The International Journal of Neuropsychopharmacology

The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine

George I. Papakostas a1c1, Timothy Petersen a1, Barry D. Lebowitz a2, David Mischoulon a1, Julie L. Ryan a1, Andrew A. Nierenberg a1, Teodoro Bottiglieri a3, Jonathan E. Alpert a1, Jerrold F. Rosenbaum a1 and Maurizio Fava a1
a1 Depression Clinical and Research Program, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA
a2 Adult and Geriatric Treatment and Preventive Interventions Research Branch, NIMH, Bethesda, MD, USA
a3 Institute for Metabolic Diseases, Baylor University School of Medicine, Waco, TX, USA

Article author query
papakostas gi   [PubMed][Google Scholar] 
petersen t   [PubMed][Google Scholar] 
lebowitz bd   [PubMed][Google Scholar] 
mischoulon d   [PubMed][Google Scholar] 
ryan jl   [PubMed][Google Scholar] 
nierenberg aa   [PubMed][Google Scholar] 
bottiglieri t   [PubMed][Google Scholar] 
alpert je   [PubMed][Google Scholar] 
rosenbaum jf   [PubMed][Google Scholar] 
fava m   [PubMed][Google Scholar] 


The objective of the present study was to examine the relationship between serum folate, vitamin B12, and homocysteine levels and the timing of clinical improvement to fluoxetine in major depressive disorder (MDD) patients. A total of 110 outpatients with MDD who responded to an 8-wk trial of fluoxetine had serum folate, B12, and homocysteine measurements at baseline (prior to fluoxetine initiation). Onset of clinical improvement was defined as a 30% decrease in Hamilton Depression Scale scores that led to a 50% decrease by week 8. Patients with low folate levels ([less-than-or-eq, slant]2.5 ng/ml) were more likely to experience a later onset of clinical improvement than eufolatemic patients (p=0.0028). B12 and homocysteine level status did not predict time to clinical improvement (p>0.05). In conclusion, low serum folate levels were found to be associated with a delayed onset of clinical improvement during treatment with fluoxetine in MDD by, on average, 1.5 wk.

(Received June 6 2004)
(Reviewed December 7 2004)
(Revised December 15 2004)
(Accepted December 21 2004)

Key Words: Fluoxetine; folate; homocysteine; onset; response; vitamin B12.

c1 Massachusetts General Hospital, Department of Psychiatry, Depression Clinical and Research Program, 15 Parkman Street, WACC 812, Boston, MA 02114, USA. Tel.: (617) 726-6697 Fax: (617) 726-7541 E-mail: