Predictors and Risk Factors of Treatment-Resistant Depression: A Systematic Review.

Objective: To systematically review the literature to identify and categorize the predictors and risk factors for treatment-resistant depression (TRD).Data Sources: Online databases (PubMed, MEDLINE, Embase, and APA PsycNet) and relevant conference sources were searched from inception up to January 24, 2022. The following keywords were used: treatment-resistant depression, depressive disorder, predictors, risk, and biomarkers.Study Selection: All studies that included a definition of TRD were included. A total of 1,686 abstracts were screened, and 57 studies were included in the final data synthesis.Data Extraction: Data were extracted using a data extraction form developed for this study.Results: The most frequently reported mental predictors/risk factors were greater symptom severity (9 studies), suicidality (8 studies), and recurrent depression (6 studies). Cardiovascular disease (4 studies), pain (3 studies), and thyroid dysfunction (3 studies) were the most common physical predictors/risk factors, while younger age (7 studies) and female gender (6 studies) were the most common demographic predictors/risk factors. Higher levels of neuroticism appeared twice in the literature. Several articles reported on genetic, biological, and imaging variables, but results were too heterogenous to identify common predictors/risk factors.Conclusions: TRD is a complex disorder with many contributing factors that need to be identified and addressed earlier in the disease course to prevent its development or facilitate better treatment outcomes. Future work should focus on replicating the key predictors/risk factors identified in this review.

Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.

Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.

Observational study to characterize treatment-resistant depression in Germany, France and the United Kingdom: analysis of real-world data collected through a survey of healthcare professionals.

OBJECTIVE: This study describes treatment patterns, productivity, healthcare resource utilization and previous episodes of depression for patients with treatment-resistant depression (TRD). METHODS: In this cross-sectional study, a quantitative survey was administered to 225 healthcare providers (HCPs) distributed evenly across Germany, France and the UK from July to August 2021. Each HCP was asked to answer based on medical records of five patients with TRD, defined as patients failing to respond to two or more treatments of adequate dose and duration in the same episode of major depressive disorder (MDD), which provided a sample size of 1125 patients. RESULTS: Of the 1125 patients with TRD, 73.2% had two or more previous episodes of MDD, 46.3% had a history of suicidal ideation and 24.8% had attempted suicide. Only 26.8% of patients were employed either full-time or part-time. During the most recent/current TRD episode, 45.5% of patients received five or more lines of treatment, and 46.0% remained on monotherapy. For multiple pharmacological treatments, too many distinct combinations were used to discern trends. Overall, 60.6% of patients had at least one mental health-related hospitalization in the last 12 months; 35.0% had two or more hospitalizations. Half of TRD patients saw a doctor five or more times per year for their depression. CONCLUSIONS: This study addresses the knowledge gap about treatment patterns and healthcare utilization in real-world practice for TRD patients in three European countries. It provides data that potentially could inform treatment guideline development and optimize patient-perceived benefits from the treatment of TRD.