An experimental drug that addresses anhedonia could increase the brain’s capacity to experience pleasure and herald a new era of precision medicine in psychiatry.
The recent story of a woman in California who was cured of depression thanks to electrodes implanted in her brain is a successful example of what in the last decade has come to be called precision medicine. Scientists at the University of California, San Francisco (UCSF) installed implants into her brain, mapped her depressive symptoms to certain specific brain circuits, delivered short bursts of electricity to those circuits, and freed her of her depression.
In a sense, that’s what precision medicine promises for any human disease: the ability to go beyond one-size-fits-all formularies and into personalized treatments, where doctors take into account things like our genomes, the places we live, our lifestyles, and how our specific anatomical features—like the circuits in our brains—influence our overall health. And wouldn’t we all love to just zap away a few of those things in our brains that ail us.
As precision medicine gathers steam and moves into the mainstream, of course, it won’t be limited to surgically implanted electrodes. A number of researchers and drug companies are looking for chemical ways to precisely zap away your disease, using a new generation of drugs designed specifically for your needs or personal symptoms.
A critical example of this came in 2020, when a different group of UCSF scientists showed how one drug could successfully address one specific symptom of depression known as anhedonia, the inability to feel pleasure.
A flat, dull gray
Anhedonia (from Greek “αν” meaning without and “ηδονή” meaning pleasure) is one of the two most prominent features of depression (the other being depressed mood). Anyone with anhedonia ceases to draw pleasure from daily activities or personal relationships and intimacy. Life, for them, often becomes a flat canvas painted in dull gray, one day melting into the next, with reduced desire and without the reinforcing effect of the thrill for what comes next, forcing the person to become socially and personally withdrawn. Mind you, anhedonia is not exclusive to depression; it manifests across a number of conditions, from psychoses to personality disorders. It can also be induced by substance abuse.
In a phase 2 clinical trial that was published in Nature Medicine in March 2020, USCF scientists gave 45 people a substance known as JNJ-67953964, which in theory could block one of the several naturally occurring receptors for opioids in brain cells, called kappa-opioid receptors (KORs), which in turn block the release of dopamine in a marble-sized nugget of the brain called the nucleus accumbens.
This region is a major component of the ventral striatum, a swirl of tissue that sits in the center of the brain, just above and behind your ears, which fires up when you do something you find pleasurable. The UCSF rationale for the clinical trial was that the experimental drug would increase the brain’s capacity to experience pleasure. And it did. They scanned the brains of people carrying out a task where they were given incentives to do things like press a button that could earn them cash or avoid losing it using functional magnetic resonance imaging (fMRI), which allowed them to measure the blood flow to the region—a proxy for increased or decreased brain activity—during the periods where the people were anticipating receiving their monetary rewards. They found that the drug indeed led to a statistically significant increase in blood flow and thus more activation of the fabric of neurons in this pleasure center.
The trial was unique in a number of ways, says Andrew Krystal, a professor of psychiatry at UCSF who led the study. It was the first trial ever proving JNJ-67953964 could block these naturally occurring KORs in human brains, he says, and it heralded a new approach for treating elements of behavior and experience that align with biology instead of those based solely on observations made during talk therapy, which is the approach recommended in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the standard reference for diagnosis and treatment in the fields of psychology. Krystal stresses the clinical assessments in DSM-5 are a product of history and consensus rather than quantitative research in neurobiology.
Another important advance in precision medicine may have occurred at the end of 2020. The trial showed that reporting anhedonia and having low blood flow in the nucleus accumbens during the anticipation-of-reward stage of the task significantly predicted who would improve with treatment. Krystal says this suggests it may be possible to identify those patients that should be preferentially prescribed this drug in clinical practice so that depression treatment can move beyond its current state, which is, at best, a series of trial-and-error therapy attempts.
Only 40–60 percent of people on antidepressants see improvements in their symptoms.
The study also championed the so-called “fast-fail” approach in drug treatment, which refers to the ability to identify failure earlier in the clinical trials with more confidence, saving pharmaceutical companies hundreds of millions of dollars poured down the wrong rabbit hole chasing late-stage clinical trials that ultimately fail. Krystal can’t stop stressing how important a step forward the study was in the field of personalized medicine, though he is equally quick to lament that, like almost all non-COVID-19 related research in the last two years, it was lost in the pandemic.
The unforgiving long game
Mainstream antidepressants, which are prescribed to over 37 million Americans every year and rake in over $4.5 billion annually in North American sales, help some people but not all. Only 40–60 percent of people on antidepressants see improvements in their symptoms.
“One of the reasons for this is because they are looking at an entire constellation of depressive signs and symptoms,” says James Giordano, a neuroethicist at Georgetown University Medical Center in Washington, D.C. Giordano believes the current study did a very nice job of isolating and tracking anhedonia, the actual cognitive emotive behavioral feature of interest. This hasn’t always been easy in the past. Anhedonia has insidious ways of messing with drug treatment, therapies like transcranial magnetic stimulation, or any form of psychotherapy. You need one crucial precondition to help the patient: their intent, says Giordano.
“A medication may take anywhere from 7–10 days to work, and a depressed patient may not be necessarily motivated to take the medication because of the pervasive anhedonia,” he says. Frank Anderson, a psychiatrist who has been administering antidepressants in his private practice for many years and is the author of Transcending Trauma, a book about resolving complex and dissociative trauma, is equally hopeful about the prospects of an anhedonia-specific drug. “When it comes to conditions like post-traumatic-stress-disorder (PTSD), we have a lot of drugs that treat anxiety, hyper arousal and panic, but very few tackling the dissociative side of PTSD, the pervasive feelings of numbness, withdrawal, and disconnection that come with the disease,” says Anderson. At the same time, JNJ-67953964 is not a “panpharmacon,” a one-size-fits-all magical sauce recommended for use at the slightest hint of lack of joy.
“Just eliminating a symptom without looking at the function of that symptom is potentially dangerous,” says Anderson. Imagine somebody is severely depressed, he says. They have extreme anhedonia, which means they don’t have the energy to act on any suicidal impulses. Then, if you eliminate the anhedonia, they will instantly get more energy, and they might become more likely to act on their suicidal impulses.” This is something many psychiatrists like Anderson have witnessed with antidepressants, particularly when they work a “little bit, but not fully,” he says.
“They start working, they get more energy, and then they kill themselves,” Anderson says.
“Precision medicine as a concept demands precision in practice.”
But Giordano tends to disagree with the notion that anhedonia is a protective mechanism against self-destructive tendencies. He adds that if there is this risk of suicidal people suddenly becoming mobilized to kill themselves in the case of a rapid reduction of anhedonia, we could tackle this by putting them on suicide watch for a week or so. The bottom line is a functional, potent, and capable drug still relies on a clinician who practices good medicine and properly evaluates his patient’s use of it.
“Precision medicine as a concept demands precision in practice,” says Giordano.
The hope and the hype
Yet, for Lisa Parker, a bioethicist at the University of Pittsburgh and director of the university’s Center for Bioethics & Health Law, the UCSF study comes with at least three ethical concerns. Parker acknowledges the biological and financial benefits studies like that of UCSF bring to the table. The fast-fail approach allows researchers and companies to save financial and intellectual capital by abandoning unpromising drugs sooner. It’s also better for the people in the study, who could be spared adverse or ineffective drug responses that would play out for many more months in longer duration studies. The proof of mechanism approach touted by the UCSF study entails identifying drugs that affect brain functions associated with important clinical symptoms and then proceeding to clinical trials to determine whether these clinical symptoms are indeed affected. And that raises ethical flags in Parker’s mind.
“Because a drug has an effect on brain function that has been associated with their symptoms does not mean that it will have the desired effect of relieving their symptoms,” Parker says. And in the event symptoms are not relieved, anhedonic patients might experience the disappointment even harder than others, which could, in essence, worsen their condition. She is skeptical about why people with anhedonia would want to participate in the clinical study in the first place (since they have a lack of anticipatory pleasure). “Will they have the information and capacity necessary to protect their own interests?” Parker wonders. Ultimately, the Pittsburgh professor sees a bit too much hype in precision medicine, which obsesses over delivering “the right drug for the right patient at the right time.”
Even with drugs tailored for people with particular biological characteristics, Parker says, “individual patient responses will vary.”
Flipping a happy pill
At the time of writing, JNJ-67953964 is still in its phase 2 clinical trial and developers requested an extension in May, 2021. When they started their project, the drug was owned by Indianapolis-based pharmaceutical giant Eli Lilly and Company, Krystal says, but it was soon purchased—first by a small Rockville, Maryland-based drug company called Cerecor, which rebranded as Avalo Therapeutics last year and then sold the experimental drug to New Brunswick, New Jersey, health care behemoth Johnson & Johnson—from whence the “JNJ” in the name JNJ-67953964 comes from.
The company remains its current owner, and though the future of the anhedonia drug lies in the hands of the pharmaceutical giant right now, Krystal says he is not aware of any data indicating limitations in the viability of drugs like JNJ-67953964 that block kappa-opioid receptors or suggesting they have less potential than has been anticipated.
In any case, the UCSF psychiatrist says we should focus on how close we are to being able to deliver some existing psychiatric treatments in a precision-medicine framework. If the industry can deliver such products, it’s likely to help both the people who are suffering from depression and society as a whole, pushing treatment ahead by supercharging clinical trials. And if you can enroll specific groups of people into trials who are more likely to respond to a drug, you are more likely to see an effect and avoid inconclusive results, which can be a problem in psychiatric drug trials.
“Clear evidence of the benefit of a new drug in an identifiable subgroup of depression patients that is substantially greater than the effects of existing therapies has the potential to drive first-line use of a new drug in a sizable chunk of the depressed population,” Krystal says.
Truth be told, he admits, precision drugs like JNJ-67953964 will probably lack the big eligible population a new and more broadly indicated antidepressant would command. They might be just as profitable, however, if companies can compensate the smaller pools of people taking such drugs in smarter ways. Each time a new antidepressant tries to penetrate the already saturated antidepressant market, insurance companies are quick to institute policies that favor the use of the existing drugs, especially if they are available as generics, Krystal points out. But if the drugs are first-in-class with no viable competitors, as JNJ-67953964 and other new precision meds are expected to be, the insurance companies will more likely cover them.
Zapping away anhedonia with a pill is an encouraging first step towards realizing precision medicine for mental illnesses, and we may well see a whole new crop of these kinds of precision medicines that together could chip away at various different aspects of the complex challenge of mental health.