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.

Stressors and coping mechanisms among pregnant women with psychiatric disorders during the COVID-19 pandemic.

BACKGROUND: Women with psychiatric disorders are vulnerable to relapse in pregnancy, and the COVID-19 pandemic has presented an additional stressor. METHODS: Data came from a supplemental study offered to women enrolled in the Massachusetts General Hospital Center for Women's Mental Health National Pregnancy Registry for Psychiatric Medications. Registry participants were also invited to complete an email questionnaire relating to their experiences of pregnancy during the pandemic. Prepartum experiences of 230 respondents were analyzed. RESULTS: The most common diagnoses in this group were depression (30%), anxiety disorders (29%), and bipolar affective disorder (17%). Common stressors included changes in employment, greater childcare and/or schooling responsibilities, more conflict in the household, and increased isolation. Participants reported negative impacts and/or coping mechanisms associated with the pandemic, such as sleep problems, reduced physical activity, changes in eating, and greater amounts of screen time. Positive impacts and/or coping mechanisms were also reported, including more quality time with family, more time in nature, and being more appreciative of aspects of life previously taken for granted. CONCLUSIONS: Our findings suggest that the COVID-19 pandemic has had an overall negative psychosocial impact on many pregnant women with preexisting psychiatric disorders. We also observed positive coping mechanisms, which could be drawn on as sources of resilience.

Pharmacotherapy: Ketamine and Esketamine.

Ketamine and esketamine have rapid-onset antidepressant effects and may be considered for the management of treatment-resistant depression. Intranasal esketamine has regulatory approval in the United States and European Union. Intravenous ketamine is often administered off-label as an antidepressant, though no standard operating procedures exist. Repeated administrations and the use of a concurrent standard antidepressant may maintain antidepressant effects of ketamine/esketamine. Possible adverse effects of ketamine and esketamine include psychiatric, cardiovascular, neurologic and genitourinary effects, and the potential for abuse. The long-term safety and efficacy of ketamine/esketamine as antidepressants require further study.

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.

Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study.

Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression (DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam.Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage.Results: Benzodiazepine users did not differ from non-users on the original study's primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 (P = .018) and Clinical Global Impressions-Severity of Illness scale (CGI-S; P = .008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1.Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion.Trial Registration: ClinicalTrials.gov identifier: NCT01920555.

Antidepressants in children and adolescents with major depressive disorder and the influence of placebo response: A meta-analysis.

BACKGROUND: There are few available antidepressants for pediatric Major Depressive Disorder (MDD). The objective of this systematic review and meta-analysis was to review industry-funded studies of antidepressants in children and adolescents with MDD, and to better understand the contribution of study design and placebo response to the findings of these studies. METHODS: Randomized, double-blind, placebo-controlled clinical trials that compared antidepressant with placebo for the acute treatment of MDD in children and/or adolescents were selected. Estimates of the standardized mean difference (SMD) in change in Children's Depression Rating Scale-Revised scores were pooled, after examining for heterogeneity. A random-effects meta-analysis was completed. RESULTS: Thirty-four antidepressant-placebo comparisons, involving 6161 subjects, were included. The SMD among all studies was 0.12 (CI 0.08, 0.17; p < 0.001), a very small effect size, lower than that seen in studies of adults with MDD. When the meta-analysis was limited to studies with a low mean placebo response, the SMD increased to 0.19 and further increased to 0.22 when studies with at least a 50% chance of receiving placebo were included. LIMITATIONS: Many studies focused on older children and younger adolescents. Our findings may not reflect antidepressant efficacy in older adolescents. CONCLUSIONS: The modest SMD identified in this analysis may reflect study design factors and the application of antidepressants developed for adults to pediatric patients. Given the urgent clinical need for more pediatric MDD treatments, the influence of placebo response and the need for drug development tailored to this population should be considered in pediatric MDD trial design.

Perinatal experiences of pregnant women with psychiatric disorders during the COVID-19 pandemic.

OBJECTIVE: We sought to examine the impact of the COVID-19 pandemic on the pregnancy, delivery and postpartum experiences of women with histories of psychiatric disorders. METHOD: Women already enrolled in a United States registry which prospectively studies the relationship between the use of psychiatric medications during pregnancy and major congenital malformations were invited to participate in this study. Subjects were asked about their experiences across the pandemic through interviews during pregnancy and the postpartum period and through an emailed questionnaire. Data were collected between May 2020 and February 2021. RESULTS: Interview and email questionnaire data were collected from 488 individuals. Most participants reported disruption, or planned changes, to their perinatal care due to the pandemic. Women expressed concerns about reduced postpartum support, and the reduction of positive social interactions and opportunities for family/friends to bond with the baby. CONCLUSION: Our findings suggest that the pandemic has had a negative impact on the experiences of many pregnant women with pre-existing psychiatric disorders, particularly in relation to changes in care and perceived social support. Given that the risk of relapse of psychiatric disorders is already high in the postpartum period, it is important to identify what factors cause most distress for this at-risk population.

Vortioxetine Versus Placebo for Major Depressive Disorder: A Comprehensive Analysis of the Clinical Trial Dataset.

Objective: To conduct a meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD).Data Sources: Abstracts were identified using PubMed by cross-referencing vortioxetine with placebo and randomized. No language or publication year restrictions were used.Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD.Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, and mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HARS), and Digit Symbol Substitution Test (DSST).Results: 7,269 subjects randomized to vortioxetine (n = 3,630) or placebo (n = 3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate = 4.1, P = .54). The standardized mean difference (SMD) (95% CI) for change in MADRS score for vortioxetine overall versus placebo was 0.33 (0.24 to 0.41) and was 0.24 (0.08 to 0.39), 0.33 (0.19 to 0.47), 0.26 (-0.06 to 0.58), and 0.44 (0.27 to 0.62) for 5-mg, 10-mg, 15-mg, and 20-mg doses, respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low rather than a high placebo response rate.Conclusions: Vortioxetine is more effective than placebo in improving depression, anxiety, and cognition. Less informative or uninformative studies obscured the true treatment effect.

The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study.

This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days post infusion. Clinically significant suicidal ideation was defined as a MADRS suicide item score ≥2. Forty patients who received IV ketamine and 16 who received IV midazolam had suicide item scores of ≥2 at baseline (IV ketamine group mean 2.90±0.74; IV midazolam group 2.69±0.70). The mean suicide scores of these groups differed significantly from each other on day 30; the IV ketamine group had a lower mean score than controls (2.03±1.59 vs. 3.00±1.41, t-test p = 0.049; Hedges' g 0.71). Among patients with a suicide score of ≥2 at baseline and <2 at day 3, the two groups did not differ significantly on mean scores changes at days 3, 5, 7, 14 or 30. Recurrence of suicidal ideation was extensive in both treatment groups. A single infusion of IV ketamine may reduce suicidal ideation in TRD out to 30 days post infusion, but early anti-suicidal effects appear to diminish rapidly. This post-hoc analysis was not powered to compare different doses of ketamine. A single infusion of IV ketamine might have a role as an adjunct to standard treatments in patients with TRD and suicidal ideation. Trial registration: NCT01920555.

Burnout, Work Satisfaction, and Well-being Among Non-consultant Psychiatrists in Ireland.

OBJECTIVE: The aim of this study was to explore the areas of psychological well-being, satisfaction at work, and burnout among non-consultant psychiatrists in Ireland, and to assess for potential contributory factors. METHODS: The College of Psychiatrists of Ireland distributed the survey online to 100 non-consultant psychiatry doctors working in Ireland. The survey contained questions relating to demographic and work-related variables, the Abbreviated-Maslach Burnout Inventory (a-MBI), Basic Needs Satisfaction at Work (BNSW) scale, and WHO-5 Well-being Index. Descriptive statistics were used by the authors to summarize the data and univariate associations were explored between baseline data and subscales. RESULTS: Sixty-nine percent of our sample completed the survey. Thirty-six percent of the sample met the criteria for burnout, with lack of supervision the only variable significantly associated with this. Lack of regular supervision was associated with lower scores across all work satisfaction domains of the BNSW scale. The WHO-5 Well-being Index identified that 30% of respondents scored low in personal well-being, indicating that this proportion screened positive for depression, based on international diagnostic criteria. Lack of regular supervision was found to be significantly associated with low psychological well-being. CONCLUSION: This study indicates that lack of supervision is significantly associated with burnout, lower satisfaction at work, and poorer psychological well-being. Close evaluation of these areas is important to identify vulnerable individuals and areas of training which can be improved upon, which may lead to relevant measures being implemented for the benefit of psychiatrists, patients, and the wider society.

Police Involvement in Involuntary Psychiatry Admission: A Report From the Dublin Involuntary Admission Study.

OBJECTIVE: The authors sought to compare diagnostic and demographic factors among patients who were involuntarily admitted to psychiatry care with or without police involvement. METHODS: All admissions to psychiatry units in two university hospitals in Ireland were studied over a 3.5-year period. RESULTS: Of 2,715 admissions, 443 (16%) were involuntary; complete data were available for 390 of these involuntary admissions, of which 78 (20%) involved police. Patients with police involvement did not differ significantly from those without police involvement in gender, marital and employment status, or diagnosis. The former patients had a longer mean admission duration and were more likely to be admitted under the "risk criterion" of the Mental Health Act 2001. Multivariable testing indicated that these variables do not independently predict police involvement. CONCLUSIONS: The diagnostic or demographic factors examined did not contribute to police involvement in involuntary admission. Features such as homelessness, social exclusion, or criminogenic factors might underlie police involvement.

Gender, diagnosis and involuntary psychiatry admission in Ireland: A report from the Dublin Involuntary Admission Study (DIAS).

Involuntary admission and treatment are common, long-standing features of psychiatry but the relationships between gender, diagnosis and other features of involuntary treatment are not clear. We studied all voluntary and involuntary psychiatry admissions at Tallaght University Hospital, Dublin over 2 years (n = 1230). Admission rates in Tallaght were lower than national rates for all admissions (224.9 admissions per 100,000 population per year in Tallaght versus 376.8 nationally), voluntary admissions (194.0 versus 328.4) and involuntary admissions (30.9 versus 48.4). Compared to men, proportionately fewer admissions of admissions of women were involuntary (11% versus 16%) and women were more commonly diagnosed with affective (mood) disorders (29.5% of women versus 22.6% of men), neuroses (anxiety disorders) (14.0% versus 8.8%) and personality and behavioural disorders (18.0% versus 9.2%), and less commonly diagnosed with schizophrenia group disorders (21.8% versus 32.0%), alcohol disorders (2.9% versus 4.3%) and drug disorders (3.6% versus 8.1%). Schizophrenia group disorders accounted for a greater proportion of male (63.2%) than female (55.6%) involuntary admissions, and affective disorders accounted for a greater proportion of female (17.5%) than male (12.3%) involuntary admissions. Duration of admission was independently associated with, in order of strength of association, involuntary status, schizophrenia group disorders and increasing age, but duration of involuntary care was not associated with any of these factors. The chief gender-related features of involuntary psychiatry admission are that (a) proportionately fewer admissions of admissions of women are involuntary compared to men, and (b) diagnoses of affective disorders are more common in women, and schizophrenia group diagnoses more common in men. Future research could usefully explore gender differences in grounds for involuntary detention and police involvement in the involuntary admission process. Future research is also warranted into whether gender associations differ in older compared to younger involuntary patients.

Validation of the actical activity monitor in middle-aged and older adults.

PURPOSE: This study was designed to validate the Actical activity monitor in middle-aged and older adults of varying body composition to develop accelerometer thresholds to distinguish between light and moderate intensity physical activity (PA). METHODS: Nonobese 45 to 64 yr (N = 29), obese 45 to 64 yr (N = 21), and ≥65 yr (N = 23; varying body composition) participants completed laboratory-based sitting, household, and locomotive activities while wearing an Actical monitor and a portable metabolic measurement system. Nonlinear regression analysis was used to identify activity count (AC) cut-points to differentiate between light intensity (<3 METs) and moderate intensity (≥3METs) PA. RESULTS: Using group-specific algorithms, AC cut points for 3 METs were 1634, 1107, and 431 for the obese 45 to 64 yr group, nonobese 45 to 64 yr group, and ≥65 yr group, respectively. However, sensitivity and specificity analysis revealed that an AC cut-point of 1065 yielded similar accuracy for detecting an activity as less than or greater than 3 METs, regardless of age and body composition. CONCLUSION: For the Actical activity monitor, an AC cut-point of 1065 can be used to determine light and moderate intensity PA in people ≥45 years of age.

Comparing physical activity measures in a diverse group of midlife and older adults.

PURPOSE: To compare self-report and objective measures of moderate- and vigorous-intensity physical activity (MVPA min·d(-1)) in midlife and older adults. METHODS: Seventy-one participants (69% female, 74.6% Caucasian, 25.4% African American) completed the Behavioral Risk Factor Surveillance System physical activity (PA) questions, the Aerobic Center Longitudinal Study PA short survey (PASS), and the Aerobic Center Longitudinal Study PA long survey (PALS) and wore an accelerometer for seven consecutive days. Accelerometer MVPA minutes per day were determined using 1- and 10-min MVPA bout methods. RESULTS: Participants were older (mean ± SD; age = 57.4 ± 9.9 yr) and overweight (body mass index = 27.9 ± 4.9 kg·m(-2)) but otherwise healthy. Median (interquartile range) MVPA minutes per day were 42.9 (51.4) from the Behavioral Risk Factor Surveillance System PA questions, 51.4 (68.6) from the PASS, 25.7 (48.6) from the PALS, 32.4 (33.5) from the 1-min MVPA bout accelerometer data, and 4.6 (16.8) from the 10-min MVPA bout accelerometer data. Pearson correlations adjusted for participant demographics revealed low to moderate correlations between self-report and 1-min MVPA bout accelerometer-determined MVPA minutes per day (r = 0.11-0.31), with the PASS (P < 0.05) and PALS (P < 0.01) having significant correlations with accelerometry. Cohen κ coefficients showed poor agreement between all three questionnaires and 1-min MVPA bout accelerometry for having ≥150 MVPA min·wk(-1) (κ = 0.26-0.38, all P < 0.05). CONCLUSIONS: Our results indicate that there was poor agreement between self-report and accelerometer-based assessments of PA in midlife and older adults.

The acute effects of static and ballistic stretching on vertical jump performance in trained women.

Traditionally stretching has been included as part of a warm-up that precedes athletic participation. However, there is mixed evidence as to whether stretching actually enhances or hinders athletic performance. Therefore, the purpose of this study was to examine the acute effects of static (SS) and ballistic stretching (BS) on vertical jump (VJ) performance and to investigate whether power was altered at 15 and 30 minutes after stretching. Sixteen actively trained women performed a series of vertical jumps (countermovement and drop jumps) after an initial nonstretching (NS) session and after participating in BS and SS sessions that were conducted in a balanced and randomized order. The results indicated that there was no significant difference (p < 0.05) in VJ scores as a result of static or ballistic stretching, elapsed time, or initial flexibility scores. This suggests that stretching prior to competition may not negatively affect the performance of trained women.