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Title: Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

Author
item Mischoulon, David - Harvard University
item Lamon-fava, Stefani - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Selhub, Jacob - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Katz, Judith - Harvard University
item Papakostas, George - Harvard University
item Iosifescu, Dan - Harvard University
item Yeung, Albert - Harvard University
item Dording, Christina - Harvard University
item Farabaugh, Amy - Harvard University
item Clain, Alisabet - Harvard University
item Baer, Lee - Harvard University
item Alpert, Jonathan - Harvard University
item Nierenberg, Andrew - Harvard University
item Fava, Maurizio - Harvard University

Submitted to: CNS Spectrums
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/2/2012
Publication Date: 6/17/2012
Citation: Mischoulon, D., Lamon-Fava, S., Selhub, J., Katz, J., Papakostas, G., Iosifescu, D.V., Yeung, A.S., Dording, C.M., Farabaugh, A.H., Clain, A., Baer, L., Alpert, J.E., Nierenberg, A., Fava, M. 2012. Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment. CNS Spectrums. 17(2):76-86.

Interpretive Summary: There are some reports that suggest that giving folic acid to depressive patients improves their response to anti-depressant drugs. The purpose of this study is to determine if a specific mutation in folate metabolism (MTHFR C677T) which is quite common (12% of Americans) is associated with a difference in response of folic acid intake in people on antidepressant drugs. We analyzed 49 patients with and without this mutation and found no difference in the response to folic acid between the two. Our conclusion is that this mutation will not interfere with folic acid action in depressive people.

Technical Abstract: To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. We screened 224 subjects (52% female, mean age 39 +/- 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 +/- 11 years) participated in a 12-week open clinical trial of fluoxetine 20-60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined. Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C = 41%, C/T = 47%, T/T = 11%, A/A = 66%, A/G = 29%, G/G = 4%). In the fluoxetine-treated subsample (n = 49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response. The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.