Transcript:

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

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. Last week, we learned how folate was discovered when the British hematologist Lucy Wills treated pregnant women with anemia with the folate-rich yeast extract, Marmite. Lucy made this discovery in 1931. By the early 1960s, new technology made it easy to measure folate in clinical practice, and that is where the link to depression began.

CHRIS AIKEN: As doctors started testing folate levels, they soon discovered a host of illnesses that were linked to folate deficiency: besides anemia, there was neuropathy, neural tube deficits, and dementia. Psychiatrists tested folate at hospital admission and found that around 1 in 4 patients had low levels, particularly those with psychosis and depression. Folate deficiency was particularly prevalent in people who did not respond to antidepressants, and supplementation often brought those patients to remission. There are at least two reasons why folate deficiency might cause depression. One is that folate is necessary for the production of serotonin, dopamine, and norepinephrine. The other is that when folate goes low, homocysteine goes high, and elevated homocysteine is linked to depression and cognitive dysfunction, as well as heart disease. Homocysteine is rough on the vasculature, and elevated levels can cause heart disease and stroke. Let’s pause for a preview of the CME quiz for this episode. You can earn CME for each episode through the link in the show notes. 

1. Which form of folate is most effective in depression?

A. Folic acid

B. Folinic acid

C. l-Methylfolate

D. They are all equally effective

KELLIE NEWSOME: But folate doesn’t just help depression when levels are low. In later trials – in the 1990s and 2000s – folate supplements proved effective in depression regardless of baseline folate levels. Those trials involved a confusing array of compounds that are involved in the folate cycle: folic acid, folinic acid, l-methylfolate, even SAMe isinvolved in there – but which one should you start with? 

CHRIS AIKEN: Until recently, we didn’t have a good answer. For folic acid, the trials were small, and one was only positive in women. Folinic acid was only tested in an uncontrolled trial, and even there, it didn’t clearly work. Then, in 2014, the first large randomized controlled trial of folic acid came out from Wales. The dose was large, 5 mg a day, and the study was fairly long, 12 weeks, but at the end, the results were surprising. Folic acid made no difference in depression. Meanwhile, other large trials did confirm that l-methylfolate treats depression and those trials also clarify the best dose. For l-methylfolate, 15 mg works better than 7.5 mg. This difference between folic acid and l-methylfolate used to put us in a quandary because folic acid is dirt cheap, and l-methylfolate was a bit expensive, available in that 15 mg dose only as an FDA-cleared, branded product called Deplin. But, generic manufacturers have busted through Deplin’s patent, and it is now available over the counter for 25 cents a day. You can find good products on my website chrisaikenmd.com/supplements.

KELLIE NEWSOME: This makes sense, as l-methylfolate is the form of folate that crosses the blood-brain barrier. The other two options - Folic acid and folinic acid - are both precursors to l-methylfolate. They are converted into l-methylfolate by the methylenetetrahydrofolate reductase (MTHFR) enzyme. Some people have a genetic deficiency in MTHFR (the c677t allele) that slows this conversion in the liver by about 70%, which may explain why they may require the l-methylfolate form is more effective.

CHRIS AIKEN: Besides this theory, the clinical evidence for l-methylfolate is much more robust. l-Methylfolate has support from nine controlled trials that enrolled over 6,000 patients. From those studies, we know that it augments antidepressants with an effect size of 0.4, which is similar to the effect size of other pharmacologic augmentation strategies like atypical antipsychotics and lithium (Maruf AA et al., Pharmacopsychiatry 2022, 55(3):139-147). The 15 mg dose is more effective than the 7.5 mg dose. Now, all of these trials tested l-methylfolate as augmentation of an antidepressant, but it did work on its own as monotherapy, as part of a B-complex vitamin in patients who were deficient in that MTHFR gene.

KELLIE NEWSOME: We cover that study more next week and also look at whether it’s useful to test for the MTHFR gene. The answer – maybe – but there are other factors that predict a methylfolate response that are just important, like obesity, inflammation, pregnancy, eating disorders, poor nutrition, renal failure, gastrointestinal disease, smoking, taking medications that lower folate like valproate, carbamazepine, and lamotrigine, or oral contraceptives; and people with alcohol use disorders.

CHRIS AIKEN: Yes, alcohol use disorders have a strong link with folate deficiency, and it is one of the ways that alcoholism leads to anemia and dementia. But not all alcohol use disorders have this strong link, as hematologist Victor Hoffbrand explains.

VICTOR HOFFBRAND: On alcohol, folate, and diet. 

CHRIS AIKEN: 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. 

KELLIE NEWSOME: 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.