My first real l-methylfolate case

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whopper

whopper

Former jolly good fellow
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Deplin is often times given by psychiatrists to those who are depressed. I think, and still think, it's just them throwing expensive folic acid. (Well something close to folic acid).

But today for the first time ever I had my first real case where L-methylfolate really might have saved the day. Pt had treatment resistant depression since her childhood and she's been on over 10 antidepressants with no benefit. An mTHFR gene test showed she had two mutations on that gene with none of them being the normal gene. One gene with one mutation, the other with a different type of mutation but both mutations decrease l-methylfolate production in the brain.

Pt got better in just a few days of the l-methyfolate treatment. I say this is my first "real" one cause this is the first one where she fit a profile of what could've been the deficiency, showed (+) results on the genetic testing, and the supplement appeared to have a good effect.

I still do not advocate that we doctors give out Deplin liberally. It's expensive and likely not needed but I am saying that for now on anyone treatment resistant, depressed since being a minor without any apparent cause, I will likely order an mTHFR gene test and if (+) order L-methylfolate.
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We used to have samples of Deplin in my training, and those were by far the most useful samples I've had available to me. I saw many patients just pop up like a cork within a week of starting Deplin. If they didn't get almost immediate results, we simply didn't continue. Many of these patients had languished on antidepressants for years and had almost a dysthymic presentation--never really getting better despite multiple antidepressants and adjunctive medications. A little Deplin, and they looked worlds better. They often still needed to be stay on at least one antidepressant, but I had several patients who I was able to wean off of several adjunctive medications. When I had samples, I rarely ordered the genetics testing--it was easier and less expensive to just give the samples.
 
She wasn't tried on folic acid supplements. I jumped to the test because at the first time I saw her she gave me a list of several meds tried and failed and told me she was depressed since childhood. At the time I saw her she was on Risperdal 1 mg (for augmentation), Wellbutrin XL maximum dose, Cymbalta maximum dose, Adderall XR for augmentation (remember she was already on this when I saw her) with no improvement and had already been tried on everything you'd suspect.

She's been on it for about 2 weeks and noticed an improvement within 3 days. Told me nothing ever got her better before. I also did all the other tests such as TSH, B12, Folic acid, Vitamin D and they were all within normal range. The mTHFR gene showed no normal genes but she had 1 mutation on one and another type of mutation on the other.

What's really opened my mind on this is I've seen some data suggesting that about 1/2 of people treatment resistant might have an mTHFR gene mutation and that while the exact frequency is not known there is some data suggesting this gene is in the double digits in frequency.
 
seriously whopper, for a smart guy you do seem to ride the wave of pseudoscience (first believing in QEEG for ADHD diagnostics and now this). The MTHFR genotyping thing is quackery of the highest order. This is what all the naturopaths are doing in my neck of the woods and selling their own version of this product (5MTHF). I had a patient ask me about this a while back. I told him naturopaths were charlatans and the MTHFR genotyping has not been shown to be helpful in depression or cardiovascular disease. Also people who actually do have MTHFR deficiency would have high levels of homocysteine so we checked this and lo and behold - his levels were normal! as were his methylmalonic acid levels. There is absolutely no evidence that people with true MTHFR deficiency have a need for L-methylfolate supplementation. In the real word of science-based medicine, these patients receive supplementation with folate (yes, regular old folate!), B12, and B6. B6 is actually the essential supplement that these individuals need.

As for L-methylfolate - there is actually decent evidence suggesting it has a role as an augmentation agent to an SSRI in depression at doses of 15mg/day. See here
Incidentally this study did not genotype these patients for MTHFR so it is absolutely not necessary. If you were concerned that patients couldn't use regular folate, then you should check homocysteine and MMA levels as this is much cheaper and easier to do. But again would not lead to the recommendation of using L-methylfolate but B6 supplementation. Folate has also been shown to be helpful for depression, MTHF is just the biologically active form that crosses the blood-brain barrier.

In sum: it is quackery and a waste of money to genotype for MTHFR. but l-methylfolate may be a fairly benign and effective treatment augmentation option for SSRI-resistant depression.
 
(first believing in QEEG for ADHD diagnostics and now this)
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EEGs for ADHD dx are FDA approved. I haven't ever ordered one cause I don't know anyone that does testing for it despite the FDA approval. Also the science behind it still doesn't lend it making the dx based on the EEG by itself. It still requires a clinical dx. I don't see why ordering one would be "quackery" given the FDA approval and that it's only one facet for diagnosis and again I never have even ordered one.

Your post does add food for thought. I did not order homocysteine levels. The patient's folic acid levels, as I mentioned before were within normal range as were her B12 level. With any new advancement there should always be some suspicion. Even FDA approved products even a few weeks after being put on the market are found to have problems not known before.

One one end you could be completely right and perhaps the l-methyfolate worked simply because it is an augmentation agent-no need to order the gene test. On the other hand my hypothesis could be right. One could argue it doesn't matter since it worked, but IMHO it could matter cause if it's due lack of l-methylfolate from the gene mutation she would likely need the supplement for the rest of her life. If this is not due to the gene mutation then perhaps folic acid in and of itself (despite that her folic acid levels are within normal range) might have helped. Also I was thinking either the l-methylfolate or Venlafaxine/mirtazapine or ECT and due to the lab results it my was decision to recommend that instead of the other two.

This does open my mind to considering asking her to stop the supplement after say 1-2 months and see if she wants to consider folic acid supplementation by itself. It also brings up placebo effect. I am doubting the latter cause she's been tried on lots of things for years with no benefit-even no placebo benefit.
 
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You can get l-methylfolate outside of a Deplin prescription, FYI, at a lower cost depending on whether insurance is paying for Deplin or not. In fact, many prenatal vitamins these days include l-methylfolate rather than folic acid. But those amounts are not in the higher range--but there are companies that do sell the Deplin dose and seem to be reputable.

Also, you might want to order a homocysteine test.
 
Medicare pays for Genesight testing and that includes mTHFR.
Splik was right to point this out. There is an emerging type of Dr. Oz type of doc and customer who'll try to use this gene as the cause of all ills and recommend Deplin for everything. Keep this in perspective. I ordered the test because this patient was literally tried on every SSRI and SNRI and Wellbutrin with no benefit, all at max dosages.
Birchswing-it is possible to order L-methylfolate online. Cheapest I know of at 15 mg a day is $30.
 
PistolPete said:
Does any commercial insurance or Medicare pay for mTHFR genetic testing without a huge or any copay?
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I don't know about GeneSight because I didn't use that one, but Genelex/YouScript has (or had--not sure now) a guarantee that if they can't get your insurance to pay they won't bill you personally. I don't know any more than that (such as why they don't). My doctor told me they would try a few times to bill my insurance and if they couldn't get payment, that would be the end of it--and it was.

Edit: If I were to do the testing over again I might do Genesight because they seem to have more genes relevant to psychiatric drugs that they test than YouScript has (or at least compared to what YouScript had when I was tested).
 
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A problem with Genesight is while it's nice to have it, it's not a coup-de-grace or anything close. I've seen in ordered lots of times and even then the meds that are ordered that are more likely to work didn't seem to work more often. In the end it's better to have it than not have it but it's not like you've been given the map to get your lost sheep out of the dark forest. It's more like you had a shot in the dark before it but now you get to peek really quickly before you take the shot.

I do get the feeling, however, that maybe 10 years from now the technology will be a heck of a lot better and it may be worth doing the test quite a bit.
 
I'd encourage those interested to go to Genesight's website as they reference the studies they did that they use to promote their product. They have 2 smaller, unblinded studies that show using their testing works better than treatment as usual for depression. The problem is that they never quite explain what the doctors actually did with the Genesight information. They do some subgroup analysis to try to bolster their claims about the green, yellow, and red bins, but the Ns start getting rather small then.

They have a larger study with blinded raters and participants that trended towards the same results but didn't reach statistical significance. That suggests to me a significant placebo effect from the testing itself, so it's not clear how much its guidance improves outcomes.
 
hamstergang said:
I'd encourage those interested to go to Genesight's website as they reference the studies they did that they use to promote their product. They have 2 smaller, unblinded studies that show using their testing works better than treatment as usual for depression. The problem is that they never quite explain what the doctors actually did with the Genesight information. They do some subgroup analysis to try to bolster their claims about the green, yellow, and red bins, but the Ns start getting rather small then.

They have a larger study with blinded raters and participants that trended towards the same results but didn't reach statistical significance. That suggests to me a significant placebo effect from the testing itself, so it's not clear how much its guidance improves outcomes.
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Agreed, we had a lecture by one of the preeminent psychiatric geneticists breakdown exactly how rarely these tests are actually useful and under which conditions it makes sense to order. I can understand it in Whooper's case above when you want to know if it's bad TMD versus hypermetabolism. In the CAP world, I've seen it be useful to justify over-max FDA doses where the doctor and the pt/pt family can feel good about it, but that's about it.
 
I have also seen a case where L-methyfolate appeared to make a significant change in a long standing treatment resistant depression. I was extremely skeptical up till that point and am still skeptical. We do have several mid-level providers, both psychiatric and medical, who order the gene testing for almost all patients and prescribe it to almost any patient that insurance will pay for it. My patients are really impressed by how "smart" these mid-levels are with all the fancy terms that they don't understand. Am I the only one that, always read the mthfr as an abbreviation for m-f'er?
 
Merovinge said:
In the CAP world, I've seen it be useful to justify over-max FDA doses where the doctor and the pt/pt family can feel good about it, but that's about it.
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One of my attendings (in CAP fellowship) has just had me check a serum level of SSRIs a few times. Makes sense to me as we really don't care about the genotype; we care only as it serves as a surrogate marker for serum level.

smalltownpsych said:
Am I the only one that, always read the mthfr as an abbreviation for m-f'er?
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I do it every time.
 
whopper said:
Also I was thinking either the l-methylfolate or Venlafaxine/mirtazapine or ECT and due to the lab results it my was decision to recommend that instead of the other two.
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Any consideration for Liothyronine (Cytomel) or Lithium for her augmentation?
Anyone know how they compare to Folate augmentation?

I wonder whether marketing behind atypicals (to expand their prescribing numbers by having approval for depression augmentation) has made Liothyroine/Folate/Lithium less used? I mean these drugs have been around much longer, even used when TCAs were the norm. Yet in my residency training (I'm in millennial age group) I have been usually trained to add atypicals. But I feel the other options may be more worthwhile initially (before going down the metabolic problems of atypicals)?
 
Igor4sugry said:
Any consideration for Liothyronine (Cytomel) or Lithium for her augmentation?
Anyone know how they compare to Folate augmentation?

I wonder whether marketing behind atypicals (to expand their prescribing numbers by having approval for depression augmentation) has made Liothyroine/Folate/Lithium less used? I mean these drugs have been around much longer, even used when TCAs were the norm. Yet in my residency training (I'm in millennial age group) I have been usually trained to add atypicals. But I feel the other options may be more worthwhile initially (before going down the metabolic problems of atypicals)?
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I like using T3 and Li as augmentation for TCAs or MAOIs. The evidence isnt really there for SSRIs (mostly because it hasn't been done but what little we know isnt too impressive). The general recommendation is if you are going to start someone on a TCA for treatment-resistant depression you should also consider adding Li (or T3) right off the bat. In contrast the evidence for atypicals is there for SSRIs so it is not unreasonable to add a little risperidone or aripiprazole to an SSRI/SNRI. personally I am quite suspicious of the trend to using atypicals in this way given the known complications including TD and metabolic syndrome so try to avoid using atypicals in non-psychotic depression, but have to concede that sometimes it does appear to be helpful. I have rarely used folate in someone without deficiency but it's not unreasonable. Another underutilized augmentation strategy is SAMe - thinks like 5MTHF, SAMe etc are quite popular in my neck of the woods amongst patients. Also don't forget omega-3 fatty acids.

When you get into people who have tried multiple drugs were in a largely evidence free zone and a combination of patient preference, balancing risks and benefits, and interpreting the data we do have should inform good clinical care.
 
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Problem with genotyping is there are 40+ known MTHFR variants with who knows how many more undiscovered. Clinically pointless anyway since a homocysteine level will tell you if you have a backup in the synthetic pathway or not. Cheaper too. Recent paper on this in J Clin Psychiatry, will come back and post link when able
 
tr said:
Problem with genotyping is there are 40+ known MTHFR variants with who knows how many more undiscovered. Clinically pointless anyway since a homocysteine level will tell you if you have a backup in the synthetic pathway or not. Cheaper too. Recent paper on this in J Clin Psychiatry, will come back and post link when able
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Thank you for this! My psychiatrist insisted on MTHFR testing and while I had a single "mutation," I researched it and found it was one that in no way affected metabolization of folic acid. I handed her the research I found and she handed it back without reading it and said she already knew all about the "conspiracy theories" on the Internet (this was a PubMed article). (The conspiracy theories, if there are any, tend to go in the opposite direction.) I then mentioned that if I really had a problem, we should measure my homocysteine level and she said it wouldn't tell us anything. I sometimes feel like I'm in a twilight zone. You're the first person I've seen say a homocysteine test makes more sense, which is what I deduced from my own research on this. It's funny how a doctor could refuse a cheaper test like that and insist on very expensive genetic tests and then disregard what the results of the genetic test actually mean once they get them. Even the people on the Internet who are very passionate about MTHFR testing don't think that the variant I had is significant in any way. I know that doctors on paper don't get kickbacks, but I really felt there was something about Deplin made my doctor desperate for me to try it. Before the genetic testing she had started asking questions about depression, which is not a condition I've ever had. I think it was a pretense for this testing and prescription. I got the script but never took the Deplin. Was too expensive (insurance wouldn't cover--with good reason in my case), no research that I had difficulty processing folic acid, I didn't have the associated condition (depression), and it was a mega-dose that many people say can be activating. Plus it's a supplement you can buy over the counter.
 
Whopper- knowing your practice group very well (and its reputation as the premier practice in our area) and having interacted with several of your partners, I am curious as to their (specifically your most famous partner) take(s) on the case.
 
Their take mimics a lot of what's been said on the forum. They won't order it quickly but have in the past.
I have only one case I can think of where gene testing was something I would've done with some highly directed reason.
I had a patient who insisted he needed 32 mg of buprenorphine to feel stable As most of you know that is twice what is recommended by the manufacturer and the patient was an ideal body weight for his height.
I speculated he might be a supermetabolizer of buprenorphine and he had always been a good patients. All drug tests were negative, he always showed up on time, and showed a lot of good factors such as being a responsible parent, homeowner, good education etc.

I told the patient that I was considering doing gene testing because his insurance company was having problems covering the amount of medication he needed. At that time there was not buprenorphine testing with Genesight. I don't have that patient anymore.
One of my colleagues here too had a super-metabolizer case and was able to justify to the insurance company to give a stimulant at a much higher dosage than the FDA maximum recommended dosage using the test. The patient also responded very well to it.

My famous partner doesn't ever order them.
 
I have a very similar history of Whopper Former Jolly Good Fellow's patient: life-long treatment-resistant depression, two mutations found on the MTHFR gene 677CT and 1298AC. Started Deplin as a monotherapy 7 months ago with remission beginning within the first 3 days. Are there any additional resources available on the web regarding this particular medical issue? Finding so little quality information, lots of conflicting statements and plenty of "snake oil" sites on the web. Just hoping to find out more solid info. Thanks very much for the original post.
 
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hamstergang said:
I'd encourage those interested to go to Genesight's website as they reference the studies they did that they use to promote their product. They have 2 smaller, unblinded studies that show using their testing works better than treatment as usual for depression. The problem is that they never quite explain what the doctors actually did with the Genesight information. They do some subgroup analysis to try to bolster their claims about the green, yellow, and red bins, but the Ns start getting rather small then.

They have a larger study with blinded raters and participants that trended towards the same results but didn't reach statistical significance. That suggests to me a significant placebo effect from the testing itself, so it's not clear how much its guidance improves outcomes.
Click to expand...

Have any of these studies been published in a peer reviewed journal?
 
Homocysteine and MTHFR Mutations

Association between MTHFR C677T polymorphism and depression: An updated meta-analysis of 26 studies. - PubMed - NCBI

mthfr depression - PubMed - NCBI

Bottom line is L-Methylfolate has been found to be useful in treating depression and this has been published in several articles including the Green Journal but does genetic testing really give us a good idea when to give it or not? That's still up in the air. I do, however, start it on patients with MTHFR mutations of the C667T and A198C variety with very good results but I don't have a comparison group without the mutation to compare them (not an actual study but based on my personal experiences. Seems when they have this mutation over 75% get improvement with L-methylfolate).

It's possible that even without the mutation the L-Methylfolate could help so I don't know if having the mutation begs that L-Methylfolate be given. Also if you don't have the mutation will this affect L-Methylfolate's efficacy? I don't know. The studies where L-Methylfolate was given to help depression I never saw any screening to see if they had the mutation or not. They just gave it out and the patients that got it did better than placebo.

Given that L-Methylfolate runs about $20 a month if you know where to get it, I recommend it. I avoid Deplin cause that''s about $280 for a month's worth and there's no superiority with vs the $20 brand.
 
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whopper said:
Homocysteine and MTHFR Mutations
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"The MTHFR mutations by themselves, in the absence of elevated homocysteine levels, are not a risk factor for cardiovascular disease or DVT and PE in countries where food is fortified with folic acid."

This would suggest to me that it would be more valuable to try to correlate homocysteine levels to depression than the MTHFR mutation. Is there any evidence that l-methylfolate helps in depression in the absence of elevated homocysteine levels?
 
whopper said:
Homocysteine and MTHFR Mutations

Association between MTHFR C677T polymorphism and depression: An updated meta-analysis of 26 studies. - PubMed - NCBI

mthfr depression - PubMed - NCBI

Bottom line is L-Methylfolate has been found to be useful in treating depression and this has been published in several articles including the Green Journal but does genetic testing really give us a good idea when to give it or not? That's still up in the air. I do, however, start it on patients with MTHFR mutations of the C667T and A198C variety with very good results but I don't have a comparison group without the mutation to compare them (not an actual study but based on my personal experiences. Seems when they have this mutation over 75% get improvement with L-methylfolate).

It's possible that even without the mutation the L-Methylfolate could help so I don't know if having the mutation begs that L-Methylfolate be given. Also if you don't have the mutation will this affect L-Methylfolate's efficacy? I don't know. The studies where L-Methylfolate was given to help depression I never saw any screening to see if they had the mutation or not. They just gave it out and the patients that got it did better than placebo.

Given that L-Methylfolate runs about $20 a month if you know where to get it, I recommend it. I avoid Deplin cause that''s about $280 for a month's worth and there's no superiority with vs the $20 brand.
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If you were replying to me I was referring to the Genesight studies about the benefits of their service.
 
This would suggest to me that it would be more valuable to try to correlate homocysteine levels to depression than the MTHFR mutation. Is there any evidence that l-methylfolate helps in depression in the absence of elevated homocysteine levels?
Click to expand...

Not to my knowledge. In all studies I've seen for L-Methylfolate for depression they never gene tested the subjects nor correlated it with their homocysteine levels.

It makes sense for an MTHFR level to correlate with depression and the studies show this. L-Methylfolate also shows it works for depression, but does this mean that L-Methylfolate is indicated with such a mutation for depression more so than other antidepressant treatments? Unknown.
 
Much to my surprise, there was a fairly large Deplin booth of all things at the APA annual meeting.

I’ve had a few patients on the inpatient unit at the university hospital come in on Deplin. It seems to be a relatively commonly-prescribed medication for the well-to-do. I haven’t been too impressed, but I can’t say I’ve ever actually started it on someone before.
 
whopper said:
I don't recommend Deplin because of the price. Methylpro sells it for about $25 a month. There's now brands on Amazon about the same price.
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You can get Deplin for $58 a month through an mail order pharmacy Brand Direct Health. Methylpro contains Extrafolate a form of Methylfolate often found in generic Methylfolates produced in China.

1mg of Extrafolate-S® equals approximately 0.76 mg of the active (6S)-5-MTHF (bioactive “free methylfolate”) that can be absorbed by your body. The significant difference between the ingredients in Extrafolate-S® and Metafolin® is the salt molecule’s form type. Basically, the Extrafolate-S® methylfolate is an amorphous salt form and the Metafolin® methylfolate is a crystalline salt form (Type I).

The difference between these salt form molecules is that a crystalline salt molecule is more stable, whereas an amorphous salt molecule is less stable. What does this mean to you or me? It means that if the amorphous ingredient is manufactured 12 months before use, it can lose up to 16%+ of its potency, compared to a crystalline form, which will only lose 1-2% of its potency.
Deplin contains Metafolin and is a Medical food FDA regulated with several studies. Methylpro is a supplement with no studies hence the $25 price.
 
Tmcc said:
Not a Rep...just take the product. A lot of confusion out there regarding L-Methylfolate as you can see from reading this thread.
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God c'mon man, you take extra care to include the registered trademark symbol 5 times in your post. No prior posts. Pushing us to take it. You work for the company in some capacity, and it ain't as the janitor.
 
Tmcc said:
Not a Rep...just take the product. A lot of confusion out there regarding L-Methylfolate as you can see from reading this thread.
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I'm not challenging the content of your post. I'm giving you a hard time because you have been a member since yesterday and have posted only on this thread and sound a lot like a pharma rep. I really don't care that much. Deplin is very much on the periphery of practice and not worth all this effort when I can be spending my time encouraging adherence to SSRI'S and therapy.
 
Shufflin said:
God c'mon man, you take extra care to include the registered trademark symbol 5 times in your post. No prior posts. Pushing us to take it. You work for the company in some capacity, and it ain't as the janitor.
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Cut and pasted from methyl-life. Not pushing you to do anything. Just sharing some information.
 
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wolfvgang22 said:
I'm not challenging the content of your post. I'm giving you a hard time because you have been a member since yesterday and have posted only on this thread and sound a lot like a pharma rep. I really don't care that much. Deplin is very much on the periphery of practice and not worth all this effort when I can be spending my time encouraging adherence to SSRI'S and therapy.
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Sounds good. Funny you say that folate can help with adherence!
 
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wolfvgang22 said:
I haven't said that.[/QUOTE

I know... you said you would rather encourage adherence to SSRI's ad therapy. I was just trying to say there is evidence Folate can improve adherence to SSRI's. Have a good one. Not trying to have a debate or push anything. My original post was to Whopper to just clarify the cost misconception. Big difference between $280 and $58/month.
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Updating from May '18 : Despite all the controversy around Deplin, I'm just one person, but I'm experiencing remission after 45 long years of chronic depression. I think this period of remission was made possible only because I already had the genetic test results in hand and was able to show the results to my doctors . I'd had genetic testing done for something unrelated and the two MTHFR mutations (677CT and 1298AC) were caught in the "trawl net" of the test result.

I didn't realize at the time that the MTHFR gene would have any significance for me until I read a blurb in an online pamphlet of a large, well-respected psychiatric practice in our major metro area. I went immediately to my internist, test -results (and a printout of the online pamphlet) in hand. She started me on a low dose of Deplin, and I continued treatment with a psychiatrist because I wanted to make sure I was on the right track and to have his objective help to monitor and oversee this whole thing.

Keep in mind I had treatment-resistant depression since age 12 and have tried at least 11 meds over that long time, with almost zero effect. I had many years of wonderful, productive therapy and practiced every healthy action possible, but still had depression until Deplin.

It's been a full year on Deplin (15mg), B6 and B12 now, with an average of 85-90% improvement for the year. Lately, it's been a 100% reduction. I am so grateful for all the good doctors and researchers who've made this happen. It's literally given me my life. I am hoping that more physicians will be willing to look at the "bottom of the decision-tree" possibility of L-methylfolate for patients who have similar stories of treatment-resistant depression.

If anyone is interested, the Chief of Psychiatry at UNC Health, Brian Andrew Farah, MD apparently thinks a lot of treatment for depression using L-methylfolate, although he uses Enlyte (also an rx) vs. Deplin. He's made a video about it on Youtube and on Enlyte's sight...
 
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