I suppose that with the drought in the PHARMA CNS pipeline, it should have been predictable that thoughts would turn towards the known feel-good drugs [drugs in the street-sense as opposed to medications]. In October, we heard about Special K, a club drug, looking to be reborn as a antidepressant …
by D. Jeffrey Newport, Linda L. Carpenter, William M. McDonald, James B. Potash, Mauricio Tohen, and Charles B. Nemeroff, The APA Council of Research Task Force on Novel Biomarkers and TreatmentsAmerican Journal of Psychiatry. 2015 172:950–966.
… Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, D-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.Conclusions: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.
… with emphasis on a couple of derivative drugs that weren’t so "clubby" [that also have a significant commercial potential and obvious author Conflicts of Interest – see a touch of paralysis… and infomercials…]. Now, there’s a lot of excitement around exploiting an old standby – the opiate receptors. Interestingly, it comes at a time of an epidemic of opiate abuse – traffic coming straight from the poppies and from the pharmaceutical pain pills. With my blog about Dr. Nemeroff et al’s Ketamine article, I spread the COI declarations throughout the text. Those connections are here too and I’m going to stick them in at the end. But to summarize them, the clinical trial from this month’s AJP is industry financed, has four academic AKA known KOL authors all with connections with the drug manufacturer, and seven authors who are actually full time employees.
by Maurizio Fava, M.D., Asli Memisoglu, Sc.D., Michael E. Thase, M.D., J. Alexander Bodkin, M.D., Madhukar H. Trivedi, M.D., Marc de Somer, M.D., M.P.H., Yangchun Du, Ph.D., Richard Leigh-Pemberton, M.D., Lauren DiPetrillo, Ph.D., Bernard Silverman, M.D., Elliot Ehrich, M.D.American Journal of Psychiatry. Published online: February 12, 2016
Objective: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of an m- and k-opioid partial agonist, buprenorphine, and an opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression.Method: A multicenter, randomized, double-blind, placebo- controlled, two-stage sequenti al parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2mg/2mg of buprenorphine/samidorphan [the 2/2 dosage group], 8mg/8mg of buprenorphine/samidorphan [the 8/8 dosage group], or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale [HAM-D], the Montgomery-Åsberg Depression Rating Scale [MADRS], and the Clinical Global Impressions severity scale [CGI-S].Results: Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures [HAM-D: -2.8, 95% CI= -5.1, -0.6; MADRS: -4.9, 95%CI= -8.2, -1.6; CGI-S: -0.5, 95% CI= -0.9, -0.1]. There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation.Conclusions: The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.
Buprenorphine along with Naloxone are the ingredients in Suboxone® – the sublingual film used in the treament of Opioid addiction. The Buprenorphine is a morphine agonist similar to Methadone. The Naloxone is there to prevent IV use as it will throw users into withdrawal [not necessarily true in people not already addicted]. In the combination described in this paper, Buprenorphine is combined with Samidorphan, another narcotic antagonist. This combination showed promise in treating depression i
n its early phase trials, but then failed in two later trials reported just last month [Alkermes Depression Drug Disappoints in Trials, Alkermes shares plunge after drug misses trial goals, Alkermes depression drug fails, shares plunge, Alkermes Falls Most Since 2002 as Depression Drug Trials Fail]. And the closely watched stock tanked in a day.
n its early phase trials, but then failed in two later trials reported just last month [Alkermes Depression Drug Disappoints in Trials, Alkermes shares plunge after drug misses trial goals, Alkermes depression drug fails, shares plunge, Alkermes Falls Most Since 2002 as Depression Drug Trials Fail]. And the closely watched stock tanked in a day.The study above, reported in the American Journal of Psychiatry today was Received: July 15, 2015 and Accepted: November 30, 2015. It was one of those earlier studies that generated all that excitement on Wall Street. It was a "Two-Stage Sequential Parallel Comparison Design Study" – it’s something of a crossover design but too complex to explain without reproducing the whole article. The same for the analysis. Speaking of complex, they had a fancy way of evaluating their crossover data that included this $50 formula:
[I sure didn’t get it]. In the end, they reported a significant difference for the lower but not the higher dose of their drug combo [HAM-D p=0.02, MADRS p=0.005, CGI p=0.03]. Of note, there were no significant differences in the patient self rating scales [Inventory of Depressive Symptomatology Self-Report, the Sheehan Disability Scale, or the SF-12].
It’s hard for me to imagine that they’ll ever succeed in engineering an opiate that has some therapeutic effect without the obvious problem of abuse and addiction – the kind that practitioners already deal with every day. I literally surrendered the narcotic part of my narcotic license in order to be able to say "I can’t prescribe pain pills." I was just so weary from being hit on for narcotics. And frankly, it feels a lot like the deepest theory herein is to over-ride depressive affect with the euphoric effect of opium. That experiment has already gone on for centuries without coming to any good end.
AUTHOR AND ARTICLE INFORMATIONFrom the Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston; Alkermes, Inc., Waltham, Mass.; the Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia; McLean Hospital, Belmont, Mass.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas. Address correspondence to Dr. Fava [mfava@partners.org].Presented at the 53rd annual meeting of the New Clinical Drug Evaluation Unit, Hollywood, Fla., May 28 – 31, 2013.Supported by Alkermes, Inc., Waltham, Mass. The authors thank Mark S. Todtenkopf, Ph.D., for assistance in the preparation of the manuscript; the ALKS 5461 investigator study group; and Richard S. Perry, Pharm.D., for editorial assistance in the preparation of the manuscript, which was supported by Alkermes, Inc.ClinicalTrials.gov identifier: NCT01500200.Dr. Fava has received research support from and/or served as an adviser or consultant to Acadia, Alkermes, AstraZeneca, Avanir, AXSOME Ther- apeutics, Biogen, Bristol-Myers Squibb, Cerecor, Dinippon Sumitomo Pharma, Eli Lilly, EnVivo, Euthymics Bioscience, Forest Pharmaceuticals, FORUM Pharmaceuticals, GenOmind, GlaxoSmithKline, Intracellular, Janssen R&D, Johnson & Johnson Pharmaceutical Research and De- velopment, Lundbeck, Merck, Methylation Sciences, MSI Methylation Sciences, the National Center for Complementary and Alternative Med- icine, the National Coordinating Center for Integrative Medicine, NIDA, NIMH, Naurex, Nestle Health Sciences, Neuralstem, Novartis AG, Nutrition 21, Osmotica, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmoRx Therapeutics, Photothera, PPD, Puretech Ventures, PsychoGenics, RCT Logic [formerly Clinical Trials Solutions], Reckitt Benckiser, Ridge Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Servier Laboratories, the Stanley Medical Research Institute, Sunovion, Taisho, Takeda, Tal Medical, and VistaGen; he has had speaking or publishing roles for the American Society of Clinical Psychopharmacology, Belvoir Media Group, CME Institute/Physicians Postgraduate Press, and MGH Psychiatry Academy; he has equity holdings in Compellis and PsyBrain; he is named on patents for sequential parallel comparison design, licensed by MGH to Pharma- ceutical Product Development and a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; and he is a copyright holder for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER and has publications with Lippincott Williams & Wilkins, Wolkers Kluwer, and World Scientific Publishing.Dr. Thase has served as an adviser or consultant to Alkermes, Allergan [includes Forest Laboratories and Naurex], Avanir, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Lundbeck, Johnson & Johnson [includes Ortho-McNeil and Janssen], MedAvante, Merck [includes Schering-Plough and Organon], Nestlé [includes Pamlab], Neuronetics, Novartis, Otsuka, Pfizer [includes Wyeth Ayerst], Roche, Sunovion, and Takeda; he has received grant support from Agency for Healthcare Research and Quality, Alkermes, Avenir, Eli Lilly, Forest, Johnson & Johnson, NIMH, Otsuka, Phar- maNeuroboost, and Roche; he has equity holdings in MedAvante and receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton; his spouse is employed by Peloton Advantage, which does business with Pfizer.Dr. Bodkin has received payment for participation in advisory panel meetings related to the investigation of ALKS 5461 as a potential treatment for psychiatric disorders and has served as a consultant and received research support from Bristol-Myers Squibb, Otsuka, and CeNeRx, served as a consultant to MyTomorrows, has received research support from Shire, and has received grant support from NIH/NIMH.Dr. Trivedi has served as a consultant to or received fees from Alkermes, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Forest, Johnson & Johnson, Lundbeck, Merck, Naurex, Neuronetics, Otsuka, Pamlab, Pfizer, Rexahn, Roche, and Shire and has served on a scientific advisory board for Rexahn; he has received research support from NIMH and NIDA.Drs. Memisoglu, de Somer, Du, Leigh-Pemberton, DiPetrillo, Silverman, and Ehrich are or have been full-time employees of Alkermes, Inc., and have stock options.
The study lasted only 4 weeks. As an addiction medicine specialist I hear quite often how pretty much any substance of abuse will relieve depressive symptoms … for a short time. But the blowback is hell.
And I couldn’t care less about the response in 4 weeks. I need a response over 4 years, or 40. And with a lot bigger effect size, especially on a patient rating scale.
I can think of a whole host of interventions that would probably give at least as much antidepressant effect at the end of 4 weeks: time off work, free child-care in the evenings, the abusive spouse going on a trip, the abusive boss going on vacation, a passionate love interest (worse blowback than a narcotic though), Swedish massage three times per week, chocolate cake with fudge mocha frosting for dessert every night, …
Papers like these are really depressing. I think I’ll go have some chocolate cake.
I laughed out loud when I saw the woo-woo hand waving attempts to create the impression that this is hypothesis-directed research. Consider this gem, “Major depressive disorder has been associated with dysregulation of the endogenous opioid system.” Or this one: “The authors sought to determine whether opioid modulation… would exhibit antidepressant activity.” By now, terms like dysregulation and modulation are overworked, hackneyed, and empty of substance. Any representation that this study has a scientific rationale is incoherent – the study is a nakedly empirical experimercial.
As for the positive claim of efficacy, we should note that no statistical corrections were applied to exclude false positive claims (Type I error). Another awkward problem is that none of the secondary outcome measures was positive – and those included the patients’ self-assessments, as Dr. Mickey pointed out. Something has changed in our conceptual paradigm when a drug can be described as efficacious for major depression but the patients do not agree that their symptoms are improved or that their lives are any better in comparison to placebo.
One wants to ask why does American Journal of Psychiatry get suckered in to publishing this kind of low quality stuff.
“One wants to ask why does American Journal of Psychiatry get suckered in to publishing this kind of low quality stuff.”
Because they are in business; in competition with Medscape?
If the real thing – matched to the real patient – ever does come along . . . who would believe it? These days, what is a “real patient?”
I went to a conference in June 2015 at Harvard for opioid prescribers (Pain clinic docs, those running methadone clinics, and those prescribing bup.) One of the presenters had done a study examining the factors associated with ODs with bup. Combining bup with an antidepressant was high on the list. Bup is a pretty safe drug unless you combine it with psych meds and alcohol. Of course, the guy presenting was selling naloxone.
The last refuge of a scoundrel, once one has emptied the potential well of opportunity, then slide into the morass of the dark side, ie substances of abuse to reap chances for feigned use.
Hell, let’s have a brutal moment of candor here, cocaine is the quickest reduction of depressive symptoms, have you ever met a person high on coke who is down and out? SO, let’s sell everyone on Adderall and Desoxyn at least what, 100mg a day in q4h dosing??? Problem solved, everyone is happy, at least until 10PM???
Make sure to buy stock in these pharma companies, NOW!
But, I think most here know this is a failed and disingenuous sales pitch, and yet, the silence in not refuting these cretins in our profession selling such false and dangerous hope, is just disgusting to witness.
I have been advocating we start using the MMPI in vetting political candidates, maybe we should branch out and make all the KOLs, academic leaders, and APA hacks take it as well.
And focus on the Lie Scale first and foremost!
“It’s hard for me to imagine that they’ll ever succeed in engineering an opiate that has some therapeutic effect without the obvious problem of abuse and addiction – the kind that practitioners already deal with every day.”
Yup. Been doing this ever since diacetylmorphine, and we still haven’t gotten there. We need different pain medicines, not newest-latest-greatest opioids. The last great white hope, the partial/complex agonists, flopped. The receptor pharmacology of this combination was beyond me; I could not follow mechanistically why buprenorphine should be combined with this other beastie. From a marketing standpoint, I did wonder if this was some way to capitalize on buprenorphine’s being available generically as well, but I understand such things less than I do opioid pharmacology.
Pat,
I think the idea was that using the samidorphan would block the mu receptor which would reduce the effect of the buprenorphine on that receptor thus reducing any euphoric effect ad reduce the risk of dependency. The problem is that is complete conjecture as it relates to the relative binding affinities in the brain which may vary from individual to individual, hence a huge risk in my opinion.
I am not sure why they would think that blocking the effects of buprenorphine on the mu receptor and letting it act as a sole agonist at the kappa receptor would do any good. Substances which are strong agonists of the kappa receptor can cause dysphoria and hallucinations. So the combination would have to allow some agonist action at the mu receptor for the subjects to tolerate it, which restores the risk of dependence.
Oops,
My bad. I got confused about which receptors buprenorphine affects in which direction. Glad I looked them up. It antagonizes the kappa-receptor and is an agonist at the mu and delta receptors. So they were hoping that blocking the mu receptor with samidorphan and the kappa receptor with buprenorhpine would be effective.
I think this attempt points to a problem in the field of psychopharmacology. The investigators were trying a combination of two chemicals to finesse an effect. Buprenorphine is an agonist at the mu-receptor which increases the risk for addiction because of its euphoric effect, and it is an antagonist at the kappa-receptor. That latter activity could make it helpful in reducing anxiety or depression. Samidorphan is a sole mu-receptor antagonist. So the combination could both reduce depression and reduce the risk of dependence.
However, the opioid system is linked to other systems in the body, in particular the HPA axis. So the idea that we know enough about neurotransmitters to try to finesse the receptor binding and be able to predict the result accurately is rather a stretch, and it is very risky for the people it is given to. The opioid system adapts over time and 4 week trials are simply not long enough to say something is safe or effective. The only useful result from a 4 week trial would be negative outcomes that would preclude further study.
Actually, think about this as a hypothesis why academia and KOLs want to use controlled 2 or even 1 substances to treat patients:
Only can give 1 month at a time, and have to see these patients monthly per the intensity of the meds, good luck giving serial prescriptions for opiates or any other controlled 1 class like pot or ketamine and see these patients every 2-3 months like you can do with stimulants.
So, another way to milk the system?
Yeah, that is so crazy and ridiculous a thought…
http://www.reidpsychiatry.com/columns/15%20Rogers%2007-03%20pp316-320.pdf
I think this is the same Richard Rogers who developed the SIRS. The reference is a little old but I think even more valid given the controversies of the MMPI revisions.