Ana Gorelova, Manager, Science Writing, UPMC, reports that when Lisa Pan, MD, a psychiatrist specializing in treating and preventing suicidal behavior in adolescents, came across the case of a 19-year-old with treatment-refractory depression, she was stunned. The young man, who attempted to end his life multiple times, did not respond to any medications, and the medical team was desperate to find a therapy to help him. Out of desperation to find clues to the root cause of his condition, Dr. Pan decided to order a test analyzing the composition of the teen’s cerebrospinal fluid – CSF for short – a liquid that washes over the spinal cord and brain.
After receiving an analogue of BH4 to correct the deficiency, the patient’s depression symptoms largely disappeared.
That finding pushed Dr. Pan and her team of collaborators across the University of Pittsburgh’s departments of Psychiatry and Human Genetics—including McGowan Institute for Regenerative Medicine affiliated faculty member David Finegold, MD (pictured), Professor of Human Genetics at the University of Pittsburgh—to launch a bigger study, looking at levels of intermediate products of the normal metabolism, including BH4 and folic acid—two key molecules involved in maintaining the brain’s normal function. They wanted to check whether patients with treatment-refractory depression who had the identified disorders could benefit from receiving BH4 and folic acid supplements as an oral medication.
The study, researchers say, was driven by urgent necessity: Working with families pushed to their breaking point from worrying about their loved ones underscored the need to find quick and effective solutions.
“As my colleague Katherine Wisner said, ‘When you are working on the cutting edge, you are going to bleed,’” said Dr. Pan, who also founded New Hope Molecular, a company in Pittsburgh that offers metabolic testing for treatment-refractory depression. “Doing this work is exhausting, but it’s important to do what we can to avoid losing individuals who contemplate ending their lives.”
After a successful pilot study, which was published in 2016 in the American Journal of Psychiatry, Dr. Pan and her team have now revealed results of a bigger trial in 141 people with treatment-refractory depression, 67 of whom had an underlying metabolic abnormality.
The paper, published in Psychological Medicine, reveals that of 11 participants with low CSF BH4 levels, seven showed improvements in their depression after treatment with BH4 supplementation. Of the 20 participants with low CFS folate, 16 responded to replacement with folate metabolites.
Unfortunately, collecting a spinal fluid sample is an invasive and costly process. While researchers hope that their work will raise awareness in the psychiatric community of the value of ordering spinal fluid tests to detect metabolic abnormalities in patients with treatment-refractory depression, this option is usually available only in large academic hospitals.
To bring the therapy to more people, the team, led by David Peters, PhD, associate professor of obstetrics, gynecology and reproductive sciences at Pitt, is now developing a diagnostic test that can be used to detect these metabolism abnormalities in the blood.
“Currently, collecting the spinal fluid sample is the only way to detect low BH4 and folate levels in the brain,” said Dr. Peters. “By performing various genomic analyses, we are searching for biomarker correlates between levels of BH4 and folate in the spinal fluid and the blood. We are hoping to develop an easy-to-use test that can be available in clinics across the country, and that can potentially save the lives of hundreds of patients, giving hope to families who have nearly lost hope to help their loved ones.”
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Abstract (Metabolomic disorders: confirmed presence of potentially treatable abnormalities in patients with treatment refractory depression and suicidal behavior. Lisa A. Pan, Anna Maria Segreti, Joseph Wrobleski, Annie Shaw, Keith Hyland, Marion Hughes, David N. Finegold, Robert K. Naviaux, David A. Brent, Jerry Vockley and David G. Peters. Published online by Cambridge University Press: 04 November 2022.)
Abstract (Neurometabolic disorders: potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. Lisa A Pan, Petra Martin, Thomas Zimmer, Anna Maria Segreti, Sivan Kassiff, Brian W McKain, Cynthia A Baca, Manivel Rengasamy, Keith Hyland, Nicolette Walano, Robert Steinfeld, Marion Hughes, Steven K Dobrowolski, Michele Pasquino, Rasim Diler, James Perel, David N Finegold, David G Peters, Robert K Naviaux, David A Brent, Jerry Vockley. The American Journal of Psychiatry, 2017 Jan 1;174(1):42-50. Published online 2016 August 13.)