An opioid treatment for depression nixed by FDA advisory committee
By Ben Goodwin
In November, an FDA advisory committee convened to hear the merits of an opioid drug as an adjunctive to treat major depressive disorder (MDD). On one side of the room sat the best bench scientists, doctors, biostatisticians, and executives that Alkermes, a Dublin based pharmaceutical company, could muster. Along the other wall sat FDA officials, and in the neutral middle was the advisory committee, which included psychiatrists, researchers, and pharmacists.
Buprenorphine/sampidorphan (BUP/SAM) combines an opioid (buprenorphine) with an opioid antagonist (sampidorphan). Buprenorphine is a widely used treatment for opioid use disorder; its long duration of action and its partial activation of opioid receptors make it well suited for keeping withdrawal symptoms at bay without sedation or euphoria. In non-opioid users, however, buprenorphine can cause euphoria, which is the opposite of depression—not an effect we aspire to in depression treatment.
An abusable drug, buprenorphine is usually combined with naloxone, an opioid antagonist that reverses buprenorphine’s effects when used intravenously. Sampidorphan, an opioid antagonist, serves the same purpose as naloxone, although less effectively.
BUP/SAM’s usefulness for treating major depressive disorder is unclear, and its potential risks are concerning. The efficacy and safety trials for BUP/SAM that have been performed so far suffer from the same fundamental problem as many other opioid trials: they are short term trials for drugs that may be prescribed for years. There is no way to assess the real long-term benefits and harms of a drug other than with longer, more robust trials. This may be especially important with opioids as dependence and addiction can develop quickly.
The antidepressant market is one of the biggest cash cows the pharmaceutical industry has: nearly 13% of individuals older than 12 took an antidepressant between 2011 and 2014, and a quarter of people who took an antidepressant had done so for a decade or longer. A new, branded antidepressant would be a huge moneymaker for Alkermes.
Opioids may temporarily improve mood but they are not an appropriate treatment for depression. As was pointed out by guest speaker Mark D. Sullivan MD PhD, depression, chronic pain, and substance abuse disorders are in many cases inextricably linked. Depression does not protect patients from addiction, respiratory depression and all of the other adverse effects of opioids. As useful as buprenorphine is in medication-assisted treatment for opioid use disorder, it’s an inappropriate drug for treating depression.
Psychiatric disorders are so complex and multifaceted that to place all of one’s hope on a single pill is reductive, especially with a disorder so over-diagnosed. The medicalization of depression as simply a chemical imbalance has done less for the stigma and the symptoms patients are suffering from, and more for the bottom line of companies peddling antidepressants. Serious research into novel non-pharmacological interventions for treatment-resistant depression remains lacking.
The advisory committee ultimately voted 21 to 2 against the approval of BUP/SAM. The FDA, almost always follows the opinion of the advisory committee; with such a resounding rejection, BUP/SAM won’t be approved this round. The company could try again, however, and could argue that more safety and efficacy data will be gathered from “real-world” patients. If BUP/SAM gets pushed through on the back of a promise that more safety and efficacy data will be gathered from “real-world” patients, it will be a case of Alkermes using unknowing patients as guinea pigs.
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