Antidepressants in the acute treatment of post-traumatic stress disorder in adults: a systematic review and meta-analysis.

Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.

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.

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.

Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis.

Importance: Whether ketamine is as effective as electroconvulsive therapy (ECT) among patients with major depressive episode remains unknown. Objective: To systematically review and meta-analyze data about clinical efficacy and safety for ketamine and ECT in patients with major depressive episode. Data Sources: PubMed, MEDLINE, Cochrane Library, and Embase were systematically searched using Medical Subject Headings (MeSH) terms and text keywords from database inception through April 19, 2022, with no language limits. Two authors also manually and independently searched all relevant studies in US and European clinical trial registries and Google Scholar. Study Selection: Included were studies that involved (1) a diagnosis of depression using standardized diagnostic criteria, (2) intervention/comparator groups consisting of ECT and ketamine, and (3) depressive symptoms as an efficacy outcome using standardized measures. Data Extraction and Synthesis: Data extraction was completed independently by 2 extractors and cross-checked for errors. Hedges g standardized mean differences (SMDs) were used for improvement in depressive symptoms. SMDs with corresponding 95% CIs were estimated using fixed- or random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Main Outcomes and Measures: Efficacy outcomes included depression severity, cognition, and memory performance. Safety outcomes included serious adverse events (eg, suicide attempts and deaths) and other adverse events. Results: Six clinical trials comprising 340 patients (n = 162 for ECT and n = 178 for ketamine) were included in the review. Six of 6 studies enrolled patients who were eligible to receive ECT, 6 studies were conducted in inpatient settings, and 5 studies were randomized clinical trials. The overall pooled SMD for depression symptoms for ECT when compared with ketamine was -0.69 (95% CI, -0.89 to -0.48; Cochran Q, P = .15; I2 = 39%), suggesting an efficacy advantage for ECT compared with ketamine for depression severity. Significant differences were not observed between groups for studies that assessed cognition/memory or serious adverse events. Both ketamine and ECT had unique adverse effect profiles (ie, ketamine: lower risks for headache and muscle pain; ECT: lower risks for blurred vision, vertigo, diplopia/nystagmus, and transient dissociative/depersonalization symptoms). Limitations included low to moderate methodological quality and underpowered study designs. Conclusions and Relevance: Findings from this systematic review and meta-analysis suggest that ECT may be superior to ketamine for improving depression severity in the acute phase, but treatment options should be individualized and patient-centered.

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.

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.

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.

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

Impact of Supplementation and Nutritional Interventions on Pathogenic Processes of Mood Disorders: A Review of the Evidence.

This narrative review was conducted using searches of the PubMed/Medline and Google Scholar databases from inception to November 2019. Clinical trials and relevant articles were identified by cross-referencing major depressive disorder (and/or variants) with the following terms: folate, homocysteine, S-adenosylmethionine (SAMe), L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, L-tryptophan, zinc, magnesium, vitamin D, omega-3 fatty acids, coenzyme Q10, and inositol. Manual reviews of references were also performed using article reference lists. Abnormal levels of folate, homocysteine, and SAMe have been shown to be associated with a higher risk of depression. Numerous studies have demonstrated antidepressant activity with L-methylfolate and SAMe supplementation in individuals with depression. Additionally, the amino acids L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, and L-tryptophan have been implicated in the development of depression and shown to exert antidepressant effects. Other agents with evidence for improving depressive symptoms include zinc, magnesium, omega-3 fatty acids, and coenzyme Q10. Potential biases and differences in study designs within and amongst the studies and reviews selected may confound results. Augmentation of antidepressant medications with various supplements targeting nutritional and physiological factors can potentiate antidepressant effects. Medical foods, particularly L-methylfolate, and other supplements may play a role in managing depression in patients with inadequate response to antidepressant therapies.

Predictive inflammatory biomarkers for change in suicidal ideation in major depressive disorder and panic disorder: A 12-week follow-up study.

Previous studies have investigated the role of inflammatory markers in suicidality of patients with major depressive disorder (MDD) or panic disorder (PD). However, few studies have investigated associations between serum inflammatory cytokine levels and suicidality. We hypothesized that MDD and PD status might be significantly associated with serum inflammatory cytokines and that we could predict levels of improvement in suicide ideation intensity using serum inflammatory biomarkers in patients with MDD and PD. For this study, 41 patients with MDD, 52 patients with PD, and 59 healthy control (HC) subjects were enrolled. Psychological measurements and serum inflammatory markers such as interleukin (IL) -6, -10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and C reactive protein (CRP) were examined. A total of five visits were completed during 12 weeks. After controlling for confounding factors, log-transformed IL-6 (ln_IL-6) at baseline (MDD: 0.297 ± 0.626; PD: 0.342 ± 0.723; HC: -0.121 ± 0.858; p = 0.007, >0.0017, 0.05/30) and mean ln_IL-6 (MDD: 0.395 ± 0.550, PD: 0.249 ± 0.544, HC: -0.139 ± 0.622, p = 0.002, >0.0017, 0.05/30) levels were trends towards significantly higher in patients with MDD and PD than in HC. In MDD patients, a higher level of basal ln_TNF-α was a significant predictor of ΔSSI (changes in SSI scores between baseline and week 12) even after controlling for changes of depression symptoms and baseline SSI scores (standardized ß = 0.541, p = 0.002 < 0.0028, 0.05/18). In conclusion, we could predict ΔSSI using baseline inflammatory biomarkers for patients with MDD.

Effect of Adjunctive Pimavanserin on Sleep/Wakefulness in Patients With Major Depressive Disorder: Secondary Analysis From CLARITY.

OBJECTIVE: This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. METHODS: For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS17) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS17 insomnia factor score and KSS score, correlation between the HDRS17 insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6. RESULTS: At baseline, HDRS17 insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo. CONCLUSIONS: Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03018340.

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.

Effect of adjunctive pimavanserin on suicidal ideation in patients with major depression: Analysis of the CLARITY study.

BACKGROUND: Up to 15% of patients with major depressive disorder (MDD) attempt suicide and up to 2% complete suicide. This was a post-hoc analysis aimed to evaluate the risk of suicide ideation and behavior associated with adjunctive pimavanserin treatment in adults with MDD. METHODS: CLARITY was a randomized, double-blind, placebo-controlled study in patients with MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). For this post-hoc analysis, the primary endpoint was mean change from baseline for HAMD item 3 (suicide). The incidence of suicidal ideation or behavior was also assessed from the Columbia-Suicide Severity Rating Scale (C-SSRS) and reports of adverse events. RESULTS: During Stage 1, LS mean change for HAMD Item 3 was reduced from baseline at each week with pimavanserin with a significant difference between pimavanserin and placebo at Week 3 (p=0.012, effect size: 0.431). At any post-baseline assessment, suicidal ideation on the C-SSRS was reported in 28 (18.1%) of patients with placebo and 9 (17.3%) with pimavanserin during Stage 1 and in 7 (20.7%) with placebo and 4 (13.8%) with pimavanserin during Stage 2. No events of suicidal behavior were observed with either placebo or pimavanserin. LIMITATIONS: The post hoc nature, exclusion of patients with any history of suicide from the primary study, and the small number of patients who demonstrated evidence of suicidal ideation. CONCLUSIONS: Adjunctive pimavanserin was not associated with an increase in suicidal ideation in patients with MDD. Further study is needed to verify these results.

Effect of pimavanserin on anxious depression in patients with major depression and an inadequate response to previous therapy: secondary analysis of the clarity study.

In a post hoc analysis, the effect of pimavanserin on anxious depression was determined from CLARITY, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy. Patients were randomized in a 3:1 ratio to placebo or pimavanserin 34 mg daily added to ongoing antidepressant therapy. At 5 weeks, placebo nonresponders were rerandomized to placebo or pimavanserin for an additional 5 weeks. Mean change from baseline to week 5 for the Hamilton depression rating scale (HAMD) anxiety/somatization (AS) factor was examined for all patients and those with a score ≥7 at baseline. Least squares (LS) mean [standard error (SE)] difference between placebo and pimavanserin for the AS factor score was -1.5 (0.41) [95% confidence interval (CI) -2.4 to -0.7; P = 0.0003; effect size: 0.634]. Among patients with an AS factor score ≥7 at baseline, LS mean (SE) difference was -2.2 (0.66) (95% CI -3.5 to -0.9; P = 0.0013; effect size: 0.781). Response rates (≥50% reduction in HAMD-17 from baseline) were 22.4 and 55.2% (P = 0.0012) and remission rates (HAMD-17 total score <7) were 5.3 and 24.1% (P = 0.0047), respectively, with placebo and pimavanserin among patients with a baseline AS factor score ≥7. Among patients with anxious major depressive disorder at baseline, adjunctive pimavanserin was associated with a significant improvement.

NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder.

BACKGROUND: NSI-189 phosphate (NSI-189) is a novel neurogenic molecule with pleiotropic properties, including antidepressant, procognitive, synaptoplastic, and neurotrophic activities demonstrated in preclinical studies. Its antidepressant activity is monoamine-independent. NSI-189 was previously tested in patients with recurrent major depressive disorder in an inpatient setting. METHODS: This study involved 220 patients randomized to an NSI-189 40-mg dose, NSI-189 80-mg dose, or placebo daily for 12 weeks. The study utilized the sequential parallel comparison design, in which the drug effect was tested in 2 separate stages of 6 weeks each. Herein, post-hoc analyses of the data are presented. RESULTS: NSI-189's antidepressant effect increased when the participants' initial baseline depression severity was dichotomized along a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 30. The NSI-189 80-mg dose showed significant benefit over placebo when utilizing the MADRS-6 (P = .046) in the subgroup of patients who were moderately depressed (MADRS < 30) but was not significant in patients who were severely depressed (MADRS ≥30). More pronounced procognitive effects were also observed in the moderate subgroup relative to the severe subgroup or the whole study group, in which 11/36 (31%), 5/36 (14%), or 7/36 (19%) of CogScreen variables significantly improved, respectively. CONCLUSIONS: These results suggest that NSI-189 is effective as a safe adjunctive therapy, with most compelling antidepressant and procognitive benefits noted in patients with moderate depression.

Low-Dose Testosterone Augmentation for Antidepressant-Resistant Major Depressive Disorder in Women: An 8-Week Randomized Placebo-Controlled Study.

OBJECTIVE: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. METHODS: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity. RESULTS: The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo. CONCLUSIONS: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.

Implementing Measurement-Based Care to Determine and Treat Inadequate Response.

​​ Measurement-based care (MBC) is an important strategy in the treatment of patients with major depressive disorder who have inadequate antidepressant response. The rating scales used in MBC can assist clinicians at critical decision points, such as when to declare a treatment failure, what to do with partial improvement, and how long to continue successful treatment. Measurement has two benefits: it gives the clinician an objective basis for comparison of symptom severity over time, and it helps patients to have insight into their illness course. Further, many of these tools do not add substantially to the length of the clinical visit. MBC can also be used to monitor and address residual symptoms such as fatigue and irritability that impact patients' functioning and quality of life.​ ​.