-sectional analysis, we compared the odds ratio between women and men with BD for seven CVD diagnoses (coronary artery disease, myocardial infarction, angina, atrial fibrillation, heart failure, stroke, and essential hypertension) and four cardiovascular biomarkers (arterial stiffness index, low-density lipoprotein, C-reactive protein, and HbA1c) in 293 participants with BD and 257,380 psychiatrically healthy controls in the UK Biobank. RESULTS: After adjusting for age, we found a two- to three-fold stronger association among women than among men between BD and rates of coronary artery disease, heart failure, and essential hypertension, with a significant sex-by-diagnosis interactions. The association remained significant after controlling for self-reported race, education, income, and smoking status. After controlling for potential confounders, there was no significant association between sex and any cardiovascular biomarkers. LIMITATIONS: These analyses could not disentangle effects of BD from its treatment. CONCLUSIONS: Our results underscore the importance of incorporating sex and mental illness in risk estimation tools for CVD, and improving screening for, and timely treatment of, CVD in those with BD. Future research is needed to better understand the contributors and mechanisms of sex differences related to CVD risk in BD.

Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions.

BACKGROUND: Subanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment. METHODS: Thirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report. RESULTS: Twenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37-0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η p2 = 0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36). CONCLUSION: A short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier NCT01945047.