Long-Term, Open-Label, Safety Study of Edivoxetine 12 to 18 mg Once Daily as Adjunctive Treatment for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor 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.

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Brexpiprazole: A review of a new treatment option for schizophrenia and major depressive disorder

Mental Health Clinician ◽

10.9740/mhc.2017.09.207 ◽

2017 ◽

Vol 7 (5) ◽

pp. 207-212 ◽

Cited By ~ 10

Author(s):

Lauren A. Diefenderfer ◽

Courtney Iuppa

Keyword(s):

Clinical Trials ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Partial Agonist ◽

Adjunctive Treatment ◽

Inadequate Response ◽

Major Depressive ◽

Two Phase ◽

New Treatment

Abstract Brexpiprazole is an atypical antipsychotic that works as a partial agonist at serotonin 5-hydroxytryptamine1A and dopamine D2 receptors and an antagonist at serotonin 5-hydroxytryptamine2A. It has US Food and Drug Administration approval for monotherapy treatment of schizophrenia and adjunctive treatment to antidepressants for major depressive disorder. Two phase-3 clinical trials demonstrated efficacy and relatively fair tolerability with regard to adverse effects for each indication. Akathisia was frequently reported in the major depressive disorder trials but less so in the schizophrenia trials. Significant increases in body weight and triglycerides were seen across all studies. Brexpiprazole appears to be a viable option for treating an acute exacerbation of schizophrenia requiring hospitalization or adjunctive treatment of major depressive disorder in patients who showed an inadequate response to 1 to 3 antidepressants. Further clinical trials are warranted to determine the long-term efficacy of brexpiprazole, and comparison trials would be beneficial to establish its place in therapy.

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Measures of suicidality in phase 3 clinical trials of levomilnacipran ER in adults with major depressive disorder

CNS Spectrums ◽

10.1017/s1092852916000663 ◽

2017 ◽

Vol 22 (6) ◽

pp. 475-483 ◽

Cited By ~ 2

Author(s):

Michael E. Thase ◽

Carl Gommoll ◽

Changzheng Chen ◽

Kenneth Kramer ◽

Arif Khan ◽

...

Keyword(s):

Major Depressive Disorder ◽

Suicidal Ideation ◽

Depressive Disorder ◽

Rating Scale ◽

Short Term ◽

Open Label ◽

Major Depressive ◽

Double Blind ◽

And Behavior

ObjectiveTo evaluate the effects of levomilnacipran extended-release (ER) on suicidal ideation and behavior in adults with major depressive disorder (MDD).MethodsPost hoc analyses were conducted in patients from 4 randomized, double-blind, placebo-controlled trials and a long-term, open-label extension study of levomilnacipran ER (40-120 mg/d) in adults with MDD. Analyses included incidence of suicide-related treatment-emergent adverse events (TEAEs); incidence of Columbia–Suicide Severity Rating Scale (C-SSRS) suicidal ideation (score=1–5) and behavior (score=6-10); percent of patients who shifted from no C-SSRS suicidal ideation/behavior at baseline to suicidal ideation during treatment (worsened from score=0 to score=1–5), or vice-versa (improved from score=1-5 to score=0).ResultsSuicide-related TEAEs occurred in<1% of patients in the levomilnacipran ER studies. The incidence of C-SSRS suicidal ideation was 22.2%, 23.9%, and 21.7% for placebo, short-term levomilnacipran ER, and long-term levomilnacipran ER, respectively; C-SSRS suicidal behavior was<1% in all of these groups. In the short-term studies, the percentage of patients with C-SSRS shifts were as follows: worsening from score=0 to score=1–5 (placebo, 8.6%; levomilnacipran ER, 11.0%); improvement from score=1–5 to score=0 (placebo, 24.0%; levomilnacipran ER, 27.7%).ConclusionIn adult MDD patients, the incidence of suicidal ideation and behavior was similar between placebo and short-term levomilnacipran ER as indicated by TEAE reports and C-SSRS scores. Worsening in C-SSRS scores was also similar between placebo and levomilnacipran ER. There was no indication of increased suicidality during longer courses of continued therapy. Together, these findings suggest that this medication is not associated with increased risks of suicidal ideation or behavior.

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