Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab’s effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab’s effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ² = 9.275, p = 0.026), NF-κB (χ² = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα)α (χ² = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ² = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = −0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

Individuals with a severe mental illness (SMI) are at least two times more likely to suffer from metabolic co-morbidities, leading to excessive and premature deaths. In spite of the many physical and mental health benefits of physical activity (PA), individuals with SMI are less physically active and more sedentary than the general population. One key component towards increasing the acceptability, adoption, and long-term adherence to PA is to understand, tailor and incorporate the PA preferences of individuals. Therefore, the objective of this study was to determine if there are differences in PA preferences among individuals diagnosed with different psychiatric disorders, in particular schizophrenia or bipolar disorder (BD), and to identify PA design features that participants would prefer. Participants with schizophrenia (n = 113) or BD (n = 60) completed a survey assessing their PA preferences. There were no statistical between-group differences on any preferred PA program design feature between those diagnosed with schizophrenia or BD. As such, participants with either diagnosis were collapsed into one group in order to report PA preferences. Walking (59.5 %) at moderate intensity (61.3 %) was the most popular activity and participants were receptive to using self-monitoring tools (59.0 %). Participants were also interested in incorporating strength and resistance training (58.5 %) into their PA program and preferred some level of regular contact with a fitness specialist (66.0 %). These findings can be used to tailor a physical activity intervention for adults with schizophrenia or BD. Since participants with schizophrenia or BD do not differ in PA program preferences, the preferred features may have broad applicability for individuals with any SMI.

Background: Depression is associated with significant morbidity and human capital costs globally. Early screening for depressive symptoms and timely depressive disorder case identification and intervention may improve health outcomes and cost-effectiveness among affected individuals. China’s public and academic communities have reached a consensus on the need to improve access to early screening, diagnosis, and treatment of depression. Objective: This study aims to estimate the screening prevalence and associated factors of subthreshold depressive symptoms among Chinese residents enrolled in the cohort study using a mobile app–based integrated mental health care model and investigate the 12-month incidence rate and related factors of major depressive disorder (MDD) among those with subthreshold depressive symptoms. Methods: Data were drawn from the Depression Cohort in China (DCC) study. A total of 4243 community residents aged 18 to 64 years living in Nanshan district, Shenzhen city, in Guangdong province, China, were encouraged to participate in the DCC study when visiting the participating primary health care centers, and 4066 (95.83%) residents who met the DCC study criteria were screened for subthreshold depressive symptoms using the Patient Health Questionnaire-9 at baseline. Of the 4066 screened residents, 3168 (77.91%) with subthreshold depressive symptoms were referred to hospitals to receive a psychiatric diagnosis of MDD within 12 months. Sleep duration, anxiety symptoms, well-being, insomnia symptoms, and resilience were also investigated. The diagnosis of MDD was provided by trained psychiatrists using the Mini-International Neuropsychiatric Interview. Univariate and multivariate logistic regression models were performed to explore the potential factors related to subthreshold depressive symptoms at baseline, and Cox proportional hazards models were performed to explore the potential factors related to incident MDD. Results: Anxiety symptoms (adjusted odds ratio [AOR] 1.63, 95% CI 1.42-1.87) and insomnia symptoms (AOR 1.13, 95% CI 1.05-1.22) were associated with an increased risk of subthreshold depressive symptoms, whereas well-being (AOR 0.93, 95% CI 0.87-0.99) was negatively associated with depressive symptoms. During the follow-up period, the 12-month incidence rate of MDD among participants with subthreshold depressive symptoms was 5.97% (189/3168). After incorporating all significant variables from the univariate analyses, the multivariate Cox proportional hazards model reported that a history of comorbidities (adjusted hazard ratio [AHR] 1.49, 95% CI 1.04-2.14) and anxiety symptoms (AHR 1.13, 95% CI 1.09-1.17) were independently associated with an increased risk of incident MDD. The 5-item World Health Organization Well-Being Index was associated with a decreased risk of incident MDD (AHR 0.90, 95% CI 0.86-0.94). Conclusions: Elevated anxiety symptoms and unfavorable general well-being were significantly associated with subthreshold depressive symptoms and incident MDD among Chinese residents in Shenzhen. Early screening for subthreshold depressive symptoms and related factors may be helpful for identifying populations at high risk of incident MDD.

Mood disorders continue to be a significant burden to those affected, resulting in significant illness-associated disability and premature mortality. In addition to mood disturbance, individuals also suffer from other transdiagnostic impairments (eg, anhedonia and cognitive impairment). Although there have been significant advancements in psychiatric treatment over the last few decades, treatment efficacy (eg, symptom remission, lack of functional recovery, and disease modification) continues to be an important limitation. Consequently, there is an urgent need to identify novel approaches capable of addressing the foregoing needs, providing the basis for the exploration of conceptual models and treatment opportunities that consider inflammation to be a key factor in mood disorder development. In part driven by metabolic comorbidities, a large proportion of individuals with mood disorders also have an imbalance in the inflammatory milieu. The aim of this review is to highlight evidence implicating inflammation in various effector systems in mood disorders, with a particular focus on the intercommunication with glutamatergic signaling, immune system signaling, as well as metabolic parameters (eg, L-methyl folate bioavailability). This article also briefly reviews novel and repurposed agents that are capable of targeting the innate immune inflammatory system and possibly correcting an abnormal immune/inflammatory milieu (eg, infliximab).