Serum Folate, Vitamin B₁₂, and Homocysteine in Major Depressive Disorder, Part 1: Predictors of Clinical Response in Fluoxetine-Resistant Depression

George I. Papakostas, M.D.; Timothy Petersen, Ph.D.; David Mischoulon, M.D., Ph.D.; Julie L. Ryan, B.A.; Andrew A. Nierenberg, M.D.; Teodoro Bottiglieri, Ph.D.; Jerrold F. Rosenbaum, M.D.; Jonathan E. Alpert, M.D., Ph.D.; and Maurizio Fava, M.D.

Objective: In the present study, we assessed the relationship between serum folate, vitamin B₁₂, and homocysteine levels and clinical response in patients with major depressive disorder (MDD) who had previously failed to respond to open treatment with fluoxetine 20 mg/day and were enrolled in a 4-week, double-blind trial of either (1) fluoxetine dose increase, (2) lithium augmentation of fluoxetine, or (3) desipramine augmentation of fluoxetine.

Method: Fifty-five outpatients (mean +/- SD age = 41.7 +/- 10.6 years; 50.9% women) with MDD as assessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had serum folate, vitamin B₁₂, and homocysteine measurements completed at baseline (prior to fluoxetine treatment initiation). Folate levels were classified as either low (<= 2.5 ng/mL) or normal. Vitamin B₁₂ levels were classified as either low (<= 200 pg/mL) or normal. Homocysteine levels were classified as either elevated (>= 13.2 mmol/L) or normal. With the use of a logistic regression, we then assessed the relationship between (1) low or normal folate levels, (2) normal or low B₁₂ levels, and (3) elevated or normal homocysteine levels and clinical response to double-blind treatment. The study was conducted from November 1992 to January 1999.

Results: Low serum folate levels (chi² = 3.626, p = .04), but not elevated homocysteine (p > .05) or low vitamin B₁₂ levels (p > .05), were associated with poorer response to treatment. The response rates for patients with (N = 14) and without (N = 38) low folate levels were 7.1% versus 44.7%, respectively.

Conclusion: Low serum folate levels were found to be associated with further treatment resistance among patients with fluoxetine-resistant MDD.

(J Clin Psychiatry 2004;65:1090-1095)

Received Sept. 16, 2003; accepted Feb. 9, 2004. From the Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston (Drs. Papakostas, Petersen, Mischoulon, Nierenberg, Rosenbaum, Alpert, and Fava and Ms. Ryan), and the Institute for Metabolic Diseases, Baylor University School of Medicine, Waco, Tex. (Dr. Bottiglieri).

Supported by National Institute of Mental Health grant #R01-MH-48-483-05 (Dr. Fava), the American College of Neuropsychopharmacology/GlaxoSmithKline Fellowship in Clinical Neuropsychopharmacology (Dr. Papakostas), and the Harvard Medical School/Kaplen Fellowship in Depression Research (Dr. Papakostas).

Financial disclosure appears at the end of this article.

Corresponding author and reprints: George I. Papakostas, M.D., Massachusetts General Hospital, Depression Clinical and Research Program, 15 Parkman Street, WACC 812, Boston, MA 02114(e-mail: gpapakostas@partners.org).