Effect of catechol-O-methyltransferase Val(108/158)Met polymorphism on antidepressant efficacy of fluvoxamine.
BACKGROUND
The catechol-O-methyltransferase (COMT) enzyme inactivates catecholamines, and the COMT Val(108/158)Met polymorphism (rs4680) influences the enzyme activity. Recent clinical studies found a significant effect of rs4680 on antidepressant response to fluoxetine and paroxetine, but several other studies were negative. No study considered drug plasma levels as possible nuisance covariate.


OBJECTIVE
We studied the effect of rs4680 on response to fluvoxamine antidepressant monotherapy.


METHODS
Forty-one consecutively admitted inpatients affected by a major depressive episode in course of major depressive disorder were administered fluvoxamine for 6 weeks. Changes in severity of depression were assessed with weekly Hamilton Depression ratings and analyzed with repeated measures ANOVA in the context of General Linear Model, with rs4680 and fluvoxamine plasma levels as factors.


RESULTS
rs4680 significantly interacted with time in affecting antidepressant response to fluvoxamine, with outcome being inversely proportional to the enzyme activity: better effects in Met-carriers, worse effects in Val/Val homozygotes. The effect became significant at the fourth week of treatment, and influence final response rates. Fluvoxamine plasma levels had marginal effects on outcome.


CONCLUSIONS
This is the first study that reports a positive effect of rs4680 on response to fluvoxamine, and the third independent report of its influence on response to selective 5-HT reuptake inhibitors (SSRIs). Our findings support the hypothesis that factors affecting catecholaminergic neurotransmission might contribute to shape the individual response to antidepressants irrespective of their primary molecular target.
Benedetti
F
F
Department of Clinical Neurosciences, Istituto Scientifico Ospedale San Raffaele, University Vita-Salute San Raffaele, San Raffaele Turro, Via Stamira d'Ancona 20, Milan, Italy. benedetti.francesco@hsr.it
Dallaspezia
S
S
Colombo
C
C
Lorenzi
C
C
Pirovano
A
A
Smeraldi
E
E
D000328:Adult; D000368:Aged; D000483:Alleles; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D016666:Fluvoxamine / Q000627:therapeutic use*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D016896:Treatment Outcome
D018687:Antidepressive Agents, Second-Generation; D002394:Catechol O-Methyltransferase; D016666:Fluvoxamine