Annals of Clinical Psychiatry

, Volume 14, Issue 1, pp 33–38 | Cite as

Folinic Acid (Leucovorin) as an Adjunctive Treatment for SSRI-Refractory Depression

  • Jonathan E. Alpert
  • David Mischoulon
  • Grace E. F. Rubenstein
  • Kathryn Bottonari
  • Andrew A. Nierenberg
  • Maurizio Fava
Article
  • 87 Downloads

Abstract

Low folate is associated with poorer response to selective serotonin reuptake inhibitors (SSRIs) in majordepressive disorder (MDD). Folate supplementation in MDD has been studied in other settings with promising results. The objective of this study was to assess the efficacy of methylfolate as an adjunctive treatment among adults with MDD and inadequate response to an SSRI. Twenty-two adults (59% female; mean age 45.2 ± 11.0 years) with DSM-IV MDD, partial or nonresponse to an SSRI after at least 4 weeks of treatment, and a 17-item Hamilton Depression Rating Scale (HAM-D-17) score ≥ 12 were enrolled in this 8-week prospective open trial. Exclusion criteria included current use of anticonvulsants or psychotropics other than an SSRI, or B12 deficiency. Leucovorin (folinic acid), which is metabolized to methylfolate, was added to SSRIs at 15–30 mg/day. Folate levels rose from 28 ± 19 ng/mL to 301 ± 203 ng/mL (p < 0.001). HAM-D-17 scores among the 16 completers decreased from 19.1 ± 3.9 to 12.8 ± 7.0 (p < 0.01). However only 31% of completers and 27% of the intent-to-treat (ITT) sample achieved response (≥50% reduction in HAM-D-17 scores), and only 19% of completers and 18% of the ITT sample achieved remission (HAM-D-17 ≤ 7). Leucovorin appears to be modestly effective as an adjunct among SSRI-refractory depressed individuals with normal folate levels. The application of leucovorin as an adjunct in the setting of refractory depression deserves further study.

depression folate leucovorin augmentation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    Herbert V: Experimental nutritional folate deficiency in man. Trans Assoc Am Physicians 1961; 75:307-320Google Scholar
  2. 2.
    Carney MWP: Serum folate values in 423 psychiatric patients. BMJ 1967; 4:512-516Google Scholar
  3. 3.
    Reynolds EH, Preece JM, Bailey J, Coppen A: Folate defi-ciency in depressive illness. Br J Psychiatry 1970; 117:287-292Google Scholar
  4. 4.
    Botez MI, Botez T, Leveille J, Bielmann P, Cadotte M: Neurological correlates of folic acid deficiency: Facts and hypotheses. In: Botez MI, Reynolds EH, eds. Folic Acid in Neurology, Psychiatry and Internal Medicine. New York: Raven Press; 1979:435-461Google Scholar
  5. 5.
    Reynolds EH: Anticonvulsant drugs, folate metabolism and mental symptoms. In: Dam M, Gram L, Penry JK, eds. Advances in Epileptology. XIIth Epilepsy International Symposium. New York: Raven Press; 1981:621-625Google Scholar
  6. 6.
    Edeh J, Toone BK: Antiepileptic therapy, folate deficiency, and psychiatric morbidity:Ageneral practice survey. Epilepsia 1985; 26:434-440Google Scholar
  7. 7.
    Shorvon SD, Carney MWP, Chanarin I, Reynolds EH: The neuropsychiatry of megaloblastic anemia. BMJ 1980; 281:1036-1038Google Scholar
  8. 8.
    Bottiglieri T, Hyland K, Laundy M, Godfrey PSA, Carney MWP, Toone BK, Reynolds EH: Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med 1992; 22:871-876Google Scholar
  9. 9.
    Carney MWP, Chary TKN, Laundy M, Bottiglieri T, Chanarin I, Reynolds EH, Toone B: Red cell folate concentrations in psychiatric patients. J Affect Disord 1990; 19:207-213Google Scholar
  10. 10.
    Ghadirian AM, Anath J, Engelsmann F: Folic acid deficiency in depression. Psychosomatics 1980; 21:926-929Google Scholar
  11. 11.
    Wilkinson A, Anderson D, Abou-Saleh M, Wesson M, Blair JA, Farrar G, Leeming RJ: 5-Methyltetrahydrofolate level in the serum of depressed subjects and its relationship to the outcome of ECT. J Affect Disord 1994; 32:163-168Google Scholar
  12. 12.
    Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T: Folate, B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997; 154:426-428Google Scholar
  13. 13.
    Ordonez LA, Wurtman RJ: Folic acid deficiency and methyl group metabolism in rat brain: Effects of L-dopa. Arch Biochem Biophys 1974; 160:372-376Google Scholar
  14. 14.
    Bottiglieri T, Hyland K, Reynolds EH: The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994; 48(2):137-152Google Scholar
  15. 15.
    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(2):228-232Google Scholar
  16. 16.
    Bressa GM: S-Adenosyl-l-Methionine (SAMe) as antidepressant: Meta-analysis of clinical studies. Acta Neurol Scand Suppl 1994; 154:7-14Google Scholar
  17. 17.
    Spillman M, Fava M: S-adenosyl-methionine in psychiatric disorders: Historical perspective and current status. CNS Drugs 1996; 6:416-425Google Scholar
  18. 18.
    Wesson VA, Levitt AJ, Joffe RT: Change in folate status with antidepressant treatment. Psychiatry Res 1994; 53:313-322Google Scholar
  19. 19.
    Levitt AJ, Wesson VA, Joffe RT: Impact of suppression of thyroxine on folate status during acute antidepressant therapy. Psychiatry Res 1998; 79(2):123-129Google Scholar
  20. 20.
    Hutto BR: Folate and cobalamin in psychiatric illness. Compr Psychiatry 1997; 38:305-314Google Scholar
  21. 21.
    Young SN, Ghadirian M: Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 1989; 13:841-863Google Scholar
  22. 22.
    Crellin R, Bottiglieri T, Reynolds EH: Folates and psychiatric disorders: Clinical potential. Drugs 1993; 45:623-636Google Scholar
  23. 23.
    Levitt A, Joffee R: Folate, B12, and life course of depressive illness. Biol Psychiatry 1989; 25:867-872Google Scholar
  24. 24.
    Bell IR, Edman JS, Marby DW, Satlin A, Dreier T, Liptzin B, Cole JO:VitaminB12and folate status in acute geropsychiatric inpatients: Affective and cognitive characteristics of a vitamin nondeficient population. Biol Psychiatry 1990; 27:125-137Google Scholar
  25. 25.
    Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am1996; 119:176-200Google Scholar
  26. 26.
    Godfrey PSA, Toone BK, Carney MWP, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH: Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990; 336:392-395Google Scholar
  27. 27.
    Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH: The effect of folic acid fortification on plasma folate and total homocysteine concentrations. New Engl J Med 1999; 340:1449-1454Google Scholar
  28. 28.
    Coppen A, Bailey J: Enhancement of the antidepressant action of fluoxetine by folic acid: A randomised, placebo controlled trial. J Affect Disord 2000; 60:121-130Google Scholar
  29. 29.
    Passeri M, Ventura S, Abate G, Cucinotta D, LaGreca P: Oral 5-methyltetrahydrofolate (MTHF) in depression association with Senile Organic Mental Disorders (OMDs): A doubleblind, multicenter study vs. trazodone (TRZ). Eur J Clin Invest 1993; 21:24Google Scholar
  30. 30.
    Guaraldi G, Fava M, Mazzi F, LaGreca P: An open trial of methyltetrahydrofolate(MTHF)in elderly depressed patients. Ann Clin Psychiatry 1993; 5:101-106Google Scholar
  31. 31.
    Hamilton M: Arating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56-62Google Scholar
  32. 32.
    Guy W, ed.: ECDEU Assessment Manual for Psychopharmacology, revised [DHEW Pub. No. (ADM)76-338]. Rockville, MD: National Institute of Mental Health; 1976Google Scholar
  33. 33.
    Nierenberg AA, McLean NE, Alpert JE, Worthington JJ, Rosenbaum JF, Fava M: Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry 1995; 152:1500-1503Google Scholar

Copyright information

© American Academy of Clinical Psychiatrists 2002

Authors and Affiliations

  • Jonathan E. Alpert
    • 1
  • David Mischoulon
    • 1
  • Grace E. F. Rubenstein
    • 1
  • Kathryn Bottonari
    • 1
  • Andrew A. Nierenberg
    • 1
  • Maurizio Fava
    • 1
  1. 1.Depression Clinical and Research Program, Department of PsychiatryMassachusetts General HospitalBoston

Personalised recommendations