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The evolution of psychiatry

Yale Medicine Magazine, Spring 2024 (Issue 172) Women's Health Special Report
by Isabella Backman


A Q&A with John Krystal

Mental illness has historically been underdiagnosed and undertreated in the United States, says John Krystal, MD, Robert L. McNeil, Jr. Professor of Translational Research and professor of psychiatry, of neuroscience, and of psychology at Yale School of Medicine (YSM). In recent years, the COVID-19 pandemic has substantially accelerated the use of mental health services.

Yale Medicine Magazine spoke with Krystal—a leading psychiatrist who specializes in the pharmacotherapy of psychiatric disorders and a pioneering researcher into the fast-acting antidepressant effects of ketamine—about the evolution of the field of psychiatry.

How has the field of psychiatry changed since you began to practice?

Early in my career, we were tweaking existing medication types to improve tolerability and safety. For example, when I was a psychiatry resident on our Clinical Neuroscience Research Unit in the 1980s, we tested some of the first selective serotonin reuptake inhibitors (SSRIs)—the prototype being fluoxetine [brand name Prozac®]. These medications acted via mechanisms similar to older tricyclic antidepressants introduced in the late 1950s but were better tolerated.

As a result, many more people decided to pursue treatment for depression than in the past. When I joined the faculty in 1988, my first project was studying a new antipsychotic medication called clozapine. While similar in many ways to antipsychotic medications introduced in the 1950s, it had a reduced propensity to cause motor side effects, and it was a little more effective. These advances in tolerability helped to encourage many more people to seek medication treatments for problems like depression, anxiety, and psychosis.

To move from incremental advances in treatment to fundamentally novel treatment mechanisms, we had to change the way that we thought about the neurobiology of psychiatric disorders. Most of the medications that psychiatrists prescribed targeted the monoamine systems, such as norepinephrine, serotonin, and dopamine, which comprise only a few percent of the synaptic connections in the brain.

To move forward, my colleague Dennis Charney and I reasoned that we had to better understand how the monoamine systems were related to the rest of the synaptic connections in the brain—particularly glutamate and GABA neurotransmission, which constitute more than 90% of the synapses in the cerebral cortex.

This change in perspective about the biology of depression led my colleagues and me to test the effects of very low doses of ketamine in depressed patients in the mid-1990s. Ketamine, in higher doses, is an anesthetic medication. In the 1980s, it had been shown to block the NMDA subtype of glutamate receptor in the brain. Our initial study shocked us. While traditional antidepressants may take months for patients to recover from depression, some of our initial patients achieved this within 24 hours of a single ketamine dose. Further, the beneficial effects of a single dose lasted up to two weeks.

Our study and subsequent replications led Johnson & Johnson to develop the s-isomer of ketamine (esketamine; Spravato®) into the first mechanistically novel antidepressant approved by the FDA since the 1960s. In addition to their distinctive rapidity of action, these medications are remarkably effective for depression symptoms that have not responded to other antidepressant treatments, are effective for suicidal patients, and are quite effective in preventing relapse to depression.

Two large studies published in 2023 suggest that for treatment-resistant symptoms, adjunctive esketamine is more effective than adjunctive antipsychotic medication, and similar in efficacy to electroconvulsive therapy (ECT). Recent findings regarding long-term effects of esketamine suggest that when compared to standard treatments, it reduces suicide attempts, death by suicide, and all-cause mortality (i.e., it reduces the chances of dying from medical problems that are worsened by depression).

Esketamine is approved by the FDA and limited to clinic-based administration. Ketamine is not yet approved by the FDA for the treatment of depression, and ketamine treatment is generally not reimbursed by insurance. As a result, some practitioners have developed the practice of prescribing ketamine for take-home use.

However, ketamine is an abused substance, and “take-home” ketamine may be associated with risks associated with misuse of this drug. The widely publicized death of [the actor] Matthew Perry makes this case. He was known to have substance use problems. At the time of his death, he had more than 10 times the amount of ketamine in his blood than that needed to treat depression— enough to anesthetize him and to contribute to his drowning. At Yale, we limit both ketamine and esketamine treatment to the clinic.

In addition, there are two new medications approved for the treatment of post-partum depression: brexanolone (Zulresso®), approved by the FDA in 2019, and zuranolone (Zurzuvae™), approved by the FDA in 2023. Both are thought to work by replacing a progesterone-derived neurohormone called allopregnanolone (ALLO). ALLO levels drop rapidly after childbirth, depriving the brain of a natural mood resilience mechanism.

These drugs restore ALLO in the body and brain, reducing post-partum mood symptoms. Brexanolone involves a 64-hour intravenous infusion, and it is impractical to use in many treatment settings. However, zuranolone is an orally administered drug and may be used more broadly.

We also are making progress in developing new treatments for psychotic disorders like schizophrenia. Since the 1950s, all antipsychotics have produced therapeutic effects by blocking the dopamine D2 receptor. These medications are helpful for many people with psychosis symptoms, but other symptoms of schizophrenia may not respond well. Further, dopamine D2 receptor blockade may make people feel dulled, and may cause tremor, restlessness, and other motor side effects.

The first two drugs to treat psychosis without blocking the dopamine D2 receptor seem to be emerging. The first medication, KarXT, is a combination of two drugs that stimulate muscarinic cholinergic receptors in the brain but block muscarinic receptors in the body. It produced very encouraging results in clinical trials and has been submitted to the FDA for approval.

The second medication, emraclidine, is a selective muscarinic M4 positive allosteric modulator. One index of how important these new drugs may be for psychosis treatment is that the companies that made these new drugs were acquired by large pharmaceutical companies. Karuna, which makes KarXT, was acquired by Bristol Myers Squibb, while Cerevel, which makes emraclidine, was acquired by AbbVie.

What are your longer-term expectations for the use of such drugs as ketamine, which have fast-acting antidepressant effects.

When ketamine was first introduced, it was originally reserved for the most severe forms of depression. At Yale, we initially reserved ketamine and esketamine for patients who had failed ECT. Now, ketamine and esketamine are generally provided to patients before they are treated with ECT. It seems like these treatments are being used for a larger group of patients, as the data support evidence of greater efficacy for a broader range of conditions.

I also expect ketamine treatment to evolve based on what we are learning about potential synergies between ketamine and esketamine and particular forms of psychotherapy, as well as the potential for next-generation versions of ketamine that may provide either greater tolerability or efficacy.

How have attitudes about ECT evolved?

ECT, which involves the application of brief electrical pulses to the brain, was highly stigmatized based on depictions of it in movies like One Flew Over the Cuckoo’s Nest. It’s taken a long time for the public to appreciate that the actual practice of ECT is nothing like what they saw in the movies. It remains an extremely effective form of antidepressant treatment, and it’s been helpful when public figures like Kitty Dukakis and our own Sherwin Nuland, a distinguished surgeon who was on the faculty here at YSM, spoke out and wrote about their positive experiences with it.

For many people, this may be the only treatment that works for them. When we suggest that a patient consider ECT, we often spend a lot of time explaining to them and to their family that they won’t be awake, they won’t have a visible seizure, and that there’s a good likelihood that the treatment will be effective for them. The most common side effects are headache or difficulty recalling what happened right before the treatment was delivered. Some people may have relatively mild memory impairment that can persist for a while, but this risk can be reduced by administering the therapy on one side of the brain at a time rather than both sides at the same time.

What role will psychedelics play in treating psychiatric conditions and for end-of-life care?

Psychedelics are being intensively studied at this point. There are now two Phase 3 studies that have been published for psilocybin [the active ingredient in Psilocybe mushrooms], that suggest that this hallucinogenic substance is rapidly effective and has a fairly robust antidepressant effect in patients with major depression.

That’s very exciting, because no treatment works for everybody, and we need a diversity of rapid-acting and highly effective treatments for patients with depression. Psilocybin is also being tested for a variety of other conditions, such as end-of-life existential distress, and there are some encouraging data reported there. It can be a deeply comforting and inspiring experience for people who are in that stage of life.

MDMA, also known as Ecstasy, which is not hallucinatory, is being tested in post-traumatic stress disorder (PTSD). It seems to be robustly effective in the published data so far. A second Phase 3 study was completed, and while we haven’t seen the results, the group that conducted the trial—MAPS, the Multidisciplinary Association for Psychedelic Studies—has submitted an application to the FDA for approval of MDMA as a treatment for PTSD.

Psychedelics are striking drugs because of the profound experiences that people report during the treatment sessions. The administration of the drugs is somewhat burdensome to go through. Psilocybin and MDMA treatment sessions last between six and eight hours. And, generally, people have several psychotherapy sessions before each treatment to prepare, and several after to process what they experienced. It’s a very intensive process, but many people find it meaningful and helpful.

How will interventional psychiatry be incorporated?

Interventional psychiatry, which was a term we started using around 2009, is now a mainstream idea. It is based onthe principle that treatment options don’t stop when a patient hasn’t responded to the usual medications that we commonly prescribe for mood, anxiety, and psychotic disorders. We have other options that can often be very effective.

Together, in partnership with our patients, we can often produce better clinical outcomes by using these more interventional kinds of treatments, which include ketamine, esketamine, ECT, and transcranial magnetic stimulation—a more subtle kind of brain stimulation than ECT. Psychedelics and MDMA are just two examples of drugs that will very likely become part of the interventional psychiatry package after they’re approved by the FDA. So interventional psychiatry is a growing field, in part because its options seem to be increasing every year.

What are the most important changes occurring in the treatment of alcoholism?

While I am not aware of a new medication coming to the FDA for approval in the near future, research on alcohol use disorder is extremely active. Our center, called the NIAAA Center for the Translational Neuroscience of Alcohol, identified one promising strategy in early studies that involves the combination of an opioid receptor blocker and a glutamate receptor antagonist. We are currently evaluating a negative allosteric modulator of the metabotropic glutamate receptor-5 (mGluR5). In other centers, an anti-inflammatory drug called apremilast has shown some promise. There is also tremendous interest in the potential role that ketamine, psychedelics, and MDMA might play in the treatment of alcohol use disorder.

What's being done to address the disproportionately high rate of mood disorders in women?

Depression is about twice as common in women as in men. In the postpartum period, the rate of depression in women doubles over the usual elevated rate. Women are at greater risk for most mood and anxiety disorders relative to men, and that’s one of the reasons why it’s important to understand the unique factors contributing to these increased rates. Some of the clues come from understanding hormone levels in the body. But we are beginning to develop a more fundamental understanding of the neurobiology of depression.

These insights are coming from studies on the genetics of depression and from analyses of post-mortem brain tissue from men and women. This work has revealed that the biology of mood disorders, such as depression and PTSD, are somewhat different in women and men. In other words, when you look at specific cells in specific parts of the brain and look at the profile of the genes that are expressed, you find some differences in the alterations of men’s and women’s brains. It’s possible that these new insights into sex differences in the biology of depression will lead us toward more specific mood and anxiety treatments for women, as well as for men.

How is the relatively new field of reproductive psychiatry helping women?

Reproductive psychiatry focuses on mood disorders associated with female reproductive health. The range of clinical conditions includes menstrual cycle-related mood disorders, post-partum or peri-partum mood disorders, and menopause-related mood and anxiety disorders. Addressing these issues is extremely important because they affect so many women, and are associated with distress and disability.

Historically, these conditions did not receive the kind of research that general mood disorder symptoms got in terms of psychiatry research. As a result, the researchers working in this area, including Dr. Ariadna Forray, associate professor of psychiatry at YSM and director of the Center for Wellbeing of Women and Mothers, have been specifically testing treatments that target women who are experiencing these mood symptoms related to their reproductive health.

That’s where new treatments, such as brexanalone and zuranolone, come into play. Clinicians may use distinctive medication treatments that are not commonly used in other areas of psychiatry, and the people who work in this field are also dedicated to studying the causes and mechanisms of these reproductive-related mood disorders.

How has telehealth affected the practice of psychiatry?

Within two weeks of the emergence of the pandemic, all of our ambulatory service was converted to telehealth. We were concerned that we would not be able to deliver effective psychotherapy via telehealth; that did not turn out to be the case. And what we discovered is that attendance in psychotherapy increased when we switched to telehealth. Because people could attend their appointments more easily, fewer were cancelled, and patients benefited from that.

Our hope is that we will be able to maintain telehealth as a part of an overall set of treatment options for patients. We are concerned that some of the payers are reducing their reimbursement for telehealth visits, which makes it financially disadvantageous to offer telehealth relative to in-person visits. We hope that will not persist, because for many patients, it’s the most viable form of treatment.

Over time, it is likely that tele-mental health might be augmented by digital health. This would include computerized psychotherapy-like programs that people can use at their convenience to work on issues that they’re also addressing in their face-to-face therapies. Treatment could also be augmented by data that can be collected easily and in an automated way. For example, there are wearable devices that inform us about a person’s quality of sleep or daily activities. These kinds of data are relevant for understanding both the symptoms that people have and how they’re responding to treatments.

What predictions do you have for the future of psychiatry?

This is an extremely exciting moment in the field of psychiatry. The science is better than it has ever been, and we are now beginning to see the emergence of treatments from our understanding of the neurobiology of psychiatric disorders. I predict that the next generation of new treatments will target very fundamental mechanisms underlying the biology of psychiatric disorders.


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