An important discovery has been made at the University of Pittsburgh. It raises the prospect that there may be an entirely new way of relieving major depression in people who repeatedly have failed to respond to existing treatments—people at elevated risk for suicide whose lives are often unrelentingly dark and full of anguish.

There are 15 million Americans suffering from major depression, and 15 percent of these (that is, 2,250,000 people in the U.S. alone) do not respond to treatment.

Last August, 2012 Young Investigator Grantee Lisa A. Pan, M.D., in collaboration with a team that includes 2001 Distinguished Investigator and 2006 Ruane Prizewinner David A. Brent, M.D., at the University of Pittsburgh, reported in the American Journal of Psychiatry that they had successfully tested—so far on a small scale—an approach to treating patients with longstanding, treatment-resistant depression.

The team’s new approach is based on the theory that in at least some people, resistance to treatment in depression is caused by abnormalities in metabolism—abnormalities that can be corrected. “Metabolism” refers to the myriad processes inside our bodies in which chemical reactions generate all of the compounds that we rely upon to function as living beings.

That covers a lot of ground. Drs. Pan, Brent and colleagues had something more specific in mind. A portion of our metabolism is involved in the manufacturing of the message-carrying chemicals called neurotransmitters that have long been implicated in many brain disorders, including depression.

“Not enough serotonin in the brain.” That vitally important observation, made three decades ago in people with depression who were at elevated risk of suicide, helped spur the development of Prozac and other drugs of the same class, called SSRIs (selective serotonin reuptake inhibitors), for depression and other disorders, (notably anxiety, which often occurs along with depression). Prozac (fluoxetine) came on the market in 1987. It and other SSRI drugs have been prescribed tens of millions of times since then, for depressed people in the U.S. and around the world.

SSRIs prevent serotonin from being soaked up by cells that make and release it. This allows it to remain longer in the tiny gaps between nerve cells, called synapses, and presumably enhances the ability of adjacent cells to communicate. This, in turn, is thought to reduce symptoms of depression, for reasons that even today are not clear.

SSRI drugs address the problem of what scientists call serotonin “re-uptake.” But what about the chain of chemical processes through which serotonin is created within cells? This involves metabolic processes. As Dr. Pan has pointed out, strategies that address “reuptake may not be effective if there is an inability to make serotonin.”

She became acutely interested in the possible role of metabolism in depression after attempting over a period of years to help a young man with treatment-resistant major depression. Dr. Pan had been caring for adolescents and young adults at risk for suicide since 2002. In the lab, some of her research involved using brain imaging to look for markers of such risk.

At the STAR Center (Services for Teens At Risk) at the University of Pittsburgh Medical Center’s Western Psychiatric Institute, Dr. Pan tried to solve the mystery of the young man’s persistent deep depression, which involved suicidal thinking and several suicide attempts and resisted all forms of treatment they tried. In 2011, in what she later called a “case of necessity,” Dr. Pan brought others in to consult. Facing the alternative of committing this young person to a psychiatric institution for long-term care, she engaged Jerry Vockley, M.D., Ph.D., chair of genetics at Pittsburgh, who had helped to train her years earlier. Another consultant was David Finegold, M.D., a professor of human genetics.

The team conducted tests that ordinarily would not be given to people with depression. Among them was a detailed analysis of the cerebrospinal fluid, or CSF. It is a colorless fluid that circulates around the spinal cord and throughout the brain, and bears evidence of the many metabolites— the chemical reactants—engaged in the synthesis of the many proteins, including hormones and neurotransmitters, that help the cells in the brain function.

Analysis of his CSF revealed the 19-year old had abnormally low levels of “intermediates”—chemical precursors—of tetrahydrobiopterin, or BH4. It has many roles, among them in the synthesis of neurotransmitters including dopamine, norepinephrine and serotonin. The doctors knew of a replacement for BH4 called sapropterin. After a few weeks of receiving it, the young man’s depression began to melt away. Rather than a psychiatric hospital, he went to college, graduating at age 24.

His dramatic result encouraged Dr. Pan and colleagues to examine the CSF of five more adolescent patients in the same clinic, all suffering from treatment-resistant major depression. Three of the five had low CSF levels of 5-MTHF. This is a chemical breakdown product of folic acid, an essential metabolite throughout the body, including in the brain.

During pregnancy, mothers must have sufficient dietary intake of folic acid to assure proper development of the fetus’s brain. Deficiency can result in neural tube defects and brain damage to the newborn. Folic acid supplementation, ideally begun before conception and continued through the perinatal period, especially in women with poor diets, is accepted practice worldwide.

That is only one of many functions of folic acid, however. Deficiency of 5-MTHF in the brain—a condition called cerebral folate deficiency (CFD)—was seen in three of the five additional adolescents studied by Dr. Pan and colleagues. This, too, could be addressed, via treatment with folinic acid over a period of weeks. The patients improved.

This provided the rationale for the more rigorous “case-control” study funded by Dr. Pan’s 2012 Young Investigator Grant and reported in the American Journal of Psychiatry in August 2016. Dr. Pan and colleagues recruited 33 young people with treatment-resistant depression and 16 healthy comparison subjects. The results were impressive and full of hope. First, none of the healthy participants had metabolite deficiencies in their CSF. In contrast, 21 of the 33 refractory depressed patients (63 percent) were found to have abnormal metabolite levels in the CSF, with 12 of the 21 (36 percent of the total group) suffering specifically from cerebral folate deficiency. Ten of these 12 made it through the treatment and a follow-up period. All 10 had reductions in depression symptoms, and four had remissions. A number of those treated also had significant reductions in suicidal thinking.

“We’re looking at the end product of multiple complicated metabolic pathways and [in patients we studied] we’re finding something missing, and we’re working backwards to replace it,” Dr. Pan told the Pittsburgh Post-Gazette.

In reporting their results, the team stressed that blood tests alone would not have identified the metabolic deficiencies that showed up in the CSF. It is not easy to obtain CSF—a lumbar (lower back) puncture with a needle is required, a procedure that is uncomfortable and involves more than nominal risk. Yet it was crucial to obtain the fluid, for in cerebral folate deficiency, folate levels in the blood are normal. The lack of folate is in the brain, where the chemical is involved in neurotransmitter synthesis. They hope to devise a blood test that will identify what the CSF tests reveal.

In addition to its known role in brain development, folate in one of its several forms (L-methylfolate) has previously been used as adjunctive treatment to improve depression symptoms. L-methylfolate is involved in neurotransmitter metabolism. But, say Dr. Pan and her colleagues “this is different from our findings” in cerebrospinal fluid. In fact, L-methylfolate addresses a different part of the metabolic pathway involving folic acid, and may not help the patients with cerebral folate deficiency, the researchers say.

At the same time, while folinic acid treatment “seems appealing,” they add, it may take several years to show its full effect due to the very slow turnover of neurons in the brain. They want to know more about the precise role of metabolite abnormalities in depression as well as in treatment resistance. They move forward on two fronts: expanding the size of their study to include more treatment-resistant patients, and trying to learn more about them by sequencing their full genomes. To date, only small portions of patient genomes have been sequenced. With the entire genomes in view, it is expected that new knowledge will be gleaned that can help to resolve the age-old mystery about depression’s root causes.

— Written By Peter Tarr, Ph.D.

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