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2 New Kappa Opioid Receptor (KOR) Antagonists For Depression

The quest to come up with a superior antidepressant is in full effect among biotech and pharmaceutical companies. Although there are some companies that are still tweaking various formulations of serotonergic, noradrenergic, and dopaminergic substances (e.g. triple reuptake inhibitors) others are thinking outside the box. Based on current trends, the next decade or two of antidepressant development will likely be investigating drugs that affect glutamate (e.g. NMDA receptor modulators) as well as those that affect opioid receptors – specifically the kappa receptor.

Individuals that have taken Suboxone for depression (an opioid replacement drug) know that it works pretty well at eliciting an antidepressant response. In fact, it tends to work so well that individuals who are classified as having treatment-resistant depression often are able to get significant relief with Suboxone. From a medical perspective, the major problem with using Suboxone to treat depression is that it affects the mu-opioid receptor, resulting in pleasurable effects and potential dependency.

New Kappa Opioid Receptor Antagonists for Depression

In recent years, researchers have discovered that developing opioid receptor kappa (OPRK) antagonists may work extremely well for the treatment of major depression. The drugs that affect the kappa receptor provide an antidepressant response without significantly increasing pleasure (as would be derived from the mu-receptor stimulation).  This gives a patient the best case scenario: an opioid-based antidepressant response without a high risk of dependency.

1. ALKS-5461

Of all kappa-receptor antagonists in development, this is perhaps the most exciting. Why? Because it combines something that we know works for depression (Buprenorphine) with another drug (Samidorphan). The Buprenorphine provides antidepressant relief, while the Samidorphan negates any significant pleasure response due to the fact that it elicits selective antagonism of the mu-receptor; leading to negligible “pleasurable” effects from the Buprenorphine.

It is being developed and promoted as an adjunct treatment option for those with “treatment-resistant” forms of depression. There is also simultaneous research being conducted on its efficacy for treating cocaine dependence. The early stages of clinical trials are promising, so much so that the FDA granted it “fast track” designation.

It is expected that Phase III clinical trials (which began in 2014) should end by 2016. This means that the drug could potentially hit the pharmaceutical market by the end of 2016 or 2017. All current research suggests that it ALKS 5461 is highly effective as an adjunctive treatment and may elicit synergistic effects when combined with an antidepressant; leading to greater improvement in mood than any currently-available standalone treatments.

2. LY-2456302

This is a new antidepressant in development by the company Eli Lily (the same company that makes Prozac). They are developing a new kappa-opioid receptor antagonist drug with short-acting properties to serve as an adjunctive treatment for refractory forms of depression. Currently the drug is in Phase II clinical trials in the United States.

In other animal studies, the substance LY-2456302 has been shown to elicit synergistic effects when combined with other antidepressants (e.g. SSRIs and TCAs). This means that combining the medication with a another treatment may work significantly better than either as a standalone option. The question still remains why the medication is being studied solely as an antidepressant augmentation strategy and not a standalone primary treatment option.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24690494


Below are some drugs that were tested in human clinical trials, but were discontinued largely due to safety concerns.

1. JDTic

This is a new (KOR) kappa-opioid receptor antagonist with long-lasting effects and extremely selective properties. In other words, its effects are limited to the kappa receptor and it doesn’t tend to affect the mu or delta receptors. It is somewhat similar in composition to various analgesic (pain relief) drugs like pethidine as well as the drug alvimopan (which works on the mu receptor).

Research has demonstrated a particularly long-lasting antidepressant effect following administration. It was noted that in animal models, the effects of JDTic were noticed for approximately 3 weeks after just one dose. Researchers believe the long-lasting effects of JDTic are a result of a functional alteration of kinases that bind to the c-Jun N-terminal.

Based on data collected from animal models, it is believed that JDTic is capable of yielding antidepressant, anxiolytic, and stress reduction effects. Not only could this medication end up being a treatment for major depression, but it may be useful for the treatment of individuals with stimulant (e.g. cocaine and nicotine) as well as opioid addictions.

Due to the data collected in animal models, researchers took the substance to Phase I human clinical trials for cocaine abuse. Unfortunately the drug’s development was stalled due to the fact that a participant experienced a form of tachycardia which had potential to be fatal. In addition to this significant adverse effect, the drug also demonstrated a poor ratio brain-to-plasma, meaning it was somewhat problematic.

While there were initially high-hopes for this medication due to its long-lasting properties, its safety and functionality were too problematic to justify further human testing. As of now drugs with more favorable safety profiles and functionality such as ALKS 5461 and LY-2456302 are thought of as being superior.

2. PF-4455242

This is another kappa-opioid receptor antagonist with short acting and selective properties. It was initially created by Pfizer in 2009 and was touted as being a new investigational treatment for bipolar disorder. It was pushed through a Phase I clinical trial for a variety of conditions including: bipolar disorder, depression, and substance abuse. Although the drug may have worked, it was quickly pulled from early trials when animal research indicated that it produced toxic effects when taken for over 90 days (approximately 3 months).

Potentially Investigational Substances

Below are a couple of substances that act as kappa opioid receptor antagonists. Whether they are capable of eliciting antidepressant effects among humans is unknown.

1. 5′-GNTI (5′-Guanidinonaltrindole)

This is a kappa-opioid antagonist drug that is extremely selective and more potent than most drugs of its kind. To give you some perspective, comparison to a similar acting drug called norbinaltorphimine indicates that 5-GNTI is five times as potent and up to five-hundred times as selective. In tests it was found to be long-acting with a slower than average onset of effect.

Studies conducted among animal models indicate that it is effective as an antidepressant. Whether it will actually be studied among humans remains unclear. As of now, it is likely that more studies be conducted in animal populations should developers test it in a small sample of human participants.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12649385

2. Norbinaltorphimine (nor-BNI)

This is a kappa-receptor antagonist that is often utilized for research purposes. It has highly-selective properties and doesn’t affect the mu or delta receptors. In animal studies, it was found to carry significant antidepressant properties. It is unlikely that this will ever be tested among humans.

3. Binaltorphimine (BNI)

Like Norbinaltorphimine, this is considered among the first discovered antagonists of the kappa receptor with highly selective properties. It is believed that it is only sold by chemical manufacturing companies to be used in rodent and animal studies. Other than small-scale rodent studies, there isn’t significant data available regarding BNI.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2882399

Thoughts on K-Opioid Receptor Antagonists for Depression

Based on the evidence, it seems as though kappa-receptor antagonists elicit powerful antidepressant effects in both animals and humans. This class of medications holds significant promise for the future treatment of refractory forms of depression. Many of these drugs like ALKS 5461 are being promoted as a synergistic adjunctive treatment option, yet most evidence would indicate that they will likely work very well as standalone options.

Why the FDA will not approve such medications as standalone treatments is somewhat confusing. My guess is that the pharmaceutical companies are hoping just to get this class of drugs on the market by any means necessary and that by marketing many as “adjuncts,” it is easier to accomplish. Once these medications have reached the market, then pharmaceutical will conduct tests as to whether they provide significant standalone benefit and/or treat other conditions (like anxiety).

If we take an objective look at antidepressants currently on the market, most are poorly understood and are targeting various neurotransmitters that don’t necessarily contribute to causing depression. This often leaves people to develop an antidepressant-induced chemical imbalance as a result of their treatment, further increasing many problems over the long-term and making withdrawal incredibly difficult.

With opioid-based medications, we should have a better idea of how they work and what they are targeting in the brain. Withdrawal will likely still be unpleasant with this class of drugs, but people will likely have better success at actually treating their depression. Ultimately this class will be significantly safer than blatantly taking opioids to treat depression, and also safer than taking opioid replacement therapy drugs like Suboxone.

The addiction potential of kappa-receptor antidepressants should be relatively low and side effect profiles may be an improvement compared to existing drugs. In other words, a person may not experience the same degree of sexual dysfunction or weight gain as they would on an SSRI. That being said, it is important to recognize that these medications are still in developmental / investigational phases and further data needs to be collected before long-term safety and tolerability can be established.

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