Searching for Chemical Clues to Uncurable Depression  

By: Ana Gorelova

When Dr. Lisa Pan, 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, 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.  

Dr. Lisa Pan

The test results were surprising – the patient’s sample was low in tetrahydrobiopterin, or BH4, a small molecule involved in the synthesis of several brain-signaling chemicals, including serotonin, dopamine and melatonin. After receiving an analogue of BH4 to correct the deficiency, the patient’s depression symptoms largely disappeared.  

That finding pushed Pan and her team of collaborators across the University of Pittsburgh’s departments of Psychiatry and Human Genetics 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 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, 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 today 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. 

Dr. David Peters

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 Dr. David Peters, 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 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.”