Transcript:

KELLIE NEWSOME: We interview Victor Hoffbrand on the discovery of folate and look at how this vitamin can help or harm the action of anticonvulsants in bipolar disorder. 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. Folate. Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.

CHRIS AIKEN: I’m Chris Aiken, the editor-in-chief of the Carlat Report.

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

CHRIS AIKEN: It is 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 in schizophrenia or altering serotonin or norepinephrine in depression – or do they 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 caiken@thecarlatreport.com. 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. Maybe even omega-3’scount. 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.

KELLIE NEWSOME: And don’t forget light therapy. It is kind of obvious, but low levels of morning light cause seasonal depression in the winter, and we treat it by adding a lightbox 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: lamotrigine and valproate. To understand the history, we interviewed Victor Hoffbrand, a physician and hematologist who recently wrote a book about a remarkable woman who discovered folate, Lucy Wills.

VICTOR HOFFBRAND: Lucy Wills came from a well-off family, which women who studied medicine in those days had to be because they needed a lot of private support. At all events, she studied at a distinguished all-girls school, Cheltenham Ladies' College, then at Cambridge, where she was at Newnham College, again devoted solely to women students. She passed her Cambridge finals in 1911, but, in fact, because she was a woman, she wasn't awarded a full degree until 1948, 37 years later. In 1915, Lucy enrolled at the London (Royal Free) School of Medicine and qualified as a doctor, MB, BS in 1920. She remained at the Royal Free Hospital setting up a laboratory mainly devoted to metabolic problems especially those in pregnancy. She made a prominent name for herself after she was invited by Margaret Balfour, another medical woman, to go to India to study the anemia that was occurring in poor pregnant women in Bombay. So Lucy Wills sets off to Bombay, where she noticed that the women who are getting anemic in pregnancy are, by and large, 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 already well known, called pernicious anemia. 

KELLIE NEWSOME: Pernicious anemia is now known to be due to vitamin B12 deficiency. That was still a new finding in the 1930s when Lucy was studying the anemia of pregnancy, It was as recent as 1926 that the discovery was made by George Minot and colleagues, that eating liver, which is rich in B12 and other vitamins including folate, corrected the anemia of pernicious anemia. Lucy Wills gave the pregnant women liver and saw improvement. But she didn’t stop there. As much as she was impressed with the similarities in the anemia between these patients and those with pernicious anemia, she couldn’t ignore that there were important differences.

VICTOR HOFFBRAND: She realized there were differences. Pernicious anemia patients were, by and large, older people, and they had stomachs that didn't produce acid, whereas the pregnant women were much younger and had acid in their stomachs.

KELLIE NEWSOME: So, Lucy experimented with different dietary supplements, first with liver, and then with one that’s near to my Australian heart, Vegemite, well, actually the British version, Marmite. Vegemite and Marmite are both concentrated brewers yeast. Both are rich in folate. Vegemite is thicker and has a stronger umami savory flavor on account of its additional ingredient - vegetable extracts – while Marmite is lighter and sweeter. Marmite helped gave British soldiers the vitamins they needed to push through World War I, and Vegemite did the same for Aussies in World War II. But no one knew about the folate in these spreads Lucy Wills. Like a lot of things in science, the discovery had a fair share of happenstance.

VICTOR HOFFBRAND: The reason she chose Marmite, was partly because one of her classmate's brother was a director of the Marmite company. She gave Marmite as a vitamin supplement to these anemic pregnant women, and lo and behold the anemia got better. That is where I feel she made a contribution that should have been recognized, possibly up to Nobel Prize standard, because here she'd shown there was a vitamin in yeast extract that was correcting this anemia in pregnant women. It later became clear that the yeast extract wouldn't correct the anemia of pernicious anemia, which we now know was due to vitamin B-12 deficiency, not folate deficiency. There were two vitamins deficiency, of which causes an anemia with an identical appearance in the blood film.

CHRIS AIKEN: 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 the theories, and after over a decade of work in the 1930's she identified folate finally, but it wasn’t called folate at first.

VICTOR HOFFBRAND: It became known as the 'Wills factor', and the scene soon shifted to the United States and to men. All the research up to 1931 had mainly been by Lucy Wills, on pregnant women, so it had been a female issue and female research. It took 10 years from 1931 -1941 before a large commercial company Lederle were able purify the vitamin, from four tons of spinach by a variety of purification processes. They produced a single compound which they because it had come from green leaves, they named folic acid (folium, Latin for a leaf). But what they had done in their purification process, and they didn't realize, is converted all the natural folates, which have additional units attached to the folate molecule, into a stable yellow compound, folic acid. It's much better now that we name the vitamin, which is an enormous numbers of compounds, as folate, and keep folic acid for the commercial pharmaceutical compound that we use in treatment and fortification. 

CHRIS AIKEN: That is still a source of confusion, as 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 in the body into its active form, methylfolate, and that conversion takes place in the liver, primarily through the enzymes dihydrofolate reductase (DHFR) and methylenetetrahydrofolate reductase (MTHFR) – something you might recognize from genetic test panels. And here’s where we’re going to shift to a psychiatric pearl because folate helps the brain produce the monoamines involved in depression – serotonin, norepinephrine, and dopamine – and several drugs interfere with folate’s activity or lower its levels in the brain – mainly anticonvulsants like phenytoin, valproic acid, carbamazepine, primidone, phenobarbital, and lamotrigine.

KELLIE NEWSOME: 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

CHRIS AIKEN: In 2015, researchers in the UK conducted the large CEQUEL trial to answer a common clinical question: Does lamotrigine augment quetiapine in bipolar depression? The trial was large enough that the investigators decided to add another test to the mix. Besides comparing lamotrigine augmentation with the placebo, they also put half the subjects on folic acid. The thinking was that lamotrigine interferes with folate metabolism, so adding some extra in might improve outcomes even further. To their surprise, they found the opposite. While lamotrigine effectively augmented quetiapine (that is good news), folic acid, at 500 μg/day, canceled out lamotrigine’s benefits. To quote the study, Folic acid seems to nullify the effect of lamotrigine. The researchers were puzzled. After all, folic acid improved depression in randomized controlled trials before this, so they reanalyzed the data to search for answers. Folic acid did not alter lamotrigine levels – so that was not it. The findings had nothing to do with the MTHFR gene – the gene for the enzyme that activates folic acid – but there was a signal in the catechol‐O‐methyltransferase or COMT gene. The folic acid interaction was only detectable in patients whose COMT gene had low activity – it is called the Met allele 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, homocysteine, by converting it through a few steps into glutathione. Now, before we get out of hand with chemical names, just remember folate gets converted into homocysteine, homocysteine is bad and increases the risk of depression, homocysteine we want that converted into glutathione, glutathione is good and is an antioxidant in the brain, and glutathione is thought to be one of the possible ways that lamotrigine treats bipolar depression because lamotrigine increases glutathione levels. So, the cause they are pointing to here is that maybe folic acid is somehow interfering with this pathway in people in this particular gene and causing homocysteine to build up and glutathione to go down. It is all a little speculative and has not been proven. But what we do know is that folic acid might interfere with lamotrigine’s benefits in some patients – I have seen that in one patient – 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 lamotrigine, it's like I am 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, Depakote. With valproate, the folic acid interaction is much more clear. Valproate, or Depakote, interferes with the transport of methylfolate into the brain as well as into the placenta. This is part of why valproate is so teratogenic that it is contraindicated in pregnancy – it causes neural tube deficits and lowers IQ at such an extent that it is the only psychiatric medication that is absolutely contraindicated in pregnancy. Folate deficiency can also cause anemia, heart disease, and depression, so here is the pearl, I recommend that patients who take valproate, supplement it with some sort of folate, and preferably the active form, methylfolate.

KELLIE NEWSOME: This folate interaction can even impact valproate’s antimanic effects. In a randomized controlled trial of 88 patients with active mania on valproate, those who took folic acid, 3 mg, had 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 Hoffbrand is Emeritus Professor of Haematology at University College, London. He has authored over 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 feed – search for Chris Aiken MD on LinkedIn, Twitter, Facebook, and that new one, BlueSky. It’s a first glimpse of the trials that inform this podcast. Thanks for tuning in and helping us stay free of industry support.