New insights into depression, medications, and L-methylfolate


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Several variables predict whether or not you are at risk for depression: genes (SNP in your MTHFR enzyme), ELA (early life adversity), obesity, and inflammation. These same factors predict that you will not respond well to antidepressants. What to do, what to do. First, consider whether you may have low central nervous system (CNS) folate levels (you likely do). Why this matters: L-methylfolate is a critical vitamin needed by your brain to transform amino acids (from dietary protein) into key brain chemicals (neurotransmitters) such as serotonin, dopamine, norepinephrine, and acetylcholine. If your brain folate levels are low, you cannot make sufficient neurotransmitters. If so, not even the best antidepressant will work optimally. You may get better, but will you get well?
Find out what the signs (fatigue, inflammation, pain, being overweight, and other sickness behaviors), causes (diet, inflammation, environmental toxins, lifestyle, genetic mutations), and risk factors (age, depression, medications, other medical conditions) for low folate.
Won’t the folic acid in your current multi-vitamin or B vitamin complex take care of this? Probably not. For many people with depression, they cannot convert this synthetic form of folate (or for that matter, they cannot convert dietary folate from green leafy vegetables) into the only form of folate – L-methylfolate - that can get through the blood-brain-barrier (BBB) and into their brains. You may be one of those.
For that reason, I (Dr. Dave) only use that specific form of folate: L-methylfolate. But be careful, not all L- methyfolate is the same. The two that I trust and use the most often, depending on your insurance coverage and whether I’m your personal physician or your health consultant, are Deplin and our own IP Formula’s Methyl Esssentials.
Deplin, a medical food, requires a prescription from your clinician, and if not covered by your insurance may make it unaffordable. It is of high quality made by a superb company supported by topnotch sales and marketing team. You cannot buy it directly, however.
I also trust our over-the-counter form of L-methyfolate: Methyl Essentials. It too is of very high quality, is competitively priced, is ideally dosed, and combines with it the most bio-active form of Vitamin B12 (methylcobalamin). This is particularly important in our elder patients and clients. Here are the specs on Methyl Essentials:
IP Formulas Methyl Essentials L 5 MTHF 6.5 mg & B12 2mg contains the most bio active form of L 5-Methyl folate and methylcobalamin-vitamin B12 and is the only form that crosses the blood brain barrier.
Increases production of dopamine, melatonin, serotonin, and DNA
It can be ordered online here:

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New insights into depression, medications, and L-methylfolate

  1. 1. Image repined from You’re are on an antidepressant and it puzzles you that YOU ARE STILL NOT WELL. You’re Not Alone
  2. 2. Significant Individual Differences in 20 Subjects Treated With An Antidepressant: Or, in Other Words, It’s a Crapshoot. Depression Severity (MADRS) 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 Time From Treatment Start (weeks) 10 11 12 MADRS = Montgomery-Asberg Depression Rating Scale. Uher R. Harv Rev Psychiatry. 2011;19(3):109-124 .
  3. 3. STAR*D Study: 2/3 of Patients Remained Symptomataic Following Antidepressant Treatment ~67% Mild symptoms ~28% Remission ~33% 8 Moderate symptoms ~23% Severe symptoms ~12% Very severe symptoms ~4% Percent of Patients 7 6 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Depressive Symptoms (QIDS-SR score) After up to 12 Weeks of Antidepressant Treatment QIDS-SR, Quick Inventory of Depressive Symptomatology Self-Report; STAR*D, Sequenced Treatment Alternatives to Relieve Depression. Trivedi MH et al. Am J Psychiatry. 2006;163(1):28-40.
  4. 4. Residual Symptoms and the Risk of Relapse in Major Depressive Disorder % of Patients Relapsing Patients without residual symptoms (n=17) 25% Patients with residual symptoms (n=40) 75% Paykel ES et al. Psychol Med. 1995;25(6):1171-1180.
  5. 5. Residual Symptoms May Hasten Relapse in Patients With MDD Time (Years) to Relapse Based on # of Residual Symptoms Median # of weeks well of patients who recovered with no residual symptoms was 3.4 times greater than that of patients who recovered having one or more mild symptoms. Recovery with no symptoms 4.4 Recovery with 1+ mild symptoms 1.3 0 1 2 3 4 5 Judd LL et al. J Affect Disord. 1998;50(2-3):97-108.
  6. 6. OK. So You Are Still Depressed! Image repinned from Increase dose? Switch Medication? Add A 2nd Medication? Change Clinicians? Go Natural? What Should You Do?
  7. 7. First, Think Inflammation People with evidence of increased inflammatory activity prior to treatment have been reported to be less responsive to antidepressants, lithium, or acute sleep deprivation. Moreover, people with a history of nonresponse to antidepressants have been found to demonstrate increased plasma concentrations of IL-6 and acute phase reactants. Miller AH, Maletic V, Raison CL.. Biol Psychiatry. 2009 May 1;65(9):732-41
  8. 8. In other words, if you are inflamed, you are less likely to respond to anti-depressant medications, and if you haven’t responded to your antidepressant, you are more likely to be inflamed!
  9. 9. Other Signs You May be Inflamed:
  10. 10. So What If You Are Inflamed? Inflammation Decreases the rate at which you make new neurotransmitters Low Serotonin Low Dopamine Low Norepinephrine Low Acetylcholine Inflammation Is associated with low levels of CNS folate. All of which leads to: Increases the rate at which you burn through your brain chemicals: neurotransmitters Inflammation (And that keeps you depressed!)
  11. 11. What Else Causes Low Folate? • Overweight • Elevated hs-CRP (a measure of systemic inflammation • Age (especially > 70) • Medications such as Lamictal, Tegretol, Depakote, methotrexate, Prozac, metformin, birth control pills, niacin • Excess alcohol/smoking and poor nutrition • Genetics
  12. 12. Genetics? Get Tested Here! T/T Polymorphism 30% C/C Normal 30% C/T Polymorphism 56% • If you suffer from depression, you have a 70% chance of having a genetic in-born error impairing your ability to make L-methylfolate from dietary folate (green leafy vegetables) or from the synthetic folic acid that is in your multivitamin. • If you have this genetic error (formally referred to as a single nucleotide polymorphism (SNP) of the enzyme – MTHFR – that converts dietary folate into L-methylfolate) then you will have low levels of Lmethylfolate in your central nervous system (CNS). • If you have low CNS L-methylfolate levels you will have low levels of the key neurotransmitters serotonin, norepinephrine, and dopamine. 1. Kelly CB et al. J Psychopharmacol. 2004;18(4):567-71. 2. Bottiglieri T et al. J Neurol Neurosurg Psychiatry. 2000;69:228-32. 3. Surtees R, Heales S, & Bowron. Clinical Science. 1994;86:697-702.
  13. 13. Second, If Inflamed or Overweight:
  14. 14. Why L-methylfolate ? Because it is Seven Times More Bioavailable Than Synthetic Folic Acid L-methylfolate vs. Synthetic Folic Acid DHF Reductase Dihydrofolate (Dietary Folate) DHF Reductase Tetrahydrofolate 10-formyl-THF MTHFD1 Polymorphism 5, 10 Methenyl THF 5, 10 Methylene THF L-methylfolate MTHFR C→T Polymorphism L-methylfolate Willems FF et al. Pharmacokinetic Study on the Utilisation of 5-methyltetrahydrofolate and Folic Acid in Patients with Coronary Artery Disease. Br J Pharmacol. 2004;141(5):825-30.
  15. 15. Because L-methylfolate is the only form of folate that crosses the blood brain barrier (BBB) and is thereby the only form of folate that your brain can use to make neurotransmitters. And
  16. 16. See. I told you so. XPH2 Inflammation and Oxidative Stress phe tyr BH2 L-methylfolate BH4 tryp arg PAH Tyr TH L-DOPA TPH 5-HTP NOS NO Haroon E et al. Neuropsychopharmacology. 2012 Jan;37(1):137-62.
  17. 17. When To Take L-Methylfolate • When to consider starting L-methylfolate: • Mild to moderate depressive symptoms for those who don’t want medications; • • At initiation of new antidepressant therapy Inadequate response to antidepressant therapy • • • Before raising/maximizing does Before switching to a different agent As a first-line augmentation/combination strategy
  18. 18. Methyl Essentials by IP Formulas