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


METHODS
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.


RESULTS
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.


CONCLUSIONS
The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.
Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. dmischoulon@partners.org
David
D
Mischoulon
Stefania
S
Lamon-Fava
Jacob
J
Selhub
Judith
J
Katz
George I
GI
Papakostas
Dan V
DV
Iosifescu
Albert S
AS
Yeung
Christina M
CM
Dording
Amy H
AH
Farabaugh
Alisabet J
AJ
Clain
Lee
L
Baer
Jonathan E
JE
Alpert
Andrew A
AA
Nierenberg
Maurizio
M
Fava
D000293:Adolescent; D000328:Adult; D000368:Aged; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D005492:Folic Acid / Q000097:blood; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D015995:Prevalence; D011569:Psychiatric Status Rating Scales; D018709:Statistics, Nonparametric; D014805:Vitamin B 12 / Q000097:blood; D055815:Young Adult
D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12