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.

RORγt-Expressing Pathogenic CD4+ T Cells Cause Brain Inflammation during Chronic Colitis.

Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohn's disease and ulcerative colitis patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease patients remains unknown. Studies have linked the Th17 subset of CD4+ T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis, ischemic brain injury, and Alzheimer's disease. To better understand how CD4+ T lymphocytes contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4+ T cells infiltrate the brain of colitic Rag1 -/- mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4+ T cells expressed Th17 cell transcription factor retinoic acid-related orphan receptor γt (RORγt) and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of RORγt-deficient naive CD4+ T cells failed to cause brain inflammation and neurobehavioral disorders in Rag1 -/- recipients, with significantly less brain infiltration of CD4+ T cells. The finding is mirrored in chronic dextran sulfate sodium-induced colitis in Rorcfl/fl Cd4-Cre mice that showed lower frequency of brain-infiltrating CD4+ T cells and astrogliosis despite onset of significantly more severe colitis compared with wild-type mice. These findings suggest that pathogenic RORγt+CD4+ T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.

What Can You Learn About Psychiatry Programs from Their Website? A Content Evaluation for Potential Applicants.

OBJECTIVE: This project aimed to assess the information contained on general psychiatry program websites and identify common themes that may be useful and informative for residency applicants. METHODS: A survey study design was used to evaluate all US general psychiatry program websites as listed in the FREIDA database. The evaluation form included 44 binary (yes or no) items. Two reviewers rated each item on all program websites between September 2021 and January 2022. Item discrepancies were settled by a third reviewer. Fisher's exact tests evaluated differences between geographic regions and program types. Multidimensional scaling and Rasch modeling were conducted to examine clustering and the probability of items reported on program websites. RESULTS: A total of 285 websites were identified; 13 were excluded. Internal consistency was high among reviewers, Cronbach's Alpha = 0.927; κ = 0.863. Websites varied considerably in quality. Significant inconsistent reporting was observed by region for current residents' photos and alumni careers (fellowship/jobs); p<0.001. Program types varied regarding information about program faculty, which included significant differences for faculty photo, faculty research interest, and faculty research publications; p<0.001. CONCLUSIONS: While inter-rater reliability was high, considerable variation among websites was observed. Residency programs could be improved by consistently reporting resident and faculty information. Results show that applicants may encounter issues finding pertinent information, as programs' FREIDA link did not direct the user to the residency program website two-thirds of the time.

Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With Depression.

OBJECTIVE: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). DESIGN: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. SETTING: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. PARTICIPANTS: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. INTERVENTION: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). OUTCOMES: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. RESULTS: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2 = 19.3, df = 2; p <0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities. CONCLUSIONS: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.

Double-blind, placebo-controlled, proof-of-concept trial of a kappa-selective opioid receptor antagonist augmentation in treatment-resistant depression.

BACKGROUND: Kappa-opioid antagonism may possess antidepressant properties. We assessed, in a proof-of-concept pilot trial among patients with major depressive disorder with inadequate response to antidepressants, the efficacy of adjunctive CERC-501 (formerly LY2456302), a kappaselective opioid receptor antagonist. METHODS: In a Sequential Parallel Comparison Design study, patients were pre-randomized to: a) 10 mg/d of CERC-501 for 6 days, b) 20 mg/d of CERC-501 for 6 days, c) placebo for 3 days followed by 10 mg/d of CERC- 501 for 3 days, d) placebo for 3 days followed by 20 mg/d of CERC-501 for 3 days, or e) placebo for 6 days. RESULTS: The study was terminated early by the National Institute of Mental Health due to slow enrollment (N = 8). The weighted mean difference of changes (drug vs placebo) in the 6-item Hamilton Depression Rating Scale (HAMD-6) (primary outcome measure) (1.28), Montgomery-Åsberg Depression Rating Scale (MADRS) (2.33), Perceived Stress Scale (1.01), Symptoms of Depression Questionnaire (9.17), Positive Affect Scale (PAS) (6.39), Symptom Questionnaire (SQ) Depression scale (2.94), SQ Anger- Hostility scale (1.67), and Patient-Reported Outcomes Measurement Information System Satisfaction with Participation in Discretionary Social Activities (4.67) scores were all numerically but not statistically greater for CERC-501 than for placebo. CONCLUSIONS: Although the small sample size limits the ability to draw conclusions, results suggest that CERC-501 may have antidepressant effects. Additional studies are necessary to further explore these effects of CERC-501.

Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. RESULTS: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. CONCLUSIONS: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

Convergent and Discriminant Validity and Utility of the DSM-5 Levels of Personality Functioning Questionnaire (DLOPFQ): Associations with Medical Health Care Provider Ratings and Measures of Physical Health.

The ability to evaluate patients' level of personality functioning in assessing personality disorders has become increasingly important since the DSM-5 Section III hybrid system of personality disorder assessment was released. One measure developed to assess this criterion is the DSM-5 Levels of Personality Functioning Questionnaire (DLOPFQ; Huprich et al., 2017 ), which assesses individuals' self and other representations in four domains-self-direction, identity, empathy, and intimacy-across two contexts-work or school and relationships. A sample of 140 psychiatric and internal medicine outpatients were administered several questionnaires, including the DLOPFQ. Provider ratings also were obtained for level of functioning and DSM-5 pathological personality traits. Several of the DLOPFQ scales were significantly correlated with self-reported and provider-reported measures of DSM-5 trait domains and levels of functioning, along with self-reported measures of effortful control, overall physical and mental health, and well-being. Certain DLOPFQ scales and subscales were associated with provider ratings of likeability and patient contact with the providers. However, relatively modest validity coefficients, as well as poor discriminant validity of domain scales, indicate further research and measure refinement might be needed. It is concluded that, although further research is necessary, the DLOPFQ could be useful for understanding patients' personality pathology in clinical settings.

Residents Perceive Limited Education on Family Planning and Contraception for Patients with Severe and Persistent Mental Illness.

OBJECTIVE: The primary goal of this study was to assess perceived adequacy of training by residents from multiple specialties on contraceptive prescribing and family planning for patients with severe and persistent mental illness (SPMI). Secondary goals included the following: (1) explore resident knowledge, attitudes, and behavior towards patients with SPMI and (2) identify barriers to meeting the reproductive health needs of patients with SPMI. METHODS: The target population was 44,237 residents from four medical specialties. Participants were from a stratified, self-selected sample. Program coordinators were asked to forward a survey link to residents. Consenting residents were provided access to a questionnaire via a secure, web-based application (REDCap). The survey assessed resident education on the reproductive health needs of patients with SPMI and included demographics (age, gender, year of residency, and specialty), perceived adequacy of training, knowledge, and attitudes, and barriers regarding contraception and family planning. Responses were summarized with frequency and compared by medical specialty. RESULTS: A total of 768 residents consented: 49% female, 20% male, and 31% did not indicate their gender; 19% were first year residents, 21% second year residents, 21% third year residents, 8% fourth year residents, and 30% did not indicate their year of training. By specialty, 30.6% of residents were from family medicine programs (n = 235), 10.8% were from internal medicine programs (n = 83), 18.1% were from OBGYN programs (n = 139), and 10.4% were from psychiatry programs (n = 80); 231 (30.1%) did not indicate specialty. Regarding training, 60% of residents disagreed or strongly disagreed that they had proper training on prescribing contraceptives for patients with SPMI (363 of 599). Sixty two percent of residents disagreed or strongly disagreed that they had proper training about family planning for patients with SPMI (368/599). Over 83% of residents surveyed (405/486) would prescribe contraception for patients with SPMI if they had adequate training. CONCLUSIONS: Results indicate the need for curricular change on the reproductive health needs of patients with SPMI.

Cognitive behavioral therapy following esketamine for major depression and suicidal ideation for relapse prevention: The CBT-ENDURE randomized clinical trial study protocol.

In 2020, esketamine received a supplemental indication as a therapy for major depression with suicidal ideation (MDSI), based on protocols enrolling hospitalized patients. Given the high risk of suicide following hospital discharge and the high relapse rates following discontinuation of esketamine, the optimal long-term treatment approach remains unclear. Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. Here we describe the study protocol for the CBT-ENDURE trial: Cognitive Behavioral Therapy Following Esketamine for Major Depression and SUicidal Ideation for RElapse Prevention. Patients with depression (N = 100) who are admitted to hospital or are outpatients with clinically significant suicidal ideation will be enrolled in the study. All patients will receive esketamine (twice weekly for four weeks) and will be randomly assigned (1:1 ratio) to receive a 16-week course of CBT plus treatment as usual (CBT group) or treatment as usual only (TAU only group). Patients are followed for a total of 6 months. Supported under a funding announcement from NIMH to conduct safety and feasibility trials for patients at high risk for suicide, the primary outcome of the CBT-ENDURE study is feasibility (as measured by recruitment and retention), with a key secondary outcome being relapse among those who experience substantial benefit following two weeks of esketamine.

Predictors of response and remission in patients with treatment-resistant depression: A post hoc pooled analysis of two acute trials of esketamine nasal spray.

This exploratory post hoc analysis of two pooled 4-week, phase 3, double-blind, placebo- and active-controlled studies that compared esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD; n = 310) with a newly initiated oral AD plus placebo nasal spray (AD+PBO; n = 208) in patients with treatment-resistant depression (TRD) examined baseline patient demographic and psychiatric characteristics as potential predictors of response (≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) and remission (MADRS total score ≤12) at day 28. Overall, younger age, any employment, fewer failed ADs in the current depressive episode, and reduction in Clinical Global Impression-Severity (CGI-S) score at day 8 were significant positive predictors of response and remission at day 28. Treatment assignment was an important predictor of both response and remission. Patients treated with ESK+AD had 68% and 55% increased odds of achieving response and remission, respectively, versus those treated with AD+PBO. In the ESK+AD group, attainment of response and remission was more likely in patients who were employed, without significant anxiety at baseline, and who experienced a reduction in CGI-S score at day 8. Identification of predictors of response and remission may facilitate identification of those patients with TRD most likely to benefit from ESK+AD. Trial Registration: ClinicalTrials.gov: NCT02417064 (clinicaltrials.gov/ct2/show/NCT02417064) and NCT02418585 (clinicaltrials.gov/ct2/show/NCT02418585).

L-Methylfolate in Antidepressant Non-responders: The Impact of Body Weight and Inflammation.

This summary provides context for the role of L-methylfolate (LMF) in treating antidepressant non-responders. Bidirectional relationships have been observed between obesity and/or inflammation and depression. Studies have shown an increased prevalence of depression among patients with elevated body mass index and/or chronic inflammation and an increased risk of becoming obese and experiencing chronic inflammation in those with depression. These relationships can negatively affect the pathophysiology of depression. Elevated cytokine levels have been found to be among the factors that correlate with poor antidepressant treatment responsiveness. Low baseline neurotransmitter levels (e.g., serotonin) can also be associated with reduced effectiveness of commonly used antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs)]. LMF is an approved nutritional adjunctive antidepressant therapy that increases central neurotransmitter levels and thereby improves the effectiveness of antidepressant therapy. LMF can increase clinical response when used adjunctively in patients with major depressive disorder (MDD) and who are SSRI-resistant. In 2 randomized controlled trials, the pooled results showed increased response rates (32.3 vs. 14.6%; P = 0.04) as measured by a ≥50% reduction or final score ≤ 7 on the Hamilton Depression Rating Scale (HAM-D) and greater mean HAM-D reductions (-5.6 vs. -3.0; P = 0.05) when LMF was added to an SSRI compared with an SSRI plus placebo. Additionally, LMF has demonstrated effectiveness in real-world studies, with 67.9% of patients responding to therapy, using the 9-item Patient Health Questionnaire (P < 0.001). Post-hoc analyses found that patients with inflammation and/or obesity responded better to adjunctive LMF therapy compared with the overall sample (mean HAM-D reduction: -2.74 vs. +0.99).

Understanding the relationship between personality pathology and attachment style in the context of the DSM-5 Alternative Model of Personality Disorders.

This study utilizes the two different criteria of the DSM-5 Alternative Model of Personality Disorder Assessment to evaluate the relationship between attachment style and personality pathology. One-hundred forty patients from a combined sample of psychiatric and internal medicine clinics were given a survey composed of the DSM-5 Levels of Personality Functioning Questionnaire (DLOPFQ), the Personality Inventory for DSM-5-Brief Form (PID-5-BF), and the Relationship Questionnaire (RQ). Analysis of variance indicated that attachment styles were differentiated across all four the DLOPFQ scales and the Detachment trait domain. Elastic net regression modeling with bootstrap was used to assess the strength of the level of personality functioning dimensions and trait domains in the prediction of attachment style, both independently and interactively while accounting for multicollinearity. This study offers readers insight to a novel statistical approach to model building that addresses two issues among psychiatric data: high correlation and small sample size.

Challenges of Assessing Resident Competency in Well-Being: Development of the Psychiatry Milestones 2.0 Well-Being Subcompetency.

Burnout and depression are major problems facing physicians, with 300-400 physicians dying by suicide each year. In an effort to address this issue, the Accreditation Council for Graduate Medical Education (ACGME) revised the Common Program Requirements for residency and fellowship programs to include a strong emphasis on well-being, and this revision has been extended to including a subcompetency on well-being in the Milestones 2.0. The Psychiatry Milestones 2.0 Work Group was convened to draft updated psychiatry milestones. As part of the open feedback period, the American Association of Directors of Psychiatric Residency Training submitted an organizational letter outlining several points to consider regarding the original draft of the well-being subcompetency. The ACGME was receptive to this feedback and allowed the Psychiatry Milestones 2.0 Work Group to revise the subcompetency. Current research indicates that burnout is largely driven by systemic factors, but well-being literature and initiatives often focus on individual factors and responsibility for burnout rather than systemic change. Program directors tasked with assessing resident well-being can additionally encounter several professionalism concerns, including how to (1) define a subcompetency within a competency that itself has not been well defined; (2) decide the appropriate balance between individual and systemic responsibility for well-being; (3) consider mental health as a parameter of well-being; (4) balance roles as physicians, psychiatrists, and training directors in thinking about the mental health of residents without overstepping boundaries and while maintaining privacy, confidentiality, and resident safety; and (5) measure well-being in a sociocultural context. This article describes how these considerations were incorporated into the revision of the Psychiatry Milestones 2.0 version of the well-being subcompetency, which has subsequently been made available to other specialty work groups for potential use as they develop their specialty-specific Milestones 2.0.

Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder.

Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial. Patients who reported taking sertraline within ≤2 weeks of the screening blood draw were included. All patients received combinatorial pharmacogenomic testing, which included a weighted assessment of individual phenotypes for multiple pharmacokinetic genes relevant for sertraline (CYP2C19, CYP2B6, and CYP3A4). Sertraline blood levels were compared between phenotypes based on: 1) the pharmacokinetic portion of the combinatorial pharmacogenomic algorithm, and 2) individual genes. When evaluated separately, individual genes (for CYP2C19 and CYP2B6) and the combinatorial algorithm were significant predictors of sertraline blood levels. However, in multivariate analyses that included individual genes and the combinatorial pharmacogenomic algorithm, only the combinatorial pharmacogenomic algorithm remained a significant predictor of sertraline blood levels. These findings support the clinical validity of the combinatorial pharmacogenomic algorithm, in that it is a superior predictor of sertraline blood levels compared to individual genes.

Combining Asian and American pedagogy to improve clinical psychopharmacology practice.

As the world becomes increasingly interconnected, psychiatrists across geographical regions and from various international organizations need to collaborate to promote global health and wellness. A necessary step is for nations of the world to develop combined teaching initiatives and curricula to ensure best practices are shared globally. In no field of medicine is this more pressing than in psychiatry - especially psychopharmacology given the recent advances in the field. This paper highlights the need to work collaboratively in developing teaching curricula in psychopharmacology in order to incorporate pedagogy and content from international partners-here from Asia and America.

How Much Education and Training Do Residents Across Specialties Receive in Neuropsychology?

INTRODUCTION: Neuropsychologists play an important role on multidisciplinary teams with physicians from multiple specialties. The extent of residency training on the use of neuropsychological services is unclear. Medical residents across multiple specialties throughout the United States were surveyed to assess resident education, training, and understanding of neuropsychological services, along with their intent to consult neuropsychologists in the future. METHODS: A survey was sent to residents in accredited psychiatry, neurology, family medicine, and internal medicine programs. After data were collected, chi-square group level analyses with post-hoc pairwise comparisons were used to analyze the data. RESULTS: A total of 434 residents took the survey. The proportion of residents exposed to neuropsychology during residency varied significantly according to specialty (χ2 (3, N = 419) = 51.4, p < 0.001), with more psychiatry and neurology residents reporting exposure than residents in family medicine or internal medicine. Similarly, the proportion of psychiatry and neurology residents who 'agree' or 'strongly agree' that they understand the nature of neuropsychological services differed significantly from family medicine and internal medicine residents (χ2 (3, N = 415) = 40.4, p < 0.001). The majority of residents across all specialties (85.7%) reported they are likely to consult/order neuropsychological services in future practice. CONCLUSIONS: The majority of residents in all specialties reported exposure to neuropsychological services in some manner, but forms of exposure varied. Results indicated a need for increased education and training in neuropsychological services, especially within family medicine and internal medicine programs.

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.

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies.

Objective: To evaluate response to esketamine nasal spray plus an oral antidepressant (ESK + AD) at day 28 in patients with major depressive disorder (DSM-5) and treatment-resistant depression (TRD) who did not meet response criteria within the first week of treatment.Methods: The current study is a pooled post hoc analysis of two phase 3, double-blind, active-controlled studies, conducted between August 2015 and February 2018, comparing ESK + AD with an oral antidepressant plus placebo (AD + PBO). Early treatment response was defined as a ≥ 50% decrease in Montgomery-Åsberg Depression Rating Scale total score at day 2 or days 2 and 8. Response rates at day 28 were determined among those not meeting early response criteria.Results: 518 patients in the analysis had day 28 observations (ESK + AD, n = 310; AD + PBO, n = 208). A greater percentage of patients treated with ESK + AD versus AD + PBO met response criteria beginning at day 2 (17.3% [55/318] vs 9.4% [19/203]) and at all subsequent timepoints, including day 28 (58.7% [182/310] vs 45.2% [94/208]). In day 2 nonresponders, 54.9% vs 44.3% (ESK + AD vs AD + PBO, respectively) achieved response at day 28 (P < .01). Similarly, among day 2 and 8 nonresponders, 52.1% vs 42.4% achieved response by day 28 (P = .01). In nonresponders at day 2 and at days 2 and 8, the odds ratio for a response at day 28 was 1.61 (95% CI, 1.09-2.40) with ESK + AD versus 1.56 (95% CI, 1.04-2.35) with AD + PBO.Conclusions: Patients with TRD without a demonstrated response within the first week of treatment may still derive benefit from a full 4-week induction course of esketamine nasal spray.Trial Registration: ClinicalTrials.gov identifiers NCT02417064 and NCT02418585.