Method development with high-throughput enhanced matrix removal followed by UHPLC-QqQ-MS/MS for analysis of grape polyphenol metabolites in human urine.

Grape and grape derived products contain many bioactive phenolics which have a variety of impacts on health. Following oral ingestion, the phenolic compounds and their metabolites may be detectable in human urine. However, developing a reliable method for the analysis of phenolic compounds in urine is challenging. In this work, we developed and validated a new high-throughput, sensitive and reproducible analytical method for the simultaneous analysis of 31 grape phenolic compounds and metabolites using Oasis PRiME HLB cleanup for sample preparation combined with ultra-performance liquid chromatography with triple quadrupole tandem mass spectrometry (UHPLC-QqQ-MS/MS). Using this new method, the accuracy achieved was 69.3 % ∼ 134.9 % (except for six compounds), and the recovery achieved was 52.4 % ∼ 134.7 % (except for two very polar compounds). For each of the 31 target analytes, the value of intra-day precision was less than 14.3 %. The value of inter-day precision was slightly higher than intra-day precision, with a range of 0.7 % ∼ 19.1 %. We report for the first time on the effect of gender and BMI on the accuracy and recovery of human urine samples, and results from analysis of variance (ANOVA), and principal component analysis (PCA) indicated there was no difference in the value of accuracy and recovery between different gender or BMI (>30) using our purposed cleanup and UHPLC-QqQ-MS/MS method. Overall, this newly developed method could serve as a powerful tool for analyzing grape phenolic compounds and metabolites in human urine samples.

Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Development and initial validation of the Mount Sinai Resilience Scale.

OBJECTIVE: The construct of psychological resilience has received increasing attention in the mental health field. This article describes the development and initial validation of a novel self-report resilience scale, which addresses gaps in the resilience measurement literature by assessing thoughts and behaviors that help promote resilience rather than traits, and simultaneously evaluating multiple factors previously associated with resilience. METHOD: Following consensus meetings focused on scale development, we conducted an online study (n = 1,864) of U.S. adults to develop and validate an initial version of the Mount Sinai Resilience Scale (MSRS). RESULTS: An exploratory factor analysis in a random 50% of the sample suggested a seven-factor solution; this solution was then generally supported by a follow-up confirmatory factor analysis in the remaining 50% of the sample. After removing poor-fitting items, a revised 24-item scale correlated in the expected directions with established measures of perceived resilience and resilience-related constructs (e.g., social support and optimism). CONCLUSIONS: Collectively, the results of this study provide initial support for the convergent and discriminant validity of the MSRS and describe its factor structure. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Social stress induces autoimmune responses against the brain.

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.

Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

Depression symptoms and cognition in multiple sclerosis: Longitudinal evidence of a specific link to executive control.

BACKGROUND: Depression symptoms are prevalent in multiple sclerosis (MS) and associated with poorer cognition in cross-sectional studies; it is unknown whether changes in depression symptoms track with cognitive changes longitudinally. OBJECTIVE: Investigate whether changes in depression symptoms correspond with cognitive changes over time in MS, and identify specific cognitive functions related to depression symptoms. METHOD: Persons with early relapse-onset MS (n = 165) completed a depression questionnaire (Beck Depression Inventory FastScreen) and tests of cognitive speed, executive control, and memory at baseline and 3-year follow-up. One-way ANOVAs assessed differences in cognitive change across participants with worsened, stable, or improved depression symptoms from baseline to year 3. RESULTS: Change in depression symptoms was related to change in executive control (p = 0.001, ηp2 = 0.08; worsened mood with worsened executive control; improved mood with improved executive control), even when adjusting for cognitive speed (p = 0.002, ηp2 = 0.08). There were no links to cognitive speed (p = 0.826) or memory (p = 0.243). Regarding individual depression symptoms, executive control was related to loss of pleasure and suicidal thoughts. CONCLUSIONS: Executive control tracks with depression symptoms, raising hope that management of mood may improve executive control. The specific link between executive control and anhedonia implicates dysfunctional reward processing as a key component of MS depression.

Using latent profile analyses to classify subjects with anhedonia based on reward-related measures obtained in the FAST-MAS study.

BACKGROUND: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. METHODS: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures. RESULTS: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures. LIMITATIONS: The main limitations include the small sample size and exploratory nature of analyses. CONCLUSIONS: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.

A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD. Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures. Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events. Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.Reprinted from Am J Psychiatry 2021; 178:193-202, with permission from American Psychiatric Association Publishing. Copyright © 2021.

Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Brain Features of Treatment-Resistant Depression: A Review of Structural and Functional Connectivity Magnetic Resonance Imaging Studies.

Increased awareness of the growing disease burden of treatment resistant depression (TRD), in combination with technological advances in MRI, affords the unique opportunity to research biomarkers that characterize TRD. We provide a narrative review of MRI studies investigating brain features associated with treatment-resistance and treatment outcome in those with TRD. Despite heterogeneity in methods and outcomes, relatively consistent findings include reduced gray matter volume in cortical regions and reduced white matter structural integrity in those with TRD. Alterations in resting state functional connectivity of the default mode network were also found. Larger studies with prospective designs are warranted.

Predictors of Mental Health Service Utilization among Frontline Healthcare Workers during the COVID-19 Pandemic.

(1) Background: This study examined the prevalence and correlates of factors associated with self-reported mental health service use in a longitudinal cohort of frontline health care workers (FHCWs) providing care to patients with COVID-19 throughout 2020. (2) Methods: The study comprised a two-wave survey (n = 780) administered in April-May 2020 (T1) and November 2020-January 2021 (T2) to faculty, staff, and trainees in a large urban medical center. Factors associated with initiation, cessation, or continuation of mental health care over time were examined. (3) Results: A total of 19.1% of FHCWs endorsed currently utilizing mental health services, with 11.4% continuing, 4.2% initiating, and 3.5% ceasing services between T1 and T2. Predisposing and need-related factors, most notably a history of a mental health diagnosis and distress related to systemic racism, predicted service initiation and continuation. Among FHCWs with a prior mental health history, those with greater perceived resilience were less likely to initiate treatment at T2. Descriptive data highlighted the importance of services around basic and safety needs (e.g., reliable access to personal protective equipment) relative to mental health support in the acute phase of the pandemic. (4) Conclusions: Results may be helpful in identifying FHCWs who may benefit from mental health services.

Reward-related self-agency is disturbed in depression and anxiety.

BACKGROUND: The sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of reward-dependent agency perception in an in-person and online cohort. METHODS: The in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort implementation for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency. RESULTS: All subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive feedback-dependent agency compared to healthy controls. Finally, in our online sample, we found that higher self-agency following negative-loss feedback was associated with worse anhedonia symptoms. CONCLUSION: Together this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety.

Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.

Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3,4,5, the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects with MDD as well as in stress-susceptible (SUS) mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), thereby altering social behaviour. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain-infiltrating monocytes of SUS mice showed increased Mmp8 expression following CSDS. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Stress-related reduction of hippocampal subfield volumes in major depressive disorder: A 7-Tesla study.

Background: Major depressive disorder (MDD) is a prevalent health problem with complex pathophysiology that is not clearly understood. Prior work has implicated the hippocampus in MDD, but how hippocampal subfields influence or are affected by MDD requires further characterization with high-resolution data. This will help ascertain the accuracy and reproducibility of previous subfield findings in depression as well as correlate subfield volumes with MDD symptom scores. The objective of this study was to assess volumetric differences in hippocampal subfields between MDD patients globally and healthy controls (HC) as well as between a subset of treatment-resistant depression (TRD) patients and HC using automatic segmentation of hippocampal subfields (ASHS) software and ultra-high field MRI. Methods: Thirty-five MDD patients and 28 HC underwent imaging using 7-Tesla MRI. ASHS software was applied to the imaging data to perform automated hippocampal segmentation and provide volumetrics for analysis. An exploratory analysis was also performed on associations between symptom scores for diagnostic testing and hippocampal subfield volumes. Results: Compared to HC, MDD and TRD patients showed reduced right-hemisphere CA2/3 subfield volume (p = 0.01, η 2 = 0.31 and p = 0.3, η 2 = 0.44, respectively). Additionally, negative associations were found between subfield volumes and life-stressor checklist scores, including left CA1 (p = 0.041, f 2 = 0.419), left CA4/DG (p = 0.010, f 2 = 0.584), right subiculum total (p = 0.038, f 2 = 0.354), left hippocampus total (p = 0.015, f 2 = 0.134), and right hippocampus total (p = 0.034, f 2 = 0.110). Caution should be exercised in interpreting these results due to the small sample size and low power. Conclusion: Determining biomarkers for MDD and TRD pathophysiology through segmentation on high-resolution MRI data and understanding the effects of stress on these regions can enable better assessment of biological response to treatment selection and may elucidate the underlying mechanisms of depression.

A randomized pilot study of the prophylactic effect of ketamine on laboratory-induced stress in healthy adults.

Background: Stress exposure is a key risk factor for the development of major depressive disorder and posttraumatic stress disorder. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced disorders. The administration of ketamine one week prior to an acute stressor prevents the development of stress-induced depressive-like behavior in rodents. This study aimed to test if the prophylactic effect of ketamine against stress also applies to humans. Methods: We conducted a double-blind, placebo-controlled study wherein 24 healthy subjects (n = 11 males) were randomized to receive either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) intravenously one week prior to an acute stress [Trier Social Stress Test (TSST)]. The primary endpoint was the anxious-composed subscale of the Profile of Mood States Bipolar Scale (POMS-Bi) administered immediately after the TSST. Salivary and plasma cortisol and salivary alpha amylase were also measured at 15-min intervals for 60 min following the stressor, as proxies of hypothalamic pituitary adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axis activity, respectively. Results: Compared to the midazolam group (n = 12), the ketamine group (n = 12) showed a moderate to large (Cohen's d = 0.7) reduction in levels of anxiety immediately following stress, although this was not significant (p = 0.06). There was no effect of group on change in salivary cortisol or salivary alpha amylase following stress. We conducted a secondary analysis excluding one participant who did not show an expected correlation between plasma and salivary cortisol (n = 23, ketamine n = 11). In this subgroup, we observed a significant reduction in the level of salivary alpha amylase in the ketamine group compared to midazolam (Cohen's d = 0.7, p = 0.03). No formal adjustment for multiple testing was made as this is a pilot study and all secondary analyses are considered hypothesis-generating. Conclusions: Ketamine was associated with a numeric reduction in TSST-induced anxiety, equivalent to a medium-to-large effect size. However, this did not reach statistical significance . In a subset of subjects, ketamine appeared to blunt SAM reactivity following an acute stressor. Future studies with larger sample size are required to further investigate the pro-resilient effect of ketamine.

Rapidity of Symptom Improvement With Intranasal Esketamine for Major Depressive Disorder: A Systematic Review and Meta-Analysis.

Objective: Rapid-acting treatment options are needed for major depressive disorder (MDD). The objective of this systematic review and meta-analysis was to estimate the magnitude of the treatment effect for intranasal esketamine over placebo at 24 hours after the first dose and at endpoint.Data Sources: PubMed, abstracts of major psychiatric meetings, and ClinicalTrials.gov were searched up to November 2020 with no language constraints, cross-referencing the term intranasal with esketamine and randomized.Study Selection: Of 27 studies reviewed, 8 articles, with a total of 1,437 patients with MDD, met study criteria and were included in the meta-analysis.Data Extraction: Randomized, double-blind clinical trials comparing adjunctive treatment of standard antidepressants with intranasal esketamine for MDD, using intranasal placebo augmentation as a comparator, were selected.Results: Estimates of the standardized mean difference (SMD) in change scores were pooled after examining for homogeneity using the test statistic proposed by DerSimonian and Laird. Findings of the random effects model were presented. Augmentation of standard antidepressants with intranasal esketamine resulted in greater Montgomery-Asberg Depression Rating Scale (MADRS) score reduction than adjunctive intranasal placebo at 24 hours. Across the trials, the SMD was 0.34 (95% CI = 0.11 to 0.46, P < .0001) with a 2.9-point greater mean MADRS score reduction following intranasal esketamine versus active control plus intranasal saline. A similar finding was evident at endpoint.Conclusions: This updated systematic review and meta-analysis found that augmentation of antidepressants with intranasal esketamine was statistically and clinically more effective in reducing depression severity than augmentation with placebo, at both 24 hours and study endpoint. Future studies are needed to evaluate dose-response relationship for esketamine.

Ventral tegmental area integrity measured with high-resolution 7-Tesla MRI relates to motivation across depression and anxiety diagnoses.

The ventral tegmental area (VTA) is one of the major sources of dopamine in the brain and has been associated with reward prediction, error-based reward learning, volitional drive and anhedonia. However, precise anatomical investigations of the VTA have been prevented by the use of standard-resolution MRI, reliance on subjective manual tracings, and lack of quantitative measures of dopamine-related signal. Here, we combine ultra-high field 400 µm3 quantitative MRI with dopamine-related signal mapping, and a mixture of machine learning and supervised computational techniques to delineate the VTA in a transdiagnostic sample of subjects with and without depression and anxiety disorders. Subjects also underwent cognitive testing to measure intrinsic and extrinsic motivational tone. Fifty-one subjects were scanned in total, including healthy control (HC) and mood/anxiety (MA) disorder subjects. MA subjects had significantly larger VTA volumes compared to HC but significantly lower signal intensity within VTA compared to HC, indicating reduced structural integrity of the dopaminergic VTA. Interestingly, while VTA integrity did not significantly correlate with self-reported depression or anxiety symptoms, it was correlated with an objective cognitive measure of extrinsic motivation, whereby lower VTA integrity was associated with lower motivation. This is the first study to demonstrate a computational pipeline for detecting and delineating the VTA in human subjects with 400 µm3 resolution. We highlight the use of objective transdiagnostic measures of cognitive function that link neural integrity to behavior across clinical and non-clinical groups.