One of the most promising new therapy ideas for brain and behavior disorders may at first seem improbable: using opioid-based medicines to reduce the symptoms of depression. Isn’t our society in the midst of an “opioid epidemic”? How might opioids help depressed people?

There are strong reasons for considering opioids, at very low doses, as antidepressants. Although many people may not realize it, we are all born with a natural—or, as researchers say, “endogenous”—opioid system. Our bodies manufacture various opioid molecules and our cells are studded with keyhole-like structures called receptors that are specifically designed to fit these naturally occurring opioid “keys.” There are four types of receptors that accept different opioid molecules. They are very common in brain cells, but also in the spinal cord, the digestive tract and in peripheral nerves.

“It has long been understood that the endogenous opioid system that we have is responsive to stress and mood—it helps regulate them,” explains Irwin Lucki, Ph.D. An expert on the opioid system, Dr. Lucki is Professor and Chair of the Department of Pharmacology at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. He is a member of the BBRF Scientific Council and a 2004 Distinguished Investigator.

Most of the opioid activity in our bodies is going on without any awareness on our part. There are exceptions, however: “Many people become aware of the opioid system’s impact on mood when they are exercising,” Dr. Lucki says. “For example, there is a release of endorphins, which are naturally occurring opioids, that many runners feel as a ‘runner’s high’ after they stop exercising.”

Opioids are also involved in the experience of pain. “One of the four opioid receptors types, called the mu-opioid receptor, or MOR, is associated with the analgesic effects of morphine, and also morphine’s mood-elevating effects,” says Dr. Lucki.

But another opioid receptor can also become involved when pain is present. The kappa-opioid receptor, or KOR, receives signals from a naturally occurring opioid in the body called dynorphin. It’s secreted during times of intense stress and distress. “Chronic pain patients who experience prolonged distress are likely experiencing the effects of increased secretion of dynorphin onto their kappa-opioid receptors,” according to Dr. Lucki.

The example of pain makes clear how different parts of the body’s opioid system can interact. One the one hand, paiespecially chronic and acute pain, causes us to feel distress—the work of dynorphin and the KOR. On the other hand, mood-elevating opioids like morphine can be administered and will interact with the MOR to help alleviate pain.

The problem is that morphine or similar opioids are so pleasurable that they are highly addictive. The opioid crisis of the present is often traced to the over-prescription of powerful and highly addictive opioids to patients experiencing pain. When taking opioid medications for prolonged periods of time, often the effects of the medication “weaken,” requiring the need for higher doses as the body becomes tolerant to the effects of lower doses. Chronic administration can also lead to dependence, and when such people are deprived of opioids, they experience withdrawal, which entails an often devastating and life-altering plunge in mood. Hence the urge to keep taking opioids.

GENESIS OF A NEW TREATMENT IDEA

This example provided an idea to Dr. Lucki and others involved in trying to develop new antidepressant medicines. In the laboratory, he and his colleagues have raised breeds of mice that lack functional mu and kappa opioid receptors. In animals that lack the kappa receptor, or in which the kappa receptor is blocked, stress is greatly reduced. In animals in which the mu receptor is stimulated, the animals are more sociable and less susceptible to environmental conditions that induce the mouse-equivalent of depressed mood.

What if these effects could be generated with medicines? It is not nearly as simple to do as it may sound. Dr. Lucki and his colleagues have been working on this problem for years.

“It occurred to us that since we have multiple opioid receptors that can mediate mood in different ways, it might be interesting to try to affect the function of the mu-and kappa-opioid receptors in a way that would be favorable for depressed patients.

One molecule he and others have extensively studied is called buprenorphine (pronounced BYOO-pren-OR-feen). It was invented to help people addicted to opioids successfully withdraw from their dependence. The molecule blocks kappa opioid receptors, helping to limit stress, and it also mildly stimulates mu opioid receptors, elevating mood. One characteristic of the drug is that it will not elevate mood beyond a certain point, a feature of its action in the body that generally prevents it from becoming addictive.

Buprenorphine has worked quite well in various animal models of depression, significantly reducing symptoms associated with both depression and anxiety. But researchers have had to be very careful in testing the drug in people. Owing to its mood-elevating characteristics, and despite evidence of its inability to do so beyond a certain point, some drug developers have worried about its potential to be abused. In various human trials, it has been administered at low dosages, a fraction of those used in the treatment of opioid addiction.

Dr. Lucki explains: “The fear was that in some individuals, buprenorphine may produce, still, too much activation of opioid receptors that could turn out to be addictive or reinforcing of addiction. Studies that have looked at the abuse potential of buprenorphine in people with former chemical dependencies, as well as in experimental animals, have shown that it has only very mild rewarding effects. But still, even at low doses, we don’t know if we need to dampen that down even more, to guard against the development of addiction in some depressed patients.”

This was the thinking behind the development of a drug called BUP/SAM, which is a combination of buprenorphine and another drug called samidorphan. The “SAM” part of the combination partially blocks mu-opioid receptors, a way of damping down the degree to which the “BUP” portion of the drug stimulates the receptor. “The purpose of SAM in combination with BUP is to address the abuse and dependence potential of BUP,” say investigators who reported results of two Phase 3 trials of the drug in the journal Molecular Psychiatry on October 29, 2018.

The researchers, led by Maurizio Fava, Ph.D., a 1994 BBRF Young Investigator now at Harvard University and Massachusetts General Hospital, tested the BUP/SAM combination (consisting of each drug at a dosage of 2 mg) in two randomized, double-blind, placebo-controlled trials, one involving 385 patients, the other, 407 patients. All had major depressive disorder (MDD) that had not responded to other treatments. Some received placebo for the first 5 weeks of the trial, then BUP/SAM for the remaining 6 weeks of the trial. Other participants received BUP/SAM for the entire 11 weeks. All participants continued to take the antidepressant drugs they had previously been taking.

Data from the two trials “support the view that the BUP/SAM combination represents a promising potenti adjunctive treatment for patients with MDD,” Dr. Fava and the team concluded. The drug was well tolerated, and there was “minimal evidence of abuse and no evidence of dependence or opioid withdrawal.”

Despite these results, the FDA in November 2018 decided it was not yet ready to issue an approval for the BUP/SAM combination, which is formulated by the pharmaceutical firm Alkermes under the designation ALKS-5461. The design of the two trials was unusual, involving a switch in some patients from placebo to the BUP/SAM drug after 5 or 6 weeks, and this generated data that the regulatory body found unpersuasive. More testing will be needed to validate the effectiveness of the combination drug, says Dr. Lucki, who was not involved in the trials.

THE APPEAL OF NEW APPROACHES

The larger point, Dr. Lucki stresses, is that BUP/SAM is one of several ideas representing a new approach to treating depression. “Since the accidental discovery of the first class of modern antidepressants in the 1950s,” he says, “all of the medicines approved by the FDA for major depression and dysthymia (depressed mood) have shared a common mechanism of action. All increase the transmission of neurotransmitters called monoamines.” This includes the extremely popular SSRI class of antidepressants, medicines like Prozac and Zoloft, which act to sustain serotonin levels in the brain, as well as so-called SNRIs, which sustain levels of serotonin as well as norepinephrine, another neurotransmitter. Earlier antidepressants, which were popular in years prior to the SSRI generation, also targeted levels of monoamine neurotransmitters.

Despite their widespread use, “as many as 50 percent of depressed patients are resistant to these therapies,” Dr. Luck notes, “and the significant length of time, often 4 to 6 weeks, to produce meaningful symptom relief, suggests that other mechanisms are likely involved” in causing depression.

Hence the appeal of drugs that modulate the working of the endogenous opioid system, like BUP/SAM. They “don’t directly target the monoamine neurotransmitter systems that all the other antidepressants work with,” Dr. Lucki stresses, which is why they are an attractive target for research. In animal testing, the evidence shows that BUP/SAM’s effect is specifically due to its modulation of the mu- and kappa-opioid receptors.

Currently, Dr. Lucki is focusing on another non-traditional drug for treatment-resistant major depression: ketamine. Developed originally as an anesthetic and tested intensively in recent years as an antidepressant, ketamine has repeatedly been shown to relieve the depression of many desperately ill depressed patients within minutes or hours. Its effect does not usually last longer than a week, however, and in its “street” form (“Special K”) has been a drug of abuse. For this reason, Dr. Lucki and man other researchers have been trying to come up with a drug that acts rapidly like ketamine to reduce or eliminate symptoms, but is not addictive.

He is now collaborating closely with Carlos Zarate, Jr., M.D., a two-time BBRF grantee and winner of the Colvin Prize in 2011. Dr. Zarate is Chief of the Experimental Therapeutics & Pathophysiology Branch at the National Institute of Mental Health.

Drs. Lucki and Zarate are currently testing a compound called HNK, which is one of the byproducts of ketamine when it is processed in the body. In previous research, HNK was found to be capable of generating ketamine’s antidepressant effects in animal models, without being addictive. Yet that remains a controversial result, in part because of recent research led by Alan Schatzberg, M.D., a member of the BBRF Scientific Council, and Nolan Williams, M.D., a 2018 and 2016 BBRF Young Investigator, both of Stanford University, which suggests that ketamine cannot exert its antidepressant effects without engaging the body’s opioid system.

Should ketamine, then, be considered an opioid? That is not yet clear. What is clear, says Dr. Lucki, is that “our field is so excited now. After many years of not being able to produce novel compounds to help people with depression, we now have a lot of ideas and interest in different ways of being able to help the treatment-resistant patient, and to help people who contemplate suicide, and to help people with PTSD. The field is energized and the people in the lab are so excited about working on these problems. I think we’re going to make a big difference in the way that depression is treated in the future.

— Written By Peter Tarr

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