5 results
50 Adjunctive Buprenorphine/Samidorphan Combination in Patients with Major Depressive Disorder: Phase 3 Long-term Extension Study Results
- Michael Thase, Arielle D. Stanford, Asli Memisoglu, William Martin, Amy Claxton, J. Alexander Bodnik, Madhukar H. Trivedi, Maurizio Fava, Sanjeev Pathak
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 203-204
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Introduction
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
Study Objective(s)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
MethodsFORWARD-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.
5 Clinical Evaluation of the Abuse Potential of Buprenorphine/Samidorphan Combination
- Andrew J. Cutler, Sanjay J. Mathew, Michael E. DeBakey, Beatrice Setnik, Narinder Nangia, Arielle D. Stanford, Sanjeev Pathak
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 176
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Introduction
Buprenorphine (BUP)/samidorphan (SAM) combination is an opioid system modulator being investigated as an adjunctive treatment for major depressive disorder (MDD). BUP/SAM is a fixed-dose combination of BUP, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and SAM, a µ-opioid receptor antagonist added to address the abuse and dependence potential of BUP.1,2
Study ObjectiveWe assessed the effects of SAM on the abuse potential of BUP in the BUP/SAM combination in two ways: (1) a human abuse potential (HAP) study in volunteers; and (2) an evaluation of the clinical experience across studies of patients with MDD.
MethodsStudy 212 (ClinicalTrials.gov ID: NCT02413281) was a HAP study in nondependent, recreational, adult opioid users. Following a qualification period, participants were randomized to 6 treatments in a blinded, crossover design: placebo (PBO), BUP/SAM at the target therapeutic dose (BUP/SAM 2mg/2mg), at 8mg/8mg and 16mg/16mg , and BUP alone (8mg and 16mg). The primary endpoint was maximum effect (Emax) for “At The Moment” Drug Liking Visual Analog Scale (VAS).
The clinical program for BUP/SAM included 4 PBO-controlled studies of patients with MDD (n=961). Pooled safety data were evaluated for adverse events (AEs) that may be associated with abuse, dependence, or withdrawal, as well as for objective signs of withdrawal with the Clinical Opioid Withdrawal Scale (COWS).
ResultsIn Study 212 (n=38), Emax Drug Liking VAS scores for the BUP/SAM 2mg/2mg dose were similar to those for PBO (median within-subject difference [90% CI]: 2.5 [0.0–9.0]). Emax Drug Liking VAS scores for all BUP/SAM dose groups, including supratherapeutic doses, were significantly lower than those observed for either of the BUP doses. The supratherapeutic doses of BUP/SAM (8mg/8mg and 16mg/16mg) had higher Emax Drug Liking VAS scores than PBO, but the differences were small.
In the MDD controlled studies, the incidence of euphoria-related AEs was low for BUP/SAM 2mg/2mg and PBO (1.6% vs 0.2%, respectively) and there was no evidence of abuse or dependence behavior. Euphoria-related events typically occurred with treatment initiation and resolved with continued treatment. There was minimal evidence of withdrawal by reported AEs or COWS assessment.
ConclusionsThese findings indicate that SAM mitigates the abuse potential of BUP in the BUP/SAM combination.
Funding Acknowledgements: Alkermes, Inc.
Long-term safety and tolerability of aripiprazole lauroxil in patients with schizophrenia
- Henry A. Nasrallah, Ralph Aquila, Yangchun Du, Arielle D. Stanford, Amy Claxton, Peter J. Weiden
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- Journal:
- CNS Spectrums / Volume 24 / Issue 4 / August 2019
- Published online by Cambridge University Press:
- 15 August 2018, pp. 395-403
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Objective
Safety and tolerability of long-term treatment with the long-acting antipsychotic aripiprazole lauroxil (AL) were evaluated in patients with schizophrenia.
MethodsThis 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.
ResultsOf 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.
ConclusionLong-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.
Switching stable patients with schizophrenia from their oral antipsychotics to aripiprazole lauroxil: a post hoc safety analysis of the initial 12-week crossover period
- Peter J. Weiden, Yangchun Du, Chih-Chin Liu, Arielle D. Stanford
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- Journal:
- CNS Spectrums / Volume 24 / Issue 4 / August 2019
- Published online by Cambridge University Press:
- 26 June 2018, pp. 419-425
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Objective
Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL).
MethodsThis was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed.
ResultsIn total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups.
ConclusionSwitching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.
4 - Section II – Focal brain stimulation approaches to psychiatric treatment
- from Part II - Summary of treatment modalities in psychiatric disorders
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- By Antonio Mantovani, Department of Psychiatry Division of Brain Stimulation and Therapeutic Modulation New York State Psychiatric Institute NY USA, Arielle D. Stanford, Department of Psychiatry Division of Brain Stimulation and Therapeutic Modulation New York State Psychiatric Institute New York, NY USA, Peter Bulow, Department of Psychiatry Division of Brain Stimulation and Therapeutic Modulation New York State Psychiatric Institute NY USA, Sarah H. Lisanby, Department of Psychiatry Columbia University; Department of Biological Psychiatry New York State Psychiatric Institute NY USA
- Edited by Peter Tyrer, Imperial College of Science, Technology and Medicine, London, Kenneth R. Silk, University of Michigan, Ann Arbor
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- Cambridge Textbook of Effective Treatments in Psychiatry
- Published online:
- 12 May 2010
- Print publication:
- 24 January 2008, pp 83-97
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Summary
Editor's note
This chapter illustrates how fast-growing are effective treatments in psychiatry. Twenty years ago the contents of this chapter would hardly be understood by the average clinician; now each new treatment is hammering on the door of clinical practice demanding to be let in. The most researched treatment is transcranial magnetic stimulation (TMS); this has been shown clearly to have antidepressant efficacy and, although not as effective as ECT in severe depression, has fewer adverse effects. All the other treatments are really at the early stage of clinical experience and are not first-line treatments. Magnetic seizure therapy and vagus nerve stimulation may have a role in treatment-resistant depression and deep brain stimulation (DBS) is likely to replace the various forms of leucotomy still practiced in some parts of the world, mainly because DBS can be controlled and directed so much more specifically than the older treatments. Transcranial direct current stimulation (tDCS) may also have antidepressant effects but more studies are needed. We will all be hearing more about these new treatments which have the potential to replace ECT, leucotomy and related treatments entirely.
Introduction
Advances in the science and technology of neuromodulation over the past two decades have led to several interventions that have rekindled clinical and research interest in nonpharmacological somatic therapies. Although electroconvulsive therapy (ECT) remains the only somatic treatment with widespread acceptance and application based upon 70 years of clinical use, transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), vagus nerve stimulation (VNS), deep brain stimulation (DBS) and transcranial direct current stimulation (tDCS), all offer novel means of potentially treating neuropsychiatric conditions and may provide a better understanding of the brain pathophysiology of these disorders.