Buprenorphine for Depression: ALKS 5461


Many of my patients have asked me if their medication also treats depression, since they noticed a lifting of their mood after starting buprenorphine (Suboxone, Zubsolv) for the treatment of their opioid addiction. I told them I thought they felt less depression because their brains no longer are in the cycle of intoxication and withdrawal, and also because their life circumstances improved.

Maybe I’m wrong about this.

A new product containing buprenorphine may soon be marketed for depression, and by that I mean just depression, not addiction and depression. Alkermes, the same company that had a disappointment with their depot buprenorphine product last year, started Phase 3 studies last summer on their new product, ALKS5461, after their Phase 1 and 2 studies had positive results.

This product under study contains buprenorphine and a new opioid blocker owned by Alkermes, called samidorphan. In theory, the samidorphan blocks the opioid receptors, leaving only kappa receptors open to buprenorphine. Buprenorphine then attaches to kappa receptors, where it acts as an antagonist. Kappa receptors are usually acted on by dynorphins, opioid peptides that stimulate kappa receptors and cause depression. Dynorphins may also be involved in the stress response, so if buprenorphine can block these kappa receptors, theoretically mood would improve.

The phase 1 and Phase 2 trials of ALKS 5461 showed rapid improvement in the mood of patients already taking antidepressants. These were small studies but of relatively high quality, with double-blinding and placebo control, so Phase 3 studies were started quickly. We won’t know results of the phase 3 study for some time, since the study won’t be over until summer of 2016, so I wouldn’t expect data until 2017.

This new medication is being studied as an adjuvant to the treatment of depression, which means it’s not meant to be used alone, but with established medications in the SSRI (selective serotonin reuptake inhibitors like paroxetine, sertraline, etc.) and SNRI (selective norepinephrine-serotonin reuptake inhibitors like venlafaxine, etc.) groups. Alkermes hopes to get it approved for treatment-resistant depression.

Alkermes is also studying ALKS 5461 as a possible treatment for cocaine addiction, though no data are available on that yet.

Theoretically, this preparation wouldn’t cause opioid addiction because the buprenorphine will be blocked from attaching to the opioid receptor. That makes sense to me, but I also know people are very different. My biggest concern when reading about this new preparation is that real life isn’t as precise as we would like for it to be.

My big questions are: What if some of the patients get an opioid effect from the buprenorphine in the ALKES 5461 product? Do we know for sure that the blocker, samidorphan, will bind to every human mu opioid receptor? Are there genetic differences that will influence response and addiction potential? We already know that people who have major depressive disorder are at increased risk for addiction, and it would be bad if these people developed an opioid addiction while being treated for depression.

On the other hand, depression can be a devastating illness. This new medication will be intended for people who don’t get responses to currently available antidepressants. These patients probably feel desperate for any improvement in their mood, and are willing to accept the risk of unintended complications.

If the Phase 3 studies show good results and this medication gets approved to manufacture and market, it would be a novel way to treat depression. I’m fascinated to see what will happen.

14 responses to this post.

  1. Posted by Bob Osborne on January 17, 2015 at 8:05 pm

    Sounds great, I’ve been taking suboxone since July, 2006 and it has helped me with depression, mood swings, etc.  I’d rather be on nothing, but as they say if it ain’t broke don’t fix it.BOB


  2. Posted by Alan Wartenberg on January 17, 2015 at 8:16 pm

    A number of years ago, several psychiatrists at a major Boston/Harvard teaching hospital started using buprenorphine (this is pre-suboxone so they used buprenex ampoules as a nasal spray) in several patients with refractory depression. It successfully improved the depression, but the women became dependent on the buprenorphine and then sued, claiming they were not informed about the dependency potential. I think the lawsuit was settled. All opioids have antidepressant and pro-depressant properties, probably owing to the differential between their mu receptor and kappa receptor activity, particularly with mixed agonist-antagonists.


  3. Posted by db312 on January 18, 2015 at 1:09 am

    You are a bit off here. First, nearly anything can pass trials as an anti-depressant. It just has to barely beat a placebo. Second, being free of their addiction surely does lift some depression, BUT, after a while you realize that everything is ‘numb’. YOU are ‘numb’. Buprenorphine is a depressant, long-term. Trust me.


    • I would challenge you to provide proof of your claim of “feeling numb.” what I mean is, is that only your personal experience, or are there studies to support this notion of emotional blunting? Because my patients aren’t numb. In fact, they are feeling more of their emotions than when in the grips of active addiction. Emotional blunting has been the complaint of anti-medication -assisted treatment, abstinence-only treatment centers, but I’ve never seen any objective studies to support these claims.


      • Posted by Solarc on January 29, 2015 at 5:15 pm

        I agree that placebo effect needs to be study a lot more, but that does not mean that the bupernorphine is a depressant nor does it create numbness.
        Alcohol is consider both a depressant and a stimulant depending on the dose and the length of time the person has taken it.

        I know that humans experiences is not always the best measurement of any claim. It is a good start to develop a hypothesis, but I do not have that experience either of depression and numbness.

        But then again the earth still looks flat to me.

      • Posted by Solarc on January 29, 2015 at 5:18 pm

        Oh, by the way, in England I understand they prefer to use Heroin over Morphine because doctors there find that heroin do elevate the moods of terminal patients while morphine has a tendency toward lowering it.

        Dieing is pretty depressing to most of us.

  4. Posted by RobH on January 19, 2015 at 12:56 am

    One other interesting and positive property of buprenorphine (for me) was that it curtailed any interest in alcohol. I am sad to admit that I often used alcohol to boost the effects of opiods when I was in active addiction…pertty much on a daily basis. I was actually as worried about alcoholism as I was about being strung out on pain pills. I stopped drinking the day I was induced on bupe. I just wasn’t interested in alcohol at all. A few days later when I got around to trying one of the beers still in my refrigerator, it tasted weird and after a couple of sips I poured it down the sink and never looked back. In addition to all the pain pills I had been buying beer or wine every day. After induction to bupe, I was amazed how much money I suddenly had to pay my bills! Any way, my point is that in addition to antidepressant effects bupe probably has other qualities that might help alcoholics. I drank every day for years and quit just like that after induction on suboxone.


  5. Posted by Neil Goldberg, MD on January 20, 2015 at 1:06 pm

    For intractable depression—why not? What is the state of opiate receptors in depression? Down regulated? As long as AlLKS 5461 doesn’t kill testosterone levels . If it does, why not just use Buprenorpine?


  6. Posted by Solarc on January 29, 2015 at 5:10 pm

    I take it for pain. Pain is what makes me relapse to ilicit opiates. I had a motorcycle in 1978 that when I had an MRI done in 2006 showed quite a bit of injury like degenerated cartilages and arthritic conditions that gives me quite a bit of pain specially in the morning. Even the dose am on some times causes me pain and I brake one of the other eight mgs, of bupernorphine and take one mg at a time for half hour at a time until the pain subsides.


  7. I struggle with chronic pain, depression and anxiety. Buprenorphine is the only medication that treats all three of my symptoms. I tried it after trying over 30 different psychiatric medications/ combinations. I am currently trying ldn. But if it doesn’t work I will go back to an opiate. I wish alks 5461 was available now. I suffer daily!!!


  8. Posted by Kris on September 13, 2015 at 8:29 pm

    I would second the above comment about buprenorphine or suboxone treating the trifecta; chronic pain, depression & anxiety. I’ve been taking Subs for 18 months now, a new Doctor recently placed me on subutex (pure buprenorphine) only because that clinic prefers its use. My dose is 3.2 mg total per day. For me a twice or three daily divided dose works better. Psychologically I sometimes feel guilty for Not dosing just once per day but multiple dosing keeps me level and avoids the “flat” feeling of just 1 dose per day (sub or bup uses may relate to this flat feeling when it wears off, especially if you are a fast metaboliser like me).

    In actual fact there is a fourth thing that suboxone treats. That is of course it’s intended use, for opiate dependence. For me it was a codeine dependence of about 10 years to treat sacrum and sciatica pain.

    I do feel that I will probably be on this medication for the rest of my life, I’m currently age 44. Whether someone on Subs would be able to rotate to ALKS 5461 I’m not certain. I’m guessing that ALKS would be a very ‘watered-down’ version of Subs and many not treat the Magic 4; opiate dependence, chronic pain, depression, anxiety. But it remains to be seen.


  9. Posted by Mrs L Thompson on January 5, 2016 at 4:08 am

    How can you find a Dr that will prescribe this for you? Reading all these posts sounds just like me. I live in a town that is all hung up on drugs. I really need help!


  10. Posted by Jane Doe on June 22, 2016 at 11:12 am

    I was prescribed Suboxone for PTSD and Depression of label. It didn’t work at all. I just ended up with a 7 year dependency on a drug I could not afford. Thankfully, a wealthy friend sent me to a very comfortable rehab and I got off of Suboxone and never looked back. It did nothing to improve my depression.


  11. Posted by Alison on August 19, 2018 at 12:00 am

    You aren’t being fair to those of us who suffer. If you’ve never experienced it please don’t talk so much about what you “think” might be bad for us. Which is worse: depression and a constant obsession with suicidal thoughts or potentially becoming dependent on something that makes you feel better, finally after all the years in misery? Diabetics are dependent on their medicine. Why is everyone so worried about us becoming “addicted” to something we will need to take the rest of our lives anyway? It’s still the stigma. It’s still the refusal to acknowledge that mental illness is as much a disease that physical illness is. Pain management doctors are always determining if their patients pain is worth the risk with a usual yes. Our pain is worth the risk. Our cure, or as close to one we can get, should not be scrutinized so much for what may or may not happen and is really the business of the patient who knows the risks. Stop withholding what works!


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