Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations

ObjectivesThe 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address.MethodOverview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high- quality data and reliance on expert opinion.ResultsNo agents met threshold for first- line treatment of DSM- 5 manic or depressive episodes with mixed features. For mania + mixed features second- line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second- line options. For DSM- IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first- line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second- line. Research on maintenance treatments following a DSM- 5 mixed presentation is extremely limited, with third- line recommendations based on expert opinion. For maintenance treatment following a DSM- IV mixed episode, quetiapine (monotherapy or combination) is first- line, and lithium and olanzapine identified as second- line options.ConclusionThe CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171126/1/bdi13135.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171126/2/bdi13135_am.pd

The association of medication use with clearance or persistence of oral HPV infection

PURPOSE: Persistent oral human papillomavirus (HPV) infection increases risk for oropharyngeal carcinoma, and people living with HIV have higher rates of oral HPV infection and related cancers. Some prescription medications have immunomodulatory effects, but the impact of medication use on oral HPV natural history is unknown. METHODS: Scope(®) oral rinse-and-gargle samples were collected semi-annually from 1,666 participants and tested for 37 types of oral HPV DNA using PCR; 594 HPV-infected participants with 1,358 type-specific oral HPV infections were identified. Data were collected on recent (past 6 months) use of medications. The relationship between medication use and oral HPV clearance was evaluated using Wei-Lin-Weissfeld regression, adjusting for biologic sex, prevalent vs. incident infection, age, HIV status and CD4+ T-cell count. RESULTS: Out of 11 medications examined, oral HPV clearance was significantly reduced in participants reporting recent use of antipsychotics (HR=0.75, 95% CI=0.57–0.99), anxiolytics/sedatives (HR=0.78, 95% CI=0.63–0.96) and antidepressants (HR=0.82, 95% CI=0.67–0.999). Among antipsychotics users, effect modification by HIV status was observed, with reduced clearance in HIV-infected (HR=0.67, 95%: CI 0.49–0.91), but not HIV-uninfected participants (p-interaction=0.009). After adjusted analysis, antipsychotic use remained significantly associated with reduced oral HPV clearance overall (aHR=0.75, 95% CI=0.57–0.99), and when restricted to only HIV-infected participants (aHR=0.66, 95% CI=0.48–0.90). After adjustment, anxiolytic/sedative use and antidepressant use were no longer significantly associated with reduced oral HPV clearance. CONCLUSIONS: Some medications were associated with decreased oral HPV clearance, most notably antipsychotic medications. These medications are prescribed for conditions that may have immunomodulating effects, so characteristics of underlying illness may have partially contributed to reduced oral HPV clearance