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Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent

Published online by Cambridge University Press:  07 November 2014

Stephen M. Stahl
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Extract

Folate deficiency may increase the risk of depression and reduce the action of antidepressants. Individuals with an inherited polymorphism that reduces the efficiency of folate formation may be at high risk for folate deficiency and for major depression. Antidepressant effects have been reported when antidepressants are augmented with folic acid, folinic acid, or the centrally active L-methylfolate (known formally as (6(S)-5-methyltetrahydrofolate [MTHF]), particularly in depressed patients with folate deficiency whose major depressive episodes have failed to respond to antidepressants. The putative mechanism of action of MTHF as an augmenting agent to antidepressants is that it acts as a trimonoamine modulator (TMM), enhancing the synthesis of the three monoamines: dopamine (DA), norepinephrine (NE), and serotonin (5-HT), resulting in a boost to the efficacy of antidepressants.

Type
Trends in Psychopharmacology
Information
CNS Spectrums , Volume 12 , Issue 10 , October 2007 , pp. 739 - 744
Copyright
Copyright © Cambridge University Press 2007

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References

REFERENCES

1.Coppen, A, Bolander-Gouaille, C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005;19:59–65.CrossRefGoogle ScholarPubMed
2.Papakostas, GI, Petersen, T, Lebowitz, BD, et al.The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsychopharmacol. 2005;8:523–528.CrossRefGoogle ScholarPubMed
3.Tolmunen, T, Voutilainen, S, Hintikka, J, et al.Dietary folate and depressive symptoms are associated in middle-aged Finnish men. J Nutr. 2003;133:3233–3236.CrossRefGoogle ScholarPubMed
4.Alpert, M, Silva, RR, Pouget, ER. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J Clin Psychopharmacol. 2003;23:309–313.CrossRefGoogle ScholarPubMed
5.Morris, MS, Fava, M, Jacques, PF, Selhub, J, Rosenberg, IH. Depression and folate status in the US Population. Psychother Psychosom. 2003;72:80–87.CrossRefGoogle ScholarPubMed
6.Bottiglieri, T, Laundy, M, Crellin, R, Toone, BK, Carney, MW, Reynolds, EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69:228–232.CrossRefGoogle ScholarPubMed
7.Alpert, JE, Fava, M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55:145–149.CrossRefGoogle ScholarPubMed
8.Fava, M, Borus, JS, Alpert, JE, Nierenberg, AA, Rosenbaum, JF, Bottiglieri, T. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry. 1997;154:426–428.Google ScholarPubMed
9.Wesson, VA, Levitt, JA, Joffe, RT. Change in folate status with antidepressant treatment. Psychiatry Res. 1994;53:313–322.CrossRefGoogle ScholarPubMed
10.Coppen, A, Swade, C, Jones, SA, Armstrong, RA, Blair, JA, Leeming, RJ. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord. 1989;16:103–107.CrossRefGoogle ScholarPubMed
11.Abou-Saleh, MT, Coppen, A. Serum and red blood cell folate in depression. Acta Psychiatr Scand. 1989;80:78–82.CrossRefGoogle ScholarPubMed
12.Abou-Saleh, MT, Coppen, A. The biology of folate in depression: implications for nutritional hypotheses of the psychoses. J Psychiatr Res. 1986;20:91–101.CrossRefGoogle ScholarPubMed
13.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;65:1090–1095.CrossRefGoogle ScholarPubMed
14.Papakostas, GI, Petersen, T, Mischoulon, D, et al.Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry. 2004;65:1096–1098.CrossRefGoogle ScholarPubMed
15.Gilbody, S, Lewis, S, Lightfoot, T. Methylene tetrahydro folate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2006;165:1–13.CrossRefGoogle Scholar
16.Coppen, A, Bailey, J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121–130.CrossRefGoogle ScholarPubMed
17.Coppen, A, Chaudhry, C, Swade, C. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986;10:9–13.CrossRefGoogle ScholarPubMed
18.Passeri, M, Cucinotta, D, Abate, G, et al.Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano). 1993;5:63–71.Google ScholarPubMed
19.Carney, MW, Chary, TK, Laundy, M. Red cell folate concentrations in psychiatric patients. J Affect Disord. 1990;19:207–213.CrossRefGoogle ScholarPubMed
20.Reynolds, EH, Preece, JM, Bailey, J, Coppen, A. Folate deficiency in depressive illness. Br J Psychiatry. 1970;117:287–292.CrossRefGoogle ScholarPubMed
21.Lerner, V, Kanevsky, M, Dwolatzky, T, Rouach, T, Kamin, R, Miodownik, C. Vitamin B12 and folate serum levels in newly admitted psychiatric patients. Clin Nutr. 2006;25:60–67.CrossRefGoogle ScholarPubMed
22.Sachdev, PS, Parslow, RA, Lux, O, et al.Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med. 2005;35:529–538.CrossRefGoogle Scholar
23.Levitt, AJ, Joffe, RT. Folate, B12, and life course of depressive illness. Biol Psychiatry. 1989;25:867–872.CrossRefGoogle ScholarPubMed
24.Wesson, VA, Levitt, AJ, Joffe, RT. Change in folate status with antidepressant treatment. Psychiatry Res. 1994;53:313–322.CrossRefGoogle ScholarPubMed
25.Wilkinson, A, Anderson, D, Abou-Saleh, M, et al.5-Methyltetrahydrofolate level in the serum of depressed subjects and its relationship to the outcome of ECT. J Affect Disord. 1994;32:163–168.CrossRefGoogle Scholar
26.Kelly, CB, McDonnell, AP, Johnston, TG, et al.The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004;18:567–571.CrossRefGoogle ScholarPubMed
27.Lewis, SJ, Lawlor, DA, Davey Smith, G, et al.The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis. Mol Psychiatry. 2006;11:352–360.CrossRefGoogle ScholarPubMed
28.Arinami, T, Yamada, N, Yamakawa-Kobayashi, K, et al.Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997;74:526–528.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
29.Gilbody, S, Lightfoot, T, Shelton, T. Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health. 2007;61:631–637.CrossRefGoogle ScholarPubMed
30.Blair, JA, Barford, PA, Morar, C, et al.Tetrahydrobiopterin metabolism in depression. Lancet. 1984;2:163.CrossRefGoogle ScholarPubMed
31.Alpert, JE, Mischoulon, D, Rubenstein, GE, Bottonari, K, Nierenberg, AA, Fava, M. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14:33–38.CrossRefGoogle ScholarPubMed
32.Guaraldi, GP, Fava, M, Mazzi, F, la Greca, P. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry. 1993;5:101–105.CrossRefGoogle ScholarPubMed
33.Godfrey, PS, Toone, BK, Carney, MW, et al.Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336:392–395.CrossRefGoogle ScholarPubMed
34.Reynolds, EH, Crellin, R, Bottiglieri, T, Laundy, M, Toone, BK, Carney, M. Methylfolate as monotherapy in depression: a pilot randomized controlled trial. Abstract presented at: the Annual Meeting of the Royal College of Psychiatrists. July 24-27, 1992: Edinburgh, UK.Google Scholar
35.Di Palma, C, Urani, R, Agricola, R, Giorgetti, V, Dalla Verde, G. Is Methylfolate effective in relieving major depression in chronic alcoholics? A hypothesis of treatment. Curr Ther Res. 1994;55:559–568.CrossRefGoogle Scholar
36.Meller, E, Friedhoff, AJ. 5-methyltetrahydrofolate and metabolism of biogenic amines; In: Botez, MI, Reynolds, EH, eds. Folic Acid in Neurology, Psychiatry and Internal Medicine. New York, NY: Raven Press; 1979:157–164.Google Scholar
37.Bottiglieri, T, Hyland, K, Laundry, M, et al.Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med. 1992;22:871–876.CrossRefGoogle ScholarPubMed
38.Ponzone, A, Spada, M, Ferraris, S, Dianzani, I, deSanctis, L. Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev. 2004;24:127–150.CrossRefGoogle ScholarPubMed
39.Goldstein, DS, Hahn, S-H, Holmes, C, et al.Monoaminergic effects of folinic acid, I-dopa and 5-hydroxytryptophan in dihydropteridine reductase deficiency. J Neurochem. 1995;64:2810–2813.CrossRefGoogle Scholar
40.Lucock, MD, Green, M, Levene, MI. Methylfolate modulates potassium evoked neuro-secretion: evidence for a role at the pteridine cofactor level of tyrosine 3-hydroxylase. Neurochem Res. 1995;20:727–736.CrossRefGoogle ScholarPubMed
41.Niederwieser, A. Inborn errors of Pterin metabolism. In: Botez, MI, Reynolds, EH, eds. Folic Acid in Neurology, Psychiatry and Internal Medicine. New York, NY: Raven Press; 1979:349–384.Google Scholar
42.Turner, AJ. The relationship between brain folate and monoamine metabolism. In: Botez, MI, Reynolds, EH, eds. Folic Acid in Neurology, Psychiatry and Internal Medicine. New York, NY: Raven Press; 1979:165–177.Google Scholar
43.Hamon, CGB, Blair, JA, Barford, PA. The effect of tetrahydrofolate on tetrahydrobipterin metabolism. J Ment Defic Res. 1986;30:179–183.Google Scholar
44.Matthews, RG, Kaufman, S. Characterization of the dihydropterin reductase activity of pig liver methylenetetrahydrofolate reductase. J Biol Chem. 1980;255:6014–6017.CrossRefGoogle ScholarPubMed
45.Vanoni, MA, Ballou, DP, Matthews, RG. Methylenetetrahydrofolate reductase. Steady state and rapid reaction studies on the NADPH-methylenetetrahydrofolate, NADPH-menadione, and methyltetrahydrofolate-menadione oxidoreductase activities of the enzyme. J Biol Chem. 1983;258:11510–11514.CrossRefGoogle ScholarPubMed
46.Farrar, G, Blair, JA. Pterins in depression: a modified monoamine hypothesis. In: Copeland, JR, Abou-Saleh, MT, Blazer, DG, eds. Principles and Practice of Geriatric Psychiatry. Hoboken, NJ: John Wiley and Sons; 1994:543–546.Google Scholar
47.Paul, RT, McDonnell, AP, Kelly, CB. Folic acid: neurochemistry, metabolism and relationship to depression. Hum Psychopharmacol. 2004;19:477–488.CrossRefGoogle ScholarPubMed
48.Stahl, SM. Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; In press.Google Scholar
49.Willems, FF, Boers, GH, Blom, HJ, Aengevaeren, WR, Verheugt, FW. Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol. 2004;141:825–830.CrossRefGoogle Scholar
50.Smith, I, Hyland, K, Kendall, B. Clinical role of pteridine therapy in tetrahydrobiopterin deficiency. J Inherit Metab Dis. 1985;8(suppl 1):39–45.CrossRefGoogle ScholarPubMed
51.Wu, D, Pardridge, WM. Blood-brain barrier transport of reduced folic acid. Pharm Res. 1999;16:415–419.CrossRefGoogle ScholarPubMed
52.Spector, R, Lorenzo, AV. Folate transport in the central nervous system. Am J Physiol. 1975;229:777–782.CrossRefGoogle ScholarPubMed
53.Scott, JM, Weir, DG. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet 1981;2:337–340.CrossRefGoogle Scholar
54.Kelly, P, McPartlin, J, Goggins, M, Weir, D, Scott, JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997;65:1790–1795.CrossRefGoogle ScholarPubMed
55.Morris, MS, Jacques, PF, Rosenberg, IH, Selhub, J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85:193–200.CrossRefGoogle ScholarPubMed
56.Akoglu, B, Schrott, M, Bolouri, H, et al.The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo-controlled study. Eur J Clin Nutr. In press.Google Scholar
57.Food and Drug Administration/Center for Food Safety and Applied Nutrition. Food Safety and Applied Nutrition, Medical Foods. Available at: http://www.cfsan.fda.gov/~dms/medfguid.html. Accessed September 13, 2007.Google Scholar
58.Mischoulon, D, Fava, M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002;76(suppl):1158S–1161S.CrossRefGoogle ScholarPubMed
59.Bottiglieri, T. S-Adenosl-L-methionine (SAMe): from the bench to the bedside – molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002:76(suppl):1151S–1157S.CrossRefGoogle Scholar
60.Vafai, SB, Stock, JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's disease. FEBS Lett. 2002;518:1–4.CrossRefGoogle ScholarPubMed
61.Mann, SP, Hill, MW. Activation and inactivation of striatal tyrosine hydroxylase: the effects of pH, ATP, cyclic AMP, S-adenosylmethionine and S-adenosylhomocysteine. Biochem Pharmacol. 1983;32:3369–3374.CrossRefGoogle ScholarPubMed
62.Curcio, M, Catto, E, Stramentinoli, G, Algeri, S. Effect of S-adenosyl-l-methionine on serotonin metabolism in rat brain. Prog Neuropsychopharmacol. 1978;2:65–71.CrossRefGoogle ScholarPubMed
63.Ruck, A, Kramer, S, Metz, J, Brennan, MJ. Methyltetrahydrofolate is a potent and selective agonist for kainic acid receptors. Nature. 1980;287:852–853.CrossRefGoogle ScholarPubMed
64.Bauman, AL, Apparsundaram, S, Ramamoorthy, S, Wadzinski, BE, Vaughan, RA, Blakely, RD. Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A. J Neurosci. 2000;20:7571–7578.CrossRefGoogle ScholarPubMed
65.Ramamoorthy, S, Gioivanetti, E, Qian, Y, Blakely, RD. Phosphorylation and regulation of antidepressant-sensitive serotonin transporters. J Biol Chem. 1998;273:2458–2466.CrossRefGoogle ScholarPubMed