Search

This corrects the article DOI: 10.1038/mp.2016.244.

This corrects the article DOI: 10.1038/mp.2016.244.

Objective: Sensory phenomena (SP) are aversive sensations driving repetitive behaviors in obsessive-compulsive disorder (OCD) and Tourette's disorder that are not well addressed by standard treatments. SP are related to the functioning of an interoceptive-sensorimotor circuit that may be modulated by the 5-HT 3 receptor antagonist ondansetron. The present study employed an experimental medicine approach to test the effects of 4 weeks of high-dose ondansetron compared to placebo on SP severity and brain connectivity in a cohort of individuals with OCD and/or Tourette's disorder., Methods: Of 51 participants who completed the study, 27 were assigned to receive 24 mg/day of ondansetron and 24 to receive placebo. Analyses examined changes in SP severity and, for participants with OCD, overall OCD severity from baseline to final visit. Functional MRI data were collected at both visits for analysis of intrinsic functional connectivity metrics characterizing global correlation (reflecting area "hubness") and local correlation (reflecting near-neighbor coherence)., Results: There were no significant differences between ondansetron and placebo in the reduction of SP or overall OCD severity in the full sample. In a subsample of participants with OCD taking concomitant serotonin reuptake inhibitors (SRIs), ondansetron was associated with a significant decrease in overall OCD severity and global connectivity of the medial sensorimotor cortex compared with placebo. Longitudinal reductions in SP severity were related to decreases in right sensorimotor hubness in both groups, and to brainstem local coherence only in participants taking ondansetron., Conclusions: There was no effect of high-dose ondansetron on SP. However, when used as an augmentation to SRIs, ondansetron reduced overall OCD severity, which may be related to changes in the "hubness" of the sensorimotor cortex. Ondansetron's ability to modulate brainstem connectivity may underlie its variable effectiveness in reducing SP., Competing Interests: Dr. Collins has served as a consultant for A. Stein Regulatory Affairs Consulting, Cronos Clinical Consulting Services, MedAvante-ProPhase, and Relmada Therapeutics. Dr. Coffey has received research support from Emalex, the New Venture Fund, and Zynerba; she has received honoraria from the American Academy of Child and Adolescent Psychiatry, Harvard Medical School/Psychiatry Academy, and Partners Healthcare; and she serves on advisory boards for Galen Mental Health, Skyland Trail, and the Tourette’s Association of America. Dr. Murrough has served as a consultant for Biohaven Pharmaceuticals, Clexio Biosciences, Cliniclabs, Compass Pathfinder, KetaMed, LivaNova, Merck, and Xenon Pharmaceuticals. Dr. Tobe has received grant support from Axial Therapeutics, F. Hoffmann-La Roche AG, Janssen Research & Development, and MapLight Therapeutics and has attended advisory boards for F. Hoffmann-La Roche. Dr. Iosifescu has served as a consultant for Alkermes, Allergan, Angelini, Autobahn, Axsome, Biogen, Boehringer Ingelheim, the Centers for Psychiatric Excellence, Clexio, Delix, Jazz, LivaNova, Lundbeck, Neumora, Otsuka, Precision Neuroscience, Relmada, Sage, and Sunovion; and he has received grant support (paid to his institutions) from Alkermes, AstraZeneca, BrainsWay, LiteCure, NeoSync, Otsuka, Roche, and Shire. Dr. Burdick has received honoraria from Breakthrough Discoveries for Thriving With Bipolar Disorder (BD-squared) and as a scientific advisory board member for Merck. Dr. Goodman receives royalties for OCDscales and Nview. The other authors report no financial relationships with commercial interests.

Background: Effective treatment of bipolar disorder (BD) requires prompt response to mood episodes. Preliminary studies suggest that predictions based on passive sensor data from personal digital devices can accurately detect mood episodes (e.g., between routine care appointments), but studies to date do not use methods designed for broad application. This study evaluated whether a novel, personalized machine learning approach, trained entirely on passive Fitbit data, with limited data filtering could accurately detect mood symptomatology in BD patients., Methods: We analyzed data from 54 adults with BD, who wore Fitbits and completed bi-weekly self-report measures for 9 months. We applied machine learning (ML) models to Fitbit data aggregated over two-week observation windows to detect occurrences of depressive and (hypo)manic symptomatology, which were defined as two-week windows with scores above established clinical cutoffs for the Patient Health Questionnaire-8 (PHQ-8) and Altman Self-Rating Mania Scale (ASRM) respectively., Results: As hypothesized, among several ML algorithms, Binary Mixed Model (BiMM) forest achieved the highest area under the receiver operating curve (ROC-AUC) in the validation process. In the testing set, the ROC-AUC was 86.0% for depression and 85.2% for (hypo)mania. Using optimized thresholds calculated with Youden's J statistic, predictive accuracy was 80.1% for depression (sensitivity of 71.2% and specificity of 85.6%) and 89.1% for (hypo)mania (sensitivity of 80.0% and specificity of 90.1%)., Conclusion: We achieved sound performance in detecting mood symptomatology in BD patients using methods designed for broad application. Findings expand upon evidence that Fitbit data can produce accurate mood symptomatology predictions. Additionally, to the best of our knowledge, this represents the first application of BiMM forest for mood symptomatology prediction. Overall, results move the field a step toward personalized algorithms suitable for the full population of patients, rather than only those with high compliance, access to specialized devices, or willingness to share invasive data., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Repetitive negative thinking (RNT) is a transdiagnostic process involving perseverative, unproductive, and uncontrollable thoughts. Although RNT may impede adaptive psychosocial functioning by prolonging negative mood states, strengthening cognitive biases, and preventing effective problem-solving, the extent to which RNT is associated with risk for poor psychosocial outcomes is unclear. Given that this has clear transdiagnostic treatment implications, the present study aimed to isolate the unique relationship of RNT with social functioning and life satisfaction in a mixed clinical and non-clinical sample., Methods: In 201 mid-to-later life adult participants (27 with primary diagnoses of bipolar disorder, 84 with major depressive disorder, and 90 healthy volunteers), we measured RNT, social functioning, life satisfaction, trait rumination, DSM-5 diagnoses, depressive symptoms, manic symptoms, cognitive control performance, and global cognitive functioning., Results: Linear regression models revealed that RNT, but not rumination, was significantly associated with poorer social functioning (β = 0.42 p < .001) and reduced life satisfaction (β = -0.42, p < .001) after controlling for clinical and cognitive covariates., Limitations: Limited demographic diversity, cross-sectional design, self-reporting of outcomes., Conclusions: Results suggest that RNT may confer risk for key psychosocial outcomes during middle to later adulthood, over and above the effects of clinical and cognitive variables and independent of diagnostic status. Findings lend support to the notion of RNT as a transdiagnostic process and suggest that RNT may be an important therapeutic target for adults with poor social functioning and/or reduced life satisfaction., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KEB receives honorarium from the Breakthrough Discoveries for thriving with Bipolar Disorder for her role as Scientific Director of the Integrated Network and as an advisory board member for Merck & Co. FMD receives financial support from the American Medical Association that is unrelated to the work presented in this manuscript. All other authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies., Methods: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning., Results: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning., Limitations: Cross-sectional design and loss of granularity due to harmonization., Conclusion: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD., Competing Interests: Declaration of competing interest FK reports no conflict of interest. Dr. Sajatovic has research grants from Otsuka, the International Society for Bipolar Disorders (ISBD), NIH, and the Centers for Disease Control and Prevention (CDC). She is a consultant to Otsuka, Janssen, Lundbeck, Teva, Neurelis and has received publication royalties from Springer Press, Johns Hopkins University Press, Oxford Press and UpToDate. Dr. Rej has salary support from the Fonds de Recherche Quebec - Sante, Grant from Mitacs, Steering Committee for Abbvie, Shareholder of Aifred Health. Dr. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. During the past five years, he has received research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He has also been an unpaid consultant to Myriad Neuroscience., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (β =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504., Competing Interests: Declaration of competing interest BS received research grant support from Mayo Clinic, National Network of Depression Centers (NNDC), and BD2 (Breakthrough Discoveries for thriving with Bipolar Disorder). SVP has received honoraria for consulting or research funds from the Canadian Institutes for Health Research, Ontario Brain Institute, and Aifred, Janssen, Merck, Mensante, Neonmind, Otsuka, Sage, and Takeda. JLVV has received a grant-in-kind for supplies and genotyping from Assurex Health. EDA has received research support from the following entities in the preceding 12 months: Alkermes, Boehringer-Ingelheim, Janssen, Karuna, Neurocrine Biosciences, Takeda, Teva, and the Vanguard Research Group. EDA also has served on advisory boards or consulted with Alkermes, Clinical Care Options, CMEology, CME Outfitters, Indivior, Karuna, and Teva. FSG has received research grant support from Janssen Therapeutics. WVB has received grant funding or research support from the NIH, AHRQ, National Science Foundation, the Watzinger Foundation, the Myocarditis Foundation, the Blue Gator Foundation, and the Mayo Foundation for Medical Education and Research. MAF has received Grant Support from Assurex Health, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and Mayo Foundation. CME/Travel/Honoraria or Consultant Carnot Laboratories, American Physician Institute. He also has financial interests in Chymia LLC. KEB has received grants from Janssen Pharmaceuticals and has received honorarium as an advisory board member for The Bipolar Roadmap Initiative (Milken Institute for Strategic Philanthropy) and Breakthrough Discoveries for thriving with Bipolar Disorder (BD2). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD., Methods: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials., Results: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias., Conclusions: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers., (© 2024 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: The suicide rate in bipolar disorder (BD) is among the highest across all psychiatric disorders. Identifying modifiable variables that relate to suicidal thoughts and behaviors (STBs) in BD may inform prevention strategies. Social connectedness is a modifiable variable found to relate to STBs in the general population, but differences exist across subgroups of the general population and findings specifically in BD have been equivocal. We aimed to clarify how perceived social connectedness relates to STBs in BD., Method: 146 adults (86 BD, 60 healthy controls) completed clinical interviews (Hamilton Depression Rating Scale; Structured Clinical Interview for DSM-5) and self-report measures of loneliness (UCLA Loneliness Scale) and social support (Interpersonal Support Evaluation List). Analyses explored differences in indicators of social connectedness (loneliness and social support) between BD participants and healthy controls, and explored relationships between STBs (lifetime suicide attempts and current suicidal ideation) and indicators of social connectedness in BD participants., Results: BD participants reported significantly higher loneliness and lower social support than healthy controls. In BD participants, perceived social support was significantly related to both ever having attempted suicide and number of lifetime attempts. Interestingly, perceived loneliness, but not social support, was significantly associated with current suicidal ideation., Conclusions: Findings expand the evidence base supporting a relationship between perceived social connectedness and STBs in BD. They suggest that this modifiable variable could be a fruitful treatment target for preventing STBs in BD., (© 2024. The Author(s).)

Purpose of Review: Symptoms of depression and cognitive dysfunction are commonly reported in mastocytosis. The aims of this review paper are to summarize the current literature on cognitive dysfunction and depressive symptoms, elucidate some of the mechanistic pathways underlying depressive symptoms in mastocytosis, identify gaps in the literature, and offer guidance for future research in this area., Recent Findings: The study of cognition and depression in mastocytosis is in its infancy and the methodological flaws of the current literature limit interpretability. There is preliminary evidence that some individuals with mastocytosis might experience mild deficits in memory. On average, depression symptom scores fell within the mild to moderate or sub-syndromal range. Regrettably, only one study utilized a standardized diagnostic instrument to assess major depressive disorder. The authors' tendency to inaccurately equate depressive symptoms with a diagnosis of major depressive disorder presents a notable issue. The prevalence of cognitive deficits and depression appears to be similar to other chronic illnesses. Future work needs to better characterize cognition and characterize "depression" in this population., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia., Methods: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns., Results: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort., Conclusions: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (P hypergeometric  = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD., (© 2023. The Author(s).)

Bipolar disorder is associated with cognitive deficits, which persist across mood states and affect functional outcomes. This article provides an overview of recent progress in measuring cognition in bipolar disorder and its implications for both research and clinical practice. The authors summarize work conducted over the past decade that has helped guide researchers and clinicians in the appropriate measurement of cognitive functioning in bipolar disorder, the design of research studies targeting this domain for treatment, and the implementation of screening and psychoeducational tools in the clinic. Much of this work was conducted by the International Society for Bipolar Disorders Targeting Cognition Task Force. Here, the authors also highlight the need for clinicians to be informed about this aspect of illness and to be equipped with the necessary information to assess, track, and intervene on cognitive problems when appropriate. Finally, the article identifies gaps in the literature and suggests potential future directions for research in this area., Competing Interests: Dr. Burdick reports receiving an honorarium from Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2) for her role as Scientific Director for the Integrated Network. Dr. Nicoloro-SantaBarbara reports receiving consulting fees from Cogent Biosciences. Dr. Miskowiak reports receiving consultancy fees for her advisory work for Gedeon Richter, Janssen, Angelini Pharma, and Lundbeck. Dr. Goldstein acknowledges his position as RBC Investments Chair in Children’s Mental Health and Developmental Psychopathology at The Centre for Addiction and Mental Health (CAMH), a joint Hospital-University Chair between the University of Toronto, CAMH, and the CAMH Foundation. The other authors report no financial relationships with commercial interests., (Copyright © 2023 by the American Psychiatric Association.)

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD., Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors., Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning., Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719 , with permission from John Wiley and Sons. Copyright © 2022., (Copyright © 2023 by the American Psychiatric Association.)

Introduction: Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil ® ), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients., Methods: Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8., Results: No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group., Discussion: Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01965925., Competing Interests: KEB serves on the steering committee for the non-profit Breakthrough Discoveries for thriving with Bipolar Disorder (BD^2) and receives grant funding and honoraria in this capacity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lipschitz, Perez-Rodriguez, Majd, Larsen, Locascio, Pike, Shanahan and Burdick.)

Purpose of the Review: Digital mental health interventions (DMHIs) are an effective and accessible means of addressing the unprecedented levels of mental illness worldwide. Currently, however, patient engagement with DMHIs in real-world settings is often insufficient to see clinical benefit. In order to realize the potential of DMHIs, there is a need to better understand what drives patient engagement., Recent Findings: We discuss takeaways from the existing literature related to patient engagement with DMHIs and highlight gaps to be addressed through further research. Findings suggest that engagement is influenced by patient-, intervention- and systems-level factors. At the patient-level, variables such as sex, education, personality traits, race, ethnicity, age and symptom severity appear to be associated with engagement. At the intervention-level, integrating human support, gamification, financial incentives and persuasive technology features may improve engagement. Finally, although systems-level factors have not been widely explored, the existing evidence suggests that achieving engagement will require addressing organizational and social barriers and drawing on the field of implementation science., Summary: Future research clarifying the patient-, intervention- and systems-level factors that drive engagement will be essential. Additionally, to facilitate improved understanding of DMHI engagement, we propose the following: (a) widespread adoption of a minimum necessary 5-element engagement reporting framework; (b) broader application of alternative clinical trial designs; and (c) directed efforts to build upon an initial parsimonious conceptual model of DMHI engagement., Competing Interests: Conflicts of Interest Jessica M. Lipschitz declares that she has no conflicts of interest. Chelsea K. Pike declares that she has no conflicts of interest. Timothy P. Hogan declares that he has no conflicts of interest. Susan A. Murphy declares that she has no conflicts of interest. Katherine E. Burdick declares that she has no conflicts of interest.

Objective: Convergent data point to an exaggerated negativity bias in bipolar disorder (BD), and little is known about whether people with BD experience the 'positivity effect' with increasing age., Method: This is a cross sectional study of 202 participants with BD aged 18-65, and a sample (n = 53) of healthy controls (HCs). Participants completed the CANTAB Emotion Recognition Task (ERT). Using analysis of variance, we tested for a main effect of age, diagnosis, and an interaction of age x diagnosis on both negative and positive conditions., Results: We observed increased accuracy in identifying positive stimuli in the HC sample as a function of increasing age, a pattern that was not seen in participants with BD. Specifically, there was a significant diagnosis by age cohort interaction on ERT performance that was specific to the identification of happiness, where the Later Adulthood cohort of HCs was more accurate when identifying happy faces relative to the same cohort of BD patients., Conclusion: Later life looks different for people with BD. With an aging population globally, gaining a clearer picture of the effects of recurrent mood dysregulation on the brain will be critical in guiding efforts to effectively optimize outcomes in older adults with BD., Competing Interests: Declaration of Competing Interest The authors have no conflicts to report., (Copyright © 2023. Published by Elsevier B.V.)

Despite a growing body of research, there is yet to be a cohesive synthesis of studies examining differences in brain morphology according to patterns of cognitive function among both schizophrenia-spectrum disorder (SSD) and bipolar disorder (BD) individuals. We aimed to provide a systematic overview of the morphological differences-inclusive of grey and white matter volume, cortical thickness, and cortical surface area-between cognitive subgroups of these disorders and healthy controls, and between cognitive subgroups themselves. An initial search of PubMed and Scopus databases resulted in 1486 articles of which 20 met inclusion criteria and were reviewed in detail. The findings of this review do not provide strong evidence that cognitive subgroups of SSD or BD map to unique patterns of brain morphology. There is preliminary evidence to suggest that reductions in cortical thickness may be more strongly associated with cognitive impairment, whilst volumetric deficits may be largely tied to the presence of disease., (© 2022. The Author(s).)

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes 1 . This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10 -6 ). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations., (© 2023. The Author(s).)

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD., Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors., Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning., Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness., (© 2022 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: While many digital mental health interventions (DMHIs) have been found to be efficacious, patient engagement with DMHIs has increasingly emerged as a concern for implementation in real-world clinical settings. To address engagement, we must first understand what standard engagement levels are in the context of randomized controlled trials (RCTs) and how these compare with other treatments., Objective: This scoping review aims to examine the state of reporting on intervention engagement in RCTs of mobile app-based interventions intended to treat symptoms of depression. We sought to identify what engagement metrics are and are not routinely reported as well as what the metrics that are reported reflect about standard engagement levels., Methods: We conducted a systematic search of 7 databases to identify studies meeting our eligibility criteria, namely, RCTs that evaluated use of a mobile app-based intervention in adults, for which depressive symptoms were a primary outcome of interest. We then extracted 2 kinds of information from each article: intervention details and indices of DMHI engagement. A 5-element framework of minimum necessary DMHI engagement reporting was derived by our team and guided our data extraction. This framework included (1) recommended app use as communicated to participants at enrollment and, when reported, app adherence criteria; (2) rate of intervention uptake among those assigned to the intervention; (3) level of app use metrics reported, specifically number of uses and time spent using the app; (4) duration of app use metrics (ie, weekly use patterns); and (5) number of intervention completers., Results: Database searching yielded 2083 unique records. Of these, 22 studies were eligible for inclusion. Only 64% (14/22) of studies included in this review specified rate of intervention uptake. Level of use metrics was only reported in 59% (13/22) of the studies reviewed. Approximately one-quarter of the studies (5/22, 23%) reported duration of use metrics. Only half (11/22, 50%) of the studies reported the number of participants who completed the app-based components of the intervention as intended or other metrics related to completion. Findings in those studies reporting metrics related to intervention completion indicated that between 14.4% and 93.0% of participants randomized to a DMHI condition completed the intervention as intended or according to a specified adherence criteria., Conclusions: Findings suggest that engagement was underreported and widely varied. It was not uncommon to see completion rates at or below 50% (11/22) of those participants randomized to a treatment condition or to simply see completion rates not reported at all. This variability in reporting suggests a failure to establish sufficient reporting standards and limits the conclusions that can be drawn about level of engagement with DMHIs. Based on these findings, the 5-element framework applied in this review may be useful as a minimum necessary standard for DMHI engagement reporting., (©Jessica M Lipschitz, Rachel Van Boxtel, John Torous, Joseph Firth, Julia G Lebovitz, Katherine E Burdick, Timothy P Hogan. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 14.10.2022.)

Objective: Harmonizing different depression severity scales often requires creation of categorical variables that may decrease the sensitivity of the measure. Our aim was to compare the associations between categorical and continuous and harmonized measures of depression and global functioning in a large dataset of older age patients with bipolar disorder (OABD)., Method: In the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) the 17-item Hamilton Depression scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) or the Center for Epidemiological Studies Depression scales (CES-D) was used to assess current depressive symptoms, while the Global Assessment of Functioning (GAF) assessed functional status. Data were harmonized from 8 OABD studies (n = 582). In each subsample, the relationship of depression severity as a continuous and categorical measure was compared to GAF. In the total sample, harmonized ordinal depression categories were compared to GAF., Results: Effect size and variance explained by the model for the categorical measure in the total sample was higher than both the categorical and continuous measure in the CES-D subsample, higher than the categorical but lower than the continuous measure in the HAM-D subsample, and lower than both the categorical and continuous measures in the MADRS subsample., Limitations: All included studies have different inclusion and exclusion criteria, study designs, and differ in aspects of sociodemographic variables., Conclusions: Associations were only slightly larger for the continuous vs categorical measures of depression scales. Harmonizing different depression scales into ordinal categories for analyses is feasible without losing statistical power., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Cognitive functioning in bipolar disorder is heterogeneous with evidence for multiple subgroups. However, cognitive subgroup change patterns over time remains unknown. While prior work suggests minimal differences in cognitive functioning patterns over time between those with bipolar disorder and controls, group-based analyses may obscure unique subgroup-based changes., Material and Methods: Participants diagnosed with bipolar disorder (I, II, NOS; n = 568) and unaffected controls (n = 234) completed baseline, one- and five-year neuropsychological assessments. Data reduction techniques were used to limit the number of neuropsychological variables. Bipolar disorder participant baseline neuropsychological data were entered into hierarchical cluster analyses and resultant clusters were entered in multilevel models, which tested for differences in baseline and longitudinal cognitive changes in cognition among the cluster groups and with controls., Results: Results were consistent with bipolar disorder participants forming three subgroups with high (n = 209), mid (n = 259), and low (n = 100) cognition. These groups were associated with unique clinical characteristics. Multilevel models demonstrated that over a five-year period, the low group improved, relative to the high and mid groups, and with controls, in auditory memory. Over the five-year period, the mid group, in comparison with the high group, improved in visual memory; additionally, the high group remained stable, in comparison with a slight decline in the control group, in inhibitory control., Conclusion: These results demonstrate that cognition-based subgroups of bipolar disorder participants have minimal differences in their longitudinal course in relation to each other and with unaffected controls., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions., Methods: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist., Results: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred., Conclusions: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests., (© 2022 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Bipolar disorder (BD) is a complex and dynamic condition with a typical onset in late adolescence or early adulthood followed by an episodic course with intervening periods of subthreshold symptoms or euthymia. It is complicated by the accumulation of comorbid medical and psychiatric disorders. The etiology of BD remains unknown and no reliable biological markers have yet been identified. This is likely due to lack of comprehensive ontological framework and, most importantly, the fact that most studies have been based on small nonrepresentative clinical samples with cross-sectional designs. We propose to establish large, global longitudinal cohorts of BD studied consistently in a multidimensional and multidisciplinary manner to determine etiology and help improve treatment. Herein we propose collection of a broad range of data that reflect the heterogenic phenotypic manifestations of BD that include dimensional and categorical measures of mood, neurocognitive, personality, behavior, sleep and circadian, life-story, and outcomes domains. In combination with genetic and biological information such an approach promotes the integrating and harmonizing of data within and across current ontology systems while supporting a paradigm shift that will facilitate discovery and become the basis for novel hypotheses., (© 2022 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Objectives: Increasing evidence supports a bidirectional relationship between major depressive disorder (MDD) and obesity, but the role of visceral adipose tissue (VAT) as a measure of obesity in relation to MDD is not well understood. Here we review literature investigating the link between MDD and VAT in terms of biomarkers, sex differences, and aging., Methods: PubMed, EMBASE, PsycINFO, and CINAHL searches were conducted on December 11, 2020. No date or language limits were imposed. Major concepts searched were Depressive Disorder linked with Adipose Tissue, White, Hypothalmo-Hypophyseal System, and Pituitary-Adrenal System in addition to keywords. A final set of 32 items meeting criteria for inclusion., Results: Converging biological evidence suggests a significant bidirectional relationship between VAT and MDD across the lifespan. In adulthood, greater VAT was associated with increased risk for depression, especially in vulnerable groups such as individuals who are overweight/obese, postmenopausal women, and individuals with comorbid medical or psychiatric illness. In older adults, sarcopenia had an impact on the relationship between abnormal VAT and risk of depression. Additionally, sex differences emerged as a potential factor affecting the strength of the association between VAT and depression., Conclusions: Elucidating the pathophysiological mechanisms associated with increased rates of depression in obese individuals will be crucial for developing specific treatment strategies that seek to improve outcomes in individuals with comorbid depression and obesity. Moreover, identifying age- and sex-specific risk factors may contribute to a more personalized medicine approach, thereby improving the quality of clinical care., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)