ALKS-5461 is a new drug that is being developed by the company Alkermes as an alternative to SSRI’s for the treatment of depression. ALKS-5461 (its trial name) is a combination of both buprenorphine (suboxone) and samidorphan, and is regarded as a non-addictive opioid modulator and antidepressant. It is currently being developed specifically as an antidepressant augmentation strategy in cases of treatment-resistant depression.

This drug is also being developed with the intention of treating cocaine dependence, and Alkermes has received a grant from the National Institute on Drug Abuse (NIDA) for the drug’s development. Initial research suggests that the drug produces a powerful antidepressant response within a week of treatment, in nearly everyone that takes it. Additionally the side effect profile appears to be relatively minimal.

What is ALKS-5461? The specific components.

ALKS-5461 is made up of both buprenorphine and samidorphan. These drugs work by influencing opioid receptor activity in the brain.

  • Buprenorphine: The buprenorphine portion of the drug acts as a partial agonist of the mu-opioid receptor (MOR) as well as an antagonist of the kappa-opioid receptor (KOR). Although not specifically prescribed to treat depression, many have found that taking suboxone for depression works better than any antidepressant they’ve ever tried.
  • Samidorphan: The samidorphan acts as a selective antagonist of the mu-opioid receptor (MOR). This works to essentially block the buprenorphine from binding to the mu-receptor, while not affecting the kappa-receptor.

How does the antidepressant ALKS-5461 work?

The combination of Buprenorphine and Samidorphan results in selectively blocking kappa-opioid receptors, while the effects on the mu-opioid receptor are thought to be minimal or insignificant. In other words, the drug gets the buprenorphine to bind to the kappa receptor, but not the mu receptor, which would minimize any “euphoric high” that opioid addicts seek. This would negate any addictive potential of the drug, while still producing an antidepressant response.

So why block the kappa receptor? When the kappa-opioid receptor becomes activated, naturally occurring peptides called “dynorphins” are released. Some research suggests that dynorphin levels are elevated among people with depression. Therefore blocking the kappa receptor will result in dynorphin reductions and may yield an antidepressant-like response.

Although dynorphins are important in a person’s stress response, at high levels they block the release of glutamate. Blocking glutamate in the brain can prevent neuroplasticity, lead to poorer learning abilities, and can induce learned helplessness. Since ALKS-5461 would be blocking dynorphin, it is thought that glutamate would get released to increase hippocampal plasticity and thereby reversing learned helplessness.

Additionally, blocking dynorphin can improve signaling of dopamine, which could lead to further reductions in depressive symptoms as a result of stress. Many researchers believe that kappa-opioid receptor antagonists may be a valid treatment option for both depression and anxiety in the future. In animal studies with kappa-opioid receptor antagonists, significant improvements in depression, anxiety, anhedonia, drug addiction, and stress-related behaviors has been shown.

Why aren’t there already kappa-opioid receptor antagonists on the market? In part because it’s difficult to develop this type of drug that provides favorable pharmacokinetic properties that isn’t toxic. Drugs need to be tested in regards to absorption, distribution, side effects, as well as efficacy. This seems to be the first drug of its type aimed at treating depression in humans.

So why not just use buprenorphine for depression?

Some people do use buprenorphine by itself as an off-label treatment for depression. Usually though, a person must have a history of opiate abuse in order to get a prescription. There have been cases where people have faked opiate addiction just to get buprenorphine for treatment-resistant depression; in many of these cases the individuals being treated were immediately relieved of depressive symptoms.

Although buprenorphine can work for depression, its activity on the mu-opioid receptor raises concerns over potential for both abuse and dependence. Additionally, it is thought that withdrawal from buprenorphine is relatively severe compared to other treatment options. Therefore, by combining samidorphan as seen in the drug ALKS-5461, it is theoretically removing the abusive potential of the buprenorphine.

ALKS-5461 Clinical Trials: Phase III To Finish in 2016

This drug already has undergone Phase II clinical trials and yielded very positive results. Due to the overwhelming positive response to the drug in trials, the FDA had granted “fast track designation” for treatment-resistant depression back in October 2013. As of June and July 2014, three major Phase III clinical trials were started in the United States.

The goal with the Phase III trials is to evaluate the efficacy of ALKS-5461 as a treatment strategy for individuals who don’t respond to modern day antidepressants in the SSRI and SNRI classes. If this drug is approved, it could treat depression from a different angle instead of relying on the hypothesis that low serotonin levels are to blame for feeling depressed.

Although the drug has been fast-tracked, it is still going to take a long time before results of the trials will be released. The trial results are likely going to come in 2016; a couple years from now. To supplement these trials, 9 smaller studies will also be done to finish up Phase III research. Assuming the drug ends up getting approval, this means we may be waiting a few more years before it hits the market.

The company Alkermes has already stated that they will be submitting a New Drug Application (NDA) to the FDA for the drug’s approve once Phase III research is complete. If the drug is approved, experts predict that the initial sales of the drug could be $25 million in 2016 and $350 million by 2019. The company also plans to out-license the drug, meaning they will collaborate with other companies for additional research, developments, and get a good initial return on the investment.

Phase I and Phase II Trial Results

In the first couple phases of clinical trials, ALKS-5461 was augmented with an SSRI or SNRI. Participants that received this drug experienced substantial improvement in treatment-resistant depression. In fact, most patients reported feeling significantly better within one week of supplementation. Up to half of all participants achieved complete remission in depressive symptoms. by the end of Phase I / II trials.

Another small trial that was conducted with a double-blind, placebo-controlled protocol demonstrated that 100% of people receiving the ALKS-5461 felt significantly less depressed. Although this was very small and only 32 people received the drug, these findings suggest that it works very quickly and very well. Many modern-day antidepressant treatments require weeks to generate a therapeutic response, whereas ALKS-5461 worked rapidly.

Comparison: Viibryd vs. ALKS-5461

A newer antidepressant on the market, Viibryd (Vilazodone) was approved by the FDA after multiple positive Phase III trials showing MADRS (Montgomery-Asberg Depression Rating Scale) decreases of 3.2 and 2.5 points in depressive symptoms. ALKS-5461 added to an SSRI and/or SNRI lead to MADRS decreases of 5.3 and 8.7 in Phase II trials. This demonstrates that people are responding between 2x and 3x better than they are while taking Viibryd as a standalone treatment.

What about ALKS-5461 side effects?

Based on research gathered from clinical trials, ALKS-5461 has been found to be pretty well-tolerated. Most common adverse effects include: nausea, vomiting, headaches, feeling sedated, and dizziness. The side effects seem to be relatively brief, affecting a person for a short duration when they begin taking the drug. With continuous usage, the nervous system adapts and most side effects completely disappear.

Final thoughts on ALKS-5461 for depression

We have known for years that opioids can improve mental health. Most people notice that they feel significantly more relaxed and experience mood improvement when they take an analgesic drug. Due to the fact that the market is largely saturated with SSRI and SNRI drugs that are associated with an array of unfavorable side effects including: sexual dysfunction and weight gain – companies are trying to come up with new options for treatment.

Personally, I am wondering why the drug is being used as an adjunctive treatment and not a standalone option. With improvements as cited in the study, why even waste time dealing with SSRI’s? Maybe the researchers are required to use it as an adjunct based on the fact that it is only for treatment-resistant or “refractory depression.”

Assuming it eventually gets approved for treatment of depression, I view it as a significantly safer option than taking something like an antipsychotic (e.g. Abilify). These days many doctors tack on an antipsychotic drug to an SSRI without realizing that the antipsychotic portion of the cocktail really has no business being used for depression.

When there’s a new breakthrough, it’s important to understand that this is not an “end all, be all.” Until the drug actually hits the market, we won’t really know how good or effective it is. In the meantime, we can hope other pharmaceutical companies begin to look at treatments other than targeting reuptake inhibition of serotonin as there are already enough of these drugs.

As a sufferer of major depression, I am frustrated that treatments like this weren’t researched years ago.  At least it seems as though some progress is being made.  If you are interested in being part of the clinical trial for this drug, it seems as though you must live in either Arizona or Georgia.  Read the source below for further information.

Source:  http://clinicaltrials.gov/ct2/show/study/NCT02158533