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SAMe and Folate
Question:
"I keep hearing about SAMe and folate as an ‘add-on’ treatment to standard antidepressant treatment. Does this make sense pharmacologically, and what is the evidence for their effectiveness?"
Rakesh Jain, MD, MPH:
You are right on many counts here. There has recently been a significant uptick in the conversation regarding SAMe and folate as “add-on” or augmentation therapies to suboptimum response to antidepressants. This conversation has been provoked by three facts: 1) we clinicians now have high quality, randomized studies with these two agents to examine for ourselves; 2) word of mouth regarding the effectiveness of these add-on agents is increasing clinician interest; and 3) the need for add-on therapy in depression care is so dire that clinicians’ ears perk up anytime an option to help these unfortunate patients is being discussed.
But dire need alone cannot drive our decision to accept every “flavor of the month” augmentation therapy. We don’t need fly by night options, popular one day and gone bust the next. We need well-studied and proven therapies. We need proof and scientific rationale for such therapies. So, let’s examine the scientific rationale then we will turn to clinical data.
Scientific Rationale
Let’s return to our roots or to be more precise, let’s go back to first-year medical school where we learned how neurotransmitters are “born.” The neurotransmitters thought to play the biggest roles in depression—serotonin, norepinephrine, and dopamine—are all generated via pathways that start with amino acids and end with the neurotransmitters. 1,2 So far, so good, right? But hold on just a minute – how in the world is this process controlled and modulated? Are we all able to make exactly the same amounts of neurotransmitters? Here’s where we learn further about the complexities of neurotransmitter generation.
Neurotransmitter genesis of all three of these neurotransmitters are controlled by enzymes that are often rate limiting, and they tightly control the rate of conversion of amino acids into neurotransmitters. 3-6 Let’s also not forget that the activity of these enzymes is controlled by our genotype for that enzyme; some of us have good activity of these enzymes, and some of us don’t. 3 Let’s also remember there are multiple cofactors needed in this process. In other words, enzymes are not sufficient by themselves to create the neurotransmitter; cofactors play a central and critical role in creating these vitally needed neurotransmitters. 1
What do these cofactors do?
These cofactors (SAMe and folate are cofactors) are considered to be “methyl donors.” This donation of a methyl group by these cofactors is needed before a neurotransmitter is generated. This donation of the methyl group ( methyl is CH3 ) is amazingly important in the one carbon metabolism cycle of neurotransmitter synthesis. 1,7
I hope I haven’t lost you in all this technical jibber-jabber! But this is important information for the modern day clinician.
Let’s summarize what we have learned so far:
- Neurotransmitters such as serotonin, norepinephrine, and dopamine are critical for mood regulation and depression to occur in part because of impairment in these neurotransmitters’ functioning.
- The pathway to neurotransmitter synthesis requires multiple things – not the least of them are enzymes and cofactors.
- Impairment in the functioning of these enzymes or cofactors will result in neurotransmitter generation impairment.
- SAMe and folate are important cofactors in neurotransmitter generation pathways.
To continue this fascinating story, let’s find out a little more about the cofactors SAMe and folate. What are they? Where do they come from? SAMe stands for s-adenosylmethionine. Yep, quite a mouthful, hence it might be easier to just call it SAMe, right?! The parent of SAMe is the amino acid methionine. SAMe is famous for being perhaps the top methyl donor in the process that creates the neurotransmitters. Once SAMe donates its methyl group, it becomes homocysteine. Homocysteine, which if it accumulates can cause adverse health effects, 4,6,8,9 needs remethylation in order to become SAMe again – and here is where folate steps in.
Turning our attention to folate, let’s remember that the active form of folate is 5-MTHF (5-methyltetrahydrofolate) – another mouthful of a word! So let’s just call it MTHF or L-methylfolate. Dietary folate and supplemental folate need conversion into L-methylfolate before they can cross the blood brain barrier and participate in the neurotransmitter synthesis. This is a tricky issue, as genetic polymorphisms for the creation of L-methylfolate are unusually common (and appear to be even more common in individuals with major depression). There is a commercially available form of L-methylfolate, which means one can bypass all the various tricky enzymatic steps by taking the active form of folate. More on this later.
At least theoretically you can see what these two substances—SAMe and folate—are of such interest to those of us who take care of people who suffer from depression, right? But at the end of day, we are less interested in these theories and more interested in finding out what happens when the “rubber meets the road” – that is, what do the clinical studies show?
Clinical Studies
SAMe has had a long and storied history in psychopharmacological research, but many older studies suffered from the challenge of small sample sizes and differing methodologies; however, the overall data suggests that SAMe is an effective agent. 10-16 Additionally, a recent, very well conducted study by Papakostas and colleagues has created quite a buzz. 17 This study showed SAMe to be an effective and well-tolerated add-on agent when SSRI alone was not fully effective. The response rates were double in the SAMe arm as compared to placebo. Impressive indeed.
In regards to folate, similar issues apply. Earlier studies dating back to 1990 and even earlier appear to show a pretty clear signal of benefit, but not until recently have we had the kind of evidence needed to convince us clinicians to give folate a second look. 2,18-21 Clinical studies over the last several decades have offered us intriguing information about folate as a potential antidepressant. 8,22-27 We now have two studies, conducted not with folic acid, which requires a large number of enzymatic changes before it becomes the active, blood-barrier crossing form of folate – L-methylfolate, 1 but with L-methylfolate itself. Ginsberg and colleagues demonstrated in an open-label, naturalized, single center study that L-methyfolate when added to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) at the beginning of therapy was more effective than only using an SSRI or SNRI. 28 Almost immediately after that, Papakostas and colleagues presented a poster at the European Congress of Psychiatry of an extremely well-conducted blinded, randomized study of L-methylfolate augmentation to SSRI nonresponders and showing a greater than twofold increase in response rates. 29
In response to your question, I will say this – the emerging basic science and clinical studies literature is supportive of considering SAMe and folate as viable antidepressant augmentation options. There is reason for caution too. We have a growing, but still limited database, and long-term studies for efficacy and safety are very limited. Excessive exuberance regarding these two options is not yet warranted. Certainly we are in need of more studies, and I suspect we will see a number of them in the next few months to years. Keep your eyes peeled for them. The needs of our antidepressant-treated, but suboptimally responsive, patients are significant and we welcome all effective options to the table.
—Rakesh Jain, MD, MPH
References
- Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Alt Med Rev. 2008;13(3):216-226.
- Abou-Saleh MT, Coppen A. The biology of folate in depression: implications for nutritional hypotheses of the psychoses. J Psychiatr Res. 1986;20(2):91-101.
- Bjelland I, Tell GS, Vollset SE, Refsum M, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618-626.
- Bottiglieri T. Homocysteine and folate metabolism in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(7):1103-1112.
- Bottiglieri T, Hyland K, Laundy M, et al. Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med. 1992;22(4):871-876.
- Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69(2):228-232.
- Morris DW, Trivedi MH, Rush AJ. Folate and unipolar depression. J Altern Complement Med. 2008;14(3):277-285.
- Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004;65(8):1090-1095.
- Tiemeier H, van Tuijl HR, Hofman A, et al. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry. 2002;159(12):2099-2101.
- Andreoli VM, Maffei F, Tonon GC. S-adenosyl-L-methionine (SAMe) blood levels in schizophrenia and depression. Monogr Gesamtgeb Psychiatr Psychiatry Ser. 1978;18:147-150.
- Baime MJ. Review: SAMe reduces symptoms in depression, osteoarthritis, and liver disease. ACP J Club. 2003;139(1):20.
- Genedani S, Saltini S, Benelli A, Filaferro M, Bertolini A. Influence of SAMe on the modifications of brain polyamine levels in an animal model of depression. Neuroreport. 2001;12(18):3939-3942.
- Janicak PG, Lipinski J, Davis JM, Altman E, Sharma RP. Parenteral S-adenosyl-methionine (SAMe) in depression: literature review and preliminary data. Psychopharmacol Bull. 1989;25(2):238-242.
- Ramos L. SAMe as a supplement: can it really help treat depression and arthritis? J Am Diet Assoc. 2000;100(4):414.
- Williams AL, Girard C, Jui D, Sabina A, Katz DL. S-adenosylmethionine (SAMe) as treatment for depression: a systematic review. Clin Invest Med. 2005;28(3):132-139.
- Young SN. Are SAMe and 5-HTP safe and effective treatments for depression? J Psychiatry Neurosci. 2003;28(6):471.
- Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.
- Abou-Saleh MT, Coppen A. Serum and red blood cell folate in depression. Acta Psychiatr Scand. 1989;80(1):78-82.
- Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55(5):145-149.
- Alpert JE, Mischoulon D, Nierenberg AA, Fava M. Nutrition and depression: focus on folate. Nutrition. 2000;16(7-8):544-546.
- Bjelland I, Ueland PM, Vollset SE. Folate and depression. Psychother Psychosom. 2003;72(2):59-60.
- Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry. 2009;70(Suppl 5):12-17.
- Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health. 2007;61(7):631-637.
- Mischoulon D, Raab MF. The role of folate in depression and dementia. J Clin Psychiatry. 2007;68(Suppl 10):28-33.
- Miyake Y, Sasaki S, Tanaka K, et al. Dietary folate and vitamins B12, B6, and B2 intake and the risk of postpartum depression in Japan: the Osaka Maternal and Child Health Study. J Affect Disord. 2006;96(1-2):133-138.
- Morris MS, Fava M, Jacques PF, Selhub J, Rosenberg IH. Depression and folate status in the US Population. Psychother Psychosom. 2003;72(2):80-87.
- Roberts SH, Bedson E, Hughes D, et al. Folate augmentation of treatment - evaluation for depression (FolATED): protocol of a randomised controlled trial. BMC Psychiatry. 2007;7:65.
- Ginsberg LD, Oubre AY, Daoud YA. L-methylfolate plus SSRI or SNRI from treatment initiation compared to SSRI or SNRI monotherapy in a major depressive disorder. Innov Clin Neurosci. 2011;8(1):19-28.
- Papakostas GI, Shelton RC, Zajecka J, et al. L-methylfolate as adjunctive therapy for selective serotonin reuptake inhibitor-resistant major depressive disorder: results of two randomized, double-blind, parallel-sequential trials. Poster presented at: European Congress of Psychiatry; March 14, 2011; Vienna, Austria.