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Buprenorphine/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.1,2
1. To characterize the safety profile following long-term treatment with BUP/SAM
2. To explore depression symptoms and remission rates in patients with MDD following long-term treatment with BUP/SAM
FORWARD-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).
Of 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%.
Long-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.
One of the challenges in schizophrenia long-term trials is that clinical outcomes are often confounded by covert nonadherence to prescribed oral antipsychotics. This is a post hoc analysis (>2 years) of the symptoms and illness trajectory of patients treated with the long-acting injectable (LAI) antipsychotic aripiprazole lauroxil (AL). As adherence to LAIs can be monitored, these data could assess outcome trajectories unaffected by medication discontinuations that may occur with oral antipsychotics.
The efficacy and safety of once-monthly AL (441 or 882mg) for the treatment of schizophrenia were previously demonstrated in a phase 3 trial, followed by a 52-week, long-term safety study of two AL doses (441 or 882mg once monthly; patients continuing from the phase 3 study remained on their fixed AL dose [NCT01626456]), after which patients could enroll in a second long-term extension study. Patients entering the second long-term study continued on their fixed AL dose, with a variable follow-up period of up to 128 additional weeks (NCT01895452). In this post hoc analysis, the extension studies were combined to provide continuous outcome data over 2 years’ follow-up. The 12-week assessment visit (rather than the first visit) in the first extension study was chosen as the baseline to account for patients entering this study with variable AL exposure histories (with/without prior AL exposure). We report on the trajectory of symptoms and illness severity for >2 years (up to 112weeks) after the 12-week visit using the Positive and Negative Syndrome Scale (PANSS) total and Clinical Global Impression–Severity (CGI-S) scale scores. Course of illness was measured as the difference in PANSS and CGI-S scale scores within dose groups from baseline to end of follow-up, analyzed using MMRM.
Overall, 432/478 patients entering the initial 52-week study were included in the post hoc analysis. For the AL 441 and 882mg groups, respectively, baseline scores (mean±SD) were 59.91±16.25 and 56.27±12.89 (PANSS), and 2.99±0.97 and 2.79±0.79 (CGI-S scale). Approximately 49% of patients (211/432) remained for the entire 112-week follow-up. Over this period, the trajectory of PANSS scores improved significantly compared with baseline for both the 441 and 882mg groups, with changes from baseline (least squares mean±SE) of −5.46±0.92 (P<.0001) and −4.99±0.53 (P<.0001), respectively. CGI-S scale scores had similar improvement: changes from baseline of −0.32±0.07 (P<.0001) and −0.28±0.04 (P<.0001) for the AL 441 and 882mg groups, respectively. Overall, AL was well tolerated, with a safety profile over a 2-year follow-up that was consistent with the initial 52-week safety results.
This post hoc analysis demonstrates the safety and continued therapeutic efficacy of long-term treatment with AL in patients with schizophrenia. There were no apparent dose differences in the trajectory of symptom changes over the course of a 2-year follow-up.
Funding Acknowledgements: This study was funded by Alkermes, Inc.
Safety and tolerability of long-term treatment with the long-acting antipsychotic aripiprazole lauroxil (AL) were evaluated in patients with schizophrenia.
This was an international, multicenter, phase 3, 52-week safety study of 2 fixed doses of AL (441 mg or 882 mg intramuscular every 4 weeks). Safety endpoints included adverse events (AEs) and extrapyramidal symptoms (EPS) including akathisia, injection-site reactions (ISRs), and clinically relevant changes in metabolic and endocrine values.
Of 478 patients entering this study, 236 (49%) continued from a previous 12-week, phase 3 efficacy study of AL, and 242 (51%) were newly enrolled. Overall, 77% and 23% of patients received AL 882 mg (N = 368) and 441 mg (N = 110), respectively. AEs occurred in 50.4% of patients; most were mild (28.7%) or moderate (18.2%). The most common AEs were insomnia (8.4%) and increased weight (5.0%). Akathisia was reported as an AE in 3.8% of the overall population, with higher rates in patients initiating AL on study entry than those continuing on AL. EPS-related AEs occurred in 9.4% of patients, and AEs related to metabolic parameters were reported in 4.6% of patients. Weight gain was minimal (0.8 kg), and no clinically relevant changes were observed for metabolic parameters. The overall incidence of ISRs was 3.8%; most were associated with the initial injections in patients receiving their first injection in this study.
Long-term treatment with AL is generally well tolerated, with a safety profile consistent with that of oral aripiprazole. It is a suitable option for patients with schizophrenia.
Patients with depression are often not prescribed antidepressants for an adequate period of time.
The impact of antidepressant prescribing patterns on the risk of relapse or recurrence of depression is examined.
The Medi Plus UK Primary Care Database was used to identify patients treated for depression with a selective serotonin reuptake inhibitor (SSRI). Records were used to construct hierarchical prescription patterns (less than 120 days, switching/augmentation, upward titration, or stable use) as indicators for the occurrence of relapse or recurrence of depression.
Patients with stable use experienced the lowest risk of relapse or recurrence. Factors significantly associated with increased risk include prior use of anxiolytic medications, more comorbid conditions and younger age.
The SSRI prescription pattern most consistent with recommended depression treatment guidelines was associated with the lowest risk of relapse or recurrence.
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