Evaluation of the Efficacy and Safety of Intravenous Immunoglobulin (IVIG) in Moderate-to-Severe Hospitalized COVID-19 Patients: A Randomized, Open-Label Parallel-Group Study.

Purpose: Since February 2020, the world has been overwhelmed by the SARS-CoV-2 outbreak, and several patients suffered interstitial pneumonia and respiratory failure requiring mechanical ventilation, threatening the capability of healthcare systems to handle this amount of critical cases. Intravenous immunoglobulins (IVIG) possess potential immunomodulatory properties beneficial for COVID-19 patients, yet evidence supporting IVIG as adjunctive therapy remains sparse. This study evaluated the outcomes of adjunctive IVIG with the standard of care (SoC) in moderate-to-severe COVID-19 patients. Methods: This randomized study included 59 moderate-to-severe COVID-19 patients with known comorbidities. One arm (n = 33) received high-dose IVIG (400 mg/kg/day) within 48 hours for five days alongside SoC, while the other arm (n = 26) received SoC, comprising steroids, enoxaparin, and remdesivir. The primary endpoint was clinical improvement, as measured by the National Early Warning Score 2 (NEWS2) and discharged/death proportions. Secondary outcomes included IVIG safety, hospitalization duration, changes in oxygen saturation, inflammatory markers, IgG titer, CTSS (CT severity score), and radiological findings. Results: There was an improvement in the NEWS2 at the end of treatment in the IVIG arm (5.67 vs. 5.96). A significant absolute effect improvement (Day 1 vs. Day 9) was seen in serum LDH, D-dimer, hs-CRP, IL-6, CTSS, procalcitonin, respiratory rate, and chest radiographic findings. SARS-CoV-2 IgG titer increased significantly in the IVIG arm. There was a statistically significant reduction in mortality in the IVIG group (5 vs. 10). Conclusion: IVIG was a safe and effective adjunctive therapy to SoC treatment in moderate-to-severe COVID-19 patients needing ventilatory support. Furthermore, studies are required to validate our findings. This trial is registered with CTRI/2021/05/033622.

Comparing Perfusion Index and Visual Analogue Scores for Postoperative Pain Assessment Following Upper Limb Surgeries Under Supraclavicular Brachial Plexus Block: An Observational Study.

BACKGROUND: Effective pain assessment is crucial to tailor the analgesic regimen post-operatively. Perfusion index (PI) has been reported to be a useful objective assessment tool for monitoring pain. This study aimed to explore the utility of PI in assessing postoperative pain in upper limb surgeries under supraclavicular block and its correlation with visual analogue scale (VAS) scores. METHODS: This prospective, observational study included 140 patients scheduled for elective upper limb surgeries. PI, VAS scores, heart rate (HR), mean arterial pressure (MAP) and physiological parameters were recorded at baseline and postoperatively. Inj. tramadol was administered when the VAS score exceeded ≥ 4 and the VAS score, PI, HR and MAP were recorded at 5, 10, 15 and 20 minutes after administration. Comparison of normally and non-normally distributed data was done using t-statistics and Mann-Whitney U-test respectively. Pearson correlation was used to establish a correlation between variables and the receiver operating characteristic (ROC) curve was used to calculate the cut-off value of PI to determine the onset of pain. RESULTS: There was a significant and moderate correlation between pre-analgesic and post-analgesic PI and VAS score (r = -0.425 and -0.448 respectively, p<0.001), while PI and MAP or PI and HR showed only a weak correlation. A cut-off value of 14.7 for PI showed 76.3% sensitivity and 100% specificity in predicting rescue analgesia requirements. CONCLUSION: The study supports the use of PI as an objective measure for postoperative pain assessment, with a notable correlation with VAS scores. The identified cut-off value for PI adds to its clinical utility in predicting the need for rescue analgesia.

Problematic substance use in depressed adolescents: Prevalence and clinical correlates.

Background: Substance use among adolescents is common and associated with significant consequences, including depression. Adolescents can experience myriad problems related to early onset substance use and depression, making further understanding of this comorbidity necessary. Method: Participants were a subset from a large-scale performance improvement project and consisted of adolescents aged 12-18 who screened positive for depression during their routine medical or psychiatric appointment and who then completed the substance use assessment Car, Relax, Alone, Forget, Friends, Trouble Version 2.1 (CRAFFT). Participants with problematic substance use had a CRAFFT score ≥2. Results: A total of 621 participants were included in this study, and 105 (16.9%) reported problematic substance use. Compared with participants without problematic substance use, those with problematic use were more likely to have moderate to severe depression and anxiety, as well as significantly higher irritability, impulsivity, suicidal propensity, and suicidal thoughts scores. Controlling for age at screening, sex, race, and ethnicity, problematic substance use remained a significant predictor of depression severity, impulsivity, suicidal propensity, and suicidal thoughts. Limitations: Participants were from a large, metropolitan area of the Southwest United States who must have screened positive for depression, so results may not generalize. Because all participants were underage, they may have been wary in responding to the substance use assessment accurately. Conclusions: By using a large, diverse sample in a real-world clinical setting, findings strengthen the association between problematic substance use and depression and depression-associated symptoms among adolescents, highlighting the need for early detection and universal depression screening.

Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Treatment of Adolescent Depression: Comparison of Psychiatric and Pediatric Settings at an Academic Medical Center Using the VitalSign6 Application.

Background: Similar outcomes and remission rates have been found for the treatment of depression in adults in primary and psychiatric care settings. However, comparatively little is known about how pediatric depression is managed across different settings. This study aims to address this gap by comparing depression treatment in pediatric and psychiatric settings. We hypothesized that pediatric care settings would be more likely to treat individuals with lower depression severity and would select pharmacotherapy less frequently as a treatment option. Methods: Patients (n = 3498) were screened for depression at a children's hospital from May 2017 to May 2022 as part of the VitalSign6 project, a web-based application for depression management. The two-item patient health questionnaire (PHQ) was used for screening, and the data set contains patient-reported measures and provider-reported diagnoses and treatment selections at each clinic visit. Patients with nine-item PHQ (PHQ-9) scores ≥10 at baseline were included in the analysis to compare diagnosis and treatment recommendations between pediatric and psychiatric settings. Results: Among the 1323 patients who screened positive for depression, those in psychiatric settings had higher PHQ-9 scores (15.9 ± 5.0 vs. 12.1 ± 5.5; p < 0.0001). Patients with PHQ-9 ≥ 10 in psychiatric settings were more likely to be diagnosed with major depressive disorder (60.6% vs. 24.7%, p < 0.0001) and receive pharmacotherapy (54.8% vs. 6.6%) than those in pediatric settings. Pediatric setting patients were more likely to receive nonpharmacological treatment alone (36.3% vs. 4.3%) or an outside referral (27.7% vs. 5.7%). Remission rates did not significantly differ between the two settings. Conclusions: Youth in psychiatric settings are more likely to screen positive for depression and to have greater depression severity than those in pediatric settings. Both settings provide treatment recommendations for moderate-to-severe depression, but treatment types vary substantially. Yet, remission rates remain similar. Further research is needed to understand the nuances of treatment differences and their implications.

Anti-suicidal effects of IV ketamine in a real-world setting.

The current study evaluated the effectiveness of intravenous ketamine treatment for suicidality in a community-based clinical sample of 295 outpatients (mean age=  40.37; 58.6 % male). We conducted growth mixture modeling to estimate latent classes of changes in symptoms of suicidality measured by the Concise Health Risk Tracking - Self-Report (CHRT-SR) across five infusions in a two-week course of treatment. Best-fit indices indicated three trajectory groups demonstrating non-linear, quadratic changes in CHRT-SR scores during ketamine treatment. The largest group of patients (n=  170, 57.6 %) had moderate CHRT-SR scores at baseline and showed gradual improvement during treatment. The other two groups of patients had severe CHRT-SR scores at baseline and diverged into one group with no improvement throughout treatment (n = 63, 21  %) and one group with rapid improvement (n = 62, 21 %). Of the clinical and demographic variables available and tested, only higher scores pertaining to active thoughts of death and/or plan were found to predict which of the patients with severe CHRT-SR scores at baseline would not benefit from treatment. The present study provides an important contribution to the knowledge of ketamine's effects on symptoms related to suicide over time. providing support for the possible effectiveness of ketamine in a proportion of patients.

Data-driven subgrouping of youths with depression reveals that resilience is associated with higher physical functioning despite high symptom burden in the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) measure, which assesses past week status of seven domains (physical function mobility, anxiety, depressive symptoms, fatigue, peer relationships, pain interference, and pain intensity), represents a new paradigm using patient-reported outcomes. We used a data-driven approach with PROMIS to identify subgroups of youths receiving depression treatment. METHODS: Youths (n = 721) enrolled in the Texas Youth Depression and Suicide Research Network who completed the PROMIS were analyzed. Latent class analyses (LCAs) identified subgroups and compared their baseline clinical/sociodemographic features. RESULTS: Compared to population norms, our sample had worse than average physical function, anxiety, depression, fatigue, and pain interference. Using LCA, four subgroups were identified: 1) lower symptom severity and higher physical functioning (14.6 %); 2) higher symptom burden, higher pain interference/intensity, and lower physical functioning (52.7 %); 3) higher symptom burden, higher pain interference/intensity, but with higher physical functioning (9.2 %); and 4) higher symptom burden, but lower physical functioning and pain interference/intensity (23.6 %). Group 3 demonstrated higher resilience than Group 2. In contrast, Group 2 had higher anxiety than Group 4. LIMITATIONS: Individuals may have different symptom profiles due to the observational nature of the study. Replication of these subgroups may be difficult, as future samples may differ in these characteristics. Further work may demonstrate the stability of these groups. CONCLUSIONS: A data-driven analysis identified a small but significant subgroup with high physical functioning despite high symptom burden and pain, and this group reported higher resilience. Resilience-enhancing interventions may help improve functional outcomes in depressed youth.

Features of immunometabolic depression as predictors of antidepressant treatment outcomes: pooled analysis of four clinical trials.

BACKGROUND: Profiling patients on a proposed 'immunometabolic depression' (IMD) dimension, described as a cluster of atypical depressive symptoms related to energy regulation and immunometabolic dysregulations, may optimise personalised treatment. AIMS: To test the hypothesis that baseline IMD features predict poorer treatment outcomes with antidepressants. METHOD: Data on 2551 individuals with depression across the iSPOT-D (n = 967), CO-MED (n = 665), GENDEP (n = 773) and EMBARC (n = 146) clinical trials were used. Predictors included baseline severity of atypical energy-related symptoms (AES), body mass index (BMI) and C-reactive protein levels (CRP, three trials only) separately and aggregated into an IMD index. Mixed models on the primary outcome (change in depressive symptom severity) and logistic regressions on secondary outcomes (response and remission) were conducted for the individual trial data-sets and pooled using random-effects meta-analyses. RESULTS: Although AES severity and BMI did not predict changes in depressive symptom severity, higher baseline CRP predicted smaller reductions in depressive symptoms (n = 376, ßpooled = 0.06, P = 0.049, 95% CI 0.0001-0.12, I2 = 3.61%); this was also found for an IMD index combining these features (n = 372, ßpooled = 0.12, s.e. = 0.12, P = 0.031, 95% CI 0.01-0.22, I2= 23.91%), with a higher - but still small - effect size compared with CRP. Confining analyses to selective serotonin reuptake inhibitor users indicated larger effects of CRP (ßpooled = 0.16) and the IMD index (ßpooled = 0.20). Baseline IMD features, both separately and combined, did not predict response or remission. CONCLUSIONS: Depressive symptoms of people with more IMD features improved less when treated with antidepressants. However, clinical relevance is limited owing to small effect sizes in inconsistent associations. Whether these patients would benefit more from treatments targeting immunometabolic pathways remains to be investigated.

Choosing Between Ketamine and Electroconvulsive Therapy for Outpatients With Treatment-Resistant Depression-Advantage Ketamine?

This Viewpoint examines key issues stemming from several recent reports of electroconvulsive therapy (ECT) vs ketamine for improving depressive symptoms in treatment-resistant depression (TRD).

Reward Behavior Disengagement, a Neuroeconomic Model-Based Objective Measure of Reward Pathology in Depression: Findings from the EMBARC Trial.

The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengagement (RBD), our proposed economic augmentation of PRT, differs between MDD participants and controls, and whether there is a level at which RBD is high enough for depressed participants to be considered objectively disengaged. Data were gathered as part of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a double-blind, placebo-controlled clinical trial of antidepressant response. Participants included 195 individuals with moderate to severe MDD (Quick Inventory of Depressive Symptomatology (QIDS-SR) score ≥ 15), not in treatment for depression, and with complete PRT data. Healthy controls (n = 40) had no history of psychiatric illness, a QIDS-SR score < 8, and complete PRT data. Participants with MDD were treated with sertraline or placebo for 8 weeks (stage I of the EMBARC trial). RBD was applied to PRT data using discriminant analysis, and classified MDD participants as reward task engaged (n = 137) or reward task disengaged (n = 58), relative to controls. Reward task engaged/disengaged groups were compared on sociodemographic features, reward-behavior, and sertraline/placebo response (Hamilton Depression Rating Scale scores). Reward task disengaged MDD participants responded only to sertraline, whereas those who were reward task engaged responded to sertraline and placebo (F(1293) = 4.33, p = 0.038). Reward task engaged/disengaged groups did not differ otherwise. RBD was predictive of reward impairment in depressed patients and may have clinical utility in identifying patients who will benefit from antidepressants.

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.

The clinical, economic, and patient-centric burden of insomnia symptom severity in adults with major depressive disorder in the United States.

INTRODUCTION: Insomnia is prevalent in adults with major depressive disorder (MDD) and is a key diagnostic criterion of MDD; however, little is understood about the burden of insomnia symptom severity in MDD. We evaluated the relationship between insomnia symptom severity and the clinical, economic, and patient-centric burden among community-dwelling individuals with MDD. METHODS: Respondents with diagnosed depression who reported insomnia symptoms in the past 12 months (N = 4402) were identified from the 2019 United States National Health and Wellness Survey. Multivariable analyses assessed the association of Insomnia Severity Index (ISI) with health-related outcomes while controlling for sociodemographic and health characteristics. Further analyses also controlled for depression severity (9-item Patient Health Questionnaire). RESULTS: Mean ISI score was 14.3 ± 5.6. Higher ISI was associated with greater depression severity (r = .51, p < .001). After adjustments, a one-standard deviation (5.6-point) increase in ISI score was significantly associated with higher depression (rate ratio [RR] = 1.36), anxiety (RR = 1.33) and daytime sleepiness (RR = 1.16) levels, more healthcare provider (RR = 1.13) and emergency room visits (RR = 1.31), hospitalizations (RR = 1.21), work productivity and activity impairment (RRs = 1.27 and 1.23, respectively), and poorer mental and physical health-related quality of life (ß = -3.853 and -1.999, respectively) (p < .001). These findings remained statistically significant when controlling for concurrent depression severity. CONCLUSION: In adults with MDD, greater insomnia symptom severity is associated with worse health-related outcomes, which suggests the importance of addressing insomnia symptoms as a clinical target for treating MDD.

Psychosocial stress and well-being in patients presenting with acute myocardial infarction in a tertiary care center.

BACKGROUND: Psychosocial factors such as stress have been previously implicated as a risk factor for cardiovascular diseases (CVDs). There is little evidence regarding the prevalence of stress among patients with acute myocardial infarction (AMI). METHODS: A total of 903 patients with AMI enrolled in the North Indian ST-Segment Elevation Myocardial Infarction (NORIN-STEMI) registry were included in this study. Perceived stress in these subjects was evaluated using the Perceived Stress Scale-10 questionnaire while the World health Organization (WHO-5) Well-being Index was used to evaluate psychological well-being. All these patients were followed up for one month and major adverse cardiac events (MACE) were determined. RESULTS: A majority of patients with AMI had either severe (478 [52.9%]) or moderate stress (347 [38.4%]) while low stress levels were observed in 78 [8.6%] patients. Additionally, most of the patients with AMI (478 [53%]) had WHO-5 well-being index <50%. Subjects with severe stress were younger (50.86 ± 13.31; P < 0.0001), more likely to be males (403 [84.30%]; P = 0.027), were less likely to have optimal level of physical activity (P < 0.0001) and had lower WHO-5 well-being score (45.54 ± 1.94%; P < 0.0001) as compared to those with low and moderate stress levels. On 30-days follow-up, subjects with moderate/severe stress had higher MACE however, the difference was non-significant (2.1% vs 1.04%; P = 0.42). CONCLUSION: A high prevalence of perceived stress and low well-being index was observed in patients presenting with AMI in India.

Predicting suicidal events: A comparison of the Concise Health Risk Tracking Self-Report (CHRT-SR) and the Columbia Suicide Severity Rating Scale (C-SSRS).

This report examines the predictive capabilities of two scales of suicidality in high-risk adolescents. Charts of adolescents with severe suicidality participating in an intensive outpatient program were reviewed. Self-report data from the 9-item Concise Health Risk Tracking Self-Report (CHRT-SR9) and clinician-completed data from the Columbia Suicide Severity Risk Scale (C-SSRS) were obtained at entry. Scales' performances in predicting suicide attempts and suicidal events were evaluated using logistic regression models and ROC analyses. Of 539 adolescents, 53 had events of which 19 were attempts. The CHRT-SR9 total score predicted events (OR=1.05) and attempts (OR=1.09), as did the C-SSRS Suicide Ideation (SI) Intensity Composite for events (OR=1.10) and attempts (OR=1.16). The CHRT-SR9 AUC was 0.70 (84.2% sensitivity; 41.7% specificity; PPV=5.0%; NPV=98.6%) for attempts. The C-SSRS Intensity Composite AUC was 0.62 (89.5% sensitivity; 24.1% specificity; PPV=4.2%; NPV=98.4%) for attempts. Both the CHRT-SR9 and C-SSRS capture important parameters related to suicidal events or attempts that can help assess suicidal risk in adolescents.

The Individual and Societal Burden of Treatment-Resistant Depression: An Overview.

Major depressive disorder is characterized by depressed mood and/or anhedonia with neurovegetative symptoms and neurocognitive changes affecting an individual's functioning in multiple aspects of life. Treatment outcomes with commonly used antidepressants remain suboptimal. Treatment-resistant depression (TRD) should be considered after inadequate improvement with two or more antidepressant treatments of adequate dose and duration. TRD has been associated with increased disease burden including higher associated costs (both socially and financially) affecting both the individual and society. Additional research is needed to better understand the long-term burden of TRD to both the individual and society.

Approach to Diagnosis and Management of Treatment-Resistant Depression.

Major depressive disorder is a chronic and recurrent illness that affects 20% of adults during their lifetime and is one of the leading causes of suicide in the United States. A systematic measurement-based care approach is the essential first step in the diagnosis and management of treatment-resistant depression (TRD) by promptly identifying individuals with depression and avoiding delays in treatment initiation. As comorbidities may be associated with poorer outcomes to commonly used antidepressants and increase risk of drug-drug interactions, their recognition and treatment is an essential component of management of TRD.

Pharmacotherapy for Treatment-Resistant Depression: Antidepressants and Atypical Antipsychotics.

Treatment-resistant depression (TRD) affects one in three patients with major depressive disorder and is associated with increased risk of all-cause mortality. Studies of real-world practices suggest that antidepressant monotherapy continues to be the most widely used treatment after inadequate response to a first-line treatment. However, rates of remission with antidepressants in TRD are suboptimal. Atypical antipsychotics are the most widely studied augmentation agent and aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination are approved for depression. Benefits of using atypical antipsychotics for TRD has to be weighted against their potential adverse events, such as weight gain, akathisia, and tardive dyskinesia.

Role of Psychedelics in Treatment-Resistant Depression.

There is increasing interest in exploring the therapeutic potential of psychedelics in treatment-resistant depression (TRD). Classic psychedelics (such as psilocybin, LSD, ayahuasca/DMT), and atypical psychedelics (such as ketamine) have been studied in TRD. The evidence for the classic psychedelics TRD is limited at the present time; early studies however show promising results. There is also recognition that psychedelic research may be subject to a "hype bubble" at the present time. Future studies focused on delineating necessary ingredients of psychedelic treatments and the neurobiological basis of their effects, will help pave the way for the clinical use of these compounds.