From Hope to Help

Interventional psychiatry answers unmet needs in treatment-resistant depression.

DEPRESSION HAS BECOME A NATIONAL EPIDEMIC

With the rising number of survivors into old age, depression among the elderly is growing, but the new crisis is among the young, whose rate of suicide increased 62% from 2007 to 2021.

The O’Donnell Brain Institute (OBI) has amassed a large multidisciplinary team of researchers and clinicians to improve existing treatments and discover new treatment options. On the clinical front, a comprehensive initial evaluation spares patients from navigating a maze of specialists and treatment options on their own. Instead, they are readily channeled to the most appropriate provider and most promising treatment or clinical trials.

Housed together, OBI’s fully integrated, broad spectrum of mental health researchers and practitioners go beyond developing and testing therapies within their siloes to understanding how they fit in relation to one another.

Among the leaders of this interventional psychiatry enterprise are Carol Tamminga, M.D., Chair of Psychiatry; Madhukar H. Trivedi, M.D., Professor of Psychiatry and Founding Director of the Center for Depression Research and Clinical Care; Nader Pouratian, M.D., Ph.D., Chair of the Department of Neurological Surgery; Kala Bailey, M.D., Vice Chair for Clinical Affairs for the Department of Psychiatry; and Frederick Hitti, M.D., Ph.D., an Assistant Professor of Neurological Surgery and Psychiatry and specialist in novel treatments for depression.

THE GAPING NEED FOR INDIVIDUALIZED CARE

Despite the growing number of available treatments for depression, even when a diagnosis is made, treatment selection has long been largely trial and error.

The challenge of providing truly individualized care is at the heart of the OBI’s mission. Together, our psychiatrists, neuropsychologists, neurosurgeons, bioinformaticians, and basic researchers are creating algorithms to enable an earlier match between an individual’s depression and the specific therapy with the greatest chance of alleviating his or her suffering.

Our team is also developing novel pharmacological, neuromodulation, and behavioral therapy techniques to address the challenge of treatment-resistant depression and suicide.

“We want to understand the different dimensions of depression, which is a very heterogenous disease – how they are represented in the brain and which circuits are involved in driving the symptoms,” Dr. Pouratian says. “Then we can tailor our therapy based on those particular symptoms and those circuits.”

EXPANDING THERAPY OPTIONS

Psychotherapy and trials of medication continue to be the first-line treatment for depression. For the approximately 30% of patients who are resistant or refractory to these therapies, however, the options have never been more promising.

Historically, electroconvulsive therapy (ECT) continues to be a first-line option for some severely ill patients or for those who fail other interventions. However, Dr. Bailey says that for some patients with depression, the group recommends transcranial magnetic stimulation (TMS), in which the stimulus is applied from outside the brain to the left dorsolateral prefrontal cortex. The OBI offers both repetitive TMS (rTMS) and intermittent theta-burst TMS (iTMS) therapies.

“ECT has been the only real choice [for patients with severe treatment-resistant depression], yet only about 1% of these patients receive this therapy. Now, there are new treatments such as TMS that, in some cases, is a more accessible and desirable step before ECT is considered,” Dr. Bailey says. “TMS works for depression about 40% of the time, though there are some exciting data on how accelerated protocols or neural navigation may improve TMS efficacy.”

Dr. Tamminga, whose research focuses mostly on psychosis, is particularly interested in TMS because of the overlap between psychosis and depression.

“Early indications show that TMS holds promise in alleviating depression symptoms in some patients with psychoses just as they do in patients with solely a depression diagnosis,” she says.

Other therapies offered for treatment-resistant depression include low-dose ketamine, which is proving particularly useful in patients who have attempted suicide. Practitioners are also using ketamine as an ongoing maintenance treatment for depression.

“About 50-60% of medication-refractory patients are finding significant benefit,” Dr. Bailey notes.

OBI practitioners are now using deep brain stimulation (DBS) for a growing number of treatment-refractory patients and committing significant resources to DBS research, which holds promise for widespread applications and compellingly rapid symptom relief.

TRIAL ON DBS FOR DEPRESSION

This promise led OBI neurosurgeons, psychiatrists, and neurologists to convene with NIH and industry representatives to brainstorm how to move forward with new DBS studies. What followed was the OBI team initiating two randomized control trials of DBS for depression.

The first trial seeks to evaluate whether advanced imaging can be used to enhance the effectiveness of subcallosal cingulate DBS for depression. The researchers are using MRI diffusion tractography in 12 patients and looking at connections within the white matter in the brain. This is part of the quest to precisely target the brain anatomy and circuits related to depression for each patient.

“We are using magnetic resonance tractography to find the precise spot for DBS to help with treatment-resistant depression. We think that the ‘best spot’ can be found based on how the different parts of the brain connect with one another,” Dr. Pouratian says.

TRIAL ON STIMULATION EFFECTIVENESS

Dr. Pouratian is leading another DBS trial, collaborating with Baylor University, to evaluate the optimal location, proper timing, and amplitude of stimulation. Six patients will be enrolled at

UT Southwestern in this first study to look at both imaging and physiology at the same time, learning if next-generation precision DBS with steering capability can be safely used to engage targeted networks and make adjustments that reduce depression.

In this work, the concept is to use the symptomatic network – rather than structural brain regions – to define the target location. The researchers will examine how brain waves change as symptoms of depression improve and how stimulation can push those brain waves toward a “less depressed” state.

“With movement disorders, we can see the tremor, we can feel the rigidity, and we can adjust the stimulation settings to fix those things. But with affective disorders, the symptoms don’t change quickly,” Dr. Hitti says.

Dr. Pouratian explains the team’s approach for narrowing in on the correct targets.

“We are not only implanting stimulators but additional electrodes across the brain, especially the prefrontal regions that are thought to be critical for mood regulation” Dr. Pouratian says. “The team uses brain signals from these recordings to judge how effective stimulation is going to be and how to make a stimulation strategy even more effective.”

The ultimate goal is to find signatures of these activities and use them to precisely match brain pathology to the location and type of stimulation, thereby accurately targeting specific presentations such as anhedonia.

“There are people for whom the reward circuit is really the major culprit, and others for whom the control and cognition circuit or the amygdala fear-and-stress circuit are affected. We have to learn to define the problem for these various groups,” Dr. Hitti says.

DBS FOR OTHER MENTAL ILLNESS

Intracranial stimulation has other applications beyond depression and movement disorders. Dr. Tamminga and Dr. Pouratian are leading a project, in collaboration with neurological surgeon Bradley Lega, M.D., exploring DBS for patients with psychosis.

“Currently, our patients with psychoses may receive TMS or ECT, and we are also using these modalities to great advantage for autism, bipolar disorder, and other serious mental illnesses,” Dr. Tamminga says. “But, if the research supports it, we are looking toward using DBS and magnetic seizure therapy (MST) in the future for a broad spectrum of these disorders.”

BIOMARKER DEVELOPMENT

Tackling the biological piece of the depression puzzle, researchers led by Dr. Trivedi are electronically combing patients’ physiological and clinical histories and using MRI diffusion tractography to identify biomarkers of depression.

“We are asking what all the factors we can gather about individual patients can tell us about how all these treatments work in the brain, to help establish brain and blood tests that can be used to individualize treatment targets,” Dr. Trivedi says.

Toward this end, he launched a large Framingham-type longitudinal study, the Texas Resilience Against Depression (T-RAD) study, to create a description of the pathology for each individual – from cells, to molecules, to circuits, to behavior. Biological samples are accessed through the nationally acclaimed University of Texas biobank.

Dr. Trivedi’s team has also published extensively on inflammation biomarkers, proteomic markers, and metabolic markers and is now looking at RNA sequencing to observe its effect on the initiation and continuation of depression.

Dr. Hitti, whose work straddles the neurosurgery and psychiatry realms, is currently performing basic research on rodents to look at depression-related brain circuits. Using viral-delivery techniques, he is turning brain areas off and on with a drug.

“We are applying stress to the rodents to look at emotional regulation processes,” Dr. Hitti explains. “For example, if I turn a brain area off, will that make their social withdrawal go away? The goal is to determine what part of the brain does what in different individuals and situations.”

RESEARCH ALONG OTHER PATHWAYS

Other modalities are also being used and researched for depression resolution. OBI clinicians are part of a multicenter study called RECOVER that is investigating the effect of vagus nerve stimulation (VNS) in Medicare patients with treatment-resistant depression. In related work, they are using responsive neurostimulation (RNS) for patients with obsessive-compulsive disorder and addiction, wherein a signal will stimulate the subthalamic nucleus of the brain when it begins to trigger unwanted thought patterns.

Supported by a National Institutes of Health grant, Dr. Trivedi is researching cutting-edge treatments for teenagers who have attempted suicide.

“There may also be patient populations who could be good candidates for research on psychedelics such as psilocybin,” he says. “These drugs can, in essence, push a reset button that breaks a pathological neural circuit they are stuck in, whether it is a fear-based circuit involving the amygdala or the reward circuit affecting motivation and pleasure, for example.”

Statistically, ECT is still the most tried-and-true therapy for treatment-resistant depression, but given the potential cognitive side effects, OBI researchers are investigating MST as an alternative.

“We have a grant to learn more about MST, and we are hoping to find that it has the same antidepressant effects as ECT but with a lower risk of cognitive side effects,” Dr. Tamminga says.

The OBI team is also testing new drugs, including KarXT, a muscarinic agonist and antagonist combination that targets the M1 and M2 receptors in the brain.

“It will likely be brought out for psychosis treatment, but it may be a cognitive enhancer for patients with depression as well,” Dr. Tamminga says.

COMMUNITY OUTREACH

The depth of depression research at the OBI is matched by its breadth, which includes outward-facing work that our clinicians, across the board, embrace.

Through funding from the Texas Child Mental Health Care Consortium (TCMHCC), for example, OBI psychiatrists partner with practitioners in primary care and pediatric settings in the Dallas-Fort Worth area and are involved in a statewide research network for youth with depression and at risk for suicide. They also lead a statewide network providing prevention and mental health awareness programs in high schools.

“A pediatrician or school counselor can call a psychiatrist for advice if their students are experiencing mental health problems,” Dr. Tamminga says. “To enable us to help young people in the future, we have created registries of children who have been involved in trauma and children who have had childhood depression, and we use those registries in our studies.”

Many OBI interventional psychiatry and psychology leaders are involved in the pediatric and adult educational programs at UT Southwestern Medical Center and Children’s Medical Center Dallas, as well as Parkland Memorial Hospital and the Dallas Veterans Affairs Medical Center.

Importantly, the state and city, along with UT Southwestern and Children’s Medical Center, are taking another giant leap forward in care for patients with severe mental illnesses by building a new psychiatric hospital, the Texas Behavioral Health Center at UT Southwestern, scheduled to open in 2025.

“We are very excited about this hospital that will have 200 adult beds and 96 children’s beds,” Dr. Tamminga says. “It will be designed for small groups to be treated with others who have similar illnesses. We have not previously had a psychiatric hospital available within 90 miles – this will be a chance for Dallas as a community to be served and will also enable new and impactful research on serious mental illness.”