Posted by: faithful | August 31, 2016

biological marker and cause of some depression identified

Pittsburgh researchers may have found ‘cure’ for some untreatable depression
August 22, 2016 12:00 AM

“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,” says Dr. Lisa Pan, a psychiatrist and researcher.
Rebecca Droke/Post-Gazette

Ben Finder remembers when the depression first hit him.

It was three years ago when he was 13, a happy and energetic eighth-grader in Obama Middle School in Pittsburgh.

“The first sign, I noticed that every few days I’d get this feeling that came over me of nothingness,” Ben recalled this past week. “It’s kind of hard to describe, but I didn’t think it was a big deal at the time.”

He did not tell his parents until a few months later, when the feelings of nothingness grew to include thoughts of committing suicide. Those thoughts became overwhelming. The illness would consume his and his parents’ lives over the next year as doctors had Ben try different drugs, different therapies, with several stays in mental health hospitals, all in a search for help that seemed increasingly unlikely to come.

Ben had what they call in the psychiatric field “treatment-refractory depression,” which is simply a way of saying that all the existing therapies did not help him, putting him in a group that is about 15 percent of all people diagnosed with depression.

But then, by chance one day on a bike ride with friends, his father had a conversation with a colleague that led him to stumble upon what he calls a “cure” for Ben, now 16 and thriving in school and life and planning for college.

What his father discovered was that two researchers, Lisa Pan, a psychiatrist, and Jerry Vockley, a biochemical geneticist, and their team at the University of Pittsburgh and UPMC had found an experimental therapy for patients just like Ben that was showing amazing promise — so much so that it could potentially change the way that people with seemingly untreatable depression, as well as those with other mental illnesses, are treated medically.

As outlined in an article posted online Aug. 11 in the American Journal of Psychiatry, Dr. Pan, Dr. Vockley and their team discovered that many people like Ben with untreatable depression may have a disorder that can be treated by finding what is missing from their central nervous system metabolism.

As Dr. Pan put it: “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.”

As with so many important discoveries, this one began with one patient: A 19-year-old man who was a psychiatric patient of Dr. Pan’s in the Services for Teens at Risk, or STAR, Center at UPMC’s Western Psychiatric Institute and Clinic in Oakland with recurring suicidal thoughts and multiple suicide attempts.

As with Ben, “we had really tried everything with him,” Dr. Pan said. “We tried experimental drugs, [electroconvulsive therapy], everything.”

Then somewhat out of desperation to help her patient — who asked not to be named — Dr. Pan asked Dr. Vockley and his colleague, David Finegold, also a biochemical geneticist: “Is there anything about this case you could help me with?”

“It really was a case of necessity being the mother of invention,” Dr. Pan recalled of that decision to ask for their help.

Dr. Vockley, who remembered Dr. Pan from her training with him earlier in her career, remembered that moment in 2011: “I was delighted. She wanted to stretch the paradigm and find other possibilities.”

She had read research from the 1980s that found evidence that low levels of a neurotransmitter of serotonin known as 5-hyroxyindoleacetic acid, or 5-HIAA, led to markedly increased risks of suicide.

Serotonin has long been thought to play a crucial role in a person’s feelings of well-being, and drugs had already been developed based on that to help some patients with depression. Now Dr. Pan was wondering if there was a metabolic gap in her patient that could be corrected.

Dr. Vockley and Dr. Finegold agreed to help. Rather than looking for problems with only serotonin issues, they told her that with a sample of the patient’s cerebral spinal fluid, they could do 10 central nervous systems tests looking for a variety of different troubled pathways.

What they found was that her 19-year-old patient had deficient levels of a protein known as tetrahydrobiopterin, or BH4. They began treating him with sapropterin, a replacement protein for BH4.

The impact on the patient began within weeks, turning his life around and allowing him to go to college. He is now 24 and working in his chosen field, Dr. Pan said.

The success with his treatment led the team to quickly take a look at five more patients at the STAR clinic who also were not responding to traditional treatments, and they found similar problems where the treatment also helped. That spurred the larger study that Dr. Pan and the team reported on in the newest journal article this month.

Beginning in 2014, they evaluated 33 depression patients who were not responding to treatment. Dr. Vockley and Dr. Finegold looked for metabolic disorders with each of them, this time using an even broader series of tests that looks at hundreds of metabolites in the cerebral spinal fluid, to see if the levels differed from that found in their blood tests.

Of the 33 patients, 21 were found to have metabolite abnormalities. Twelve of the 21 had the same abnormality: cerebral folate deficiency, a disorder sometimes found in infants that slows their development but is also associated with a variety of adult medical problems.

Folate is a vitamin found in leafy green vegetables like asparagus and broccoli. But to try to fill the gap in the patients they found, Dr. Pan’s team prescribed pills of high doses of folinic acid to the 12 patients. Ten of the 12 showed improvement at the first follow-up, with most showing reductions in thoughts of suicide not long after treatment began.

Testing found different gaps in the central nervous system metabolisms for the other nine patients, and they benefited from treatment as well, Dr. Pan said.

The stunning results — with a group of patients for whom nothing else had worked — at first left the team anxious.

When the initial tests showed patient after patient with the same abnormality — cerebral folate deficiency — Dr. Pan asked the lab to check the samples a second time to make sure they were correct.

Dr. Vockley, a longtime, celebrated researcher and the chief of medical genetics at Children’s Hospital of Pittsburgh of UPMC, had a similar anxiety.

“I kept asking myself, ‘Is this too good to be true? Are we doing something that’s tipping the scales in our favor?’ ” he recalled.

Though the team only just published the article on their findings, Dr. Pan has been presenting the results at conferences for the last year and it excited the research community.

Gustavo Turecki, a prominent research psychiatrist and director of the McGill Group for Suicide Studies at McGill University in Montreal, heard Dr. Pan talk in May at small seminar on suicide research in Washington, D.C.

“I immediately thought her results were compelling and very interesting,” he said.

“Others have tried before to look for underlying conditions” in such patients, he said. “But I don’t think before there was any systemic way to detect inborn errors.”

Dr. Turecki’s clinic works with about 800 people in the Montreal area with depression who do not respond to traditional treatment, and he hopes to be able to try to duplicate Dr. Pan’s study with some of his patients — an important next scientic step to confirm the result.

Perhaps the best outcome from the knowledge of the results occurred this year when an anonymous donor gave $1 million to Children’s Hospital of Pittsburgh of UPMC to fund a three-year study to look at an even larger group of patients, perhaps 150, which would help prove that the group of 33 patients were not in some way cherry-picked.

Another main aim of the study will be to try to identify markers in blood for each of the identified abnormalities, so that they could be found via a simple blood test rather than the sometimes anxiety-causing procedure of having spinal fluid drawn through a lumbar puncture.

The team hopes to answer other questions with future study, including what is it that causes these abnormalities in the first place.

“That would be key,” Dr. Vockley said. “It is always better to prevent than to treat.”

Jonathan and Jana Finder, Ben’s parents, have even higher hopes.

“I’d love to see this treatment flip, so that they do this workup first and this treatment and save patients a year of hell like we went through,” said Ms. Finder, an attorney who works on health policy issues.

That year of hell only found an end one day in late fall 2014 when on one of his regular bike rides with a group of fellow doctors, a colleague of Dr. Finder, a pediatric lung researcher at UPMC and Pitt, said he had a patient who was in Dr. Vockley’s study, which was already underway.

“I called Jerry and we got Ben tested as soon as possible,” Dr. Finder said. “They found he had a folate deficiency.”

Within a month of starting to take the high doses of folinic acid, “we felt like we had our Ben back,” Ms. Finder said.

He’s now doing well in school, heading into his junior year at University School in Oakland, has a steady girlfriend, and is trying to decide if he will pursue computer science or medicine in college.

The Finders — parents and son alike — said part of the reason they want to talk about Ben’s case is not only because they want people to know about Dr. Pan and Dr. Vockley’s work but to take away the stigma of depression.

“If I say our son has treatment resistant depression, people look at you and think, ‘What is going on in the Finder household? You must be terrible parents,’ ” Dr. Finder said. “It’s a terrible stigma.”

“But if I say my son had a metabolic disorder manifested by depression and cured by a pill, people don’t look at you — or him — so funny anymore. And there could be many people in the same situation.”

Sean D. Hamill: or 412-263-2579 or Twitter: @SeanDHamill

Folic Acid, Folate & Methylfolate: Potential Problems & Critical Distinctions
Basic RGB

Folate, folic acid, Folinic acid and 5-methyl folate are not the same. Knowing the difference between the different types of folates could have very important implications for your health.

The terms “folic acid” and “folate” are often used interchangeably to describe Vitamin B9. The truth, however is that they are not the same. Folic acid, is actually a synthetic form of Vitamin B9, which is not found in nature, nor is it naturally found in the human body. In order for folic acid to be metabolized, it must undergo metabolism via the enzymes FOLR2 and DHFR, primarily in the liver. However, natural folates found in whole foods appear to be metabolized via the intestinal mucosa.

Wright, et al have discussed the specific metabolism of folic acid and proposed that there may be associated risks (1). Rogers, et al and Wright et al discuss that folic acid is an oxidized form of B9, and in order to become biologically active, the nutrient must be reduced via the DHFR (di-hydrofolate reductase) enzyme in the liver (1, 2). The major problem here is that the liver and other human tissues lack significant amounts of DHFR enzymes to metabolize folic acid (3).

As a result of the fortification of refined flour products with synthetic folic acid, plasma and red blood cell levels doubled the predicted target saturation of folic acid in these blood markers. The implication here is that synthetic, oxidized folic acid is poorly metabolized, and has a high propensity towards accumulating in the body in a non-metabolized state. Other studies have found a correlation between high levels of un-metabolized folic acid as well, following the consumption of folic acid fortified foods or folic acid supplements (5). Further studies on folic acid-fortified bread consumption have found elevated levels of non-metabolized folic acid following consumption of a single slice of bread (6).

What Are The Possible Implications of Un-Metabolized Folic Acid?

Statistical correlations have been found between folic acid consumption and the formation of cancer (7, 8). One study actually found low folate levels may protect against colorectal cancer (9). An epidemiological study conducted in 2007 found that men and women with previous colorectal adenomas, who took 1000 mcg of folic acid daily for 6-8 years had increased risk factors for colorectal cancer (10).

It is certainly plausible to consider the possible cancer risks associated with excessive folic acid, considering that folate methylation is critical for cell proliferation, including in the formation of neoplastic cancer cells. It is for this reason that certain conventional cancer treatments use folate-blocking drugs such as methotrexate. Additionally, glutamatic acid is well established to increase the growth factors in various cancers. The class of folic acids and folates all consist of varying numbers of glutamic acid conjugates.

From a clinical perspective, folic acid, folate and 5-methylfolate are a common cause of adverse reactions. Some of these common symptoms include: headaches, insomnia, and anxiety.  These are likely at least partially caused by the increasing pool of free glutamate in the system.

Others Forms Of Vitamin B9

The richest naturally-occurring sources of Vitamin B-9 are: animal liver, dark green leafy vegetables (such as kale, collards, chard, spinach), whole cereal grains and legumes. Folates appear to be heat labile nutrients, so be aware that over-heating your food may reduce the amount of folate present.

Supplementally, aside from folic acid, there are 2 forms of Vitamin B9 commercially available: Folinic acid (5-formyl tetrahydrofolate) and 5-methyltetrahydrofolate. Folinic acid is a metabolically active form of folate, a downstream folate metabolite, and a precursor to the active form of folate known as 5-methyltetrahydrofolate (or 5-MTHF for short).

5-MTHF is the most popular form known today. Individuals with MTHFR gene mutations are often recommended to supplement with this form of folate, because in certain cases (primarily +/+ homozygous gene carriers of MTHFR SNPs A1298C and C677T) these individuals may not be able to generate this important methylated form of folate.

As mentioned previously, folates in general are prone towards inducing adverse reactions and various symptoms. An important quote by Paracelsus is:

“the dose makes the poison”.

Its significant to address that how much, or which type of folate (or for that matter any nutrient) your body needs may be unique to you. Too much, too little, or the wrong form of a nutrient could become problematic.

Remember also that Vitamin B12 and folate are intrinsically connected. A B12 deficiency can actually cause a folate deficiency, because B12 is necessary to properly methylate folate.

Further research on the deleterious effects of folic acid are critically needed, as well as the metabolic distinctions between folic acid, folinic acid and 5-methyltetrahydrofolate.


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