How Novel Treatments Target the Neurobiology of Depression
Over the last century, clinicians have relied primarily on psychotherapy, lifestyle changes, and antidepressant medications to treat major depressive disorder (MDD). While these approaches can significantly alleviate the disorder’s often-debilitating symptoms, they leave behind the nearly one-third of individuals who don’t respond to those modalities.
Interventional psychiatry is an emerging subspecialty that offers novel treatments for people living with treatment-resistant depression. At Yale School of Medicine (YSM), researchers in the Yale Depression Research Program collaborate closely with clinicians at Yale New Haven Psychiatric Hospital’s Interventional Psychiatry Service. Together, they work to accelerate these much-needed advances.
“Our Interventional Psychiatry Service is unique because we have a hybrid research-clinical model,” says Rachel Katz, MD, assistant professor of psychiatry. “The Yale Depression Research Program’s work helps drive our state-of-the-art clinical care.”
The Burden of MDD
Nearly a fifth of adults in the United States will be diagnosed with MDD at some point in their lives. It is a leading cause of disability globally, according to the World Health Organization, and it is a heavy burden on society. The disorder cost adults in the United States alone more than $333 billion in 2019.
The symptoms of MDD extend beyond a depressed mood, and can also include low energy, loss of appetite, sleep disturbances, difficulty with concentration, and suicidal ideation. Suicide is among the country’s most common causes of death, and is the second leading cause of death among adolescents and young adults.
For a third of patients with MDD, the condition remains debilitating even after they try standard interventions. “The reality is that standard medications and psychotherapy are not successful for all patients,” says Katz. A 2006 clinical trial found that the greater number of medications a patient had tried without relief, the lower the likelihood that they would have success with a different intervention.
The Emergence of Interventional Psychiatry
Interventional psychiatry utilizes novel techniques targeting the functional brain circuitry that underlies psychiatric disorders. Experts coined the term around 2009, but some of the treatments used in this specialty have been used for decades.
Researchers discovered electroconvulsive therapy (ECT)—which uses small controlled electric currents to trigger a brief seizure in the brain and reset neural activity—in 1938. And while clinicians initially used transcranial magnetic stimulation (TMS), which has been around since the 1980s for stroke rehabilitation, psychiatrists now use this therapy today to help modulate certain parts of the brain and improve mood symptoms. In addition, it was YSM researchers who discovered the potential of ketamine in the 1990s for its potent and fast-acting antidepressant properties.
“Interventional psychiatry in its individual pieces has existed for a while,” says Katz. “But the unification of these treatments under the umbrella of interventional psychiatry has been novel over the past five to 10 years.”
Yale New Haven Psychiatric Hospital launched its Interventional Psychiatry Service in 2013. The Yale program pioneered comprehensive interventional psychiatry services, bringing together cutting-edge interventions into a unified clinical and research program shortly after the term was popularized, with early integrated services in place by 2019.
The program currently offers services that include ECT therapy, TMS therapy, intravenous ketamine therapy, and esketamine nasal spray, as well as the opportunity to participate in clinical trials. A unique aspect of Yale’s program, says Robert Ostroff, MD, co-medical director of the Interventional Psychiatry Service at the hospital, is that the program requires practitioners to have expertise in all treatment modalities. “You want to avoid only having a hammer and thinking everybody is a nail,” he says. “We make sure everybody is cross-trained in the different interventions so that they are comfortable tailoring treatment options to the individual’s needs.”
Katz is co-director of Yale New Haven Psychiatric Hospital’s transcranial magnetic stimulation (TMS) service—a therapy in which psychiatrists use pulsatile magnetic fields emitted from a coil placed on top of the patient’s skull to stimulate the brain tissue. “By modulating the frequency of the pulses and the area of stimulation, we can manipulate the underlying activity of the brain,” Katz explains. It is a safe, noninvasive form of neuromodulation that clinicians can perform without anesthesia and with few side effects.
Research shows interventional modalities can be highly effective in treating mood disorders like MDD that haven’t responded to traditional therapies. Katz says she was drawn to this subspecialty because she enjoys working with patients with severe illness. “I find fulfillment in how quickly some of these treatments help patients recover,” she says.
Interventional Psychiatry Research at YSM
The Yale Depression Research Program is run by two attendings from the Interventional Psychiatry Service—Gerard Sanacora, MD, PhD, George D. and Esther S. Gross Professor of Psychiatry, who is also co-director of the Interventional Psychiatry Service, and Samuel Wilkinson, MD, associate professor of psychiatry. Sophie Holmes, PhD, assistant professor of psychiatry and neurology, directs the program’s research on the mechanisms of depression and treatment responses. The ongoing research helps inform Yale’s clinical care, and patients often have opportunities to participate in the clinical trials overseen by the program.
Research in interventional psychiatry at YSM dates back to the 1990s, when scientists including John Krystal, MD, Robert L. McNeil, Jr. Professor of Translational Research; Dennis Charney, MD, former YSM professor of psychiatry; and Robert Berman, MD , adjunct professor of psychiatry, pioneered the work that led to the discovery of ketamine as a treatment for severe depression.
Traditional antidepressants are believed to work primarily by targeting the physiological actions of certain neurotransmitters in the brain, particularly serotonin, but they can take weeks to improve mood. The YSM team was interested in targeting a different system in the brain—the glutamatergic system, the most widespread neurotransmitter system within the brain. Glutamate serves as the brain’s main excitatory (stimulating) chemical messenger, sending signals between neurons and providing important information that helps to regulate the brain’s adaptive mechanisms and neuroplasticity. Ketamine most directly modulates the passage of glutamate signals between neurons by blocking a type of glutamate receptor called the N-methyl-D-aspartate (NMDA) receptor.
In 2000 the Yale team reported the results of a small proof-of-concept clinical trial that found that ketamine rapidly treats the symptoms of severe depression. Patients showed improvement within the span of a few hours. “That early study was the initiating force that got researchers very interested in ketamine,” says Sanacora. This work would help pave the way for the Food and Drug Administration’s (FDA) approval of esketamine nasal spray—a derivative of ketamine that is thought to be the most potent part of the molecule—for treatment-resistant depression in 2019.
Today, the Yale Depression Research Program is continuing to study how ketamine and esketamine work, whom they work best for, and their safety and efficacy in the real world. The researchers recently published a study in the American Journal of Psychiatry in which they analyzed data from 58,000 patients receiving over 1.4 million doses of esketamine over the first five years of its availability. The goal of the study was to better understand the risks and use patterns associated with the newly approved therapy.
“The Yale research program was involved in the very initial study on ketamine and continues its commitment into the late phases of research,” says Sanacora. “We’re trying to use the best data available to accurately understand the true balance between the effectiveness of the treatment with the risks it poses to both individuals and potentially society, especially if not used correctly or done with the right precautions.”
Holmes leads a parallel line of research investigating how ketamine brings about its antidepressant effects at the level of brain biology. Using positron emission tomography (PET), her team conducted the first study to measure ketamine’s effects on synaptic density in the living human brain. “We’re trying to visualize neuroplasticity in action—to see whether ketamine actually helps rebuild lost connections between neurons,” Holmes explains.
One of the program’s largest studies is exploring whether the FDA-approved intranasal esketamine formulation is superior to intravenous ketamine. “There’s a lot of controversy in the field as to whether there’s a difference between the two,” says Wilkinson. “But there’s really no good, high-quality evidence to support these opinions.” The ongoing study will be the first to randomize patients to receive one of the therapies and then compare outcomes.
Inducing Neuroplasticity to Treat Depression in Parkinson’s Disease
The researchers are also wrapping up the first clinical trial that uses ketamine infusions to treat depression in patients with Parkinson’s disease. “Major depressive disorder symptoms are really common in neurological disorders but are often overlooked,” says Holmes. “Traditional antidepressants don’t tend to work as well in these populations because they’re likely not targeting the underlying mechanisms.”
Parkinson’s disease is associated with the loss of neurons in certain parts of the brain, and the use of ketamine to restore these deficits holds potential for treating depressed mood and potentially other symptoms of the disease. Over the coming months, the researchers will analyze the data to see whether ketamine alleviates mood symptoms, and whether these effects are underpinned by changes in neural plasticity as measured by PET and MRI scans.
Future research in the Yale Depression Research Program will examine the potential of novel therapeutics in treating depression. The researchers are collaborating with colleagues at the University of California, San Francisco, for example, to launch a clinical trial that studies the potential of psilocybin, the psychoactive compound in “magic mushrooms,” for treating depression in patients with Parkinson’s disease. “We think that psilocybin may induce mechanisms similar to ketamine in terms of inducing neuroplasticity,” says Holmes.
New Oral Antidepressant on the Horizon
Holmes’ team will also be involved in a different clinical trial focused on a new oral antidepressant that mimics ketamine’s effect on the NMDA receptor. While ketamine can quickly put patients with MDD into remission, relapses are common. The scientists hope the new drug will help patients experience a more enduring response to ketamine. “What I tell patients clinically is that our first order is to get them well,” says Ostroff. “Our second order is to think about the best way to keep them well.”
The researchers are hopeful that these emerging therapeutics will reduce the overall burden of depression on society. And at the Interventional Psychiatry Service, Katz is looking forward to a growing toolbox of strategies that offer hope to even her most severe cases. “We are learning more and more about how to get people well quickly, and how to do so in a way that’s as safe as possible,” says Katz. “There are many exciting neuromodulation modalities that are coming down the line.”
This story was originally published by Yale University on December 1, 2025.