Friday, February 17, 2017

Antidepressant News: Just the Right Amount of Opiate?

In the early 1950s, opium was considered an effective treatment for depression, but gradually it fell out of favor as its addiction risk became clear. Nonetheless, there's no denying that opioids rapidly elevate the mood of just about anybody, even the very depressed. So that's a pretty tantalizing challenge: Is it possible to harness the elating effects of opiates while avoiding the addictive "side effects," as it were.

A recent contender is a drug made by Alkermes code named ALKS 5461. This drug is a combination of buprenorphine and samidorphan. Buprenorphine is an opioid which is often combined with naltrexone to produce drugs for opioid use disorder, such as Suboxone. Samidorphan is a derivative of naltrexone, and it doesn't antagonize opioid receptors quite as avidly as its cousin. So combining these two might just allow enough opioid receptor stimulation to squeeze through to treat depression, without it being too appealing to potential addicts.

Early phase I and phase II clinical trials with small numbers of subjects were promising. Based on these results, the company conducted larger phase III trials, called the FORWARD (Focused On Results With A Rethinking of Depression) trials. Unfortunately, the first two of the larger trials failed, showing no improvement over placebo. The third trial (FORWARD-5) was more successful. In that trial, 407 patients with depression unresponsive to a trial of standard antidepressants were randomized to receive ALKS 5461 as an adjunct, or placebo as an adjunct. The company reports that patients receiving the higher dose of 2mg of ALKS 5461 did significantly better than placebo, as measured by the MADRS rating scale. Side effects were nausea, dizziness, and fatigue.

Will this drug see the light of day? It’s unclear, but according to pharmaceutical industry news sources, Alkermes has been talking up its latest results with the FDA and hopes to get approval at some point within a year or two. It sure would be nice to have another antidepressant at our disposal.


Unknown said...

Hi Dr. Carlat,

Greetings from Boston. I am glad to see new posts from you, and also talk about the mu opioid receptor as a novel antidepressant target. I have a clinical diagnosis of PTSD and bipolar. After years of unsuccessful therapy on various combos of SSRIs, antipsychotics, benzos, and mood stabilizers, I have finally found relief with a TCA not marketed in the US called tianeptine. Although an old drug, tianeptine has recently been shown to have affinity for the mu opioid receptor.

My hope is that more and more research like this (along with the recent ketamine studies) will shift focus away from monoamine reuptake in antidepressant drug design.


Joel Hassman MD said...

Wow, the road to hell paved again with a premise of good intentions, but, once the fourth "P" of poison comes out from the process of pharmacology (the other three in order being promise, panacea, and placebo), what did Einstein warn us again about the true meaning of insanity?...

Well, at least then psychiatrists can be prescribing opiates without being accused of writing scripts out of their specialty, a silver lining there?!

Joel Hassman, MD