Opioids have a bad name these days. But let’s not forget that they were once consid­ered a first-line treatment for depression before the discovery of MAOIs and tricy­clics in the 1950s. That history has been revived recently by buprenorphine, a par­tial opioid agonist that was fast-tracked by the FDA for treatment-resistant depression. Buprenorphine showed promise in early studies, where it reduced both depression and suicidality. The effect was rapid, much like we see with ketamine, which may also work through the opioid system (see Re­search Update in TCPR, Jan 2019).

In the end, the FDA handed this novel therapy a thumbs down. The issue was not safety but efficacy, although there were also concerns that short-term trials might not be adequate to assess the addictive liability of buprenorphine.

The manufacturer submitted 4 trials, but only 2 of those trials had positive results, and there were sev­eral flaws in the data. The company switched the primary outcome mea­sures after their initial choices failed; they relied on averaged ratings from each time point instead of the final score; and they abbreviated the main rating scale, the MADRS, in ways that appeared to bias the results. Buprenorphine acts differently at high (8 mg) and low (2 mg) doses, but that did not appear to be the issue—neither dose worked well in these studies.

Buprenorphine remains available as Suboxone, which is FDA-approved for opioid dependence and became generic in June 2018. However, there is an important difference between Suboxone and its antidepressant cousin that failed to make it to market. Both drugs com­bine buprenorphine with an opioid antagonist to prevent abuse. Suboxone uses naloxone, a broad antagonist, while buprenorphine is paired with samidor­phan, which selectively antagonizes the mu-opioid receptors. Samidorphan is not currently available, but we may hear from it again. It is undergoing phase II studies as a combo pill with olanzapine in hopes that it will curb the weight gain on that antipsychotic.