Experimental New Therapy Shows Promise For Treating Severe Depression

Aug 22, 2016

Correcting metabolite deficiencies could help patients with treatment-resistant depression.
Credit hipponotized / Flickr

Five years ago, Dr. Lisa Pan had a patient whose depression was so severe that no form of treatment would take away his suicidal thoughts.

At age 16, he had tried every medication available. He had been subjected to electro-convulsive therapy more than 30 times. He was hospitalized and on 17 different medications.

Nothing was working.

On a hunch, the assistant professor of psychiatry and clinical and translational research at UPMC ordered a neurologic panel – the kind of tests usually run for seizure patients. The results showed that the young man had a deficiency of a protein called tetrahydrobiopterin, or bh4, in the cerebrospinal fluid that flows between the brain and spine.

Without bh4, his brain couldn’t make the neurotransmitters, such as dopamine and serotonin, essential for mood regulation and healthy brain function.

Typical depression medications are selective serotonin re-uptake inhibitors, or SSRIs, which prevent the brain from destroying serotonin. But Pan theorized that the brains of people with treatment-refractory depression – defined as a depression resistant to at least three different drugs – are not creating serotonin in the first place, so there is nothing to preserve.

“When we replaced (bh4) with an oral medication it took time, but he improved,” Pan said. “He’s now a college student, an honor student, he has a productive life and he’s much better. That’s why we started looking at other patients like him.”

Among 33 adolescent and young adult patients, Pan and her co-authors found that 21 had deficiencies in bh4 or other molecules necessary for the synthesis of neurotransmitters. The most common deficiency was in a vitamin called folate.

“Blood levels of the vitamin folate are totally normal, but when we sample the cerebrospinal fluid, we find evidence that the folate is not getting to the brain,” Pan said. “In those individuals, we were able to give a form of folate that’s already broken down that the body doesn’t have to metabolize that can get across the blood-brain barrier to the brain.”

The majority of patients saw improvement in their depression symptoms and some even experienced complete remission.

Pan said it was not clear from the research why individual patients’ brains weren’t getting the needed metabolites such as bh4 and folate. Because there are multiple metabolites needed for neurotransmitter synthesis and multiple pathways for each to reach the brain, every patient’s circumstance was a little bit different.

Pan said the treatment method represents a shift in thinking about depression, from a behavioral issue to a medical one.

“I’m really glad for it, looking at both mood disorder and suicide as a more biologic condition that needs to be treated medically,” she said.

Nearly 15 million Americans suffer from depression, and at least 15 percent of those patients are afflicted with treatment-refractory depression.

The results of Pan’s study are published in the latest issue of the American Journal of Psychiatry.