Target engagement of the subgenual anterior cingulate cortex with transcranial temporal interference stimulation in major depressive disorder: a protocol for a randomized sham-controlled trial.

Background: Transcranial temporal interference stimulation (tTIS) is a new, emerging neurostimulation technology that utilizes two or more electric fields at specific frequencies to modulate the oscillations of neurons at a desired spatial location in the brain. The physics of tTIS offers the advantage of modulating deep brain structures in a non-invasive fashion and with minimal stimulation of the overlying cortex outside of a selected target. As such, tTIS can be effectively employed in the context of therapeutics for the psychiatric disease of disrupted brain connectivity, such as major depressive disorder (MDD). The subgenual anterior cingulate cortex (sgACC), a key brain center that regulates human emotions and influences negative emotional states, is a plausible target for tTIS in MDD based on reports of its successful neuromodulation with invasive deep brain stimulation. Methods: This pilot, single-site, double-blind, randomized, sham-controlled interventional clinical trial will be conducted at St. Michael's Hospital - Unity Health Toronto in Toronto, ON, Canada. The primary objective is to demonstrate target engagement of the sgACC with 130 Hz tTIS using resting-state magnetic resonance imaging (MRI) techniques. The secondary objective is to estimate the therapeutic potential of tTIS for MDD by evaluating the change in clinical characteristics of participants and electrophysiological outcomes and providing feasibility and tolerability estimates for a large-scale efficacy trial. Thirty participants (18-65 years) with unipolar, non-psychotic MDD will be recruited and randomized to receive 10 sessions of 130 Hz tTIS or sham stimulation (n = 15 per arm). The trial includes a pre- vs. post-treatment 3T MRI scan of the brain, clinical evaluation, and electroencephalography (EEG) acquisition at rest and during the auditory mismatch negativity (MMN) paradigm. Discussion: This study is one of the first-ever clinical trials among patients with psychiatric disorders examining the therapeutic potential of repetitive tTIS and its neurobiological mechanisms. Data obtained from this trial will be used to optimize the tTIS approach and design a large-scale efficacy trial. Research in this area has the potential to provide a novel treatment option for individuals with MDD and circuitry-related disorders and may contribute to the process of obtaining regulatory approval for therapeutic applications of tTIS. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05295888.

Increased Odds of Cognitive Impairment in Adults with Depressive Symptoms and Antidepressant Use.

INTRODUCTION: The relationship between antidepressant use and class with cognition in depression is unclear. This study aimed to evaluate the association of cognition with depressive symptoms and antidepressant use (class, duration, number). METHODS: Data from the National Health and Nutrition Examination Survey were examined for cognitive function through various tests and memory issues through the Medical Conditions questionnaire. Depressive symptoms were assessed using the Patient Health Questionnaire-9. RESULTS: A total of 2867 participants were included. Participants with depressive symptoms had significantly higher odds of cognitive impairment (CI) on the animal fluency test (aOR=1.89, 95% CI=1.30, 2.73, P=0.002) and Digit Symbol Substitution test (aOR=2.58, 95% CI=1.34, 4.9, P=0.007), as well as subjective memory issues (aOR=7.25, 95% CI=4.26, 12.32, P<0.001) than those without depression. There were no statistically significant associations between any of the CI categories and depressive symptoms treated with an antidepressant and antidepressant use duration. Participants who were using more than one antidepressant had significantly higher odds of subjective memory issues than those who were using one antidepressant. Specifically, users of atypical antidepressants, selective serotonin reuptake inhibitors, or tricyclic antidepressants (TCAs) had significantly higher odds of subjective memory issues in comparison to no antidepressants, with TCAs showing the largest odds (aOR=4.21, 95% CI=1.19, 14.86, P=0.028). DISCUSSION: This study highlights the relationship between depressive symptoms, antidepressant use, and CI. Future studies should further evaluate the mechanism underlying this phenomenon.

Predicting treatment response to ketamine in treatment-resistant depression using auditory mismatch negativity: Study protocol.

BACKGROUND: Ketamine has recently attracted considerable attention for its rapid effects on patients with major depressive disorder, including treatment-resistant depression (TRD). Despite ketamine's promising results in treating depression, a significant number of patients do not respond to the treatment, and predicting who will benefit remains a challenge. Although its antidepressant effects are known to be linked to its action as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, the precise mechanisms that determine why some patients respond and others do not are still unclear. OBJECTIVE: This study aims to understand the computational mechanisms underlying changes in the auditory mismatch negativity (MMN) response following treatment with intravenous ketamine. Moreover, we aim to link the computational mechanisms to their underlying neural causes and use the parameters of the neurocomputational model to make individual treatment predictions. METHODS: This is a prospective study of 30 patients with TRD who are undergoing intravenous ketamine therapy. Prior to 3 out of 4 ketamine infusions, EEG will be recorded while patients complete the auditory MMN task. Depression, suicidality, and anxiety will be assessed throughout the study and a week after the last ketamine infusion. To translate the effects of ketamine on the MMN to computational mechanisms, we will model changes in the auditory MMN using the hierarchical Gaussian filter, a hierarchical Bayesian model. Furthermore, we will employ a conductance-based neural mass model of the electrophysiological data to link these computational mechanisms to their neural causes. CONCLUSION: The findings of this study may improve understanding of the mechanisms underlying response and resistance to ketamine treatment in patients with TRD. The parameters obtained from fitting computational models to EEG recordings may facilitate single-patient treatment predictions, which could provide clinically useful prognostic information. TRIAL REGISTRATION: Clinicaltrials.gov NCT05464264. Registered June 24, 2022.

Virtual Reality and Stress Management: A Systematic Review.

Amidst the growing prevalence of chronic stress and its potential negative impacts on mental health, this review explores the use of virtual reality (VR) as a stress management solution, aiming to assess its viability and effectiveness in this context. A comprehensive search was conducted on MEDLINE, PsycINFO, and Embase from inception until February 2024. Eligible studies were primary research papers that focused on the use of VR as an intervention to mitigate psychological stress and/or distress. We included studies where the assessment of stress levels primarily relied on self-report measures. A total of 50 studies involving 2885 participants were included in our systematic review. VR-based interventions varied across studies, implementing tools such as cognitive behavioural therapy, exposure therapy, mindfulness and relaxation, repetition tasks, and psychoeducation. The reviewed studies yielded mixed results; however, a strong indication was present in highlighting the promising potential of VR-based interventions. Many studies observed a decrease in psychiatric symptoms in participants and reported increased quality of life. Various studies also found VR to be a valuable tool in promoting stress reduction and relaxation. VR was proven useful in exposing participants to stressors in a safe, controlled way. These potential benefits appear to come with no risk of harm to the participants. Although the findings are heterogenous, there is sufficient evidence supporting the use of VR for stress management across a range of contexts and populations. Overall, VR appears to be a generally low-risk, feasible intervention for those struggling with stress.

Transcranial alternating current stimulation for neuropsychiatric disorders: a systematic review of treatment parameters and outcomes.

Background: Transcranial alternating current stimulation (tACS) alters cortical excitability with low-intensity alternating current and thereby modulates aberrant brain oscillations. Despite the recent increase in studies investigating the feasibility and efficacy of tACS in treating neuropsychiatric disorders, its mechanisms, as well as optimal stimulation parameters, are not fully understood. Objectives: This systematic review aimed to compile human research on tACS for neuropsychiatric disorders to delineate typical treatment parameters for these conditions and evaluate its outcomes. Methods: A search for published studies and unpublished registered clinical trials was conducted through OVID (MEDLINE, PsycINFO, and Embase), ClinicalTrials.gov, and the International Clinical Trials Registry Platform. Studies utilizing tACS to treat neuropsychiatric disorders in a clinical trial setting were included. Results: In total, 783 published studies and 373 clinical trials were screened; 53 published studies and 70 clinical trials were included. Published studies demonstrated a low risk of bias, as assessed by the Joanna Briggs Institute Critical Appraisal Tools. Neurocognitive, psychotic, and depressive disorders were the most common disorders treated with tACS. Both published studies (58.5%) and registered clinical trials (52%) most commonly utilized gamma frequency bands and tACS was typically administered at an intensity of 2 mA peak-to-peak, once daily for 20 or fewer sessions. Although the targeted brain locations and tACS montages varied across studies based on the outcome measures and specific pathophysiology of the disorders, the dorsolateral prefrontal cortex (DLPFC) was the most common target in both published studies (30.2%) and registered clinical trials (25.6%). Across studies that published results on tACS outcome measures, tACS resulted in enhanced symptoms and/or improvements in overall psychopathology for neurocognitive (all 11 studies), psychotic (11 out of 14 studies), and depressive (7 out of 8 studies) disorders. Additionally, 17 studies reported alterations in the power spectrum of the electroencephalogram around the entrained frequency band at the targeted locations following tACS. Conclusion: Behavioral and cognitive symptoms have been positively impacted by tACS. The most consistent changes were reported in cognitive symptoms following gamma-tACS over the DLPFC. However, the paucity of neuroimaging studies for each neuropsychiatric condition highlights the necessity for replication studies employing biomarker- and mechanism-centric approaches.

The Association Between Depressive Symptoms and the Weekly Duration of Physical Activity Subset by Intensity and Domain: Population-Based, Cross-Sectional Analysis of the National Health and Nutrition Examination Survey From 2007 to 2018.

BACKGROUND: Prior literature suggests a dose-response relationship between physical activity (PA) and depressive symptoms. The intensity and domain of PA are suggested to be critical to its protective effect against depression; however, existing literature has shown mixed results. OBJECTIVE: The purpose of this population-based study is to examine the associations between depressive symptoms and weekly duration of (1) total PA and (2) PA subset by intensity, domain, or both. METHODS: A cross-sectional analysis of National Health and Nutrition Examination Survey data from 2007 to 2018 was conducted using multivariable logistic and linear regression models and survey weights. Participants (N=29,730) were 20 years and older and completed the Physical Activity Questionnaire and Depression Screener. The primary outcome was the presence of depressive symptoms, and the secondary outcomes were cognitive-affective and somatic symptoms of depression. RESULTS: Participants (N=29,730) had a weighted mean age of 47.62 (SD 16.99) years, and 15,133 (51.34%) were female. On average, participants without depressive symptoms engaged in 10.87 hours of total PA per week, whereas participants with depressive symptoms engaged in 8.82 hours (P<.001). No significant associations were seen between the weekly duration of total PA and depressive symptom odds, somatic, or cognitive-affective symptoms (all P>.05). Participants with an increased weekly duration of recreational PA had decreases in depressive symptom odds (adjusted odds ratio [aOR] 0.965, 95% CI 0.944-0.986) and in somatic (adjusted coefficient [aß]=-0.016, 95% CI -0.022 to -0.009) and cognitive-affective (aß=-0.015, 95% CI -0.023 to -0.007) symptoms. When recreational PA was subset by intensity, participants with an increased weekly duration of vigorous-intensity recreational PA had decreases in depressive symptom odds (aOR 0.926, 95% CI 0.883-0.972) and in somatic (aß=-0.021, 95% CI -0.032 to -0.010) and cognitive-affective (aß=-0.022, 95% CI -0.035 to -0.009) symptoms. However, significant associations were not seen for the weekly duration of work-related, moderate- or vigorous-intensity PAs (all P>.05). CONCLUSIONS: Findings suggest that recreational, not work-related PA is associated with reduced symptoms of depression. Future studies should explore the impact of the different types and contexts of PA on depressive symptomatology.

Depressive symptoms among adults is associated with decreased food security.

OBJECTIVE: We aim to evaluate the association of depressive symptoms, depressive symptoms severity and symptom cluster scores (i.e., cognitive-affective and somatic) with food security (FS). We will also evaluate the interaction effect of sex, income and ethnicity on these associations. METHODS: Data from the 2005-2018 National Health and Nutrition Examination Survey cycles were used in this study. Participants included survey respondents 20+ years who had completed Depression and Food Security questionnaires. Multivariable logistic regression was used to estimate the associations between depressive symptoms and FS. RESULTS: A total of 34,128 participants, including 3,021 (7.73%) with depressive symptoms, were included in this study. In both unadjusted and adjusted models, participants with depressive symptoms had lower odds of FS (aOR = 0.347, 95% CI: 0.307,0.391, p<0.001). Moreover, in both unadjusted and adjusted models, for each 1-point increase in cognitive-affective (aOR = 0.850, 95% CI = 0.836,0.864, p <0.001) and somatic symptoms (aOR = 0.847, 95% CI = 0.831,0.863, p <0.001), odds of high FS decreased correspondingly. Our study found no significant interaction effects of sex on depressive symptoms-FS association. Statistically significant interactions of ethnicity and poverty-to-income ratio on depressive symptoms-FS association were observed, revealing higher odds of FS among Non-Hispanic Black and Mexican American groups, and lower odds of FS in Non-Hispanic White and high-income subgroups. CONCLUSION: Our study demonstrated an association between depressive symptoms and decreased FS. Further research is required to deepen our understanding of the underlying mechanisms and to develop focused interventions.

Digital Interventions to Understand and Mitigate Stress Response: Protocol for Process and Content Evaluation of a Cohort Study.

BACKGROUND: Staffing and resource shortages, especially during the COVID-19 pandemic, have increased stress levels among health care workers. Many health care workers have reported feeling unable to maintain the quality of care expected within their profession, which, at times, may lead to moral distress and moral injury. Currently, interventions for moral distress and moral injury are limited. OBJECTIVE: This study has the following aims: (1) to characterize and reduce stress and moral distress related to decision-making in morally complex situations using a virtual reality (VR) scenario and a didactic intervention; (2) to identify features contributing to mental health outcomes using wearable, physiological, and self-reported questionnaire data; and (3) to create a personal digital phenotype profile that characterizes stress and moral distress at the individual level. METHODS: This will be a single cohort, pre- and posttest study of 100 nursing professionals in Ontario, Canada. Participants will undergo a VR simulation that requires them to make morally complex decisions related to patient care, which will be administered before and after an educational video on techniques to mitigate distress. During the VR session, participants will complete questionnaires measuring their distress and moral distress, and physiological data (electrocardiogram, electrodermal activity, plethysmography, and respiration) will be collected to assess their stress response. In a subsequent 12-week follow-up period, participants will complete regular assessments measuring clinical outcomes, including distress, moral distress, anxiety, depression, and loneliness. A wearable device will also be used to collect continuous data for 2 weeks before, throughout, and for 12 weeks after the VR session. A pre-post comparison will be conducted to analyze the effects of the VR intervention, and machine learning will be used to create a personal digital phenotype profile for each participant using the physiological, wearable, and self-reported data. Finally, thematic analysis of post-VR debriefing sessions and exit interviews will examine reoccurring codes and overarching themes expressed across participants' experiences. RESULTS: The study was funded in 2022 and received research ethics board approval in April 2023. The study is ongoing. CONCLUSIONS: It is expected that the VR scenario will elicit stress and moral distress. Additionally, the didactic intervention is anticipated to improve understanding of and decrease feelings of stress and moral distress. Models of digital phenotypes developed and integrated with wearables could allow for the prediction of risk and the assessment of treatment responses in individuals experiencing moral distress in real-time and naturalistic contexts. This paradigm could also be used in other populations prone to moral distress and injury, such as military and public safety personnel. TRIAL REGISTRATION: ClinicalTrials.gov NCT05923398; https://clinicaltrials.gov/study/NCT05923398. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54180.

Adults with depressive symptoms have lower odds of dietary supplement use.

OBJECTIVE: In this study, we aim to evaluate dietary supplement and complementary and alternative medicine (CAM) use in individuals with depressive symptoms. Furthermore, we conducted a comparative analysis of the usage of these agents among individuals with depressive symptoms, differentiating between those who were using antidepressants and those who were not. Additionally, we compared individuals with depressive symptoms who were not using antidepressants with participants who did not have depressive symptoms as well as individuals with depressive symptoms who were using antidepressants with individuals without depressive symptoms. METHOD: The National Health and Nutrition Examination Survey 2007-2018 data was collected. Depressive symptoms were assessed using patient health questionnaire-9. Dietary supplement and antidepressants use was evaluated using Dietary Supplement Use and Prescription Medications Questionnaires. RESULTS: 31,445 participants, with 2870 (8.05%) having depressive symptoms were included. Participants with depressive symptoms had significantly lower odds of dietary supplement use compared with those without depressive symptoms (aOR = 0.827, 95% CI: 0.700,0.977, p = 0.026). Participants with depressive symptoms who were using antidepressants had significantly higher odds of dietary supplement (aOR = 1.290, 95% CI: 1.038,1.604, p = 0.022) compared with participants with depressive symptoms who were not using antidepressants. Furthermore, Participants with depressive symptoms who weren't using antidepressants had significantly lower odds of dietary supplement use (aOR = 0.762, 95% CI: 0.632,0.918, p = 0.005) compared with participants without depressive symptoms. In individuals with treated depressive symptoms compared to those without depressive symptoms, CAM use was significantly lower (aOR = 0.763, 95% CI = 0.598,0.973, p = 0.030). CONCLUSION: Individuals with depressive symptoms have lower odds of dietary supplement use. Further studies are needed to replicate these findings and examine the underlying mechanisms for this association.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders.

Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms.

The association between depressive symptoms and high-sensitivity C-reactive protein: Is body mass index a moderator?

Objective: Depression and obesity are highly comorbid conditions with shared biological mechanisms. It remains unclear how depressive symptoms and body mass index (BMI) interact in relation to inflammation. This cross-sectional study investigated the independent associations of depressive symptoms and BMI with high sensitivity C-reactive protein (hs-CRP), as well as the moderating role of BMI on the depressive symptoms-hs-CRP association. Methods: Participants (n = 8827) from the 2015-2018 National Health and Nutrition Examination Surveys were aged ≥20 with a BMI ≥18.5 kg/m2, completed the Depression Screener, and had hs-CRP data. Multivariable linear regression was used to analyze hs-CRP in relation to depressive symptoms and BMI. An interaction term was included to examine whether the depressive symptoms-hs-CRP relationship differs depending on BMI. Results: There was a slight, albeit non-significant, increase in hs-CRP levels with each one-point increase in depressive symptoms (aCoef.Estm. = 0.01, 95% CI = -0.05, 0.06, p = 0.754). Participants with overweight (aCoef.Estm. = 1.07, 95% CI = 0.61, 1.53, p < 0.001) or obese (aCoef.Estm. = 3.51, 95% CI = 3.04, 3.98, p < 0.001) BMIs had higher mean hs-CRP levels than those with a healthy BMI. There were no significant interactions between depressive symptoms and overweight (aCoef.Estm. = 0.04, 95% CI = -0.04, 0.13, p = 0.278) or obese (aCoef.Estm. = 0.11, 95% CI = -0.01, 0.22, p = 0.066) BMI indicating a lack of difference in the depressive symptoms-hs-CRP association across participants in the healthy versus overweight and obese ranges. Conclusions: This study suggests that BMI might not act as a moderator in the association between depressive symptoms and hs-CRP. Results should be replicated in larger samples. Further research is warranted to understand underlying mechanisms.

Decreased odds of depressive symptoms and suicidal ideation with higher education, depending on sex and employment status.

BACKGROUND: Higher education is associated with reduced depressive symptoms and requires investment without guaranteed employment. It remains unclear how sex and employment status together contribute to the association between mental health and educational attainment. This study investigated the role of sex and employment status together in the associations of 1) depressive symptoms and 2) suicidal ideation with education. METHODS: Using 2005-2018 National Health and Nutrition Examination Survey data, cross-sectional analyses were conducted on individuals ≥20 years who completed the depression questionnaire and reported their employment status and highest level of education. Survey-weighted multivariable logistic regression models were used to explore how depressive symptoms and suicidal ideation are associated with educational attainment in an analysis stratified by sex and employment status. To account for multiple testing, a significance level of a < 0.01 was used. RESULTS: Participants (n = 23,669) had a weighted mean age of 43.25 (SD = 13.97) years and 47% were female. Employed females (aOR = 0.47, 95% CI 0.32, 0.69), unemployed females (aOR = 0.47, 95% CI 0.29, 0.75), and unemployed males (aOR = 0.31, 95% CI 0.17, 0.56) with college education had reduced odds of depressive symptoms compared to those with high school education. Employed females with college education also had reduced suicidal ideation odds compared to those with high school education (aOR = 0.41, 95% CI 0.22, 0.76). CONCLUSIONS: Females demonstrated significant associations between depressive symptoms and education, regardless of employment status, whereas males demonstrated an association only if unemployed. Employed females, in particular, demonstrated a significant association between suicidal ideation and education. These findings may inform future research investigating the underlying mechanisms and etiology of these sex-employment status differences in the association between mental health and education.

Botulinum Toxin Injections for Psychiatric Disorders: A Systematic Review of the Clinical Trial Landscape.

Botulinum toxin type A (BONT-A) has shown promise in improving the mood-related symptoms of psychiatric disorders by targeting muscles linked to the expression of negative emotions. We conducted a systematic review of past and ongoing efficacy trials of BONT-A therapy for psychiatric disorders to identify relevant trends in the field and discuss the refinement of therapeutic techniques. A comprehensive search for published clinical trials using BONT-A injections for psychiatric disorders was performed on 4 May 2023 through OVID databases (MEDLINE, Embase, APA PsycINFO). Unpublished clinical trials were searched through the ClinicalTrials.gov and International Clinical Trial Registry Platform public registries. The risk of bias was assessed using the JBI Critical Appraisal tools for use in systematic reviews. We identified 21 studies (17 published, 4 unpublished clinical trials) involving 471 patients. The studies focused on evaluating the efficacy of BONT-A for major depressive, borderline personality, social anxiety, and bipolar disorders. BONT-A was most commonly injected into the glabellar area, with an average dose ranging between 37.75 U and 44.5 U in published studies and between 32.7 U and 41.3 U in unpublished trials. The results indicated significant symptom reductions across all the studied psychiatric conditions, with mild adverse effects. Thus, BONT-A appears to be safe and well-tolerated for psychiatric disorders of negative affectivity. However, despite the clinical focus, there was a noted shortage of biomarker-related assessments. Future studies should focus on pursuing mechanistic explorations of BONT-A effects at the neurobiological level.

Development and Implementation of a Stress Monitoring Paradigm Using Virtual Reality Simulation During the COVID-19 Pandemic.

Healthcare providers, particularly during the COVID-19 crisis, have been forced to make difficult decisions and have reported acting in ways that are contrary to their moral values, integrity, and professional commitments, given the constraints in their work environments. Those actions and decisions may lead to healthcare providers' moral suffering and distress. This work outlines the development of the Moral Distress Virtual Reality Simulator (Moral Distress VRS) to research stress and moral distress among healthcare workers during the COVID-19 pandemic. The Moral Distress VRS was developed based on the agile methodology framework, with three simultaneous development streams. It followed a two-week sprint cycle, ending with meetings with stakeholders and subject matter experts, whereby the project requirements, scope, and features were revised, and feedback was provided on the prototypes until reaching the final prototype that was deployed for in-person study sessions. The final prototype had two user interfaces (UIs), one for the participant and one for the researcher, with voice narration and customizable character models wearing medical personal protective equipment, and followed a tree-based dialogue scenario, outputting a video recording of the session. The virtual environment replicated an ICU nursing station and a fully equipped patient room. We present the development process that guided this project, how different teams worked together and in parallel, and detail the decisions and outcomes in creating each major component within a limited deadline. Finally, we list the most significant challenges and difficulties faced and recommendations on how to solve them.

Does Self-Reported BMI Modify the Association Between Stroke and Depressive Symptoms?

BACKGROUND: Depressive symptoms are common in stroke survivors. While obesity has been associated with stroke and depression, its influence on the association between stroke and depressive symptoms is unknown. METHODS: Cross-sectional data from 2015 to 2016 Canadian Community Health Survey was used. History of stroke was self-reported and our outcome of interest was depressive symptoms in the prior 2 weeks, measured using the 9-item Patient Health Questionnaire. Self-reported body mass index (BMI) was modeled as cubic spline terms to allow for nonlinear associations. We used multivariable logistic regression to evaluate the association between stroke and depressive symptoms and added an interaction term to evaluate the modifying effect of BMI. RESULTS: Of the 47,521 participants, 694 (1.0%) had a stroke and 3314 (6.5%) had depressive symptoms. Those with stroke had a higher odds of depressive symptoms than those without (aOR = 3.13, 95% CI 2.48, 3.93). BMI did not modify the stroke-depressive symptoms association (P interaction = 0.242) despite the observed variation in stroke-depressive symptoms association across BMI categories,: normal BMI [18.5-25 kg/m2] (aOR† = 3.91, 95% CI 2.45, 6.11), overweight [25-30 kg/m2] (aOR† = 2.63, 95% CI 1.58, 4.20), and obese [>30 kg/m2] (aOR† = 2.76, 95% CI 1.92, 3.94). Similar results were found when depressive symptoms were modeled as a continuous measure. CONCLUSION: The association between stroke and depressive symptoms is not modified by BMI, needing additional work to understand the role of obesity on depression after stroke.

Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression.

BACKGROUND: Nitrous oxide has shown potentially as an efficacious intervention for treatment-resistant depression, yet there remains insufficient evidence pertaining to repeated administration of nitrous oxide over time and active placebo-controlled studies with optimal blinding. Thus, we aim to examine the feasibility and preliminary efficacy of a six-week follow up study examining the effects of a 4 week course of weekly administered nitrous oxide as compared to the active placebo, midazolam. METHODS: In this randomized, active placebo-controlled, pilot trial, 40 participants with treatment-resistant depression will receive either inhaled nitrous oxide (1 hour at 50% concentration) plus intravenous saline (100mL) or inhaled oxygen (1 hour at 50% concentration) plus intravenous midazolam (0.02 mg/kg in 100mL, up to 2mg) once per week, for 4 consecutive weeks. Participants will be followed up for 6 weeks starting from the first treatment visit. Primary feasibility outcomes include recruitment rate, withdrawal rate, adherence, missing data, and adverse events. The primary exploratory clinical outcome is change in Montgomery-Åsberg Depression Rating Scale (MADRS) score at day 42 of the study. Other exploratory clinical outcomes include remission (defined as MADRS score <10), response (defined as ≥ 50% reduction in MADRS score), and adverse side effects. DISCUSSION: This pilot study will provide valuable information regarding the feasibility and preliminary efficacy of repeated nitrous oxide administration over time for treatment-resistant depression. If feasible, this study will inform the design of a future definitive trial of nitrous oxide as an efficacious and fast-acting treatment for treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov NCT04957368. Registered on July 12, 2021.

Amygdala biomarkers of treatment response in major depressive disorder: An fMRI systematic review of SSRI antidepressants.

Functional neuroimaging studies have demonstrated abnormal activity and functional connectivity (FC) of the amygdala among individuals with major depressive disorder (MDD), which may be rectified with selective serotonin reuptake inhibitor (SSRI) treatment. This systematic review aimed to identify changes in the amygdala on functional magnetic resonance imaging (fMRI) scans among individuals with MDD who received SSRIs. A search for fMRI studies examining amygdala correlates of SSRI response via fMRI was conducted through OVID (MEDLINE, PsycINFO, and Embase). The end date was April 4th, 2023. In total, 623 records were screened, and 16 studies were included in this review. While the search pertained to SSRIs broadly, the included studies were escitalopram-, citalopram-, fluoxetine-, sertraline-, and paroxetine-specific. Decreases in event-related amygdala activity were found following 6-to-12-week SSRI treatment, particularly in response to negative stimuli. Eight-week courses of SSRI pharmacotherapy were associated with increased event-related amygdala FC (i.e., with the prefrontal [PFC] and anterior cingulate cortices, insula, thalamus, caudate nucleus, and putamen) and decreased resting-state effective connectivity (i.e., amygdala-PFC). Preliminary evidence suggests that SSRIs may alter amygdala activity and FC in MDD. Additional studies are needed to corroborate findings. Future research should employ long-term follow-ups to determine whether effects persist after treatment termination.

Temporal associations of BMI and glucose parameters with depressive symptoms among US adults.

As the prevalence of obesity, diabetes, and depression increases, it is important to examine how their associations are changing overtime. We investigated the temporal trends in the association between depressive symptoms, body mass index (BMI) and glucose profile parameters using data from 2005 to 2018 National Health and Nutrition Examination Survey. Depressive symptoms were assessed using the Patient Health Questionnaire. A total of 32,653 participants were included. Risk of depressive symptoms increased with higher BMI (aOR = 1.586, 95 % CI [1.364, 1.843]), insulin (aOR = 1.327, 95 % CI [1.159, 1.519]), HbA1c (aOR = 1.330, 95 % CI [1.116, 1.585]), or fasting glucose (aOR = 1.565, 95 % CI [1.247, 1.964]) levels compared to those with low levels. Sex differences were found, as overweight males had lower odds of depressive symptoms compared to healthy males, while overweight and obese females had higher odds compared to healthy females. High BMI and glucose parameters were consistently associated with higher depressive symptoms prevalence over time. Temporal variations were observed in the depressive symptoms-BMI and depressive symptoms-HbA1c associations, particularly at the 2007-2008 cycle. This study provides analytic insights into population level trends concerning physical and mental health problems.

Digital Interventions for Stress Among Frontline Health Care Workers: Results From a Pilot Feasibility Cohort Trial.

BACKGROUND: The COVID-19 pandemic has challenged the mental health of health care workers, increasing the rates of stress, moral distress (MD), and moral injury (MI). Virtual reality (VR) is a useful tool for studying MD and MI because it can effectively elicit psychophysiological responses, is customizable, and permits the controlled study of participants in real time. OBJECTIVE: This study aims to investigate the feasibility of using an intervention comprising a VR scenario and an educational video to examine MD among health care workers during the COVID-19 pandemic and to use our mobile app for longitudinal monitoring of stress, MD, and MI after the intervention. METHODS: We recruited 15 participants for a compound intervention consisting of a VR scenario followed by an educational video and a repetition of the VR scenario. The scenario portrayed a morally challenging situation related to a shortage of life-saving equipment. Physiological signals and scores of the Moral Injury Outcome Scale (MIOS) and Perceived Stress Scale (PSS) were collected. Participants underwent a debriefing session to provide their impressions of the intervention, and content analysis was performed on the sessions. Participants were also instructed to use a mobile app for 8 weeks after the intervention to monitor stress, MD, and mental health symptoms. We conducted Wilcoxon signed rank tests on the PSS and MIOS scores to investigate whether the VR scenario could induce stress and MD. We also evaluated user experience and the sense of presence after the intervention through semi-open-ended feedback and the Igroup Presence Questionnaire, respectively. Qualitative feedback was summarized and categorized to offer an experiential perspective. RESULTS: All participants completed the intervention. Mean pre- and postintervention scores were respectively 10.4 (SD 9.9) and 13.5 (SD 9.1) for the MIOS and 17.3 (SD 7.5) and 19.1 (SD 8.1) for the PSS. Statistical analyses revealed no significant pre- to postintervention difference in the MIOS and PSS scores (P=.11 and P=.22, respectively), suggesting that the experiment did not acutely induce significant levels of stress or MD. However, content analysis revealed feelings of guilt, shame, and betrayal, which relate to the experience of MD. On the basis of the Igroup Presence Questionnaire results, the VR scenario achieved an above-average degree of overall presence, spatial presence, and involvement, and slightly below-average realism. Of the 15 participants, 8 (53%) did not answer symptom surveys on the mobile app. CONCLUSIONS: Our study demonstrated VR to be a feasible method to simulate morally challenging situations and elicit genuine responses associated with MD with high acceptability and tolerability. Future research could better define the efficacy of VR in examining stress, MD, and MI both acutely and in the longer term. An improved participant strategy for mobile data capture is needed for future studies. TRIAL REGISTRATION: ClinicalTrails.gov NCT05001542; https://clinicaltrials.gov/study/NCT05001542. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/32240.