Differential contributions of circadian clock genes to cell survival in bipolar disorder patient derived neuronal progenitor cells distinguishes lithium responders and non-responders.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past research identified that circadian rhythms in BD patient neurons are associated with lithium response (Li-R) or non-response (Li-NR). However, the underlying cellular mechanisms remain unknown. To study interactions among circadian clock genes and cell survival, and their role in BD and predicting lithium response, we tested selected genes (PER1, BMAL1 and REV-ERBα) and small molecule modulators of ROR/REV-ERB nuclear receptors in models of cell survival using mouse neurons and stem-cell derived neuronal progenitor cells (NPC) from BD patients and controls. In apoptosis assays using staurosporine (STS), lithium was neuroprotective. Knockdown of PER1, BMAL1 and REV-ERBα modified cell survival across models. In NPCs, reduced expression of PER1 and BMAL1 led to more extensive cell death in Li-NR vs. Li-R. Reduced REV-ERBα expression caused more extensive cell death in BD vs. control NPCs, without distinguishing Li-R and Li-NR. In IMHN, The REV-ERB agonist GSK4112 had strong effects on circadian rhythm amplitude, and was neuroprotective in mouse neurons and control NPCs, but not in BD NPCs. Expression of cell survival genes following STS and GSK4112 treatments revealed BD-associated, and Li-R associated differences in expression profiles. We conclude that the neuroprotective response to lithium is similar in NPCs from Li-R and Li-NR. However, knockdown of circadian clock genes or stimulation of REV-ERBs reveal distinct contributions to cell death in BD patient NPCs, some of which distinguish Li-R and Li-NR.

Greater social jetlag predicts poorer NIH Toolbox crystallized cognitive and academic performance in the Adolescent Brain Cognitive Development (ABCD) study.

Academic performance plays a crucial role in long-term educational attainment and occupational function. Chronotype refers to an individual's daily tendencies for times for waking, activity, and sleep. Social jetlag reflects the mismatch between an individual's chronotype and their social schedule. Because school typically starts early in the morning, later chronotype is often associated with daytime sleepiness, insufficient sleep, and poor academic performance. However, the relationship between academic performance, chronotype, and social jetlag has not been extensively examined in large samples like the Adolescent Brain Cognitive Development (ABCD) study. We hypothesized that greater social jetlag would predict poorer cognitive and academic performance. Year 2 (ages 11-14) cross-sectional data from the ABCD cohort (n = 6,890 adolescents) were used to evaluate academic performance (i.e. self-reported past year grades), NIH Toolbox cognitive performance measures, chronotype, and social jetlag from the Munich Chronotype Questionnaire. We found that later chronotype and greater social jetlag predicted poorer cognitive and academic performance with small effect sizes. Our findings emphasize the importance of individual differences in chronotype and social jetlag when designing class schedules, as aligning school activities with student optimal sleep-wake times may contribute to improved academic performance.

Feasibility and utility of mobile health interventions for depression and anxiety in rural populations: A scoping review.

Despite the potential of mobile health (mHealth) to address high rates of depression and anxiety in underserved rural communities, most mHealth interventions do not explicitly consider the realities of rural life. The aim of this scoping review is to identify and examine the available literature on mHealth interventions that consider the needs of rural populations in order to gauge their feasibility and utility for addressing depression and anxiety. Additionally, we provide an overview of rural users' perceptions about and preferences for mHealth-delivered mental health screening and intervention systems. Out of 169 articles identified, 16 met inclusion criteria. Studies were conducted across a wide range of countries, age groups, and rural subpopulations including individuals with bipolar disorder, anxiety, perinatal depression, PTSD, and chronic pain, as well as refugees, veterans, and transgender and LGBTQ+ individuals. All interventions were in the feasibility/acceptability testing stage for rural users. Identified strengths included their simplicity, accessibility, convenience, availability of support between sessions with providers, and remote access to a care team. Weaknesses included problems with charging phone batteries and exceeding data limits, privacy concerns, and general lack of comfort with app-based support. Based upon this review, we provide recommendations for future mHealth intervention development including the value of developer-user coproduction methods, the need to consider user variation in access to and comfort with smartphones, and potential data or connectivity limitations, mental health stigma, and confidentiality concerns in rural communities.

The relations between chronotype, stressful life events, and impulsivity in the Adolescent Brain Cognitive Development (ABCD) study.

Circadian rhythm disturbances, especially circadian phase delays are associated with impulsive behaviors and have been implicated in psychiatric disorders. Chronotype is a developmentally regulated proxy measure of circadian phase. Past studies have investigated the relationship between chronotype and trauma and found that trauma is associated with evening chronotypes, suggesting the course of chronotype development may be affected by adverse childhood experiences (ACEs). However, the relationships among chronotype, impulsivity and ACEs have largely been studied in a pairwise manner using small, cross-sectional cohorts. We hypothesized that in a cohort of high-risk youth, childhood trauma would be associated with later chronotype, and later chronotype would be associated with higher rates of impulsivity. We analyzed a cross-sectional sample (n = 966) from Year 2 of adolescents at high risk for psychiatric disorders from the ABCD study who were characterized for chronotype, stressful life events, and impulsivity. We used a hierarchical regression model to examine the relationship between chronotype, stressful life events, and impulsivity using the Munich Chronotype Questionnaire (MCTQ), the Life Events Scale, Urgency, Premeditation, Perseverance and Sensation Seeking (UPPS) Impulsive Behavior scale. We found associations between eveningness, stressful life events, and all dimensions of impulsivity. Increased eveningness was associated with a higher number of stressful life events and increased impulsivity. Understanding the role of stressful life events and impulsivity in those predisposed towards eveningness is useful because it may improve our understanding of the biological mechanisms that contribute to psychiatric disorders, and lead to better prevention and treatment efforts using interventions such as increased lifestyle regularity and daytime light exposure.

Serum from Myalgic encephalomyelitis/chronic fatigue syndrome patients causes loss of coherence in cellular circadian rhythms.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling disorder characterized by disrupted daily patterns of activity, sleep, and physiology. Past studies in ME/CFS patients have examined circadian rhythms, suggested that desynchronization between central and peripheral rhythms may be an important pathological feature, and identified associated changes in post-inflammatory cytokines such as transforming growth factor beta (TGFB). However, no previous studies have examined circadian rhythms in ME/CFS using cellular models or studied the role of cytokines on circadian rhythms. In this study, we used serum samples previously collected from ME/CFS patients (n = 20) selected for the presence of insomnia symptoms and matched controls (n = 20) to determine the effects of serum factors and TGFB on circadian rhythms in NIH3T3 mouse immortalized fibroblasts stably transfected with the Per2-luc bioluminescent circadian reporter. Compared to control serum, ME/CFS serum caused a significant loss of rhythm robustness (decreased goodness of fit) and nominally increased the rate of damping of cellular rhythms. Damping rate was associated with insomnia severity in ME/CFS patients using the Pittsburgh Sleep Quality Index (PSQI). Recombinant TGFB1 peptide applied to cells reduced rhythm amplitude, caused phase delay and decreased robustness of rhythms. However, there was no difference in TGFB1 levels between ME/CFS and control serum indicating the effects of serum on cellular rhythms cannot be explained by levels of this cytokine. Future studies will be required to identify additional serum factors in ME/CFS patients that alter circadian rhythms in cells.

Five-year mortality after traumatic central cord syndrome in Wales.

Aims: Traumatic central cord syndrome (CCS) typically follows a hyperextension injury and results in motor impairment affecting the upper limbs more than the lower, with occasional sensory impairment and urinary retention. Current evidence on mortality and long-term outcomes is limited. The primary aim of this study was to assess the five-year mortality of CCS, and to determine any difference in mortality between management groups or age. Methods: Patients aged ≥ 18 years with a traumatic CCS between January 2012 and December 2017 in Wales were identified. Patient demographics and data about injury, management, and outcome were collected. Statistical analysis was performed to assess mortality and between-group differences. Results: A total of 65 patients were identified (66.2% male (n = 43), mean age 63.9 years (SD 15.9)). At a minimum of five years' follow-up, 32.3% of CCS patients (n = 21) had died, of whom six (9.2%) had died within 31 days of their injury. Overall, 69.2% of patients (n = 45) had been managed conservatively. There was no significant difference in age between conservatively and surgically managed patients (p = 0.062). Kaplan-Meier analysis revealed no significant difference in mortality between patients managed conservatively and those managed surgically (p = 0.819). However, there was a significant difference in mortality between the different age groups (< 50 years vs 50 to 70 years vs > 70 years; p = 0.001). At five years' follow-up, 55.6% of the patient group aged > 70 years at time of injury had died (n = 15). Respiratory failure was the most common cause of death (n = 9; 42.9%). Conclusion: Almost one-third of patients with a traumatic CCS in Wales had died within five years of their injury. The type of management did not significantly affect mortality but their age at the time of injury did. Further work to assess the long-term functional outcomes of surviving patients is needed to generate more reliable prognostic information.

Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder.

Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from non-responders (Li-NR). The circadian clock regulates molecular pathways involved in apoptosis and cell survival, but how this overlap impacts BD and/or lithium responsiveness is unknown. In primary fibroblasts from Li-R/Li-NR BD patients and controls, we found patterns of co-expression among circadian clock and cell survival genes that distinguished BD vs. control, and Li-R vs. Li-NR cells. In cellular models of apoptosis using staurosporine (STS), lithium preferentially protected fibroblasts against apoptosis in BD vs. control samples, regardless of Li-R/Li-NR status. When examining the effects of lithium treatment of cells in vitro, caspase activation by lithium correlated with period alteration, but the relationship differed in control, Li-R and Li-NR samples. Knockdown of Per1 and Per3 in mouse fibroblasts altered caspase activity, cell death and circadian rhythms in an opposite manner. In BD cells, genetic variation in PER1 and PER3 predicted sensitivity to apoptosis in a manner consistent with knockdown studies. We conclude that distinct patterns of coordination between circadian clock and cell survival genes in BD may help predict lithium response.

Rapid Detection of Lithium Concentrations in Oral Fluid.

BACKGROUND: Lithium medication is considered to be the first-line treatment for bipolar disorder as a monotherapy, and for treatment-resistant depression with lithium augmentation. However, because of potential toxicity, lithium levels must be monitored frequently. Recent studies have demonstrated a significant correlation between lithium levels measured in serum and those detected in oral fluid, suggesting that oral fluid analysis may represent an easy, noninvasive means to monitor lithium levels. The aim of this study was to evaluate the analytical performance of rapid assays for lithium measurements in oral fluid. METHODS: Levels of lithium in oral fluid from psychiatric patients (n = 108 in total) taking lithium medications were quantified using 2 rapid techniques: an automated clinical chemistry analyzer and a novel, commercially available colorimetric lithium assay. These results were compared with those obtained using inductively coupled plasma optical emission spectrometry (ICP-OES). RESULTS: The mean and median oral fluid lithium levels in this cohort were 1.43-1.61 mM and 1.32-1.52 mM, respectively, depending on the method, with the overall range, across all methods, being 0.213-4.42 mM. Linear regression analysis showed excellent agreement between the oral fluid values measured using ICP-OES and the colorimetric method (r 2 value = 0.926; P < 0.0001; slope = 1.084 ± 0.038). Similarly, excellent agreement was observed between ICP-OES and the automated method (r 2 = 0.872; P < 0.0001; slope = 1.019 ± 0.057). CONCLUSIONS: These results demonstrate that lithium levels in oral fluid can be rapidly and reliably quantified using colorimetric approaches. These findings may facilitate the development of point-of-care lithium monitoring systems for use in oral fluid.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

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 (Phypergeometric = 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.

Neural progenitor cells derived from lithium responsive and non-responsive bipolar disorder patients exhibit distinct sensitivity to cell death following methamphetamine.

Bipolar disorder (BD) is characterized by manic and depressive mood episodes and loss of brain gray matter. Lithium has antimanic and neuroprotective properties, but only 30% BD patients respond to lithium pharmacotherapy. Dopamine signaling has been implicated in BD and may contribute to lithium response. Methamphetamine (METH) stimulates dopamine release and models the clinical features of mania but has never been used to study cell death in BD patient neurons. We used BD patient derived neuronal progenitor cells (NPCs) to determine whether the vulnerability to cell death differed in samples from lithium responder (Li-R) and non-responder (Li-NR) BD patients and healthy controls following METH exposure in vitro. We hypothesized that NPCs from Li-R and Li-NR would differ in vulnerability to METH, dopamine signaling and neuroprotection from lithium. Following METH, NPCs from controls and Li-NR showed significantly greater cell loss compared to Li-R. Pre-treatment of NPCs with the D1 dopamine receptor antagonist SCH 23390 reversed the neurotoxic effects of METH. In Li-R NPCs, expression of phosho-ERK1/2 was significantly increased. In Li-NR NPCs, phospho-AKT, D1 and D2 dopamine receptor proteins were significantly increased. Pre-treatment of NPCs with lithium before METH reversed the neurotoxic effects of METH in control NPCs, whereas Li-NR showed less protective benefit. Li-R cells showed decreased levels of cell death after METH and comparatively high viability, and lithium treatment did not increase viability any further. This novel NPC model of mania reveals differences in cell death that could help identify mechanisms of lithium response in BD.

Diverse rural caregivers for individuals with Alzheimer's disease or related dementias: analysis of health factors at the individual, interpersonal, and community level.

Objectives: Approximately 6.2 million Americans aged 65 or older have Alzheimer's disease or related dementias (ADRD). Unpaid family members and friends provide the bulk of caregiving for these individuals. Caregiving in rural areas adds unique challenges, particularly for ethnically/racially diverse caregivers. This study provides a profile of diverse, rural ADRD caregivers with an emphasis on multi-level factors that influence physical and mental health.Methods: A cross-sectional survey was conducted with 156 diverse rural ADRD caregivers.Results: 65% of participants identified as White/Non-Hispanic (WNH; n = 101) and 35% identified as ethnically/racially diverse (ERD; n = 55). The majority of participants reported economic deprivation. More ERD caregivers were uninsured and had at least one chronic health condition. Higher proportions of ERD caregivers smoked cigarettes, consumed alcohol regularly, and had not seen or talked to a doctor in the previous year. There were no ethnic/racial group differences in stress, anxiety, depressive symptoms, subjective health, or sleep quality.Conclusion: Rural caregivers, regardless of ethnicity/race, may benefit from extra supports in order to maintain optimal health. Further research is needed to disentangle the complex relationship between culture, caregiving, and health.

Disagreement about perceptions of patient disability between the stroke patient and caregiver: a cross sectional study exploring the association to patient and caregiver quality of life.

OBJECTIVES: This study explored the association of disagreement in the perception of patient disability between patients and family caregivers with physical and psychological quality of life (QOL) in both parties. METHODS: A cross-sectional analysis of data collected from male stroke patients and family caregivers was conducted. Physical and psychological QOL in patients and caregivers were measured using the WHOQOL BREF. Perceptions of patient disability were measured using the 12-item WHO Disability Assessment Schedule 2.0 (DAS). Using DAS scores reported independently by patients and caregivers, dyads were categorized into one of four groups representing agreement or disagreement about patient disability. Generalized estimating equations were used to examine the associations between WHOQOL scores in patients and caregivers and these four groups. RESULTS: Among 56 dyads enrolled, approximately 52% were categorized into 'agreement' groups and 48% were categorized into 'disagreement' groups. The disagreement in perception about patient disability were significantly associated with poor patient physical QOL. However, the disagreement in perception were not significantly associated with caregiver QOL. CONCLUSION: Findings suggest the association of disagreement with QOL differs between patients and caregivers. Further research is needed to carefully appraise the relationship and interaction between patient and caregiver.

"We Live on an Island": Perspectives on Rural Family Caregivers for Adults with Alzheimer's Disease and Related Dementias in the United States.

As the United States' aging population grows, there will be increased prevalence of individuals living with Alzheimer's Disease and related dementias (ADRD), who largely rely on the support of their family caregivers. Family caregivers residing in rural areas face additional challenges with managing caregiving responsibilities and navigating support services. The purpose of this multilevel phenomenological qualitative study was to explore the assets, unique needs, and resources of rural-residing ADRD caregivers from the caregiver, provider, and policy influencers' perspectives. The study took place between 2019 through 2021 in northern Arizona, a largely rural and geographically vast area home to caregivers from diverse backgrounds. Twenty-seven caregivers to a loved one with ADRD participated in focus groups. Twelve health and social services providers and twelve policy influencers, those involved in leadership positions for aging programs or advocacy groups, completed individual interviews. Caregivers demonstrate many assets which contribute to their ability to manage and cope with their caregiving role. However, caregivers face a series of issues related to their caregiving role and need early and ongoing education regarding ADRD. There is a lack of resources available in rural areas, in particular providers, making it challenging to obtain needed resources necessary to support their loved one with ADRD. Furthermore, there is a need for more providers trained in working with aging adults and those experiencing ADRD, and a need for more culturally relevant resources.

Antipsychotic-induced weight gain and metabolic effects show diurnal dependence and are reversible with time restricted feeding.

Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side-effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side-effects is not well-known. We hypothesized that time of AP dosing impacts the development of metabolic side-effects. Weight gain and metabolic side-effects were compared in C57Bl/6 mice and humans dosed with APs in either the morning or evening. In mice, AP dosing at the start of the light cycle/rest period (AM) resulted in significant increase in food intake and weight gain compared with equivalent dose before the onset of darkness/active period (PM). Time of AP dosing also impacted circadian gene expression, metabolic hormones and inflammatory pathways and their diurnal expression patterns. We also conducted a retrospective examination of weight and metabolic outcomes in patients who received risperidone (RIS) for the treatment of serious mental illness and observed a significant association between time of dosing and severity of RIS-induced metabolic side-effects. Time restricted feeding (TRF) has been shown in both mouse and some human studies to be an effective therapeutic intervention against obesity and metabolic disease. We demonstrate, for the first time, that TRF is an effective intervention to reduce AP-induced metabolic side effects in mice. These studies identify highly effective and translatable interventions with potential to mitigate AP-induced metabolic side effects.

The impact of lithium on circadian rhythms and implications for bipolar disorder pharmacotherapy.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms affecting sleep, arousal, and mood. Lithium is among the most effective mood stabilizer treatments for BD, and in addition to improving mood symptoms, stabilizes sleep and activity rhythms in treatment responsive patients. Across a variety of experimental models, lithium has effects on circadian rhythms. However, uncertainty exists as to whether these actions directly pertain to lithium's therapeutic effects. Here, we consider evidence from mechanistic studies in animals and cells and clinical trials in BD patients that identify associations between circadian rhythms and the therapeutic effects of lithium. Most evidence indicates that lithium has effects on cellular circadian rhythms and increases morningness behaviors in BD patients, changes that may contribute to the therapeutic effects of lithium. However, much of this evidence is limited by cross-sectional analyses and/or imprecise proxy markers of clinical outcomes and circadian rhythms in BD patients, while mechanistic studies rely on inference from animals or small numbers of patients . Further study may clarify the essential mechanisms underlying lithium responsive BD, better characterize the longitudinal changes in circadian rhythms in BD patients, and inform the development of therapeutic interventions targeting circadian rhythms.

Circadian rhythm disruption in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for the post-acute sequelae of COVID-19.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a common and disabling disorder primarily characterized by persistent fatigue and exercise intolerance, with associated sleep disturbances, autonomic dysfunction, and cognitive problems. The causes of ME/CFS are not well understood but may coincide with immune and inflammatory responses following viral infections. During the current SARS-CoV2 coronavirus pandemic, ME/CFS has been increasingly reported to overlap with persistent "long COVID" symptoms, also called the post-acute sequelae of COVID-19 (PASC). Given the prominence of activity and sleep problems in ME/CFS, circadian rhythm disruption has been examined as a contributing factor in ME/CFS. While these studies of circadian rhythms have been pursued for decades, evidence linking circadian rhythms to ME/CFS remains inconclusive. A major limitation of older chronobiology studies of ME/CFS was the unavailability of modern molecular methods to study circadian rhythms and incomplete understanding of circadian rhythms outside the brain in peripheral organ systems. Major methodological and conceptual advancements in chronobiology have since been made. Over the same time, biomarker research in ME/CFS has progressed. Together, these new developments may justify renewed interest in circadian rhythm research in ME/CFS. Presently, we review ME/CFS from the perspective of circadian rhythms, covering both older and newer studies that make use of modern molecular methods. We focus on transforming growth factor beta (TGFB), a cytokine that has been previously associated with ME/CFS and has an important role in circadian rhythms, especially in peripheral cells. We propose that disrupted TGFB signaling in ME/CFS may play a role in disrupting physiological rhythms in sleep, activity, and cognition, leading to the insomnia, energy disturbances, cognition problems, depression, and autonomic dysfunction associated with ME/CFS. Since SARS-like coronavirus infections cause persistent changes in TGFB and previous coronavirus outbreaks have caused ME/CFS-like syndromes, chronobiological considerations may have immediate implications for understanding ME/CFS in the context of the COVID-19 pandemic and possibly suggest new avenues for therapeutic interventions.

Systematic Review of the Evidence for Stroke Family Caregiver and Dyad Interventions.

Stroke family caregiver and dyad literature has expanded over the past few years. The purpose of this review was to build upon 2 prior systematic reviews to critique, analyze, and synthesize the evidence pertaining to the impact of family caregiver and dyad interventions on stroke survivor and family caregiver outcomes. CINAHL, PsychINFO, PubMed, and reference lists were searched from December 1, 2016 through March 31, 2021. Using PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), articles were identified that tested outcomes from stroke family caregiver or dyad interventions that targeted the health or well-being of family caregivers. Data from the articles were abstracted into tables for analysis, then compared with recommendations from the 2 prior systematic reviews. A total of 18 articles met inclusion criteria (10 caregiver interventions; 8 dyad interventions) representing sample sizes ranging from 7 to 349 caregivers or dyads. Most were randomized controlled trials (n=13); 2 were cluster randomized trials; and 3 were single-group quasi-experimental designs. Of the 18 studies, 8 had <50 caregivers or dyads and 5 were small feasibility studies that reported data trends rather than testing for significance. Only 6 studies reported significant survivor outcomes. Eleven studies reported significant caregiver outcomes, the most common being burden. A number of survivor and caregiver outcomes were not significant, or only significant for certain subgroups. The limited number of studies, small sample sizes, and conflicting results, made it difficult to draw firm conclusions regarding the impact of these interventions on outcomes. Based on the available evidence from these 18 studies, recommendations from the 2 prior reviews were generally supported. Well-designed and well-powered randomized controlled clinical trials are still needed to confirm efficacy of stroke family caregiver and dyad interventions.

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology.

AIM: Symptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD. METHOD: Drawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework. RESULTS: Evidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings. CONCLUSIONS: Future research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.