Bruce had tried everything. And yet, for three decades, he could not find any relief from his debilitating depression and suicidal thoughts.

Twenty medications. Electroconvulsive therapy. Countless hours of counseling and cognitive behavioral therapy. Nothing had worked.

Of the 15 million American adults diagnosed with major depression, 15 percent do not respond to any available treatments. They, like Bruce, have treatment-refractory depression. In many cases the illness poses significant risk of suicide.

Bruce’s symptoms began early in his teens. As time went on, they became worse, slowly consuming all aspects of his life. He went from being a high-functioning professional, designing and repairing submarines for the Department of Defense, to someone who could barely muster enough willpower and cognitive capacity to shower, eat, and show up for work.

“But even this was becoming a tremendous struggle,” Bruce recalls.

By the time Bruce turned 35, in 2000, his depression became so debilitating that he lost the ability to function day-to-day, and had to resign from his job. The realization that he was once successful and independent, but now on the verge of assisted living, caused him great anguish.

“How could that possibly be? With my career accomplishments, how could I now lack the capacity to even minimally function?” Bruce wondered.

Bruce turned into a “professional appointment keeper.” His entire day was spent keeping up with doctor’s appointments and managing his symptoms and the side effects from his medications.

Last year, at age 51, Bruce’s current doctor referred him to Dr. Lisa Pan, who was leading research that offered great promise for those with untreatable depression. Dr. Pan, a 2012 Brain & Behavior Research Foundation Young Investigator Grantee, had long worked with teens at risk for suicide. It was one such young person, under her care at the STAR (Services for Teens At Risk) Center at the University of Pittsburgh Medical Center’s Western Psychiatric Institute, that led her to draw a connection between metabolism and depression.

For years, Dr. Pan struggled to treat a teenager with debilitating, persistent depression, suicidal thoughts, and a history of multiple near-lethal suicide attempts.

Out of desperation and out of options, and recalling research from the 1980s that linked low levels of the neurotransmitter serotonin to suicide, Dr. Pan asked colleagues at the University of Pittsburgh, Dr. David Finegold, a professor of human genetics, and Dr. Jerry Vockley, a biochemical geneticist, if they could glean any clues by examining the young man’s neurotransmitter profile. Our metabolism is responsible for manufacturing message-carrying chemicals called neurotransmitters, like serotonin and dopamine and norepinephrine, which help regulate our mood.

After running an extensive neurologic panel by analyzing the young man’s cerebrospinal fluid (CSF), her colleagues found he was missing small molecules of tetrahydrobiopterin, or BH4, which helps synthesize neurotransmitters. The young man was given a synthetic BH4 replacement. Within weeks his symptoms greatly improved. The young man went off to college and was able to turn his life around.

Dr. Pan began analyzing the cerebrospinal fluid of other patients with treatment-refractory, life-threatening depression. The next three patients she tested all showed low levels of folate, an essential metabolite, in their cerebrospinal fluid, even though the levels in their blood were normal. After being treated with folinic acid over a period of weeks, these patients began to show improvement.

Encouraged by these results, Dr. Pan, through her 2012 Young Investigator Grant from BBRF, conducted a small pilot study, the results of which were published in the American Journal of Psychiatry in August 2016.

Beginning in 2014, Dr. Pan and her team evaluated 33 patients with treatment-refractory depression. They found that 21 patients had metabolite abnormalities, with the majority suffering from cerebral folate deficiency.

Once treated, most patients showed a reduction in suicidal ideation and an improvement in their symptoms. In some cases, their depression disappeared altogether.

“The thing that is really exciting about these findings is that they suggest that we may have underlying metabolic abnormalities that are contributing to psychiatric illness, particularly depression,” says Dr. Pan.

Dr. Pan’s best theory is that in most cases these patients’ bodies cannot make the neurotransmitters the same way other people can. That would also explain why they don’t respond to traditional psychiatric medications.

A common class of depression medications, called selective serotonin reuptake inhibitors (SSRIs), blocks the “re-uptake” of serotonin, which means that they stop neurons from reabsorbing serotonin after it has been released into the gap, or synapse, that separates communicating cells. However, if the body does not create enough serotonin to begin with, there is no “re-uptake” to block, she suggests.

Dr. Pan and her team are trying to fully understand the physiology behind the results to comprehend “why we are finding what we are finding,” she says.

She has so far expanded her study to 140 participants. To qualify for the study, patients must have had three maximum dose anti-depressant trials for at least six weeks. However, Dr. Pan points out that most participants have undergone more treatments than that.

“Many have had multiple treatments trials, and so much therapy that they can almost teach it. Quite a few had suicidal behavior and ideation,” she says. “This is a chronically ill population, who is at risk for death. Their life is very hard. I admire these people more than anyone because they really fight every day.”

Last fall, Bruce joined the study.

“Dr. Pan’s staff have been incredibly engaging, and involved to a depth I have never experienced in the medical community,” he remembers.

An analysis of Bruce’s CSF revealed that he too, like the suicidal teenager earlier, had drastically low levels of BH4. He began oral BH4 replacement therapy in late April 2017. Within a few days, he knew “something was happening.” Tackling his monthly bills had usually taken him a painfully long time, but by the first of May he was able to get them done in 15 minutes.

As time went on, the improvements kept coming. Before he had spent his whole day managing his condition, but now Bruce found free-time in his day to actually “live.”

Almost two months into his treatment, Bruce cooked a barbecue dinner from scratch for his extended family on Father’s Day, after he spent five hours working on his car. This would have been impossible before he started treatment.

“I did not need one moment of time to manage my illness,” Bruce recalls.

Bruce’s cognitive functioning and willpower have improved so much that he is now contemplating a return to the professional scientific community.

This is “a remarkable contrast” to his life before, he says.

Bruce was one of the study participants who showed immediate and drastic improvement. Dr. Pan remembers Bruce as a very “slowed down” person.

“He moved slowly, spoke slowly. And now we have a very energetic and excited person, who is motivated,” she says.

In her larger sample of patients, Dr. Pan’s initial findings stand. More than 50 percent of those tested have a treatable metabolic disorder.

So far, Dr. Pan’s team has found seven disorders, most commonly cerebral folate deficiency and BH4 deficiency. There are also patients for whom the team has yet to find a known metabolic disorder.

The study requires patients to come back for a follow-up visit six months after beginning treatment, and Dr. Pan says most are showing improvements in their symptoms.

“We see everything from a really startling change [such as with Bruce] which is very impressive, to a gradual improvement over time,” says Dr. Pan.

Every day, Dr. Pan receives calls and emails from fraught patients and family members across the country.

“I really hope that Dr. Pan’s diagnostic technology is made available to as many doctors throughout the U.S. and the world, because depression is a true biological, medical condition that can be diagnosed under a microscope,” says Bruce. “It is not a moral or character flaw.”

Depression by itself is difficult, if not disabling. “But to have a depression that has been going on for years, or even decades, without any relief is an incredible burden to bear,” says Dr. Pan. And Dr. Pan’s research could change the way we treat those who bear that burden. “The promise of that, even though it’s very early, is very exciting,” says Dr. Pan.

— Written By Fatima Bhojani

Click here to read the Brain & Behavior Magazine's March 2018 issue