Today we're going to the source, a vitamin that forms the building blocks of serotonin, dopamine and norepinephrine, and has some significant interactions with mood stabilizers and antidepressants. Ball late. Welcome to the Carlette Psychiatry Podcast, keeping psychiatry on a since 2003. I'm Chris Hickin, the Editor-in-Chief of the Carlette Psychiatry Report. And I'm Kelly Newsom, the Psychiatric NP and to dedicate a reader of every issue. It's often said that we don't treat the underlying cause in psychiatry, and that's basically true. The brain is complex, and it's hard to tell if our drugs are directly addressing a cause, such as by blocking dopamine and schizophrenia, or altering serotonin and norepinephrine depression, or do those meds exert their effects through some downstream mechanism like neuroprotection. But there are a few areas where we can arguably say that we treat depression by addressing an underlying biological deficit. I've thought of a few, and maybe you can think of more. If you do, write me at
[email protected]. Here they are. There's vitamin D deficiency. This one is controversial, but if the vitamin D level does go real low below 20, there is evidence that it causes depression and treating the problem improves it. There's gut dysbiosis, lots of evidence links deficiencies in the gut microbiome, by which I mean lack of healthy bacteria and lack of variety with depression, and adding probiotics improves depression. And maybe even omega-3's count. These essential fatty acids are lower in people with depression, and their lowness correlates with the severity of depression, and adding omega-3 treats mood disorders. And don't forget light therapy. It's kind of obvious, but low levels of morning light cause seasonal depression in the winter, and we treat it by adding a light box for an hour in the morning. Today, we're going to talk about one of the oldest deficiencies that is linked to depression, folate. We're going to start in the 1930s when folate was discovered. Then we'll learn how it impacts two treatments for bipolar disorder in very different ways. Lymotrogen and Valproate. To understand the history, we interviewed Victor Houghbrand, a physician and hematologist who recently wrote a book about a remarkable woman who discovered folate, Lucy Willes. Lucy Willes came from a fairly well-off family, which women who studied medicine, and there was a nearly. It had to be because they needed a lot of private support. But all of that, she studied at a distinguished girl school, Cheltenham ladies' college, then at Cambridge, where she was as a college devoted solely to women's students. She got her finals, but in fact because she was a woman, wasn't awarded full degree until about 17 years later. She made her name for herself, and she was invited by another woman to go to India to study the anemia that was occurring in poor pregnant women in Bombay. So Lucy Willes sets off to Bombay and notices these women who are getting anemic in pregnancy, our bar nods very poor, on a very poor diet. She also noticed that looking down the microscope, the appearances of the blood film were identical to those in another anemia that was well known for Phoenicious anemia. Phoenicious anemia is due to vitamin B12 deficiency. That was a new finding in the 1930s when Lucy was doing this work. This was the discovery that eating liver, which is rich in B12 and other vitamins, including folate, corrected the anemia. So she gave the pregnant women liver and sore improvement, but she didn't stop there. As much as she was impressed with the similarities between these patients and those with Phoenicious anemia, she couldn't ignore that there were important differences. She realized there were differences. The people who finished my minor to Murphy had treated with bandwards older people and they had stomach abnormalities, didn't use acid, whereas the pregnant women were much, obviously much younger had acid in their stomach. So something a bit different. So Lucy experimented with different dietary supplements. First with liver and then won this near to my Australian heart, Veggie Mide. Well, actually the British version, Marmide. Veggie Mide and Marmide are both concentrated bruised, both rich and folate. Veggie Mide is thicker and has a stronger umami savory flavor on account of its additional ingredient, vegetable extracts. While Marmide is lighter and sweeter, Marmide helped give British soldiers the vitamins they needed to push through World War I and Veggie Mide did the same for Aussies in World War II. But no one knew about the folate in these spreads until Lucy wills. And like a lot of things in science, the discovery had a fair share of happenstance. The reason she showed Marmide, she decided Marmide was partly because one of her classmates at the Royal Free brother was a director of the Marmide company. At all of the games she gave Marmide as a vitamin supplement to these women and lo and behold though anemia got better. And that's where I feel she made a contribution that should have been recognised possibly up to novel ice standard. Because here she's shown there was a vitamin in yeast extract that was correcting this anemia impregnant woman. It later became clear that the yeast extract wouldn't correct be anemia of penicillinemia which we now know was due to vitamin B12 deficient, not folate deficient, not to two vitamins causing anemia with an identical appearance and a blood film. We're skipping over a lot of steps in this discovery. Lucy looked for infectious causes but to no avail. She did studies in animals to prove her theories and over a decade of work in the 1930s she identified folate finally. But it wasn't called folate at first. It became known as the Will's factor and the scene soon shifted to the United States and to men. All this Margaret Balfour, Lucy Will's, pregnant women told me in a female issue and female research. But it took ten years before a large commercial company, Lattely, decided to try and purify the vitamin and what they took was four tons of spinach. By a variety of purification processes came out with a single compound which they, because it had come from green leaves, they named folium Latin for alief. But what they had done in their purification process and they didn't realise is converted all the natural folates which are have additional units attached to the folate molecule. All those had gone and they'd finished up with this stable yellow compound folic acid. It's much better now that we know the vitamin is enormous numbers of compounds to call it folate and keep folic acid for the commercial pharmaceutical compound that we use in treatment and fortification. That is still a source of confusion and you'll often see products or even research papers confuse the terms folate with folic acid. Folate is the natural form, a varied collage of many forms of folate, while folic acid is synthetic. Folic acid is not directly active. It needs to be converted into its active form, methyl folate. And that conversion takes place in the liver, primarily through the enzymes, DHFR and MTHFR, something you might recognise from genetic test panels. And here's where we're going to shift to a psychiatric pearl, because folate helps the brain produce the monolamines involved in depression, serotonin, noripinephrine and dopamine. And several drugs interfere with folate's activity or lower its levels in the brain. Mainly anticonvulsins like fennytoin, valproic acid that's depacote, carbamazepine, primadone, phenobarbital and lymotrogen. But before we get into that psychiatric stuff, a brief pause to preview the CME quiz for this episode. Earn CME for each episode through the link in the show notes. 1. Which psychiatric medication is absolutely contraindicated in pregnancy? A. Valproate. B. carbamazepine. C.
lithium, D, clonazepam. In 2015, researchers in the UK conducted the large SQL trial to answer a common clinical question, "Does Lomoetrogen augment quityapine in bipolar depression?" The trial was large enough that the investigators decided to add another test into the mix. Besides comparing Lomoetrogen augmentation with the placebo, they also put half the subjects on folic acid. The thinking was that Lomoetrogen interferes with folate metabolism, so adding some extra in might improve the outcomes even further. To their surprise, they found the opposite. While Lomoetrogen effectively augmented quityapine, that's good news, folic acid at 500 micrograms a day, can't sold out Lomoetrogen's benefits. To quote the study, folic acid seems to nullify the effect of Lomoetrogen. The researchers repuzzled, after all, folic acid improved depression and randomized controlled trials before this, so they re-analyzed the data to search for the answer. Folic acid did not alter Lomoetrogen levels, so that wasn't it. The findings had nothing to do with the famous MTHFR gene, the gene for the enzyme that activates folic acid, but there was a signal in the COMT-COM-T gene. The folic acid interaction was only detectable in patients whose COMT gene had low activity. It's called the MET-METILIL. If you test that on genetic panels, which I know some people do. COMT is involved in folate metabolism, where it helps get rid of one of the byproducts of that pathway, Homo-Systeen, by converting Homo-Systeen through a few steps into dilute the oen. Now, before we get out of hand with chemical names, just remember, folate gets converted into Homo-Systeen. Homo-Systeen is bad, increases the risk of depression. Homo-Systeen we want that converted into dilute the oen. Glute the oen is good. It's an antioxidant in the brain. And dilute the oen is thought to be one of the possible ways that Lomoetrogen treats bipolar depression, because Lomoetrogen increases glutathione levels. So the cause they're pointing to here is that maybe folic acid is somehow interfering with this pathway in people in this particular gene, and causing Homo-Systeen to build up and glutathione to go down. It's all a little speculative, has not been proven, but what we do know is that folic acid might interfere with Lomoetrogen's benefits in some patients. I have seen that in one patient. You know, he called me back after adding folic acid to his regimen, and he said, "Dr. Aiken, I feel like I did before I ever even started Lomoetrogen. It's like I'm not taking it at all." Hmm, I told him to stop the folic acid right away. But until this study is replicated, I wouldn't count it in as a widespread or definite interaction, just something to be aware of. But the next interaction is something more grounded and something you can use in practice with Valproic Acid Depacote. With Valproate, the folic acid interaction is much more clear. Valproate or depacote interferes with the transport of methylfolate into the brain, as well as into the placenta. And that's part of the reason Valproate is so taratogenic that it's contraindicated in pregnancy. It causes neuro-tube deficits and lowers IQ at such an extent that it is the only psychiatric medication that is absolutely contraindicated in pregnancy. Valproate deficiency can also cause anemia, heart disease, and depression. So here's the pearl. I recommend that patients who take Valproate supplement it with some sort of folate and preferably the active form methylfolate. This folate interaction can even impact Valproates anti-many effects. An erandemized controlled trial of 88 patients with active mania on Valproate, those who took folic acid, 3 milligrams, have much better mania scores after a few weeks than those on placebo. Carbamazepine also lowers folate levels, and though we know less about this interaction, there are recommendations to supplement carbamazepine with folate. One reason is that when folate is low, homocysteine gets high, and you don't want too much homocysteine around. It causes heart disease, stroke, osteoporosis, depression, and cognitive decline. But should you supplement with folic acid or methylfolate? Join us next week for the answer. Victor Hofbrand is emeritus professor of hematology at University College London. He is author of a 700 scientific articles and chapters, several textbooks on hematology, and the 2023 book, The Folate Story, a vitamin under the microscope. Want to keep up with the latest in psychiatric research? We post new studies in the daily psych of feed, search for Chris Aiken MD on LinkedIn, Twitter, Facebook, and that new one, Blue Sky. It's a first glimpse of the trials that inform this podcast. Thanks for tuning in and helping us stay free of industry support.
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