scholarly journals Major Depressive Disorder (MDD) and Schizophrenia– Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review

2019 ◽  
Vol 22 (10) ◽  
pp. 651-664
Author(s):  
Jasmina Mallet ◽  
Philip Gorwood ◽  
Yann Le Strat ◽  
Caroline Dubertret
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Unmet Needs ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Adjunctive Treatment ◽  
Major Depressive ◽  
Partial Agonism ◽  
Partial Agonists ◽  
Second Generation Antipsychotics

Abstract Second-generation antipsychotics are common candidates for the adjunctive treatment of major depressive disorder and for the treatment of schizophrenia. However, unmet needs remain in the treatment of both disorders. Considering schizophrenia, antipsychotics are the most common treatment and have demonstrated good efficacy. Still, side effects of these treatments are commonly reported and may impact adherence to the medication and functioning in patients with schizophrenia. Regarding major depressive disorder, despite the availability of several classes of antidepressants, many patients do not achieve remission. Adjunctive treatment with antipsychotics may improve clinical and functional outcomes. Compared with dopamine D2 receptor antagonism that is exhibited by most antipsychotics, partial agonism may result in improved outcomes in major depressive disorder and in schizophrenia. Aripiprazole, cariprazine, and brexpiprazole have partial agonism at the dopamine D2 receptor and could potentially overcome limitations associated with D2 antagonism. The objectives of this review were (1) to discuss the goal of treatment with second-generation antipsychotics in major depressive disorder and schizophrenia, and the clinical factors that should be considered, and (2) to examine the short- and long-term existing data on the efficacy and safety of D2 receptor partial agonists (aripiprazole, cariprazine, and brexpiprazole) in the adjunctive treatment of major depressive disorder and in the treatment of schizophrenia.

scholarly journals 50 Adjunctive Buprenorphine/Samidorphan Combination in Patients with Major Depressive Disorder: Phase 3 Long-term Extension Study Results

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 203-204 ◽  
Author(s):  
Michael Thase ◽  
Arielle D. Stanford ◽  
Asli Memisoglu ◽  
William Martin ◽  
Amy Claxton ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Safety Profile ◽  
Rating Scale ◽  
Remission Rate ◽  
Term Treatment ◽  
Adjunctive Treatment ◽  
Major Depressive ◽  
Long Term Treatment

AbstractIntroductionBuprenorphine/samidorphan (BUP/SAM), a combination of BUP (a µ-opioid receptor partial agonist and κ-antagonist) and SAM (a sublingually bioavailable µ-opioid antagonist), is an investigational opioid system modulator for depression. BUP/SAM has shown efficacy versus placebo as an adjunctive treatment for major depressive disorder (MDD) and a consistent safety profile in previously reported, placebo-controlled clinical studies.1,2Study Objective(s)1. To characterize the safety profile following long-term treatment with BUP/SAM2. To explore depression symptoms and remission rates in patients with MDD following long-term treatment with BUP/SAMMethodsFORWARD-2 (Clinicaltrials.gov ID: NCT02141399) enrolled patients who had participated in 1 of 4 controlled studies as well as de novo patients. All patients had a confirmed diagnosis of MDD, had a history of inadequate response to standard antidepressant therapies (ADTs), and had been treated with an adequate dose of an established ADT for ≥8weeks before BUP/SAM initiation. ADT dosage could be titrated, but the ADT could not be changed. During the study, patients received open-label, sublingual BUP/SAM 2mg/2mg as adjunctive treatment for up to 52weeks. Safety (primary objective) was assessed via adverse events (AEs), vital signs, laboratory analytes, and electrocardiography. Suicidal ideation or behavior (SIB) was evaluated by the Columbia Suicide Severity Rating Scale. Abuse potential, dependence, and withdrawal were assessed by AEs and the Clinical Opiate Withdrawal Scale. Exploratory efficacy endpoints included mean Montgomery–Åsberg Depression Rating Scale (MADRS) scores and remission rate (MADRS ≤10).ResultsOf 1454 total patients, 49% completed the 52-week study, 11% discontinued due to an AE, and 40% discontinued because of other reasons as of the interim data cutoff date (April 30, 2017). Most AEs were of mild/moderate severity. Serious AEs were reported in 3.2% of patients. AEs occurring in ≥10% of patients were nausea, headache, constipation, dizziness, and somnolence. There was no evidence of increased risk of SIB with BUP/SAM. Incidence of euphoria-related events was low (1.2%). After abrupt discontinuation of BUP/SAM, there was little evidence of withdrawal. BUP/SAM was not associated with meaningful changes in laboratory or metabolic parameters or in bodyweight. The mean MADRS score decreased from 22.9 (±9.7) at baseline to 9.8 (±8.8) after 52weeks. The remission rate at 52weeks was 52.5%.ConclusionsLong-term treatment with BUP/SAM did not reveal any new safety findings and confirmed that the risk of abuse and dependence with BUP/SAM was low. BUP/SAM maintained an antidepressant effect for up to 52weeks of treatment in patients with MDD.Funding Acknowledgements: Alkermes, Inc.

scholarly journals 181 A Phase-2 Sequential Parallel Comparison Design Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Major Depressive Disorder

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 314-315
Author(s):  
Maurizio Fava ◽  
Bryan Dirks ◽  
Marlene P. Freeman ◽  
Richard C. Shelton ◽  
Michael E. Thase ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
General Hospital ◽  
Massachusetts General Hospital ◽  
Weighted Average ◽  
Least Square ◽  
Adjunctive Treatment ◽  
Inadequate Response ◽  
Major Depressive ◽  
Stage 1

Abstract:Study Objectives:Depression is the leading cause of disability worldwide, with fewer than 50% of treated patients achieving full remission. This study (“CLARITY,” ACP-103-042: NCT03018340) examined the 5-HT2A inverse agonist pimavanserin (PIM) as a potential adjunctive treatment for major depressive disorder (MDD).Method:Adult female and male subjects with a DSM-5 primary diagnosis of a major depressive episode as part of MDD, inadequate response to ongoing SSRIs or SNRIs of adequate dose and duration as confirmed by the Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and a MADRS total score >20 were randomized to PIM 34 mg/day or placebo (PBO) added to their SSRI/SNRI treatment. A sequential parallel comparison design was used, consisting of two 5-week stages. PBO nonresponders in Stage-1 who met prespecified criteria were re-randomized to PIM or PBO for the second period (Stage-2). The primary efficacy measure was the weighted average of Stage-1 and Stage-2 total scores of the HAMD-17.Results:Of the 207 patients enrolled, 52 received PIM, and 155 received PBO in Stage 1. Mean age was 46.2 years, and 72.9% of patients were female. Baseline MADRS total (mean [SD]: 31.5 [0.4]) and HAMD-17 total scores (22.2 [0.3]) indicated a moderate overall severity of illness. PIM met the primary endpoint, reducing the weighted Stage-1/Stage-2 HAMD-17 total score relative to PBO (least-square means [LSM] difference, –1.7; standard error [SE], 0.9; P=0.04). Stage-1 PIM patients demonstrated highly significant 5-week improvement on the HAMD-17 (LSM difference=–4.0, SE=1.1; P<0.001; effect size, Cohen’s d: 0.626), separating from placebo by the end of Week 1 (LSM difference=–1.7, SE=0.8; P=0.04). Stage-2 results showed no significant separation among Stage-1 placebo nonresponders (P=0.69). In Stage 2, a substantively smaller number of subjects (n=58) were rerandomized than planned, likely due to restrictive criteria for re-randomization. Greater overall improvement was seen with PIM relative to PBO on the key secondary endpoint, the Sheehan Disability Scale (LSM difference=–0.8, SE=0.3; P=0.004), and positive results were also seen on 7 of the 11 other secondary endpoints, including responder rate (≥50% reduction in HAMD-17 total; P=0.007), Massachusetts General Hospital Sexual Functioning Index (P<0.001), and Karolinska Sleepiness Scale for daytime sleepiness (P=0.02). Discontinuations due to adverse events were low (PIM 1.2%, PBO 3.2%). One serious adverse event was reported in each treatment group, deemed unrelated to treatment. No deaths were reported. Laboratory assessments, electrocardiography, and changes in vital signs were unremarkable, and no new safety signals were reported.Conclusions:Study data provide evidence of the efficacy, safety, and tolerability of adjunctive PIM in treating MDD inadequately responsive to SSRI or SNRI therapy. Efforts to confirm these results are ongoing in a Phase 3 program.Funding Acknowledgements:ACADIA Pharmaceuticals Inc.

scholarly journals Treatment Response of Add-On Esketamine Nasal Spray in Resistant Major Depression in Relation to Add-On Second-Generation Antipsychotic Treatment

2020 ◽  
Vol 23 (7) ◽  
pp. 440-445 ◽  
Author(s):  
Markus Dold ◽  
Lucie Bartova ◽  
Siegfried Kasper
Keyword(s):  
Major Depressive Disorder ◽  
Confidence Interval ◽  
Depressive Disorder ◽  
Nasal Spray ◽  
Second Generation ◽  
Mean Difference ◽  
Inadequate Response ◽  
Major Depressive ◽  
Second Generation Antipsychotics ◽  
Second Generation Antipsychotic

Abstract In this meta-analysis, we aimed to estimate and compare the efficacy of add-on treatment of antidepressants with esketamine nasal spray and second-generation antipsychotics in patients with nonpsychotic major depressive disorder and inadequate response to antidepressants. Searching for acute-phase, double-blind, placebo-controlled, randomized trials, we found 22 second-generation antipsychotic (n = 8363) and 3 intranasal esketamine (n = 641) studies. Mean change in the Montgomery Åsberg Depression Rating Scale total score served as outcome. We determined a higher mean difference (vs placebo) for the pooled esketamine nasal spray trials (mean difference = 4.09, 95% confidence interval: 2.01 to 6.17) than for the pooled second-generation antipsychotic augmentation trials (mean difference  = 2.05, 95% confidence interval: 1.51 to 2.59). Thus, the effect size for intranasal esketamine was nearly twice as high as those for the second-generation antipsychotics. This indicates high efficacy of add-on esketamine nasal spray in treatment-resistant major depressive disorder compared with other well-established, evidence-based pharmacological options such as augmentation with second-generation antipsychotics.

scholarly journals Brexpiprazole as Adjunctive Treatment for Major Depressive Disorder Following Treatment Failure With at Least One Antidepressant in the Current Episode: a Systematic Review and Meta-Analysis

2019 ◽  
Vol 22 (11) ◽  
pp. 698-709
Author(s):  
Taro Kishi ◽  
Kenji Sakuma ◽  
Ikuo Nomura ◽  
Yuki Matsuda ◽  
Kazuo Mishima ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Scale Score ◽  
Response Rate ◽  
Meta Analysis ◽  
Weight Increase ◽  
Adjunctive Treatment ◽  
Number Needed To Treat ◽  
Major Depressive ◽  
Severity Scores

Abstract Background This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5–3 mg/d) for major depressive disorder where antidepressant treatment had failed. Methods The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression–Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose). Results We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89−0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93−0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = −0.20, 95% CI = −0.29, −0.11), Sheehan Disability Scale score (standardized mean difference = −0.12, 95% CI = −0.21, −0.04), and Clinical Global Impression–Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50). Conclusions Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d.

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