Researchers Look Beyond the Brain for Answers About Intractable Depression

This story, written by Elaine Vitone, first appeared in Pitt Med magazine's summer 2017 issue.

Eve was 12 when she first started thinking about suicide. By the time she was a senior in high school, she’d tried several times. Then one morning, alone at home, she downed a lethal dose of pills. The only reason Eve lived to graduation day was that her parents unexpectedly doubled back that morning. She wound up in the ICU and barely survived.

As her classmates were moving on to start college, pick roommates and majors, and fall in and out of love, Eve (not the patient’s real name) and her medical team were trying everything under the sun for her severe and unrelenting depression: antidepressants, mood stabilizers, antipsychotics, even experimental medications typically prescribed to ALS patients. She had dozens of electroconvulsive therapy treatments, and for a few days she seemed to improve. Then she crashed again, suddenly and horribly. At this point, Eve was hospitalized and on 17 medicines, and she was still trying to end her life.

“I went up to see her,” recalls her doctor, Lisa Pan, years later, “and there was nothing. No side effects. No response. Nothing. … And I thought, I have never seen anything like this. What is this?”

Of the 15 million American adults with major depression, 15 percent do not respond to any available treatments. 

For all we know about risk factors, says Pan, the problem is that we still can’t tell which young adults with depression will die of suicide. Solving this puzzle is her life’s work.

A professor of psychiatry and of clinical and translational science, Pan began her research career studying neuroimaging markers of suicide risk in young people. In the clinic, she trained under the wing of David Brent, a professor of psychiatry and pediatrics who holds Pitt’s Endowed Chair in Suicide Studies and is arguably among the world’s foremost experts on treatment-resistant depression (also called treatment-refractory depression) and suicidal behavior in teens. Thirty years ago, Brent envisioned and cofounded Services for Teens at Risk, or STAR, at Western Psychiatric Institute and Clinic. STAR remains one of only a handful of clinics in the country that specialize in this population. Over the years, the crosstalk between research and care at STAR has helped to elucidate suicide epidemiology, risk factors and treatments and to establish national guidelines for the management of adolescent depression and suicidal behavior.

It was on this fertile ground for discovery that Pan, an up-and-coming physician-scientist, found the inspiration to take a way-out-of-the-box approach, with Brent’s support.

In Eve's case, Pan also consulted another mentor, David Finegold, professor of human genetics in Pitt’s Graduate School of Public Health, and asked what he thought of examining a lumbar-puncture test (a sampling of cerebrospinal fluid, or CSF) for clues of what was circulating in Eve’s central nervous system. Could they check her neurotransmitters, look for any new leads at all? Finegold’s answer: Absolutely. In fact, why not do a bigger workup, the kind that is standard when a child presents with signs of a neurological disorder?

As it turned out, Eve’s CSF level of biopterin, a chemical the body uses to synthesize several neurotransmitters, was through the floor. Pan and Brent started her on a replacement-therapy regimen, and over the next few months, the team observed the gradual return of this long-absent chemical so crucial to the production of serotonin, dopamine, norepinephrine, pain modulators and melatonin. And it had a profound effect on Eve.

Within the first week, her affect changed dramatically. She landscaped the family’s entire yard in a day. At week three, she became more emotional. Suddenly she was crying over TV commercials and falling in love with the stranger on the line when she phoned in her order for a pizza.

And then, on day 31, a calm after the storm.

Her mood was low at first, but it gradually improved. She had bouts of shaking, insomnia and trouble finding the right words, but as Pan adjusted Eve’s medication dosage and frequency, the side effects subsided. Ten weeks in, she was feeling what psychiatrists call euthymia — medicalspeak for normal.

Of these young people with treatment-resistant depression, 64 percent had some form of metabolic deficiency of the central nervous system; controls had absolutely none. And once the patients’ deficiencies were treated, the majority of their symptoms improved. For two of them, depression vanished altogether.

Pan and her team were skeptical at first. This must be a fluke, the scientists told themselves, an incredibly lucky break. Then they tried the same screening on three more patients suffering from treatment-resistant depression, figuring they were long shots as well.

But all three turned out to have similar metabolic disorders, all of which improved once their systems were regularly “fed” with pills, powders or IVs of special forms of what were essentially vitamins.

In most of these patients, the trouble was folate metabolism. Psychiatrists routinely order blood tests for this vitamin because its depletion is known to affect mood. But these patients’ blood levels checked out fine. “So either something was happening with the body’s ability to break down the folate enough to have it cross the blood-brain barrier or [with] the body’s ability to move it across the blood-brain barrier,” Pan says.

The scientists’ disbelief sharpened to questions: How did these biochemical anomalies happen to these young people in the first place? Could there be others who are one lumbar-puncture test away from finding their own paths to recovery? And what if the team could do one better — build a cheaper and easier test? Could even more patients be spared years of suffering, or even death?

Practically overnight, these investigations became the new focus of Pan’s career. Their first phase culminated this past August in a study in the American Journal of Psychiatry, which was one of the most lauded psychiatry papers of 2016. Though the study was small — just 33 patients — the results were striking. Of these young people with treatment-resistant depression, 64 percent had some form of metabolic deficiency of the central nervous system; controls had absolutely none. And once the patients’ deficiencies were treated, the majority of their symptoms improved. For two of them, depression vanished altogether.

Pan now divides her time between seeing patients at STAR, many of whom travel from out of state; overseeing a small yet mighty testing-referral and care-coordination service for those calling and writing in from around the country; and conducting her research with an ever-expanding list of collaborators both inside and outside the University of Pittsburgh.

In psychiatry, she says, “we’re not so far along yet that we know exactly what we’re treating. ... When we approach mental illness, we need to keep an open mind about what might be occurring that we don’t understand.”

Pan is careful to note that she is not conducting a treatment study. What she has embarked on is an effort to understand some of the molecular mechanics of treatment-resistant depression and suicidal behavior, to begin to characterize the biological bases of the many diseases we now lump together under the same umbrella.

Read more about how Pan and a multidisciplinary team are working to validate their findings in a larger patient sample, examining possible genetic and environmental factors, widening their scope to include more metabolites and developing a bigger, better test.