Influence of ACE gene on differential response to sertraline versus fluoxetine in patients with major depression: a randomized controlled trial.
BACKGROUND
Extensive distribution of the different components of renin angiotensin system (RAS) in the brain, along with their roles in promoting anxiety, depression and brain inflammation, opposes RAS as a potential therapeutic target in major depression. Actions of angiotensin II, the main product of RAS, are reduced by antidepressants and this signifies the complex interplay of different mechanisms involved in response to therapy. Here, we hypothesized that genetic polymorphisms of RAS may affect the outcome of therapy in depressed patients.


METHODS
The frequencies of variants of genes encoding for angiotensin-converting enzyme (ACE) insertion/deletion (I/D), rs4291 and rs4343 polymorphisms were determined in extracted DNAs of 200 newly diagnosed depressed patients. Patients were randomly divided into two groups, one treated with fluoxetine and the other treated with sertraline for 12 weeks. Responsive patients were determined by psychiatrist using Hamilton questionnaire and were compared with regard to their genetic variants.


RESULTS
Carriers of the D allele and patients with DD genotype responded significantly better to sertraline than to fluoxetine (P = 0.0006, odds ratio (OR) = 3.0, 95 % confidence interval (CI) = 1.80-5.08; P = 0.006, OR = 3.7, 95 % CI = 1.66-8.29, respectively). Mutant genotypes (GG and TT) of rs4343 and rs4291 polymorphisms were also more frequent in patients responding to sertraline, though not achieving the significance level (P = 0.162 and P = 0.256, respectively).


CONCLUSIONS
These findings suggest that special genetic variants of RAS may influence or be an indicator for better response to sertraline.
Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.
Ehsan
E
Bahramali
Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran. firouzabadi@sums.ac.ir.|Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. firouzabadi@sums.ac.ir.
Negar
N
Firouzabadi
School of Pharmacy, Shiraz University of Medical Sciences, International Branch, Shiraz, Iran.
Ilnaz
I
Yavarian
Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Mohammad Reza Hooshangi
MR
Shayesteh
Cancer Immunology Group, Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Nasrallah
N
Erfani
Department of Psychiatry, School of Medicine, Hafez Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
Ali Alavi
AA
Shoushtari
School of Pharmacy, Shiraz University of Medical Sciences, International Branch, Shiraz, Iran.
Roja
R
Asadpour
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic; D020280:Sertraline / Q000627:therapeutic use*; D055815:Young Adult
D000928:Antidepressive Agents; D005473:Fluoxetine; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D020280:Sertraline
Angiotensin-converting enzyme; Fluoxetine; Genetic polymorphism; Major depressive disorder; Sertraline