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Aims: Four Phase 3 studies evaluated efficacy and safety of viloxazine extended‐release in the treatment of attention‐deficit/hyperactivity disorder (ADHD). The primary efficacy objective—change from baseline in ADHD Rating Scale‐5 (ADHD‐RS‐5) Total score at end of study (EOS)—was not met in one of the studies (812P304). A band‐pass analysis was performed to evaluate the impact of placebo response on the results. Methods: The distribution of placebo response at EOS of each trial was evaluated. The 2.5th and 97.5th percentiles of the distribution of ADHD‐RS‐5 Total score were used as boundaries for the band‐pass analysis. An independent mixed model for repeated measures analysis was conducted for each trial using all eligible data (active and placebo) from the total and band‐pass filtered populations. Results: The 2.5th and 97.5th percentiles at EOS were 3.5 and 53.5, respectively. Application of the band‐pass filter (filtering out all subjects [active, n = 305 (32.1%) and placebo, n = 134 (33.5%)] of clinical sites with placebo scores <3.5 or >53.5) revealed statistically significant improvement at the primary endpoint (600‐mg/d viloxazine ER vs. placebo) in Study 812P304 (mean [confidence interval] = 4.9537 [0.5405–9.3669]), previously masked by a high placebo response (mean [confidence interval] = 3.5756 [−0.3332–7.4844]). The outcome of the analysis indicated that the impact of the band‐pass adjustment is greater when placebo response is higher. Conclusion: This analysis indicated that a higher placebo response in Study 812P304 confounded the assessment of treatment effect. Application of the band‐pass methodology confirmed the positive results of the 3 prior studies and the signal detection confounder in the fourth study. [ABSTRACT FROM AUTHOR]

Background: Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. Methods: In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. Results: Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. Conclusion: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response. [ABSTRACT FROM AUTHOR]

In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient's expectations for the treatment. Its presence makes the classical parallel study design suboptimal and can bias the inference. The sequential parallel comparison design (SPCD), a two‐stage design where the first stage is a classical parallel study design, followed by another parallel design among placebo subjects from the first stage, was proposed to address the shortcomings of the classical design. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized subjects and the mean treatment difference in Stage II among placebo non‐responders was proposed as the efficacy measure. However, by linking two possibly different populations, this weighted average lacks interpretability, and the choice of weight remains controversial. In this work, under the principal stratification framework, we propose a causal estimand for the treatment effect under each of three clinically important principal strata: Always Responders, Never Responders, and Drug‐only Responders. To make the stratum treatment effect identifiable, we introduce a set of assumptions and two sensitivity parameters. By further considering the strata as latent characteristics, the sensitivity parameters can be estimated. An extensive simulation study is conducted to evaluate the operating characteristics of the proposed method. Finally, we apply our method on the ADAPT‐A study data to assess the benefit of low‐dose aripiprazole adjunctive to antidepressant therapy treatment. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis. Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0. Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials. [ABSTRACT FROM AUTHOR]

Background: Cohort and cost-effectiveness studies suggest that measuring variation in genes that influence metabolism of common drugs could improve antidepressant treatment outcomes. Prior randomized trials have yielded inconsistent results.Method: Multicenter randomized double-blind (subject and rater), controlled trial of pharmacogenomic testing among outpatients with nonpsychotic major depressive disorder. Study participants (n = 304) were randomized 1:1 to assay-guided treatment (AGT; N = 151) or treatment-as-usual (TAU; N = 153). Participants and raters were blinded to study arm; unblinded clinicians received results of a pharmacogenomic test and adjusted treatment in light of the test report. Primary outcome was change over 8 weeks in Hamilton Depression Rating Scale (SIGH-D-17).Results: For the primary comparison of interest, change in SIGH-D-17, no significant difference was detected between AGT and TAU at Week 8 (p = .53). Rates of study completion also did not differ between the arms (AGT 92.7%, TAU 92.2% (χ2  = 0.03, df = 1, p = .86). Exploratory analyses suggested significantly fewer individuals experienced worsening of depressive symptoms following AGT, and that treatment concordant with assay results was associated with greater likelihood of remission.Conclusion: Pharmacogenomic testing using a panel of pharmacokinetic and pharmacodynamic variants was not associated with significant improvement in the primary efficacy outcome when providers were unconstrained by the assay results. Further investigation is needed to understand the discordance with cost-effectiveness results and among randomized trials. [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]

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]

One of the most important reasons for failure of placebo‐controlled randomized controlled clinical trials (RCTs) is the lack of appropriate methodologies for detecting treatment effect (TE; difference between placebo and active treatment response) in the presence of excessively low/high levels of placebo response. Although, the higher the level of placebo response in a trial, the lower the apparent detectable TE. TE is usually estimated in a conventional analysis of an RCT as an "apparent" TE value conditional to the level of placebo response in that RCT. A model‐informed methodology is proposed to establish a relationship between level of placebo response and TE. This relationship is used to estimate the "typical" TE associated with a "typical" level of placebo response, irrespective of the level of placebo response observed. The approach can be valuable for providing a reliable estimate of TE, for conducting risk/benefit analysis, and for determining dosage recommendations. [ABSTRACT FROM AUTHOR]

Background About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. Methods This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested. Results Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: –3.2 [–6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was –4.1 [–7.67, –0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. Conclusions Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. Trial Registration ClinicalTrials.gov identifier: NCT02417064 [ABSTRACT FROM AUTHOR]

Objectives: There are no known studies of concurrent exposure to high temperature and yoga for the treatment of depression. This study explored acceptability and feasibility of heated (Bikram) yoga as a treatment for individuals with depressive symptoms. Design: An 8-week, open-label pilot study of heated yoga for depressive symptoms. Subjects: 28 medically healthy adults (71.4% female, mean age 36 [standard deviation 13.57]) with at least mild depressive symptoms (Hamilton Rating Scale for Depression [HRSD-17] score ≥10) who attended at least one yoga class and subsequent assessment visit. Intervention: Participants were asked to attend at least twice weekly community held Bikram Yoga classes. Assessments were performed at screening and weeks 1, 3, 5, and 8. Hypotheses were tested using a modified-intent-to-treat approach, including participants who attended at least one yoga class and subsequent assessment visit (N = 28). Results: Almost half of our subjects completed the 8-week intervention, and close to a third attended three quarters or more of the prescribed 16 classes over 8 weeks. Multilevel modeling revealed significant improvements over time in both clinician-rated HRSD-17 (p = 0.003; dGLMM = 1.43) and self-reported Beck Depression Inventory (BDI; p < 0.001, dGLMM = 1.31) depressive symptoms, as well as the four secondary outcomes: hopelessness (p = 0.024, dGLMM = 0.57), anxiety (p < 0.001, dGLMM = 0.78), cognitive/physical functioning (p < 0.001, dGLMM = 1.34), and quality of life (p = 0.007, dGLMM = 1.29). Of 23 participants with data through week 3 or later, 12 (52.2%) were treatment responders (≥50% reduction in HRSD-17 score), and 13 (56.5%) attained remission (HRSD score ≤7). More frequent attendance was significantly associated with improvement in self-rated depression symptoms, hopelessness, and quality of life. Conclusions: The acceptability and feasibility of heated yoga in this particular sample with this protocol warrants further attention. The heated yoga was associated with reduced depressive symptoms, and other improved related mental health symptoms, including anxiety, hopelessness, and quality of life. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits. Methods: Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics. Results: Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58). Conclusions: A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations. [ABSTRACT FROM AUTHOR]

The conventional statistical methodologies for evaluating treatment effect are based on hypothesis testing (P-value). Alternative measurements of treatment effect have been proposed for anti-infective treatments using the probability of target attainment. A general framework is proposed to extend this methodology to other therapeutic areas. A disease trial model is used for estimating the probability of reaching a treatment effect associated with relevant clinical benefits, in complement to the evaluation of the probability of rejecting the null hypothesis.A case study is presented in depression, where disease status is evaluated using bounded clinical scores (Hamilton Depression Rating Scale), and detectable treatment effect is inversely proportional to placebo response. The β-regression approach is used to model Hamilton scale scores, and a placebo-related criterion is proposed for determining the clinical benefit. The probability of reaching a clinical benefit represents a reliable criterion for replacing the P-value paradigm in the assessment of the outcomes of clinical trials. [ABSTRACT FROM AUTHOR]

Background: Depression is a common comorbidity in psoriasis, and both conditions are associated with systemic inflammation. The efficacy of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, was evaluated in patients with moderate-to-severe plaque psoriasis (psoriasis) and depressive symptoms that were at least moderately severe.Methods: Data were integrated from 3 randomized, double-blind, controlled phase 3 trials. At baseline and week 12, depressive symptoms and inflammation were assessed by the 16-item Quick Inventory of Depressive Symptomology - Self-Report (QIDS-SR16) and by a high-sensitivity assay of serum C-reactive protein (hsCRP), respectively. A subgroup of patients with at least moderately severe depressive symptoms at baseline (QIDS-SR16 total score ≥11) was analyzed. Improvement in psoriasis was assessed by the Psoriasis Area and Severity Index (PASI).Results: Approximately 10% of the overall psoriasis population had at least moderately severe depressive symptoms at baseline. At week 12, comorbid patients treated with ixekizumab had significantly greater improvements in their QIDS-SR16 total score (ixekizumab 80 mg every 2 weeks [Q2W], -7.1; ixekizumab 80 mg every 4 weeks [Q4W], -6.1) vs. placebo (-3.4) (p < 0.001, both comparisons) and higher rates of remission of depressive symptoms (ixekizumab Q2W, 45.2%; ixekizumab Q4W, 33.6%) vs. placebo (17.8%) (p ≤ 0.01, both comparisons). Patients treated with ixekizumab also had significant reductions in hsCRP and PASI compared to placebo. Etanercept treatment was not associated with significant improvements in depressive symptoms compared to placebo.Conclusions: In this comorbid population, 12 weeks of ixekizumab therapy resulted in remission of depression for approximately 40% of patients and improved systemic inflammation as indicated by hsCRP. [ABSTRACT FROM AUTHOR]

Introduction: To determine if mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive-compulsive disorder (OCD) resistant to SSRI treatment.Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and mavoglurant or placebo was added on. Non-smoking men and women aged 18-65 years primarily diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria were randomized (1:1) to mavoglurant or placebo groups. After 50 patients were randomized, an interim analysis was conducted to determine whether the study should be continued. The primary outcome measure was absolute change in Y-BOCS from baseline at week 17. Safety was assessed by recording adverse events (AEs) and serious adverse events (SAEs).Results: Interim analysis led to a decision to terminate the study. In total 38 (76.0%) participants completed 17 weeks of treatment and 37 (74.0%) completed the study. There was no significant difference in least squares (LS) mean change from baseline at week 17 in Y-BOCS total score for mavoglurant compared with placebo groups [-6.9 (1.75) vs. -8.0 (1.78), respectively; LS mean difference 1.1; 95% CI -3.9, 6.2; p = 0.671]. The incidence of AEs was higher in the mavoglurant compared with the placebo group (80.8% vs. 70.8%, respectively).Conclusion: This study of mavoglurant in OCD was terminated because of the lack of efficacy at interim analysis. The study did not support the use of an antagonist of mGluR5 receptors for OCD treatment.Trial Registration: The study was registered with ClinicalTrials.gov: NCT01813019.Funding: This study was sponsored by Novartis Pharma AG, Basel, Switzerland. [ABSTRACT FROM AUTHOR]

Objective: Preliminary evidence supports the safety and efficacy of subanesthetic ketamine as an experimental antidepressant, although its effects are often not sustained beyond one week. Studies are lacking that have examined the sustained effects of escalating ketamine doses as augmentation in outpatients with treatment-resistant depression. Therefore, the aims of this study were twofold: (1) to assess the safety and antidepressant efficacy of two-step, repeated-dose ketamine augmentation and (2) to assess the duration of ketamine's antidepressant efficacy as augmentation to ongoing antidepressant pharmacotherapy for 3 months after the final infusion. Methods: Fourteen patients with treatment-resistant depression were eligible to receive augmentation with six openlabel intravenous ketamine infusions over 3 weeks. For the first three infusions, ketamine was administered at a dose of 0.5 mg/kg over 45 minutes; the dose was increased to 0.75 mg/kg over 45 minutes for the subsequent three infusions. The primary outcome measure was response (as measured on Hamilton Depression Rating Scale-28 items). Results: After the completion of three ketamine infusions, 7.1% (1/14) responded; after all six ketamine infusions, 41.7% (5/12) completers responded and 16.7% (2/12) remitted. Intent-to-treat response and remission rates at the end of the final infusion were 35.7% (5/14) and 14.3% (2/14), respectively. However, all but one responder relapsed within 2 weeks after the final infusion. Conclusion: Repeated, escalating doses of intravenous ketamine augmentation were preliminarily found to be feasible, efficacious and well tolerated. Interaction with concomitant medications and elevated level of treatment resistance are possible factors for non-response. [ABSTRACT FROM AUTHOR]

This Viewpoint revisits the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study design 20 years after its initiation and assesses it in light of current strategies to treat major depression. [ABSTRACT FROM AUTHOR]

Objective: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a μ- and κ-opioid partial agonist, buprenorphine, and a μ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression.Method: A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S).Results: Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation.Conclusions: The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to test the efficacy of adjunctive ziprasidone in adults with nonpsychotic unipolar major depression experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram.Method: This was an 8-week, randomized, double-blind, parallel-group, placebo-controlled trial conducted at three academic medical centers. Participants were 139 outpatients with persistent symptoms of major depression after an 8-week open-label trial of escitalopram (phase 1), randomly assigned in a 1:1 ratio to receive adjunctive ziprasidone (escitalopram plus ziprasidone, N=71) or adjunctive placebo (escitalopram plus placebo, N=68), with 8 weekly follow-up assessments. The primary outcome measure was clinical response, defined as a reduction of at least 50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D). The Hamilton Anxiety Rating scale (HAM-A) and Visual Analog Scale for Pain were defined a priori as key secondary outcome measures.Results: Rates of clinical response (35.2% compared with 20.5%) and mean improvement in HAM-D total scores (-6.4 [SD=6.4] compared with -3.3 [SD=6.2]) were significantly greater for the escitalopram plus ziprasidone group. Several secondary measures of antidepressant efficacy also favored adjunctive ziprasidone. The escitalopram plus ziprasidone group also showed significantly greater improvement on HAM-A score but not on Visual Analog Scale for Pain score. Ten (14%) patients in the escitalopram plus ziprasidone group discontinued treatment because of intolerance, compared with none in the escitalopram plus placebo group.Conclusions: Ziprasidone as an adjunct to escitalopram demonstrated antidepressant efficacy in adult patients with major depressive disorder experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram. [ABSTRACT FROM AUTHOR]

One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the 'true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach. The new method for estimating TE was based on a nonlinear longitudinal modeling of clinical scores (NLMMRM). NLMMRM estimates TE by associating a weighting factor to the data collected in each center. The weight was defined by the posterior probability of detecting a clinically relevant difference between active treatment and placebo at that center. Data from five RCTs in depression were used to compare the performance of MMRM with NLMMRM. The results of the analyses showed an average improvement of ~15% in the TE estimated with NLMMRM when the center effect was included in the analyses. Opposite results were observed with MMRM: TE estimate was reduced by ~4% when the center effect was considered as covariate in the analysis. The novel NLMMRM approach provides a tool for controlling the confounding effect of high placebo response, to increase signal detection and to provide a more reliable estimate of the 'true' TE by controlling false negative results associated with excessively high placebo response. [ABSTRACT FROM AUTHOR]

To compare outcomes from two different treatment strategies in Latino patients with major depressive disorder (MDD) and psychosis-like symptoms: antidepressant medications alone versus a combination of antipsychotic and antidepressant medications, we retrospectively examined the clinical charts of 37 Latino patients with MDD and psychosis-like symptoms from one of our community affiliated clinics, admitted from January 2010 to June 2011. Outcomes included depressive response and remission based on improvement in Patient Health Questionnaire-9 scores. Psychosis-like symptoms were assessed through a specific database created for the study. To qualify for outcomes analysis, patients had to have had adequate treatment with relevant medications for at least eight weeks at therapeutic doses. In all, 24 subjects met the criteria for analysis, and 11 received an antipsychotic medication. Of the 10 subjects who received an antipsychotic, 3 (30%) achieved depressive response. Of the 14 subjects who did not receive any antipsychotic, 10 (71%) attained depressive response. However, significance for the comparison was lost when Fisher's correction was applied (p= .095). Remission rates from depression were lower in both groups, with the same distribution in favor of subjects treated without antipsychotic, although it was not significant because of the small sample size (10% versus 43%;p= .172). Remission from psychosis-like symptoms occurred in 4 of 9 (44%) and in 12 of 15 (80%) subjects treated with and without antipsychotic (p= .099). Our preliminary data suggest that patients affected by MDD with psychosis-like symptoms are likely to achieve remission from both depressive and psychosis-like symptoms even without antipsychotic augmentation of their antidepressant regimen. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the author discusses an article in the journal dealing with America's Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) Study, and it mentions the effectiveness of treatments for major depressive disorder.

There are high rates of comorbidity between heavy drinking and depressive symptoms among college students, often resulting in severe alcohol-related consequences. No empirically supported treatment exists that concurrently addresses both of these problems in this population. Research with college students has demonstrated that brief motivational interventions (BMIs) reduce heavy drinking and alcohol-related consequences, and that cognitive behavioral therapy for depression (CBT-D) is effective in reducing depressive symptoms. Thus, a program combining BMI and CBT-D appears ideal for college students with co-occurring binge drinking and depressive symptoms. This manuscript presents the rationale and format of a BMI + CBT-D treatment protocol for this population, and provides a case example of a female college student who received the protocol and experienced improvement in depressive symptoms, a reduction in alcohol use and alcohol-related negative consequences, and an increase in readiness to change alcohol consumption. We discuss theoretical and clinical implications of these findings, and suggest directions for future research. [ABSTRACT FROM AUTHOR]

Background. This pilot study examined the feasibility and efficacy of providing Qigong treatment in a health center to Chinese Americans with major depressive disorder (MDD). Methods. Fourteen Chinese Americans with MDD were enrolled, and they received a 12-week Qigong intervention. The key outcome measurement was the 17-item Hamilton Rating Scale for Depression (HAM-D17); the Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I), the Quality of Life Enjoyment and Satisfaction Questionnaire, Short Form (Q-LES-Q-SF), and the Multidimensional Scale of Perceived Social Support (MSPSS) were also administered. Positive response was defined as a decrease of 50% or more on the HAM-D17, and remission was defined as HAM-D17 ≤ 7. Patients' outcome measurements were compared before and after the Qigong intervention. Results. Participants (N = 14) were 64% female, with a mean age of 53 (±14). A 71% of participants completed the intervention. The Qigong intervention resulted in a positive treatment-response rate of 60% and a remission rate of 40% and statistically significant improvement, as measured by the HAM-D17, CGI-S, CGI-I, Q-LES-Q-SF, and the family support subscale of the MSPSS. Conclusions. The Qigong intervention provided at a health care setting for the treatment of primary care patients with MDD is feasible. Further studies with larger sample sizes are warranted. [ABSTRACT FROM AUTHOR]

The objective of this paper was to determine whether the presence of more vs. fewer anxious symptom features, at baseline, are associated with other clinical features and treatment outcomes in out-patients with major depressive disorder (MDD). This single-blind, randomized trial enrolled 665 MDD out-patients to compare the efficacy of two antidepressant medication combinations against escitalopram after 12-wk acute treatment and follow-up (total 28 wk). The sample was divided into those with greater (vs. fewer) anxiety features using the anxiety/somatization subscale of the baseline 17-item Hamilton Rating Scale for Depression. Baseline sociodemographic and clinical features, treatment features and outcomes compared these two groups. Overall, 74.7% of participants met the threshold for ‘anxious features’. They were more likely to be female, have other concurrent anxiety disorders, more severe depression, more lethargic and melancholic features and poorer cognitive and physical functioning, quality of life and work and social adjustment. In acute treatment, participants with anxious features received comparatively higher doses of mirtazapine and venlafaxine and reported more side-effects. The groups with and without anxious features did not differ in treatment outcomes and side-effect burden. Despite being associated with a distinct clinical profile, baseline anxious features were not clinically useful in predicting acute treatment outcomes or differential treatment response. [ABSTRACT FROM PUBLISHER]

Background Despite the availability of effective treatments for depression, many patients under the care of primary care physicians do not achieve remission. Clinical Outcomes in Measurement-based Treatment ( COMET) was designed to assess whether communicating patient-reported depression symptom severity to primary care physicians affects patient outcomes at 6 months. Methods Nine hundred fifteen patients (intervention: n = 503; control: n = 412) diagnosed with major depressive disorder were enrolled in a prospective trial in which physician practice sites were assigned to either the intervention or control study arm. Only patients who were prescribed an antidepressant by their physician were eligible, but medication type was independent of the study protocol. Intervention-arm physicians received monthly updates on their patients' depression severity, which was determined with the nine-item Patient Health Questionnaire (PHQ-9) administered during telephone interviews. Remission was defined as a PHQ-9 score <5 at 6 months; response was defined as a score reduction ≥50%. Results Among patients with baseline PHQ-9 score ≥5, 45.0% achieved remission (46.7% intervention versus 42.8% control) and 63.9% responded (67.0% intervention versus 59.7% control) at 6 months. After adjusting for baseline demographic and clinical variables, odds of remission (odds ratio [OR], 1.59 [95% CI, 1.07-2.37]) or response (OR, 2.02 [95% CI, 1.36-3.02]) were significantly greater for the intervention group than for control patients. Conclusions This study demonstrated that regular patient symptom monitoring with feedback to physicians improved outcomes of depression treatment in the primary care setting. Determining reasons for the high observed nonremission rates requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Whether the acute outcomes of major depressive disorder (MDD) treated in primary (PC) or specialty care (SC) settings are different is unknown.Objective: To compare the treatment and outcomes for depressed outpatients treated in primary versus specialty settings with citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org), a broadly inclusive effectiveness trial.Design: Open clinical trial with citalopram for up to 14 weeks at 18 primary and 23 specialty sites. Participants received measurement-based care with 5 recommended treatment visits, manualized pharmacotherapy, ongoing support and guidance by a clinical research coordinator, the use of structured evaluation of depressive symptoms and side effects at each visit, and a centralized treatment monitoring and feedback system.Participants: A total of 2,876 previously established outpatients in primary (n = 1091) or specialty (n = 1785) with nonpsychotic depression who had at least 1 post-baseline measure.Measurements and Main Results: Remission (Hamilton Depression Rating Scale for Depression [Hamilton] or 16-item Quick Inventory of Depressive Symptomatology-Self-Rated [QIDS-SR(16)]); response (QIDS-SR(16)); time to first remission (QIDS-SR(16)). Remission rates by Hamilton (26.6% PC vs 28.0% SC, p = .40) and by QIDS-SR(16) (32.5% PC vs 33.1% SC, p = .78) and response rates by QIDS-SR(16) (45.7% PC vs 47.6% SC, p = .33) were not different. For those who reached remission or response at exit, the time to remission (6.2 weeks PC vs 6.9 weeks SC, p = .12) and to response (5.5 weeks PC vs 5.4 weeks SC, p = .97) did not differ by setting.Conclusions: Identical remission and response rates can be achieved in primary and specialty settings when identical care is provided. [ABSTRACT FROM AUTHOR]

Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared to major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in severity of both depressive and anxiety symptoms in outpatients with major depression with comorbid anxiety disorder following fluoxetine treatment. We enrolled 123 outpatients (mean age 38.9 +/- 10.8 years; 49% women) with major depressive disorder accompanied by one or more current comorbid anxiety disorders in our study. Patients were treated openly with fluoxetine 20 mg/day for 8 weeks. Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D) and the patient-rated Symptom Questionnaire (SQ) Scales for Depression and Anxiety. The mood and anxiety disorder modules of the Structured Clinical Interview for DSM-III-R were administered at screen and endpoint. We used 'intent-to-treat' analysis in examining all patients assigned to treatment and completing the baseline visit. The mean number of comorbid anxiety disorders per patient was 1.5 +/- 0.68. The mean HAM-D-17 score and mean Clinical Global Impressions-Severity scores decreased significantly from baseline to endpoint (week 8) following fluoxetine treatment (p < 0.0001). There were significant decreases in all four SQ scale scores, from baseline to endpoint: depression, anxiety, somatic symptoms and anger-hostility (p < 0.0001). Fifty-three percent of patients (n = 65) were depression responders (i.e. > or = 50% decrease in HAM-D-17 score at endpoint) and 46% (n = 57) were remitters (HAM-D-17 < or = 7 at endpoint). Patients with panic disorder had significantly higher baseline HAM-D-17 scores compared to those without panic disorder (p < 0.01). Patients with comorbid obsessive-compulsive disorder (OCD) were significantly less likely to be responders to fluoxetine at endpoint (> or = 50% decrease in HAM-D-17) and to be remitters (HAM-D-17 score of s 7 at endpoint) compared to patients without comorbid OCD (p < 0.01). Of the 41 patients on whom endpoint Structured Clinical Interview for DSM-III-R modules for anxiety disorders were available, 49% (n = 20) no longer met criteria for one or more of their anxiety disorder diagnoses at endpoint. Our preliminary findings suggest that fluoxetine is effective in treating outpatients with major depression with comorbid anxiety disorders, with a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are required in larger samples to confirm our findings. [ABSTRACT FROM AUTHOR]

• Uncontrolled levels of placebo response is a major reason of trial failure. • Individual propensity to respond to placebo is not controlled by randomization. • Artificial intelligence propensity weighting is used to estimate treatment effect. • The estimated a treatment effect is adjusted for high/low placebo response. One of the major reasons for trial failures in major depressive disorders (MDD) is the presence of unpredictable levels of placebo response as the individual baseline propensity to respond to placebo is not adequately controlled by the current randomization and statistical methodologies. The individual propensity to respond to any treatment or intervention assessed at baseline was considered as a major non-specific prognostic and confounding effect. The objective of this paper was to apply the propensity score methodology to control for potential imbalance at baseline in the propensity to respond to placebo in clinical trials in MDD. Individual propensity was estimated using artificial intelligence (AI) applied to observations collected in two pre-randomization occasions. Cases study are presented using data from two randomized, placebo-controlled trials to evaluate the efficacy of paroxetine in MDD. AI models were used to estimate the individual propensity probability to show a treatment non-specific placebo effect. The inverse of the estimated probability was used as weight in the mixed-effects analysis to assess treatment effect. The comparison of the results obtained with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect size significantly larger than the conventional analysis. [ABSTRACT FROM AUTHOR]

Cognitive deficits are often associated with acute depressive episodes and contribute to the functional impairment seen in patients with Major Depressive Disorder (MDD). Many patients sustain residual cognitive deficits after treatment that may be independent of the core MDD disorder. We tracked changes in cognitive deficits relative to antidepressant treatment response using the patient self-rated Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) during a 6-week, double-blind trial of a combination antidepressant treatment (buspirone 15 mg with melatonin-SR 3 mg) versus buspirone (15 mg) monotherapy versus placebo in MDD patients with acute depressive episodes. The CPFQ includes distinct cognitive and physical functioning dimension subscales. Treatment response was determined using the Inventory of Depressive Symptomatology (IDSc30). Treatment responders improved significantly more on the total CPFQ than non-responders (p < 0.0001) regardless of treatment assignment. The cognitive dimension of the CPFQ score favored the combination treatment over the other two groups (ANCOVA: p = 0.050). Among the treatment non-responders , the effect size for the CPFQ cognitive dimension was 0.603 favoring the combination treatment over the over two groups and 0.113 for the CPFQ physical dimension. These preliminary findings suggest that a combination of buspirone with melatonin may benefit cognitive function distinct from mood symptoms and that some aspects of cognition may be specific targets for treatment within a population of patients with MDD. [ABSTRACT FROM AUTHOR]

Background: Non-racemic amisulpride (SEP-4199) is an 85:15 ratio of aramisulpride:esamisulpride with a 5-HT7 and D2 receptor binding profile optimized for the treatment of bipolar depression. The aim of this study was to evaluate the efficacy and safety of SEP-4199 for the treatment of bipolar depression.Methods: Patients meeting DSM-5 criteria for bipolar I depression were randomized to 6 weeks of double-blind, placebo-controlled treatment with SEP-4199 200 mg/d or 400 mg/d. The primary endpoint was change in the Montgomery-Asberg Depression Rating Scale (MADRS) at Week 6. The primary efficacy analysis population consisted of patients in Europe and US (n = 289); the secondary efficacy analysis population (ITT; n = 337) included patients in Japan.Results: Endpoint improvement in MADRS total score was observed on both the primary analysis for SEP-4199 200 mg/d (P = 0.054; effect size [ES], 0.31) and 400 mg/d (P = 0.054; ES, 0.29), and on the secondary (full ITT) analysis for SEP-4199 200 mg/d (P = 0.016; ES, 0.34) and 400 mg/d (P = 0.024; ES, 0.31). Study completion rates were 81% on SEP-4199 200 mg/d, 88% on 400 mg/d, and 86% on placebo. SEP-4199 had low rates of individual adverse events (<8%) and minimal effects on weight and lipids; median increases in prolactin were +83.6 μg/L on 200 mg/d, +95.2 μg/L on 400 mg/d compared with 0.0 μg/L on placebo.Limitations: The study excluded patients with bipolar II depression and serious psychiatric or medical comorbidity.Conclusion: Study results provide preliminary proof of concept, needing confirmation in subsequent randomized trials, for the efficacy of non-racemic amisulpride in bipolar depression. [ABSTRACT FROM AUTHOR]

Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556. [ABSTRACT FROM AUTHOR]

Background: The optimal dose of S-adenosyl methionine (SAMe) for major depressive disorder (MDD) remains unclear. The objective of this analysis was to address whether a dose increase provided further improvement in cases of insufficient response using data from an existing randomized clinical trial.Methods: Sixty-five patients with MDD who failed to respond to SAMe 1,600 mg/day, escitalopram 10 mg/day, or placebo for 6 weeks were treated with doubled doses of the allocated treatments for the following 6 weeks. Changes in 17-item Hamilton Depression Rating Scale, Inventory of Depressive Symptomatology-Self Rated, and Systematic Assessment for Treatment Emergent Events-Specific Inquiry were compared between the lower and higher dose treatments in each treatment group and among the higher dose treatments of SAMe, escitalopram, and placebo.Results: Various depression severity scores decreased significantly for all three treatment arms during the higher dose treatment. No within-group and between-group differences were found in any of the efficacy measures when comparing the doses and treatments. There was a significant difference in reported abdominal discomfort among patients receiving the higher dose of SAMe (31.3%), compared to escitalopram (8.7%) and placebo (3.8%) (χ2=7.32, p = 0.026).Limitations: The sample size was relatively small. The study duration for dose increase was relatively short.Conclusions: Patients with MDD failing to respond to 1,600 mg/day of SAMe may improve after increasing the dose to 3,200 mg/day, but we cannot rule out the contribution of a placebo effect and time-related improvement. The risk of abdominal discomfort may be increased with higher doses of SAMe. [ABSTRACT FROM AUTHOR]

Background: Heart Rate Variability (HRV) parameters have been used to evaluate the autonomic nervous system. We hypothesized that patients with major depressive disorder (MDD) and panic disorder (PD) showed different HRV profiles compared to healthy controls. We also hypothesized that we could predict the responder groups in the MDD and PD patients, using differences in HRV indices between the stress and rest phases.Methods: 28 MDD patients and 29 PD patients were followed for 12 weeks, and we also followed 39 healthy control subjects. We measured HRV parameters at the rest, stress, and recovery phases.Results: Patients with MDD and PD demonstrated lower pNN50 than controls during the stress (F = 7.49, p = 0.001), and recovery phases (F = 9.43, p = 0.0001). Patients with MDD and PD also showed higher LF/HF ratio than controls during the stress phase (F = 6.15, p = 0.002). Responders in the PD group presented a lower level of LF/HF ratio during the stress phase compared to non-responders (F = 10.14, p = 0.002), while responders in the MDD group showed a lower level of heart rate during all three phases, compared to non-responders. Additionally, we could predict treatment response in patients with MDD using ΔLF/HF ratio (OR: 1.33, 95% CI = 1.07-1.65, p = 0.011) and ΔpNN50 (OR: 1.49, 95% CI 1.09-1.77, p = 0.014).Conclusion: The changes of HRV parameters of pNN50 and LF/HF ratio between the stress and recovery phase may be clinical markers of predictors of treatment responsiveness in MDD and PD patients. [ABSTRACT FROM AUTHOR]

Background: Despite the fact that higher levels of anxiety and anhedonia in Major Depressive Disorder (MDD) are linked to poorer treatment outcomes, mechanisms contributing to these clinical presentations remain unclear. Neuroticism, impaired cognitive control, and blunted reward learning may be critical processes involved in MDD and may help to explain symptoms of anxiety and anhedonia.Methods: Using baseline data from patients with early-onset MDD (N = 296) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) trial, we conducted a path analysis to model relationships between neuroticism, cognitive control, and reward learning to levels of anxiety and anhedonia.Results: Neuroticism was positively associated with both anhedonia (standardized coefficient = 0.26, p < .001) and anxiety (standardized coefficient = 0.40, p < .001). Cognitive control was negatively associated with anxiety (standardized coefficient = -0.18, p < .05). Reward learning was not significantly associated with either anxiety or anhedonia.Limitations: Extraneous variables not included in the model may have even more influence in explaining symptoms of anxiety and anhedonia. Restricted range in these variables may have attenuated some of the hypothesized relationships. Most important, because this was a cross-sectional analysis in a currently depressed sample, we cannot draw any causal conclusions without experimental and longitudinal data.Conclusions: These cross-sectional findings suggest that neuroticism may contribute to anxiety and anhedonia in patients with early onset and either chronic or recurrent MDD, while enhanced cognitive control may protect against anxiety. [ABSTRACT FROM AUTHOR]

Background: Patients with major depressive disorder (MDD) often experience a re-emergence or worsening of symptoms despite ongoing treatment with previously effective antidepressant pharmacotherapy. This lost or reduced antidepressant response during maintenance, referred to as tachyphylaxis, negatively impacts treatment outcomes and quality of life for patients with MDD. This review assesses the prevalence of antidepressant tachyphylaxis as well as the evidence for interventions to manage it.Methods: We searched PubMed/Medline for the relevant clinical trials and meta-analyses on antidepressant tachyphylaxis up to January 2017. Search terms included "depression" paired with "treatment" (n = 186,674), "tachyphylaxis" paired with "depression" (n = 112), "tachyphylaxis" paired with "major depressive disorder" (n = 21), and "antidepressant" paired with "tachyphylaxis" (n = 68). Studies were included if they reported on a clinical trial or meta-analysis exploring tachyphylaxis in MDD and were excluded if the sample population did not have a primary DSM diagnosis of MDD.Results: Rates of tachyphylaxis varied from 9% to 57% depending on the patient population and duration of follow-up. Limited evidence suggests potentially beneficial strategies for managing tachyphylaxis, including change in antidepressant dosing, switch of class of antidepressant medication, augmentation or combination pharmacotherapy, and psychotherapy.Limitations: Studies of antidepressant tachyphylaxis are largely heterogeneous in nature and employ strict inclusion/exclusion criteria; thus, these findings may not be generalizable to all depressed populations.Conclusion: Few established treatment strategies exist to manage antidepressant tachyphylaxis. Further interventional research is needed to provide symptomatic relief for patients with tachyphylaxis in MDD. [ABSTRACT FROM AUTHOR]

BACKGROUND: In treated patients with major depressive disorder (MDD), residual symptoms are common and challenging to disentangle from possible antidepressant side effects. Our objective was to prospectively differentiate between rates of residual symptoms and treatment-emergent side effects. METHODS: Participants in an episode of MDD were enrolled in a 6-week trial of an antidepressant. Assessments occurred at baseline and after 6 weeks of treatment, using the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH CPFQ). Among treatment responders, residual symptoms were those that remained the same or improved. Side effects were defined as newly emergent or worsening symptoms. RESULTS: Of 403 participants, 284 completed (70.5%) the trial; 93 (32.7%) were treatment responders. Residual symptoms were common and represented a substantially greater burden than side effects at end point. This was true across symptoms of depression broadly, as captured by items with the QIDS-SR and the MGH CPFQ. CONCLUSIONS: Prospective assessment is crucial to discriminate between residual symptoms and side effects during antidepressant treatment. This study demonstrated that after 6 weeks of active treatment, symptoms are likely to persist despite response to treatment and are much less likely to represent side effects of medication treatment. [ABSTRACT FROM AUTHOR]

Background: Given the proposed dopaminergic mechanism of low-dose naltrexone (LDN), we examined its efficacy as augmentation for depressive breakthrough on pro-dopaminergic antidepressant regimens.Methods: 12 adults (67% female, mean age = 45±12) with recurrent DSM-IV major depressive disorder (MDD) on dopaminergic antidepressant regimens (stimulants, dopamine agonists, bupropion [≥300mg/day], aripiprazole [≤2.5mg/day], or sertraline [≥150mg/day]) were randomized to naltrexone 1mg b.i.d. (n=6) or placebo (n=6) augmentation for 3 weeks.Results: All subjects completed the trial. Hamilton Depression Rating Scale (HAM-D-17) scores (primary outcome measure) decreased from 21.2±2.0 to 11.7±7.7 for LDN, from 23.7±2.3 to 17.8±5.9 for placebo (Cohen's d=0.62; p=0.3 between treatment groups). HAM-D-28 scores decreased from 26.2±4.0 to 12.0±9.8 for LDN, from 26.3±2.6 to 19.8±6.6 for placebo (d=1.15; p=0.097). Montgomery-Asberg Depression Rating Scale (MADRS-10 item) scores decreased from 30.4±4.9 to 12.2±8.4 for LDN, from 30.7±4.3 to 22.8±8.5) for placebo (d=1.45; p=0.035). MADRS-15 item scores decreased from 36.6±6.2 to 13.2±8.8 for LDN, from 36.7±4.2 to 26.0±10.0 for placebo (d=1.49; p=0.035). Clinical Global Improvement Scale-Severity (CGI-S) scores decreased from 4.3±0.5 to 3.0±1.1 for LDN, from 4.3±0.5 to 4.0±0.6 for placebo (d=1.22; p=0.064).Limitations: Small study; restrictions on allowed antidepressants.Conclusion: LDN augmentation showed some benefit for MDD relapse on dopaminergic agents. Confirmation in larger studies is needed. [ABSTRACT FROM AUTHOR]

Background: There is increased interest in the impact of new long-acting treatments on health-related quality of life (HRQoL) in patients with schizophrenia. The aim of this study was to evaluate the impact of treatment with subcutaneous injections of RBP-7000, a new sustained-release formulation of risperidone, compared with placebo on health status, subjective well-being, treatment satisfaction, and preference of medicine in subjects with acute schizophrenia.Methods: HRQoL data were derived from an 8-week double-blind, randomized, placebo-controlled, phase 3 study that assessed efficacy, safety, and tolerability of once monthly RBP-7000 (90mg and 120mg) compared with placebo in subjects with acute schizophrenia (n=337). HRQoL was measured with the EuroQol EQ-5D-5L, well-being using the Neuroleptic Treatment-Short Version (SWN-S), satisfaction using the Medication Satisfaction Questionnaire (MSQ), and preference using the Preference of Medicine Questionnaire (POM).Results: The EQ-5D-5L VAS increased significantly in the RBP-7000 120mg group compared to Placebo (p=0.0212). In RBP-7000 120mg, subjects reported significant improvements in SWN-S physical functioning (p=0.0093), social integration (p=0.0368), and total score (p=0.0395). Subjects were significantly more satisfied with RBP-7000 versus placebo (90mg p=0.0009, 120mg p=0.0006) and preferred RBP-7000 over their previous medication (90mg p<0.0001, 120mg p=0.0619).Conclusions: Significantly greater improvements in HRQoL and overall well-being were demonstrated in patients randomized to RBP-7000 compared to placebo. The effect was more pronounced in the RBP-7000 120mg group. Patient satisfaction improved significantly and patient preference for their medicine favored RBP-7000 90mg and 120mg versus Placebo. [ABSTRACT FROM AUTHOR]

We examined efficacy and safety of one specific cranial electrical stimulator (CES) device at a fixed setting in subjects with treatment-resistant major depressive disorder (MDD). Thirty subjects (57% female, mean age 48.1 ± 12.3 years) with MDD and inadequate response to standard antidepressants were randomized to 3 weeks of treatment with CES (15/500/15,000 Hz, symmetrical rectangular biphasic current of 1–4 mAmp, 40 V) or sham CES (device off) for 20 min, 5 days per week. The primary outcome measure was improvement in the 17-item Hamilton Depression Rating Scale (HAM-D-17). Adverse effects (AEs) were assessed using the Patient Related Inventory of Side Effects (PRISE). Completion rates were 88% for CES, 100% for sham. Both treatment groups demonstrated improvement of about 3–5 points in HAM-D-17 scores (p < 0.05 for both), and no significant differences were observed between groups. Remission rates were 12% for CES, and 15% for sham, a nonsignificant difference. CES was deemed safe, with good tolerability; poor concentration and malaise were the only distressing AEs that differed significantly between CES and sham (p = 0.019 and p = 0.043, respectively). Limitations include a small sample and lack of an active comparator therapy. Although both treatment groups improved significantly, this CES at the setting chosen did not separate from sham in this sample. Thus we cannot rule out that the benefit from this setting used in this particular form of CES was due to placebo effects. Since this form of CES has other settings, future studies should test these settings and compare it against other CES devices. Clinicaltrials.gov ID: NCT01325532 [ABSTRACT FROM AUTHOR]

BACKGROUND: Psychosocial treatments and medications both have been shown to be effective in treating major depressive disorder. We hypothesized that cognitive-behavioral therapy (CBT) would outperform medication on measures of cognitive change. METHODS: We randomized depressed individuals to 12 weeks of CBT (n = 15) or escitalopram (n = 11). In an intent-to-treat analysis (n = 26), we conducted a repeated measures analysis of variance to examine changes in depressive symptoms (ie, 17-item Hamilton Depression Rating Scale, Beck Depression Inventory), anhedonia (ie, Snaith-Hamilton Pleasure Scale), cognitive measures (ie, Dysfunctional Attitudes Scale, Automatic Thoughts Questionnaire, Perceived Stress Scale), and quality of life (ie, Quality of Life Enjoyment and Satisfaction Questionnaire) at 4 time points: baseline, week 4, week 8, and week 12. Treatment for both groups started at baseline, and patients received either 12 weeks of individual CBT or 12 weeks of escitalopram with flexible dosing (10 to 20 mg). RESULTS: Collapsing the escitalopram and CBT groups, there were statistically significant pre-post changes on all outcome measures. However, there were no statistically significant differences between treatment groups on any of the outcome measures, including cognitive measures across time points. CONCLUSIONS: Our results suggest that both CBT and escitalopram have similar effects across a variety of domains and that, in contrast to our a priori hypothesis, CBT and escitalopram were associated with comparable changes on cognitive measures. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine whether isolated psychotic symptoms are more likely to be endorsed by depressed Latinos as opposed to other ethnic–racial groups; whether these symptoms affect Latinos similarly to other ethnic–racial groups in terms of treatment response; and whether they are more likely to be associated with anxiety disorders in depressed Latinos. Methods: We analyzed data from STAR⁎D subjects who self identified as White, Black, or Latino. Rates of isolated psychotic symptoms were assessed by the self-rated Psychiatric Diagnostic Screening Questionnaire (PDSQ) and compared between ethnic–racial groups. Depressive remission outcomes were compared within each ethnic–racial group between subjects who endorsed psychotic symptoms versus no psychotic symptoms. Associations between isolated psychotic symptoms and anxiety disorders were also examined. Results: Among 2597 eligible subjects with at least one post-baseline assessment and available PDSQ data excluding first-rank symptoms, the prevalence of auditory–visual hallucination was 2.5% in Whites (n=49/1928), 11.3% in Blacks (n=45/398) 6.3% in Latinos (n=17/270) (χ 2=64.9; df=2; p<0.001). Prevalence of paranoid ideation was 15.5% in Whites (n=299/1927), 31.5% in Blacks (n=126/400), and 21.1% in Latinos (n=57/270) (χ 2=57.3; df=2; p<0.001). Among Whites and Blacks but not Latinos, depressive remission rates were worse in subjects with auditory–visual hallucinations compared to those without them. Paranoid ideation had a significant negative impact on remission in Whites only. In all ethnic–racial groups, a significant association was found between auditory–visual hallucinations and PTSD and panic disorder. Limitations: The STAR*D study did not include any structured clinician-based assessment of psychotic symptoms. Conclusion: Latinos do not appear to have worse outcomes when treated for MDD with auditory–visual hallucinations, differently from Whites and Blacks. [Copyright &y& Elsevier]

Abstract: Background: Anxious depression, defined as MDD with high levels of anxiety symptoms, has been associated with lower rates of antidepressant response and remission as well as greater chronicity, suicidality and antidepressant side-effect burden. The primary aim of this study was to assess the effectiveness of cognitive therapy (CT) alone or in combination with medications for anxious versus non-anxious depression. Methods: We assessed the STAR⁎D study participants who were partial or non-responders to citalopram. Subjects were then either switched (n=696) to a new antidepressant or to CT alone, or they were kept on citalopram and augmented (n=577) with another antidepressant or CT. We compared response and remission rates, across treatment conditions, between those who met criteria for anxious depression and those who did not. Results: Those with anxious depression had significantly lower remission rates based on the QIDS, whether assigned to switch or augmentation, compared to those with non-anxious depression. Those with anxious depression, compared to those without, had significantly lower response rates based on the QIDS only in the switch group. There was no significant interaction between anxious depression and treatment assignment. Limitations: Limitations include the use of citalopram as the only Level 1 pharmacotherapy and medication augmentation option, the relatively small size of the CT arms, use of depression-focused CT rather than anxiety-focused CT, and focus on acute treatment outcomes. Conclusions: Individuals with anxious depression appear to experience higher risk of poorer outcome following pharmacotherapy and/or CT after an initial course of citalopram and continued efforts to target this challenging form of depression are needed. [Copyright &y& Elsevier]

Abstract: Objective: In this secondary analysis from the Clinical Outcomes in MEasurement-based Treatment trial (COMET), we evaluated whether providing primary care physicians with patient-reported feedback regarding depression severity affected pharmacological treatment patterns. Method: Intervention-arm physicians received their patients'' 9-item Patient Health Questionnaire scores monthly. Odds of having no change in antidepressant treatment during the 6-month study period were calculated. Relationships between depression symptom status (partial or nonresponse) at month 3 and treatment changes in months 3 through 6 were assessed. Results: Among 503 intervention and 412 usual care (UC) patients with major depressive disorder, most received antidepressant monotherapy at baseline (79.4% UC vs. 88.4% intervention; P=.047). Few switched their baseline antidepressant (17.4%), increased their dose (12.4%) or augmented with a second medication (2%). Odds of having no change in antidepressant therapy did not differ significantly between study arms (odds ratio 1.21; 95% confidence interval 0.78–1.88; P=.392). Few month 3 partial or nonresponders had a regimen change over the following 3 months; the study arms did not differ significantly (partial responders: 4.1% UC vs. 7.7% intervention; P=.429; nonresponders: 14.6% UC vs. 15.9% intervention; P=.888). Conclusions: Among depressed patients treated in primary care, little active management was observed. The lack of treatment modification for the majority of partial and nonresponders was notable. [Copyright &y& Elsevier]

Abstract: Background:: Acupuncture is widely used for treating major depressive disorder (MDD). There is evidence supporting acupuncture as an antidepressant monotherapy, but its efficacy as augmentation in antidepressant partial and non-responders has not been well-investigated. Methods:: Thirty subjects (47% female, mean age 48±11years) with a history of SCID-diagnosed MDD and partial or non-response after ≥8weeks of antidepressant therapy were assigned 8weeks of standardized 30-min open acupuncture augmentation sessions on a weekly (n=24) or twice-weekly (n=6) basis. Change in the Hamilton-D-17 score was the primary outcome measure, and response rates (based on HAM-D-17 score improvement of ≥50%) the secondary outcome. Results:: Twenty subjects (40% female; 18 in weekly and 2 in twice-weekly treatment) completed the study. In the intent-to-treat (ITT) sample (N=30), HAM-D-17 scores decreased from 18.5±3.8 to 11.2±5.3 in the weekly group (p<0.001), and from 18.5±3.3 to 11.8±4.8 in the twice-weekly group (p=0.03). Improvement did not differ significantly between treatment arms (p=0.76). Response rates were 47% for all ITT subjects, 50% for the weekly group and 33% for the twice-weekly group (p=0.66). The most common side effects included soreness/pain (n=7), bruising (n=4), and mild bleeding (n=1) at the needle site. One subject discontinued because of side effects (pain). Limitations:: Open design, small sample, polypharmacy with antidepressants. Conclusions:: Once or twice-weekly acupuncture augmentation was safe, well-tolerated and effective in antidepressant partial and non-responders, suggesting good feasibility in outpatient settings. Replication in controlled trials is warranted. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the efficacy of rEEG®-guided pharmacotherapy for the treatment of depression in those circumstances where rEEG and STAR*D provided different recommendations. Materials and methods: This was a randomized, single-blind, parallel group, 12 center, US study of rEEG-guided pharmacotherapy vs. the most effective treatment regimens reported in the NIH sponsored STAR*D study. Relatively treatment-resistant subjects ≥18 years who failed one or more antidepressants were required to have a QIDS-16-SR score ≥13 and a MADRS score ≥26 at baseline. All subjects underwent a washout of all current medications (with some protocol-specified exceptions) for at least five half-lives before receiving a QEEG and rEEG report. Subjects randomized to rEEG were assigned a regimen based on the rEEG report. Control subjects who had failed only SSRI’s in their current episode were randomized to receive venlafaxine XR. Control subjects who had failed antidepressants from ≥2 classes of antidepressants were randomized to receive a regimen from Steps 2–4 of the STAR*D study. Treatment lasted 12 weeks. The primary outcome measures were change from baseline for self-rated QIDS-SR16 and Q-LES-Q-SF. Results: A total of 114 subjects were randomized and 89 subjects were evaluable. rEEG-guided pharmacotherapy exhibited significantly greater improvement for both primary endpoints, QIDS-SR16 (−6.8 vs. −4.5, p <0.0002) and Q-LES-Q-SF (18.0 vs. 8.9, p <0.0002) compared to control, respectively, as well as statistical superiority in 9 out of 12 secondary endpoints. Conclusions: These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression. If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice. [Copyright &y& Elsevier]

Abstract: We examined the Antidepressant Treatment Response (ATR) index as a predictor of differential response and remission to escitalopram, bupropion, or a combination of the two medications, in subjects with major depressive disorder (MDD). Three hundred seventy-five subjects had a baseline quantitative electroencephalographic (QEEG) study preceding 1 week of treatment with escitalopram, 10 mg, after which a second QEEG was performed and the ATR index was calculated. Subjects then were randomized to continue escitalopram, switch to bupropion, or receive a combination of the two. Clinical response was assessed using the 17-item Hamilton Depression Rating Scale at 49 days of treatment. Accuracy of ATR in predicting response and remission was calculated. There were no significant differences between response and remission rates in the three treatment groups. A single ATR threshold was useful for predicting differential response to either escitalopram or bupropion monotherapy. Subjects with ATR values above the threshold were more than 2.4 times as likely to respond to escitalopram as those with low ATR values (68% vs. 28%). Subjects with ATR values below the threshold who were switched to bupropion treatment were 1.9 times as likely to respond to bupropion alone as those who remained on escitalopram treatment (53% vs. 28%). The ATR index did not provide a useful prediction of response to combination treatment. The ATR index may prove useful in predicting responsiveness to different antidepressant medications. [Copyright &y& Elsevier]