TRD: Matching Patients to the Right Treatment

When asked about the greatest challenge today in treating depression, Michael E. Thase, MD, noted it “is finding novel treatments that are well enough tolerated and affordable to help someone where standard therapies haven't helped." For patients who have not responded to standard antidepressants, he sees a widening set of options in interventional psychiatry, telling Psychiatric Times that the work is in matching the right one to the right patient, faster.

When Standard Antidepressants Aren't Enough

Treatment-resistant depression (TRD) is not a diagnosis, said Thase, professor of psychiatry and chief of the Division of Mood and Anxiety Disorders Treatment and Research Program at the Perelman School of Medicine at the University of Pennsylvania. The underlying diagnosis is still major depressive disorder or bipolar disorder in a depressive episode, he explained, and TRD describes a phase in that patient's history in which they have gotten stuck, unable to benefit from treatments that could have, and should have, worked. Although regulators currently define TRD as 2 failed treatments within a single episode, Thase said he understands some clinicians consider that bar too low, "but you do need to start somewhere."

In practice, Thase said, response rates tend to fall off meaningfully once a patient reaches that point, which is part of why many newer therapies have focused specifically on patients who have already failed at least 2 standard treatments.

Matching Patients to the Right Treatment, Sooner

For Thase, who sees patients referred after other providers haven't been able to help them, the bigger frustration is the process itself. "You try and about half the time it doesn't succeed," he said. "I call it iterative," rather than trial and error, but the goal going forward is matching treatments with a better chance of success, or recognizing sooner when a treatment is unlikely to work, he told Psychiatric Times.

A patient's own treatment history can help guide treatment decisions. If someone needed 3, 4, or 5 treatments to get better during a prior depressive episode, clinicians may be able to skip the classes that failed the first time around. In a patient's first treated episode, the standard path still runs through at least 2 unsuccessful or poorly tolerated antidepressant trials before considering options like transcranial magnetic stimulation (TMS).

The Interventional Psychiatry Ladder

TMS uses a magnetic field to target brain regions implicated in depression, he explained. It's well tolerated, with 95 of 100 patients completing an adequate trial, although it requires daily visits for 4 to 6 weeks to know if it will work, followed by a taper if it does.

Beyond TMS, Thase generally favors ketamine or esketamine for younger patients and those with less extensive treatment histories, reserving electroconvulsive therapy (ECT) for patients who have already responded to it in the past or who have failed more treatments.

"In older patients with more extensive treatment histories, ECT still delivers a 50% or 60% response rate even when 4, 5, 6 treatments haven't worked," he said.

Vagus nerve stimulation sits at the end of that sequence, reserved for patients who've exhausted pharmacotherapy and ketamine or esketamine — slower to work than ECT, often taking months to show benefit, but still meaningful for patients who have run out of other options.

Psychedelics on the Horizon

The newest addition to that ladder, Thase told Psychiatric Times, is psychedelics, but where they ultimately land is still an open question. He pointed to esketamine as a cautionary parallel. Although it was approved by the FDA in 2019, its clinical uptake was "disappointing" for the first several years, complicated by the pandemic, and only gained real traction roughly 7 years after its introduction. He predicts psychedelics may follow a similar early path, likely limited at first to patients with TRD while cost, access, and longer-term data play out.

Even so, Thase sees real upside. "We have no idea what the future is going to hold here, because from one vantage point, psychedelics could become first-line treatments," he told Psychiatric Times, which is one more sign, in his view, that patients who have run out of options today may have more of them tomorrow.

Dr Thase is professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania.