Wellcome Leap Trial Aims To Improve Depression Care Through Precision Medicine

January 25, 2024

Depression has become the leading cause of disability worldwide across all illnesses, according to the World Health Organization. In only a single year, 264 million people deal with depression, and 800,000 lives are lost to suicide.

Yet psychiatrists are often forced to resort to a trial-and-error approach when considering pharmaceutical treatments for individuals experiencing depression.

Diego A. Pizzagalli, PhD, director of research in the Division of Depression and Anxiety Disorders at McLean Hospital, is part of a nationwide study whose goal is to diagnose and treat this illness in much the same way doctors currently treat cancer.

“Other fields in medicine, like oncology, have genetic or molecular biomarkers that have been used to develop novel treatments that will immediately address the underlying molecular abnormality or to determine how to treat patients,” he said.

“Many types of cancer that had a low survival rate now have a 90% survival rate. In psychiatry, adopting this type of approach has been enormously more difficult, and the reason is that obviously psychiatric disorders arise due to multiple factors.”

Puzzle piece fitting into place in a larger puzzle

Unlike oncologists who can take biopsies “to understand in a dish what’s happening, with psychiatric disorders, we cannot go in and take a biopsy of the brain,” Pizzagalli said.

So clinicians are often required to use what some have described as “brute force” methods guided by limited data and patient self-reporting.

That reality is behind the $22 billion the National Institutes of Health has spent on depression research over the past 20 years.

Despite this massive investment, only one in three patients substantially responds to currently available medication or psychotherapy treatments for depression.

It is also the purpose behind Wellcome Leap, a trial to understand the mechanisms behind anhedonia, the reduced ability to experience pleasure.

“The treatment for depression is trial and error,” Pizzagalli said. Two widely prescribed drugs are Zoloft and Wellbutrin, which act on different neurochemical pathways in the brain.

Patients are often on Zoloft for 4-6 weeks, and data show only 50-55% of patients with depression will do very well on the drug. If Zoloft doesn’t work, they might be shifted to Wellbutrin.

In earlier studies led by Pizzagalli, using “big data” techniques, researchers were able to identify sets of markers that were truly specific for either drug.

The goal of the new Wellcome Leap trial, he said, is to “use these biomarkers to prospectively decide how to treat patients.”

“Basically, what we’re trying to do is to ensure that people get better at a higher rate and actually faster.”

The Wellcome Leap trial will recruit individuals with depression and perform MRIs and other behavioral testing. Using an algorithm developed for the trial, the results will be analyzed to determine which medication an individual is most likely to respond to favorably.

As with any clinical trial, participants will be assigned to an intended or non-intended treatment, in effect, a placebo.

“The goal is to show that individuals assigned to their ‘intended medications’ will do remarkably better,” he said.

“We need to show a benefit, because after all these years of digging into the neurobiology of depression to try to find potential details of response, we think we have them now. If so, we want to implement them.”

While he hopes hard data will make prescribing a drug to treat depression as easy as outlining a course of cancer treatment, Pizzagalli said there are also “critical, you might say intangible, issues.”

“With every unsuccessful treatment, people lose hope. Or they might believe that ‘it’s just me; for some reason I’m not able to overcome this disease.’ That’s also dangerous, because these people might not continue to engage in treatment. And this obviously compounds the issue.”

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