Major Depressive Disorder Trials Research Articles

The Power Threat Meaning Framework: a qualitative study of depression in adolescents and young adults.

Depression constitutes one of our largest global health concerns and current treatment strategies lack convincing evidence of effectiveness in youth. We suggest that this is partly due to inherent limitations of the present diagnostic paradigm that may group fundamentally different conditions together without sufficient consideration of etiology, developmental aspects, or context. Alternatives that complement the diagnostic system are available yet understudied. The Power Threat and Meaning Framework (PTMF) is one option, developed for explanatory and practical purposes. While based on scientific evidence, empirical research on the framework itself is still lacking. This qualitative study was performed to explore the experiences of adolescents and young adults with depression from the perspective of the PTMF. We conducted semi-structured interviews with 11 Swedish individuals aged 15- 22 years, mainly female, currently enrolled in a clinical trial for major depressive disorder. Interviews were transcribed verbatim and analyzed with framework analysis informed by the PTMF. A complex multitude of adversities preceding the onset of depression was described, with a rich variety of effects, interpretations, and reactions. In total, 17 themes were identified in the four dimensions of the PTMF, highlighting the explanatory power of the framework in this context. Not all participants were able to formulate coherent narratives. The PTMF provides a framework for understanding the complexities, common themes, and lived experiences of young individuals with depression. This may be essential for the development of new interventions with increased precision and effectiveness in the young.

Dropout in a clinical trial for comorbid PTSD and MDD among US service members: Are pretreatment characteristics predictive?

Objective Despite effective treatment options for posttraumatic stress disorder (PTSD), many patients do not complete therapy. This includes U.S. active duty service members, yet factors linked to attendance in this population remain understudied and dropout remains difficult to predict. Additionally, most studies have not examined samples with PTSD and co-occurring major depressive disorder (MDD) despite high rates of comorbidity. Method The current study explored predictors of dropout among service members with comorbid PTSD and MDD (N = 94) randomized to cognitive processing therapy enhanced with behavioral activation (BA + CPT) or CPT as part of a clinical trial. Results Using the Fournier approach, only two predictors were associated with lower dropout risk among over 20 examined: shorter duration between pretreatment assessment and Session 1 (p = .041) and past 3-month PTSD treatment engagement (p = .036). Conclusion Results suggest the possible utility of early momentum in starting therapy and leveraging recent treatment to improve attendance. However, this study also highlights the possible limitations of commonly assessed pretreatment factors in predicting attendance and current challenges in measuring dropout risk. Strategies to improve prediction, such as shifting focus to assess modifiable factors and processes more proximal to dropout during treatment, may be needed. Trial registration: ClinicalTrials.gov identifier: NCT02874131.

The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder.

We examined if the therapeutic alliance between study participants and intervention facilitators in a psilocybin-assisted therapy (PAT) trial changed over time and whether there were relationships between alliance, acute psilocybin experiences, and depression outcomes. In a randomized, waiting list-controlled clinical trial for major depressive disorder in adults (N = 24), participants were randomized to an immediate (N = 13) or delayed (N = 11) condition with two oral doses of psilocybin (20mg/70kg and 30mg/70kg). Ratings of therapeutic alliance significantly increased from the final preparation session to one-week post-intervention (p = .03, d = .43). A stronger total alliance at the final preparation session predicted depression scores at 4 weeks (r = -.65, p = .002), 6 months (r = -.47, p = .036), and 12 months (r = -.54, p = .014) post-intervention. A stronger total alliance in the final preparation session was correlated with higher peak ratings of mystical experiences (r = .49, p = .027) and psychological insight (r = .52, p = .040), and peak ratings of mystical experience and psychological insight were correlated with depression scores at 4 weeks (r = -.45, p = .030 for mystical; r = -.75, p < .001 for insight). Stronger total alliance one week after the final psilocybin session predicted depression scores at 4 weeks (r = -.85, p < .001), 3 months (r = -.52, p = .010), 6 months (r = -.77, p < .001), and 12 months (r = -.61, p = .001) post-intervention. These findings highlight the importance of the therapeutic relationship in PAT. Future research should explore therapist and participant characteristics which maximize the therapeutic alliance and evaluate its relationship to treatment outcomes. Trial registration: Registration: Clinicaltrials.gov NCT03181529. https://classic.clinicaltrials.gov/ct2/show/NCT03181529.

Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder.

Low-grade inflammation is considered as a pathophysiological mechanism in a subtype of patients with major depressive disorder (MDD). Anti-inflammatory drugs have shown efficacy in treating MDD. However, it remains unclear how to identify suitable patients for anti-inflammatory treatment of depression. This study investigates the predictive value of pre-treatment high-sensitivity C-Reactive Protein (hsCRP) stratification on the outcome of celecoxib augmentation of vortioxetine. The PREDDICT study was conducted as a randomized, double-blind, placebo-controlled 6-week trial on augmentation of vortioxetine with celecoxib between December 2017 and April 2020 at the University of Adelaide (Australia). The present analysis focusses on the question of whether the pre-treatment hsCRP measurement and stratification of patients to depression with inflammation (hsCRP >3 mg/L) or without inflammation (hsCRP ≤3 mg/L) has an impact on the outcome of anti-inflammatory treatment with celecoxib. A total of n = 119 mostly treatment-resistant MDD patients with moderate to severe symptomatology were recruited in the trial. There was no effect of treatment group (celecoxib or placebo), pre-treatment hsCRP strata (with/without inflammation), or interaction between the two terms on treatment outcome. The results of the current analysis do not support the hypothesis that pre-treatment hsCRP level is predictive for response to anti-inflammatory treatment with celecoxib in MDD patients. Further research is needed to identify appropriate biomarkers for the prediction of anti-inflammatory treatment outcome in depression. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.

Categorical Improvement in Depressive Symptom Severity: Results From a Randomized Controlled Trial of Cariprazine for Adjunctive Treatment of MDD

AbstractBackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.MethodsPost hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal &lt;6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).ResultsOf the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).ConclusionsIn this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.FundingAbbVie

Cariprazine’s efficacy in treating depressive symptoms – pooled data from schizophrenia, bipolar depression and major depression trials

IntroductionDepressive symptoms are a common feature of schizophrenia (SCH) and define bipolar disorder and major depressive disorder (MDD). Their emergence is related to altered neurotransmission at the serotonin receptors and potentially at dopamine D3 receptors.ObjectivesThe aim of this analysis was to examine the efficacy of cariprazine (CAR) in treating depressive symptoms in SCH, bipolar depression (BD) and MDD.MethodsClinical trials with randomised, double-blind, placebo (PLB)-controlled designs were included in these analyses. Data from 3 SCH [NCT00694707, NCT01104766, NCT01104779; 1.5-9 mg/d] and 3 BD [NCT01396447, NCT02670538, NCT02670551; 1.5-3 mg/d] studies were pooled. In MDD, add-on CAR to antidepressant treatment was evaluated against PLB in two studies [NCT03738215: 1.5 and 3 mg/d; NCT01469377: 1-2 mg/d and 2-4.5 mg/d).Least square (LS) mean changes were analysed using Mixed Model Repeated Measures: from baseline (BL) to Week 6 in the Positive and Negative Syndrome Scale (PANSS)-derived Marder anxiety/depression factor items (schizophrenia); from BL to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (bipolar depression); and from BL to Week 6 [NCT03738215] and Week 8 [NCT01469377] in MADRS total score (major depressive disorder).ResultsAltogether, 1466 SCH (PLB=442, CAR=1024) patients were included in the pooled analysis. In the BD analysis, data from 1383 (PLB=460, CAR=923) patients were pooled. In the MDD trials, there were 502 CAR (1.5mg/d=250, 3 mg/d=252) and 249 PLB-treated patients [NCT03738215], and 544 CAR (1-2 mg/d=273, 2-4.5 mg/d=271) and 264 PLB patients in the other study [NCT01469377]. In SCH, CAR achieved significantly greater reductions than PLB on the Marder anxiety/depression factor domain (LS mean change: PLB= -2.66, CAR= -3.26, p&lt;0.01): the effect was driven by 3 out of 4 items. In BD, CAR yielded significantly greater improvement on the MADRS compared to PLB (LS mean change: PLB= -12.05, CAR= -14.69, p&lt;0.001), which was driven by 9 out of 10 items. In MDD [NCT03738215], CAR 1.5 mg/d add-on significantly alleviated depressive symptoms compared to PLB (LS mean change: PLB= -11.5, CAR 1.5mg/d= -14.1, p&lt;0.01), while in the other MDD trial [NCT01469377], CAR 2-4.5 mg/d add-on produced significantly greater reductions than PLB (LS mean change: PLB= -12.5, CAR 2-4.5 mg/d= -14.6, p&lt;0.01).ConclusionsThese findings indicate that CAR is an effective treatment option for the treatment of depressive symptoms independent of disease (in SCH, BD and MDD), being a transdiagnostic broad-spectrum treatment option.Disclosure of InterestR. McIntyre Grant / Research support from: CIHR/GACD/National Natural Science Foundation of China (NSFC), the Milken Institute, Consultant of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Gedeon Richter, Recordati, Atai Life Sciences, Speakers bureau of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Gedeon Richter, Recordati, Atai Life Sciences, R. Csehi Employee of: Gedeon Richter Plc., G. Németh Employee of: Gedeon Richter Plc.

A Prospective, Multi-center Randomized, Controlled, Blinded Trial of Vagus Verve Stimulation for Difficult to Treat Depression: the RECOVER Trial

Abstract Introduction: Therapeutic Vagus Nerve Stimulation (VNS) has been FDA-approved for treatment-resistant depression (TRD). In 2007, the US Centers for Medicare and Medicaid Services (CMS) issued a non-coverage decision, making access difficult for patients. In 2019, CMS requested a “coverage with evidence development trial” to determine potential VNS efficacy in the US Medicare TRD population. This trial, RECOVER, is co-sponsored by CMS and the device maker (LivaNova) to assess VNS efficacy over 12 months is large, multi-centered (N=71, US sites), randomized, and placebo-controlled. Methods: Inclusion criteria include: ≥18 years old, diagnosis of Major Depressive Disorder (MDD) or Major Depressive Episode (MDE) in bipolar disorder, chronic (2 years) or recurrent (≥ 4 MDEs), failure of four medical record-verified AD treatments in the current MDE, a score of ≥ 22 on the Montgomery Asberg Depression Rating Scale (MADRS). Exclusion criteria include: substance use and psychotic disorders, acute suicidal ideation/intention, severe personality disorder. All subjects undergo VNS implantation then randomized to active treatment (device on) or sham (implanted, not activated) for 12 months. Depression ratings are performed by blinded, offsite raters. The trial’s primary measure is number of months in response (active –vs- placebo). Results: 480 patients enrolled; subject mean age is 54.0, 34.6 mean MADRS, mean age of onset is 20.9, and 20.4 years of lifetime MDE. Average failed lifetime ADs is 14.1, with many receiving aggressive treatments: ECT (41.9%), TMS (46.7%), and ketamine (21.3%). Many report psychiatric hospitalizations (64.0%); attempted suicide (43.8%). To date, 222 patients (including 40 early terminated) have completed the trial’s first year. Conclusions: RECOVER is the largest prospective, randomized, device-based, placebo-controlled MDD trial ever undertaken; enrolling severe TRD patients not studied in most MDD clinical trials. It will provide a thorough understanding of the nature of VNS response (e.g., onset of response and potential baseline outcome predictors). Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Treatment-Resistant Depression, Vagus Nerve Stimulation, Difficult to Treat Depression, Major Depressive Disorder

Ensaio clínico randomizado sobre a eficácia de novo equipamento de estimulação transcraniana por corrente contínua (ETCC) no tratamento da depressão: uma opção de baixo custo para países em desenvolvimento?

ABSTRACT Objective: Verify the clinical efficacy and safety of a low-cost tDCS device, in a clinical trial for major depressive disorder. Methods: 168 persons were recruited; 32 depressed individuals with moderate or severe depressive symptoms (HDRS17 scores higher than 18) were included and randomized for the trial (16 individuals in each group). The intervention consisted of 10 active anodal tDCS sessions at 2 mA for 30 minutes over the left dorsolateral prefrontal cortex; or sham. The main outcome was HDRS17; secondary outcomes included satisfaction (TSQM II) and quality of life (WHOQOL-BREF). Assessments at baseline, endpoint and at 30 days follow-up. Results: The sample was composed by a total of 11 men and 21 women, mean age of 42.75 years (95% CI: 38.10-47.40). Active treatment was superior than sham: There was a significant interaction between group and time regarding HDRS-17 scores (F = 4.089, df = 2, p = 0.029; partial Eta squared = 0. 239). Post hoc analyses exhibited a statistically significant difference between active and sham group symptoms after a 30 days follow-up (difference = -7.75, p = 0.008, Cohen’s d = 1.069). There were 3 dropouts, all in the active group, due schedule issues. No severe adverse effects reported. Conclusion: The current active tDCS protocol was related with clinical improvement of depressive symptoms. Intervention was well-tolerated. Non-invasive brain stimulation techniques are still not routinely used, although a viable strategy for treatment-resistant patients, partial responders and people unable to use pharmacological treatment. We aim to increase knowledge and use of tDCS for the Brazilian population.

Placebo Effect in Randomized Trials of Major Depressive Disorder With Psychotic Features: A Systematic Review and Descriptive Meta-Analysis.

In the 1980s, the response rate of major depressive disorder with psychotic features (MDD-Psy) to placebo pills was reported to be close to 0%. To our knowledge, this placebo response rate has not been systematically reassessed. We undertook a systematic review of randomized controlled trials (RCTs) that have used a placebo or sham control group for MDD-Psy. We searched MEDLINE and identified 9 relevant publications reporting on 10 studies comparing a placebo or sham interventions versus an active intervention. We extracted reported rates of response or of dropout for all causes associated with placebo versus active intervention(s) and aggregated response and dropout rates across trials. Two sham-controlled electroconvulsive therapy (ECT) trials did not provide response rates. In the 3 pharmacotherapy studies published in the 1980s, 0 of 12 participants (0%) responded to placebo versus 13 of 38 (34.2%) responding to the active interventions. In contrast, 5 RCTs published in the 2000s, 114 of 339 participants (33.6%) randomized to placebo responded versus 149 of 373 participants (39.9%) randomized to active interventions; dropout rates were 71/236 (30.1%) for placebo versus 84/282 (29.8%) for the active interventions. As expected, response rates to placebo pills in RCTs for MDD-Psy increased markedly from the 1980s to the 2000s. Methodological issues in the design and conduct of more recent RCTs may have contributed to the high placebo response. However, one needs to consider this placebo response rate when interpreting the result of recent trials of MDD-Psy, which typically have not included a "pure" placebo condition.

Should the Food and Drug Administration Limit Placebo-Controlled Trials?

Should the Food and Drug Administration Limit Placebo-Controlled Trials?

Multiple Domain and Multiple Kernel Outcome-Weighted Learning for Estimating Individualized Treatment Regimes

Individualized treatment rules (ITRs) recommend treatments that are tailored specifically according to each patient’s own characteristics. It can be challenging to estimate optimal ITRs when there are many features, especially when these features have arisen from multiple data domains (e.g., demographics, clinical measurements, neuroimaging modalities). Considering data from complementary domains and using multiple similarity measures to capture the potential complex relationship between features and treatment can potentially improve the accuracy of assigning treatments. Outcome weighted learning (OWL) methods that are based on support vector machines using a predetermined single kernel function have previously been developed to estimate optimal ITRs. In this article, we propose an approach to estimate optimal ITRs by exploiting multiple kernel functions to describe the similarity of features between subjects both within and across data domains within the OWL framework, as opposed to preselecting a single kernel function to be used for all features for all domains. Our method takes into account the heterogeneity of each data domain and combines multiple data domains optimally. Our learning process estimates optimal ITRs and also identifies the data domains that are most important for determining ITRs. This approach can thus be used to prioritize the collection of data from multiple domains, potentially reducing cost without sacrificing accuracy. The comparative advantage of our method is demonstrated by simulation studies and by an application to a randomized clinical trial for major depressive disorder that collected features from multiple data domains. Supplementary materials for this article are available online.

Adjunctive D-Cycloserine with Intermittent Theta-Burst Stimulation: A Randomized Placebo-Controlled Trial in Major Depressive Disorder

Intermittent theta-bust stimulation (iTBS) is emerging as a first-choice transcranial magnetic stimulation (TMS) protocol in the treatment of refractory Major Depressive Disorder (MDD). While the mechanisms for antidepressant efficacy remain unclear, physiological studies suggest that N-Methyl-D-Aspartate (NMDA) receptor activation is required for iTBS related synaptic plasticity. No study to date has directly targeted the NMDA receptor as a means of enhancing clinical efficacy in MDD.

Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from the early medication change trial in major depressive disorder

Objectives Previous studies indicated a relationship between aldosterone, the mineralocorticoid receptor (MR), and antidepressant treatment outcome. Physiological indicators of MR function (blood pressure and electrolytes) are easily accessible and may therefore serve as useful predictors. Thus, our aim was to investigate the predictive value of peripheral MR-related markers for antidepressant treatment outcomes. Methods 826 MDD patients who had participated in the randomised-controlled Early Medication Change (EMC) trial were analysed. Depression severity and MR-related markers were assessed weekly. In 562 patients, genetic variation of five MR-related genes was determined. Results Patients with blood pressure <120mmHg showed higher depression severity (p = 0.005) than patients with blood pressure ≥120mmHg. Patients with a melancholic subtype had significantly lower blood pressures (p = 0.004). Na+/K+ ratio was positively and K+-concentration was negatively correlated to depression severity and to relative changes in HAMD from baseline to day 14, and 56 respectively (p < 0.001). For none of the MR-related genes, genetic variation was associated with treatment outcomes. Conclusions We confirmed early observations of an altered peripheral MR sensitivity, reflected by lower blood pressure, low K+ or high Na+/K+ ratio in patients with more severe depression. These routinely collected biomarkers may potentially be useful for risk stratification in an early stage of treatment. Trial Registration: clinicaltrials.gov Identifier: NCT00974155; https://www.clinicaltrials.gov/ct2/results?term=NCT00974155

Desvenlafaxine in the treatment of major depression: an updated overview

ABSTRACT Introduction: Major depressive disorder (MDD) remains one of the most prevalent mental health conditions. It is a chronic, relapsing condition and despite multiple treatment options, many patients fail to achieve remission of symptoms. Inadequacy of treatment has stimulated the search for agents with significant therapeutic advantages. Areas covered: This review examines literature concerning the use of desvenlafaxine in the treatment of MDD published since a previous analysis in this journal in 2014. Published papers were identified via a PubMed and Web of Science search and excluded congress presentations. Results from clinical trials in MDD, systematic reviews, and post hoc analyses in patient subgroups, are reviewed. Expert opinion: Desvenlafaxine was an effective antidepressant with favorable safety and tolerability in adults. Efficacy was demonstrated in the subgroup of peri- and post-menopausal women with MDD but not in children and adolescents. There is a relatively low potential for drug–drug interactions due to its metabolic profile. Hepatic impairment does not significantly alter dose requirements, whereas severe renal disease requires some adjustments of dose. Desvenlafaxine maybe suitable in patients with comorbid physical illnesses. Desvenlafaxine can be a first line consideration for the treatment of cases of MDD uncomplicated by medical comorbidities.

Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches.

Background:Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose.Aims:The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose.Methods:We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N = 288) in which psilocybin was administered in the range 20 to 30 mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg (n = 120), participants receiving 30 mg/70 kg (n = 182), and participants whose weight-adjusted dose was about 25 mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n = 103).Results:In the 20 mg/70 kg and 30 mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113 kg) the present results showed no evidence that body weight affected subjective effects of psilocybin.Conclusions:These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.

Selective Serotonin Reuptake Inhibitor Pharmaco-Omics: Mechanisms and Prediction.

Selective serotonin reuptake inhibitors (SSRIs) are a standard of care for the pharmacotherapy of patients suffering from Major Depressive Disorder (MDD). However, only one-half to two-thirds of MDD patients respond to SSRI therapy. Recently, a “multiple omics” research strategy was applied to identify genetic differences between patients who did and did not respond to SSRI therapy. As a first step, plasma metabolites were assayed using samples from the 803 patients in the PGRN-AMPS SSRI MDD trial. The metabolomics data were then used to “inform” genomics by performing a genome-wide association study (GWAS) for plasma concentrations of the metabolite most highly associated with clinical response, serotonin (5-HT). Two genome-wide or near genome-wide significant single nucleotide polymorphism (SNP) signals were identified, one that mapped near the TSPAN5 gene and another across the ERICH3 gene, both genes that are highly expressed in the brain. Knocking down TSPAN5 and ERICH3 resulted in decreased 5-HT concentrations in neuroblastoma cell culture media and decreased expression of enzymes involved in 5-HT biosynthesis and metabolism. Functional genomic studies demonstrated that ERICH3 was involved in clathrin-mediated vesicle formation and TSPAN5 was an ethanol-responsive gene that may be a marker for response to acamprosate pharmacotherapy of alcohol use disorder (AUD), a neuropsychiatric disorder highly co-morbid with MDD. In parallel studies, kynurenine was the plasma metabolite most highly associated with MDD symptom severity and application of a metabolomics-informed pharmacogenomics approach identified DEFB1 and AHR as genes associated with variation in plasma kynurenine levels. Both genes also contributed to kynurenine-related inflammatory pathways. Finally, a multiply replicated predictive algorithm for SSRI clinical response with a balanced predictive accuracy of 76% (compared with 56% for clinical data alone) was developed by including the SNPs in TSPAN5, ERICH3, DEFB1 and AHR. In summary, application of a multiple omics research strategy that used metabolomics to inform genomics, followed by functional genomic studies, identified novel genes that influenced monoamine biology and made it possible to develop a predictive algorithm for SSRI clinical outcomes in MDD. A similar pharmaco-omic research strategy might be broadly applicable for the study of other neuropsychiatric diseases and their drug therapy.

ERICH3: vesicular association and antidepressant treatment response

Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human ERICH3 gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.

An Alternative Implementation of Reference-Based Controlled Imputation Procedures

Reference-based controlled imputations have become a popular tool to assess the sensitivity of primary analysis inference to different post-dropout assumptions and to yield an alternative effectiveness estimand of treatment effect. As the imputation and analysis models are uncongenial in this setting, Rubin’s variance estimator overestimates the repeated sampling variability of the multiple imputation estimator of treatment effect. On the other hand, since reference-based methods borrow information across arms, the sampling variance of treatment effect estimator decreases as the proportion of missing data increases, rendering it inappropriate for use in sensitivity analysis. We propose to decouple the variance estimation from information borrowing by using a delta-adjusted pattern mixture model with delta-adjustments fixed at the maximum likelihood estimate. Reference-based pattern-mixture models can thus be embedded in the sensitivity analysis using delta-adjusted pattern-mixture models by identifying a scalar sensitivity parameter value to match the treatment effect estimate. We provide both theoretical and empirical justifications of the proposed approach and illustrate its use in the analysis of a clinical trial of major depressive disorder.

Clinical and methodological considerations for psychological treatment of cognitive impairment in major depressive disorder.

Cognitive impairment is considered a core feature of major depressive disorder (MDD) and research into psychological treatments aiming to address cognitive impairment are gaining momentum. Compared with the well-established research base of cognitive treatment trials in schizophrenia, including meta-analyses, mood disorder research is much more preliminary. To focus on identifying the important factors to consider in developing larger-scale psychological treatment trials targeting cognitive impairment in mood disorders. Trial design recommendations have been published for cognitive treatment trials in bipolar disorder. An in-depth discussion of methodological considerations in the development of cognitive treatment trials for MDD. Methodological considerations include: screening for, and defining, cognitive impairment; mood state when cognitive intervention begins; medication monitoring during cognitive interventions; use of concomitant therapy; level of therapist involvement; duration and dose of treatment; choice of specific cognitive training exercises; home practice; improving adherence; appropriate comparison therapies in clinical trials; and choice of primary outcomes. As well as guidance for clinical trial development, this review may be helpful for clinicians wanting to provide cognitive interventions for individuals with MDD.

0535 Evaluation of Insomnia Symptoms in a Double-Blind, Randomized, Placebo-Controlled Phase 3 Trial of Sage-217 in Postpartum Depression

Abstract Introduction Postpartum depression (PPD) is a specifier of major depressive disorder (MDD) with peripartum onset. SAGE-217, an investigational, oral neuroactive steroid GABAA receptor positive allosteric modulator, demonstrated improvements in depressive and anxiety symptoms versus placebo in a Phase 3 trial in PPD (NCT02978326; ROBIN) and a pivotal trial in MDD (NCT03000530). In PPD and MDD, insomnia symptoms are key diagnostic features, comorbid sleep disorders are frequent, and insomnia is a common residual symptom. Here we conducted post-hoc analyses to assess insomnia symptoms in the ROBIN trial. Methods Women (n=151) ages 18-45, ≤6 months postpartum, with PPD (major depressive episode beginning in 3rd trimester or ≤4 weeks postpartum) and a Hamilton Rating Scale for Depression (HAM-D) total score ≥26, were randomized 1:1 to receive outpatient SAGE-217 30mg or placebo for two weeks, with 4 weeks follow-up. Change from baseline (CFB) in HAM-D score at Day 15 was the primary endpoint. Secondary endpoints included CFB in HAM-D at other time points and the Montgomery-Åsberg Depression Rating Scale (MADRS). Post-hoc analyses assessed HAM-D insomnia subscale (HAM-D-Ins) and MADRS individual insomnia item (MADRS-Ins) scores. HAM-D and MADRS measures were evaluated using a mixed-effects model for repeated measures. Safety and tolerability were assessed by adverse event (AE) reporting. Results SAGE-217 demonstrated statistically significant Day 15 CFB versus placebo in HAM-D (primary endpoint: -17.8 vs. -13.6, p=0.0028), MADRS (-22.1 vs. -17.6, p=0.0180), and associated insomnia sub-scales/items (difference SAGE-217 vs. placebo; HAM-D-Ins: -1.003, p=0.0038; MADRS-Ins: -0.773, p=0.0116). Significant CFB in insomnia sub-scales/items favoring SAGE-217 were observed by Day 3 (HAM-D-Ins: -0.841, p=0.0142; MADRS-Ins: -0.710, p=0.017) and at Day 45 (HAM-D-Ins: -0.730, p=0.0207; MADRS-Ins: -0.636, p=0.0221). Most common (≥5%) AEs were somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, and sedation. Conclusion SAGE-217 demonstrated improvements in depression symptoms, including insomnia symptoms, and was generally well tolerated. Support This study was sponsored by Sage Therapeutics, Inc.