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

Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects. Studies suggest that inhibition of nitric oxide synthesis plays a role in the mechanism of action of ketamine. This randomized, placebo-controlled study investigated whether co-administration of sodium nitroprusside, a nitric oxide donor, compared to placebo, would attenuate the antidepressant and dissociative effects of ketamine. Sixteen ketamine responders were randomized to a double-blind infusion of ketamine co-administered with placebo or sodium nitroprusside. Our findings show no difference between the two conditions suggesting that the nitric oxide pathway may not play a primary role in ketamine's antidepressant or dissociative effects. The study is registered at clinicaltrials.gov (NCT03102736). [ABSTRACT FROM AUTHOR]

Background: This report seeks to evaluate improvements in symptoms of irritability with sertraline (a selective serotonin reuptake inhibitor antidepressant) versus placebo.Methods: Participants of Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study who were randomized to 8 weeks of treatment with either sertraline or placebo and completed 5-item irritability domain of Concise Associated Symptom Tracking scale (CAST-IRR) at baseline were included (n = 292). Repeated measures mixed model analysis with CAST-IRR as the outcome variable and treatment arm-by-time interaction as the independent variable of interest evaluated whether changes in irritability with treatment differed between sertraline and placebo arms. A separate analysis controlled for levels of overall depression severity (17-item Hamilton Depression Rating Scale). Covariates included age, sex, race, ethnicity, and site.Results: There was a significant treatment arm-by-time interaction (F = 6.96, df = 6, 1418, p <0.0001) suggesting that changes in irritability with sertraline differed from placebo. The magnitude of reduction in irritability from baseline to week-8 was greater with sertraline than with placebo (Cohen's d effect size = 0.56). After controlling for levels of overall depression severity at each visit, reduction in irritability with time continued to be significant with sertraline but not with placebo.Limitations: Secondary analysis, limited generalizability, lack of non-serotonergic antidepressants.Discussion: There is greater improvement in irritability with sertraline than with placebo. Improvement in irritability with sertraline was independent of its effects on overall depression severity. CLINICALTRIALS.Gov Identifier: NCT01407094. [ABSTRACT FROM AUTHOR]

Background: Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study.Methods: Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined.Results: Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo.Conclusions: Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction. [ABSTRACT FROM AUTHOR]

Importance: Despite the widespread awareness of functional magnetic resonance imaging findings suggesting a role for cortical connectivity networks in treatment selection for major depressive disorder, its clinical utility remains limited. Recent methodological advances have revealed functional magnetic resonance imaging-like connectivity networks using electroencephalography (EEG), a tool more easily implemented in clinical practice.Objective: To determine whether EEG connectivity could reveal neural moderators of antidepressant treatment.Design, Setting, and Participants: In this nonprespecified secondary analysis, data were analyzed from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care study, a placebo-controlled, double-blinded randomized clinical trial. Recruitment began July 29, 2011, and was completed December 15, 2015. A random sample of 221 outpatients with depression aged 18 to 65 years who were not taking medication for depression was recruited and assessed at 4 clinical sites. Analysis was performed on an intent-to-treat basis. Statistical analysis was performed from November 16, 2018, to May 23, 2019.Interventions: Patients received either the selective serotonin reuptake inhibitor sertraline hydrochloride or placebo for 8 weeks.Main Outcomes and Measures: Electroencephalographic orthogonalized power envelope connectivity analyses were applied to resting-state EEG data. Intent-to-treat prediction linear mixed models were used to determine which pretreatment connectivity patterns were associated with response to sertraline vs placebo. The primary clinical outcome was the total score on the 17-item Hamilton Rating Scale for Depression, administered at each study visit.Results: Of the participants recruited, 9 withdrew after first dose owing to reported adverse effects, and 221 participants (150 women; mean [SD] age, 37.8 [12.7] years) underwent EEG recordings and had high-quality pretreatment EEG data. After correction for multiple comparisons, connectome-wide analyses revealed moderation by connections within and between widespread cortical regions-most prominently parietal-for both the antidepressant and placebo groups. Greater alpha-band and lower gamma-band connectivity predicted better placebo outcomes and worse antidepressant outcomes. Lower connectivity levels in these moderating connections were associated with higher levels of anhedonia. Connectivity features that moderate treatment response differentially by treatment group were distinct from connectivity features that change from baseline to 1 week into treatment. The group mean (SD) score on the 17-item Hamilton Rating Scale for Depression was 18.35 (4.58) at baseline and 26.14 (30.37) across all time points.Conclusions and Relevance: These findings establish the utility of EEG-based network functional connectivity analyses for differentiating between responses to an antidepressant vs placebo. A role emerged for parietal cortical regions in predicting placebo outcome. From a treatment perspective, capitalizing on the therapeutic components leading to placebo response differentially from antidepressant response should provide an alternative direction toward establishing a placebo signature in clinical trials, thereby enhancing the signal detection in randomized clinical trials.Trial Registration: ClinicalTrials.gov identifier: NCT01407094. [ABSTRACT FROM AUTHOR]

Objective: Major depressive disorder is associated with aberrant resting-state functional connectivity across multiple brain networks supporting emotion processing, executive function, and reward processing. The purpose of this study was to determine whether patterns of resting-state connectivity between brain regions predict differential outcome to antidepressant medication (sertraline) compared with placebo.Methods: Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study underwent structural and resting-state functional MRI at baseline. Participants were then randomly assigned to receive either sertraline or placebo treatment for 8 weeks (N=279). A region of interest-based approach was utilized to compute functional connectivity between brain regions. Linear mixed-model intent-to-treat analyses were used to identify brain regions that moderated (i.e., differentially predicted) outcomes between the sertraline and placebo arms.Results: Prediction of response to sertraline involved several within- and between-network connectivity patterns. In general, higher connectivity within the default mode network predicted better outcomes specifically for sertraline, as did greater between-network connectivity of the default mode and executive control networks. In contrast, both placebo and sertraline outcomes were predicted (in opposite directions) by between-network hippocampal connectivity.Conclusions: This study identified specific functional network-based moderators of treatment outcome involving brain networks known to be affected by major depression. Specifically, functional connectivity patterns of brain regions between and within networks appear to play an important role in identifying a favorable response for a drug treatment for major depressive disorder. [ABSTRACT FROM AUTHOR]

The article discusses the challenges in discontinuing selective serotonin reuptake inhibitors (SSRIs). Topics include the risk of discontinuation symptoms, the differential diagnosis, and pathophysiology of discontinuation symptoms. Discontinuation signs and symptoms including shortness of breath, palpitation, and chills and the best strategies to manage discontinuation symptoms including patient education, increasing dosage,and adding psychotherapy are elaborated.

Background: Currently, there are no valid clinical or biological markers to personalize the treatment of depression. Recent evidence suggests that body mass index (BMI) may guide the selection of antidepressant medications with different mechanisms of action.Methods: Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants with BMI measurement (n = 662) were categorized as normal- or underweight (<25), overweight (25-<30), obese I (30-<35), and obese II+ (≥35). Logistic regression analysis with remission as the dependent variable and treatment arm-by-BMI category interaction as the primary independent variable was used to evaluate if BMI differentially predicted response to escitalopram (SSRI) monotherapy, bupropion-escitalopram combination, or venlafaxine-mirtazapine combination, after controlling for gender and baseline depression severity.Results: Remission rates among the three treatment arms differed on the basis of pre-treatment BMI (chi-square=12.80, degrees of freedom=6, p = .046). Normal- or under-weight participants were less likely to remit with the bupropion-SSRI combination (26.8%) than SSRI monotherapy (37.3%, number needed to treat or NNT = 9.5) or venlafaxine-mirtazapine combination (44.4%, NNT = 5.7). Conversely, obese II+ participants were more likely to remit with bupropion-SSRI (47.4%) than SSRI monotherapy (28.6%, NNT = 5.3) or venlafaxine-mirtazapine combination (37.7%, NNT = 10.3). Remission rates did not differ among overweight and obese I participants.Limitations: Secondary analysis, higher rates of obesity than the general population.Conclusions: Antidepressant selection in clinical practice can be personalized with BMI measurements. Bupropion-SSRI combination should be avoided in normal- or under-weight depressed outpatients as compared to SSRI monotherapy and venlafaxine-mirtazapine combination and preferred in those with BMI≥35. [ABSTRACT FROM AUTHOR]

Objective: Depression symptom severity, the most commonly studied outcome in antidepressant treatment trials, accounts for only a small portion of burden related to major depression. While lost work productivity is the biggest contributor to depression's economic burden, few studies have systematically evaluated the independent effect of treatment on work productivity and the relationship between changes in work productivity and longer-term clinical course.Method: Work productivity was measured repeatedly by the Work Productivity and Activity Impairment self-report questionnaire in 331 employed participants with major depression enrolled in the Combining Medications to Enhance Depression Outcomes trial. Trajectories of change in work productivity during the first 6 weeks of treatment were identified and used to predict remission at 3 and 7 months.Results: Participants reported reduced absence from work and increased work productivity with antidepressant treatment even after controlling for changes in depression severity. Three distinct trajectories of changes in work productivity were identified: 1) robust early improvement (24%), 2) minimal change (49%), and 3) high-impairment slight reduction (27%). Compared with other participants, those with robust improvement had 3-5 times higher remission rates at 3 months and 2-5 times higher remission rates at 7 months, even after controlling for select baseline variables and remission status at week 6.Conclusions: In this secondary analysis, self-reported work productivity improved in depressed patients with antidepressant treatment even after accounting for depressive symptom reduction. Early improvement in work productivity is associated with much higher remission rates after 3 and 7 months of treatment. [ABSTRACT FROM AUTHOR]

Background: Although normal Quality of Life (QoL) is the outcome desired by patients, it is unclear if QoL changes early in course of antidepressant treatments are independent of depression severity, and can predict subsequent remission.Methods: The Quality of Life Inventory was obtained repeatedly in the Combining Medications to Enhance Depression Outcomes trial. Mixed model analyses assessed QoL change. Using population-based norms, participants were grouped as very low, low, or normal QoL at week 4, and association with remission was evaluated.Results: Overall baseline to week 4 QoL improved significantly (p=0.0015) even after controlling for change in depression severity and baseline variables (gender, age, education, race, ethnicity, income, employment status, anxious features, depression onset before age 18, suicidal ideations, and treatment-arm). At week 4, participants with low and normal QoL had higher unadjusted odds ratio (OR) for remission at 3 months (low QoL OR=2.36, 95% confidence interval (CI)=1.25,4.44; normal QoL OR=2.59, 95% CI=1.53,4.39) and 7 months (low QoL OR=2.07, 95% CI=1.00,4.31; normal QoL OR=3.98, 95% CI=2.06,7.69) compared to those with very low QoL. Remission rates, adjusted for baseline variables, were higher only for participants with normal QoL (3 months OR=2.83, 95% CI=1.42,5.68; 7 months OR=6.10, 95% CI=2.40,15.63).Limitations: Secondary analysis, short period of assessment for QoL change, remission instead of functional recovery as long-term outcome.Conclusion: Quality of life improves early, independent of depression severity. Normal QoL at week 4 is associated with 2-6 times higher remission rates. Findings support QoL beyond symptomatic change as a potential mediator of remission. [ABSTRACT FROM AUTHOR]

Background: Functional impairments often remain despite symptomatic improvement with antidepressant treatment, supporting the need for novel treatment approaches. The present study examined the extent to which exercise augmentation improved several domains of psychosocial functioning and quality of life (QoL) among depressed participants.Methods: Data were collected from 122 partial responders to antidepressant medication. Participants were randomized to either high- (16 kcal/kg of weight/week [KKW]) or low-dose (4-KKW) exercise. Participants completed a combination of supervised and home-based exercise for 12 weeks. The Short-Form Health Survey, Work and Social Adjustment Scale, Social Adjustment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Satisfaction with Life Scale were collected at 6 and 12 weeks. Participants with data for at least one of the two follow-up time points (n = 106) were analyzed using a linear mixed model to assess change from baseline within groups and the difference between groups for each psychosocial outcome measure. All analyses controlled for covariates, including baseline depressive symptomatology.Results: Participants experienced significant improvements in functioning across tested domains, and generally fell within a healthy range of functioning on all measures at Weeks 6 and 12. Although no differences were found between exercise groups, improvements were observed across a variety of psychosocial and QoL domains, even in the low-dose exercise group.Conclusions: These findings support exercise augmentation of antidepressant treatment as a viable intervention for treatment-resistant depression to improve function in addition to symptoms. [ABSTRACT FROM AUTHOR]

Objective: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo.Methods: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38).Results: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network.Conclusion: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]