Posts Tagged ‘kappa blocker’

Buprenorphine for Depression: ALKS 5461

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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.