I’ve written a few optimistic lines about ALKS 5461 as a potential solution for people suffering from refractory major depressive disorder.  Those unfortunate will have to keep waiting. The buprenorphine depression drug doesn’t bring cheer. 

ALKS 5461 is a product in Alkermes’ pipeline that combines buprenorphine with ALKS 33, or Samidorphan.  The combination drug is purported to ‘stabilize opioid pathways’, which is a very simple explanation for a complicated, poorly-understood system.  The results of two late-stage trials were disappointing, in part– according to Alkermes– because the placebo groups did better than usual.  Beating the placebo is a common problem in trials involving antidepressants, because of the high susceptibility to the placebo effect in the patients in such trials.  Over half of patients get better from taking the sugar pill, so a medication that helps half the patients will not move the needle to signal success.

I receive emails now and then from patients treated with buprenorphine for depression.  If the emails are any measure of reality, buprenorphine is not going to cure the world of depression.  While I occasionally read success stories, I just as often read angry descriptions from people complaining that they were never warned of the difficulty of stopping the medication.   I’ve written before that for that reason, I am reluctant to start buprenorphine for depression alone, in patients who are not already opioid-tolerant.  I have patients who struggled with depression before becoming addicted to opioids, and I believe the drug benefits their mood symptoms.  But I continue to hold back in a couple patients who have very severe depression, who have failed traditional treatments.  The news from Alkermes doesn’t push me in either direction.

I’ll take a moment to respond to the angry person who recently commented on one of my other blogs about this topic, who wrote that ‘depressed people are no more likely to get addicted than other people’, and ‘buprenorphine makes people happy and productive’ and therefore should be used for depression.  People with histories of depressive disorders DO have a higher incidence of addiction, but that is not the major issue holding me back from using buprenorphine for depression.  I would also disagree that buprenorphine makes everyone happy and productive.  The mood effects of buprenorphine, like all opioids, are subject to tolerance…  which gets closer to my concern.  I fear that the effects of buprenorphine would fade with tolerance, leaving patients stuck on an ineffective drug.  And we all know what happens to mood during discontinuation of buprenorphine.

ALKS 5461, though, works by a mechanism that may not be susceptible to tolerance.  Buprenorphine is a partial agonist at mu receptors and a kappa-receptor antagonist, and the latter effect is thought responsible for the effects on mood.  Samidorphan selectively blocks mu receptors, so that the combined drug is left with only the kappa effects.  Patients are supposedly spared from mu-receptor activation, tolerance, and withdrawal.   I wonder if it is really all that simple, or if the competition between buprenorphine and Samidorphan at mu receptors will create other problems.    Opioids cause a number of side effects, especially in patients who tend to focus on somatic symptoms, as some depressed patients do.   Starting an antagonist in the presence of an agonist, such as inducing with buprenorphine in patients on methadone or fentanyl, triggers a great deal of misery.  And even stable patients on buprenorphine alone tend to struggle with dry mouth, hot flashes, and GI complaints, most-commonly constipation.  But then again, major depression is a horrible illness.  I’m sure there are many people out there who would make the trade without regret– IF the ALKS 5461 works.

Alkermes continues to study ALKS 5461.  The higher dose ranges in the study, using 2 mg of buprenorphine, appeared to work better than the 0.5 mg dosage, so future studies will focus on buprenorphine doses of 1 and 2 mg per day (paired with equal doses of Samidorphan).  If you’re a believer, the stock is selling pretty cheap these days.  This is not an investment blog…. but I’m betting on Apple instead!


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