PMID- 30374191 OWN - NLM STAT- MEDLINE DCOM- 20210317 LR - 20220408 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 25 IP - 7 DP - 2020 Jul TI - Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies. PG - 1580-1591 LID - 10.1038/s41380-018-0284-1 [doi] AB - The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery-Asberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and -10 versus placebo: -1.5, P = 0.018; -1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (-1.8, P = 0.010; -1.8, P = 0.004, respectively). The overall effect size (Hedges' g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in >/=5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT. FAU - Fava, Maurizio AU - Fava M AD - Massachusetts General Hospital Clinical Trials Network and Institute (CTNI), Harvard Medical School, Boston, MA, USA. MFAVA@mgh.harvard.edu. FAU - Thase, Michael E AU - Thase ME AD - University of Pennsylvania Perelman School of Medicine and the Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. FAU - Trivedi, Madhukar H AU - Trivedi MH AUID- ORCID: 0000-0002-2983-1110 AD - University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Ehrich, Elliot AU - Ehrich E AD - Alkermes, Inc., Waltham, MA, USA. FAU - Martin, William F AU - Martin WF AD - Alkermes, Inc., Waltham, MA, USA. FAU - Memisoglu, Asli AU - Memisoglu A AD - Alkermes, Inc., Waltham, MA, USA. FAU - Nangia, Narinder AU - Nangia N AD - Alkermes, Inc., Waltham, MA, USA. FAU - Stanford, Arielle D AU - Stanford AD AD - Alkermes, Inc., Waltham, MA, USA. FAU - Yu, Miao AU - Yu M AD - Alkermes, Inc., Waltham, MA, USA. FAU - Pathak, Sanjeev AU - Pathak S AD - Alkermes, Inc., Waltham, MA, USA. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20181029 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Analgesics, Opioid) RN - 0 (Antidepressive Agents) RN - 40D3SCR4GZ (Buprenorphine) RN - 5S6W795CQM (Naltrexone) RN - 7W2581Z5L8 (3-carboxamido-4-hydroxynaltrexone) SB - IM MH - Analgesics, Opioid/*therapeutic use MH - Antidepressive Agents/therapeutic use MH - Buprenorphine/*therapeutic use MH - Depressive Disorder, Major/*drug therapy/psychology MH - Double-Blind Method MH - Drug Therapy, Combination MH - Female MH - Humans MH - Male MH - Middle Aged MH - Naltrexone/*analogs & derivatives/therapeutic use MH - Treatment Outcome PMC - PMC7303008 COIS- MF reports 3-year disclosures below, and all lifetime disclosures can be viewed online at: http://mghcme.org/faculty/facultydetail/maurizio_fava; research support: Alkermes, Inc., Johnson & Johnson, Axsome, Acadia Pharmaceuticals, Cerecor, Lundbeck Inc., Neuralstem, Otsuka, Taisho, Marinus Pharmaceuticals, BioHaven, Takeda, Vistagen, Relmada Therapeutics Inc., Stanley Medical Research Institute (SMRI), National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH), and PCORI. Dr. Fava has not done any personal consulting. Any consulting he has done has been on behalf of Massachusetts General Hospital. Stock/Other Financial Options: Equity Holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: patents for Sequential Parallel Comparison Design (SPCD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd. MET has served as an advisor or consultant to Acadia, Akilii, Alkermes, Allergan (includes Forest Laboratories and Naurex), AstraZeneca, Cerecor, Eli Lilly, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson Pharmaceutical Research & Development LLC (Janssen, Ortho-McNeil), Lundbeck, MedAvante, Merck, Moskha8, Nestle (PamLab), Novartis, Otsuka, Pfizer, Shire, Sunovion, and Takeda; he has received grant support from Acadia, Agency for Healthcare Research and Quality, Alkermes, Avanir, Forest, Intracellular, Janssen, National Institute of Mental Health, Otsuka, Patient Centered Outcomes Research Institute, and Takeda; he has received royalties from American Psychiatric Press, Guilford Publications, Herald House, and WW Norton & Company Inc.; his spouse is employed by Peloton Advantage, which does business with a number of pharmaceutical companies. MHT has served as an advisor or consultant to AcademyHealth, Alkermes Inc., Akili Interactive, Allergan Pharmaceuticals, ACADIA Pharmaceuticals Inc., American Society of Clinical Psychopharmacology, Brain Institute Canada (CAN-BIND), Brintellix Global, Global Medical Education, Healthcare Global Village, Health Research Associates, Jazz Pharmaceuticals, Lundbeck Research USA, Medscape LLC, MSI Methylation Sciences Inc., Nestle Health Science-Pamlab Inc., Naurex Inc., Navitor, One Carbon Therapeutics, Otsuka America Pharmaceutical Inc., Saatchi, and Takeda Global Research; he has received grant support from National Institute of Mental Health, National Institute on Drug Abuse, Johnson & Johnson Pharmaceutical Research & Development LLC, and Janssen Research and Development LLC; he has received royalties from Janssen Research and Development LLC; he has publications for Janssen Asia Pacific and Oxford University Press. EE, WFM, AM, NN, ADS, MY, and SP are employees and stockholders of Alkermes, Inc. EDAT- 2018/10/31 06:00 MHDA- 2021/03/18 06:00 PMCR- 2018/10/29 CRDT- 2018/10/31 06:00 PHST- 2018/03/30 00:00 [received] PHST- 2018/10/03 00:00 [accepted] PHST- 2018/10/31 06:00 [pubmed] PHST- 2021/03/18 06:00 [medline] PHST- 2018/10/31 06:00 [entrez] PHST- 2018/10/29 00:00 [pmc-release] AID - 10.1038/s41380-018-0284-1 [pii] AID - 284 [pii] AID - 10.1038/s41380-018-0284-1 [doi] PST - ppublish SO - Mol Psychiatry. 2020 Jul;25(7):1580-1591. doi: 10.1038/s41380-018-0284-1. Epub 2018 Oct 29.