Studies target new approaches for treatment-resistant depression

Research underway in UAB’s Mood Disorders Program is investigating promising new therapies, including novel drugs and low field magnetic stimulation.
Written by: Matt Windsor
Media contact: Savannah Koplon

mix studies target main 550He has seen too many hopeless stares to offer hope lightly, but in decades of depression research, UAB psychiatrist Richard Shelton, M.D., has never been so optimistic. “Up to this point, most of the new treatments that we’ve had to offer patients were really variations on a theme,” said Shelton, who is Charles B. Ireland Professor and Vice Chair for Research in the UAB School of Medicine Department of Psychiatry. “Now we’re testing treatments that are really novel and different.”

UAB’s Mood Disorders Program, directed by Shelton, is evaluating new genetic tools that point clinicians to the most appropriate medications for individual patients. Preliminary results at UAB show that these tests could help up to 80 percent of patients achieve full remission. UAB researchers are also studying several treatments — including novel drugs and electromagnetic stimulation therapy — that give them hope of reaching a large portion of the remaining 20 percent.

Personalized treatment prescriptions

For more than a decade, Shelton’s research program has included studies “on matching patient to treatment,” he said — identifying characteristics, including genetic mutations, that predict how well a patient will respond to a particular antidepressant medication. It has long been clear that genetic information could be very useful in making treatment decisions in depression. Shelton was an investigator in the landmark STAR-D depression study eight years ago that discovered mutations in two key genes — the serotonin 2A receptor and serotonin transporter — that are associated with poor response to many antidepressant medications. Clinical tests that can identify these gene mutations, and other pharmacologically significant mutations, have been around for years, Shelton says. The problem was that earlier tests reported back on a large number of potentially relevant genetic results, which made it very difficult to be able to use the results clinically.

mix sheltonDepression research is entering a new era, says Richard Shelton. "We're testing treatments that are really novel and different."But the latest tests simplify this mass of information into a handful of categories. The GeneSight test, being tested and used clinically at UAB, has three: green for drugs that can be prescribed as normal, red for ones that should be avoided, and yellow for those that can be used, but at nonstandard dosages. “That allows us to distill the genetic information into what’s really critical for a patient,” Shelton said. A simple cheek swab from the patient is shipped overnight to the company’s headquarters, and results are back the following day, he says.

The results are probabilistic, Shelton notes. “It doesn’t necessarily mean that you’re going to respond to treatment A, just that you’re more likely to respond to that than to treatment B.” But, “based on our observations from a study we just completed, and what we see clinically,” Shelton said, these tests “seem to optimize treatment.”

Standard treatment helps about two-thirds of patients with depression get well — that is, experience full remission of symptoms — Shelton says. “With advanced treatment, we can push that number up significantly, probably to around 80 percent.”

Reaching the core

That’s a “big jump,” Shelton said. But at least 20 percent of patients are still desperately in need of new treatment options. To reach them, Shelton explained, the Mood Disorders Program is taking part in “a wide range of new studies.”

Several different studies are examining ketamine, an anesthetic medication that has been in use since the 1970s. Low-dose infusions of ketamine “have been shown by us and other groups to have a rapid antidepressant effect,” Shelton said. But the current IV-based delivery is less than ideal. “So the next iteration of studies we are doing is using a ketamine spray delivered through the nose,” Shelton said. Even newer versions of ketamine can be taken orally in pill form. “We’ve tested one already and are getting ready to test another in the new year.”

Whatever the form, ketamine can have dramatic effects. “About 70 percent of that 20 percent get improvement within a couple of weeks,” Shelton said. “They are much better in 24 hours, and within about two weeks they are back to themselves, as opposed to six to eight weeks with a standard antidepressant medication.” The logistics of long-term treatment with ketamine — the number of maintenance doses required, for instance — remain a major research question.

Blocking the “feel-bad” response

Antidepressant medications generally work by affecting neurotransmitters, brain chemicals that influence mood and emotions. Ketamine targets a specific receptor of the neurotransmitter glutamate, known as the NMDA receptor. Most standard antidepressants used today target receptors for serotonin. Later this year, Shelton’s team will begin to test an entirely novel drug. It focuses on the neurotransmitter dynorphin, which is “released when the body is in pain,” Shelton said. Laboratory studies have shown that drugs that block dynorphin through its kappa opiate receptor have very potent antidepressant and anti-anxiety properties. The NIH-funded Kappa Opiate Receptor Antagonist Trial will begin recruiting soon, Shelton says.

Lifting depression with magnets

Shelton is equally enthusiastic about another NIH-funded study now ongoing in the Mood Disorders Program. For nearly 20 years, physicians have noted that patients with depression improve temporarily after they have had an MRI. The electromagnetic stimulation from that device, the hypothesis goes, causes neurons to develop new connections, many of which are regulatory — helping to dampen the hyperactive cross-talk that contributes to depression and anxiety.

“Neurons are electrical organs that work through a process of depolarization,” Shelton explained. “The more a neuron is depolarized, the greater the likelihood that it will start growing connections to other neurons. And magnetic fields stimulate a greater frequency of these depolarizations.”

UAB is now testing a treatment, known as low field magnetic stimulation, “that essentially divorces that effect from the MRI machine,” Shelton said. The device being tested is an actual product, and UAB is among the first to study its effectiveness, he added. “It’s pretty simple — it’s just a big coil, and people stick their head partway into the coil and it creates a magnetic field.”

Hope for remission

“What we hope will happen with time is that more advanced treatments like electroconvulsive therapy (ECT) may become unnecessary,” Shelton said. “We’ll be able to take folks who have very resistant depression and, for example, give them ketamine treatment or electromagnetic stimulation treatment and relieve their depression fully.”

Several of UAB’s ketamine studies have involved patients who have suicidal depression. They have produced remarkable results, Shelton said. “These patients are extremely sick, and wanting to die. They are on death’s door, and we have been able to pull them back. To reverse that in 24 hours is the most gratifying thing I’ve seen in my professional life.”

To find out more about current studies enrolling patients in the Mood Disorders Program, call 205-934-2484 or