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LY-2456302 For Depression: Kappa Opioid Receptor (KOR) Antagonist

In recent years, biotech and pharmaceutical companies have been developing new classes of antidepressants. These new classes attempt to improve on older classes of medication in regards to efficacy, side effects, and tolerability. One such class that is being developed is that which targets opioid receptors, particularly the kappa receptor.

These drugs are classified as “kappa opioid receptor” (KOR) antagonists. Although none have been approved for the treatment of major depression, a couple are currently involved in clinical trials. One such drug tentatively called “LY-2456302” is being developed by the pharmaceutical heavyweight Eli Lilly for the treatment of major depression as an augmentation strategy.

What is LY-2456302?

LY-2456302 is an investigational drug under development by the company Eli Lilly. It initially began clinical trials sometime in 2013 to be tested as an adjunct treatment for TRD (treatment-resistant depression). Should the substance demonstrate significant efficacy in forthcoming stages of clinical trials with high tolerability and no adverse effects, the FDA may grant it “fast track” status.

How does LY-2456302 function?

The drug LY-2456302 elicits its antidepressant effect by affecting the kappa-opioid receptor on which it acts as a short-acting antagonist with selective properties. This drug will is believed to help regulate the mood in a depressed individual through its influence on “dynorphin A.” Think of “dynorphins” as being the opposite of “endorphins.”

Levels of dynorphins such as dynorphin A tend to increase in cases of drug abuse (e.g. cocaine), significant stress, depression, and learned helplessness. When rodents are administered with substances that act as kappa-opioid antagonists, it essentially decreases the levels of dynorphins and the rodents recover from learned helplessness, depression, etc.

LY-2456302 is functioning to reduce dynorphin levels, which tends to improve mood, positive emotion, and helps individuals recover from depression. At the moment, the drug is purely in an investigational phase of development (early in clinical trials). It will take a few years before this drug has potential to hit the pharmaceutical market.

Benefits of LY-2456302 for Depression

There are several notable benefits of this particular drug including its: antidepressant properties, ability to treat refractory cases of depression, and potential synergistic effect when used as an adjunctive treatment.

  • Antidepressant effect: Based on animal studies and early clinical trial data, one would speculate that this particular drug is capable of treating depression. Assuming the safety of the drug can be established, it should hold significant promise at treating cases of major depression. Some would argue that its potential as an antidepressant significantly exceeds that of other medication classes regardless of being used as an adjunct.
  • Anxiolytic effect: There are some clinical trials investigating the anxiolytic potential of this drug. Those particular trials are not as advanced as that for refractory depression, but may hold promise. There is evidence that dynorphin levels can be directly related to stress and anxiety. When a person’s stress level decreases, they tend to have less dynorphins. Taking this drug will essentially reduce dynorphin levels and in theory, anxiety will likely also be reduced.
  • Drug addiction treatment: Among individuals with cases of drug addiction, levels of dynorphins seem to elevate. This drug would effectively reduce the level of dynorphins in the brain, leading to less drug-seeking behavior and lower levels of addiction. A person wouldn’t likely be experiencing the same stress and/or low mood, and therefore wouldn’t be as likely to seek out the drugs to which they are addicted.
  • Efficacy: Prior to conducting human trials, this drug showed significant antidepressant potential when used in animal models. While that doesn’t necessarily indicate that it will be equally effective among humans, drugs that act on the kappa opioid receptor as antagonists could be highly effective antidepressants. It has potential to be more effective than traditional treatments even as a standalone antidepressant.
  • Mechanism of action: It targets the kappa opioid receptor which is significantly different than other antidepressants on the market. Most drugs attempt to target variations of three neurotransmitters: serotonin, norepinephrine, and dopamine. This drug doesn’t directly target reuptake inhibition of these neurotransmitters, rather it decreases levels of peptides called “dynorphins.”
  • Reverse “learned helplessness”: Those who have treatment-resistant depression often feel completely helpless to change. After all, many of these people have tried every “recommended” treatment option in the book. They have subjected themselves to “antidepressant roulette” and have found no relief. After awhile, a person feels as if they simply cannot change regardless of what they do; this is called “learned helplessness.” In animal models, this substance has been demonstrated as effective at reversing “learned helplessness.”
  • Synergistic effect: The fact that this substance has been demonstrated as eliciting a “synergistic” effect when combined with a traditional antidepressant like an SSRI is promising. Not many drugs are capable of significantly increasing the effect size of another drug when combined for treatment. However, since the drug is being tested as an “adjunct” one would question as to whether the effect size would have significantly increased even when used as a standalone treatment option. The reports of the synergistic potential of this drug are somewhat muddied by the fact that researchers “speculate” the SSRI is providing some benefit, and this is adding to the antidepressant effect. Among those who aren’t getting benefit from the SSRI, using this drug as a standalone option may provide even more benefit.

Research: LY-2456302 Clinical Trials

The drug is being pushed by Eli Lilly through clinical trials as an antidepressant augmentation strategy. The reason it is being promoted as an augmentation or “adjunct” treatment option is due to the fact that it will likely be easier to get approved than if it were a standalone treatment. Additionally once it is approved and demonstrated as being safe as an adjunct, it will likely be prescribed by may psychiatrists as a standalone option.

There is also significant need for drugs that help individuals with refractory or “treatment-resistant” forms of depression. These are individuals that fail to respond to traditional treatments and therapies. The current antidepressant options on the market are relatively depressing to those who fail to find relief. The drug LY-2456302 offers hope due to the fact that it has an entirely different mechanism of action compared to other antidepressants.

It is currently in Phase II clinical trials in the United States which are expected to end in 2015. Prior to initiating the clinical trials, the substance had demonstrated a powerful antidepressant effect in animal subjects with depression. Early results suggest that it works extremely well when combined with other antidepressants such as SSRIs and TCAs – resulting in a synergistically larger effect.

Final thoughts on LY-2456302

It is extremely necessary for the sake of those with treatment-resistant depression that new drugs like LY-2456302 are developed. While in the future a kappa opioid receptor (KOR) antagonist with longer-acting properties may be preferred to a shorter-acting drug like LY-2456302, it still may work quite well. It is known that it would be similarly classified to the drug ALKS 5461, but less is known about this drug from a comparative standpoint.

My guess is that in the future, a variety of companies will pursue these kappa opioid receptor antagonists and eventually one with longer-acting properties will get FDA approval. Just like when SSRIs and SNRIs became the hot “trend” in the 1990s and early 2000s, expect the KOR antagonists and various subtypes to become trendy in future years. Competition for a better performing antidepressant should increase as the global population and quest to eradicate mental illness continues.

In the meantime, one would speculate that this drug will be superior in comparison to an SSRI for improving depression universally. Nearly everyone feels better when certain areas of the brain are targeted, whereas treatment with SSRIs don’t necessarily always help everyone. This may have the potential to act as a more universalized treatment for depression. If you have any thoughts on this particular drug or are partaking in clinical trials, feel free to share in the comments section below.

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