Prediction of Response to Paroxetine and Venlafaxine by Serotonin-Related Genes in Obsessive-Compulsive Disorder in a Randomized, Double-Blind Trial
Department of Psychiatry, the Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. The Journal of Clinical Psychiatry
(Impact Factor: 5.5).
05/2007; 68(5):747-53. DOI: 10.4088/JCP.v68n0512
Serotonin reuptake inhibitors (SRIs) are the most effective pharmacologic treatment currently available for patients with obsessive-compulsive disorder (OCD). Still, up to 40% to 60% of OCD patients do not respond to SRI treatment. The purpose of the present study was to determine whether polymorphisms of the serotonin transporter (5-HTT), 5-HT1B, and 5-HT2A receptor genes affect the efficacy of SRI treatment in OCD.
91 outpatients with OCD according to DSM-IV criteria consented to the study and were randomly assigned in a 12-week, double-blind trial to receive dosages titrated upward to 300 mg/day of venlafaxine or 60 mg/day of paroxetine. Primary efficacy was assessed by the change from baseline on the Yale-Brown Obsessive Compulsive Scale (YBOCS), and response was defined as a > or = 25% reduction on the YBOCS. Responders and nonresponders were stratified according to 5-HTT, 5-HT1B, and 5-HT2A genotypes and differentiated in paroxetine-or venlafaxine-treated groups. The study was conducted from August 1998 to July 2002.
In the whole group, 64% of responders carried the S/L genotype of the 5-HTTLPR polymorphism (chi2 = 7.17, df = 2, p = .028). In the paroxetine-treated patients, the majority of responders carried the G/G genotype of the 5-HT2A polymorphism (chi2 = 8.66, df = 2, p = .013), whereas in the venlafaxine-treated patients, the majority of responders carried the S/L genotype of the 5-HTTLPR polymorphism (chi2 = 9.72, df = 2, p = .008).
The results of this study suggest that response in venlafaxine-treated OCD patients is associated with the S/L genotype of the 5-HTTLPR polymorphism and in paroxetine-treated OCD patients with the G/G genotype of the 5-HT2A polymorphism.
Available from: Makoto Kinoshita
- "Finally, we did not examine interactions between the COMT gene and other genes, such as 5-HTTLPR and 5-HT2A, which have been associated with drug response in OCD (Denys et al., 2007). "
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ABSTRACT: Catechol-O-methyltransferase (COMT) is an enzyme that participates in the metabolic inactivation of dopamine and norepinephrine, and the Met allele of the COMT Val158Met polymorphism is associated with lower enzymatic activity. The purpose of the present study was to investigate whether this functional variant is associated with obsessive-compulsive disorder (OCD) and the clinical responses in OCD.
We first performed a case-control association study between the COMT Val158Met polymorphism and OCD (171 cases and 944 controls). Then, we examined the association between this polymorphism and the clinical responses in 91 of the OCD patients.
Our study did not find a significant association between the Met allele and OCD risk or between the Met allele and clinical responses (p > 0.05).
The present case-control/pharmacogenetic study did not provide clear evidence that the COMT Val158Met polymorphism is a predictor of OCD or of OCD patients' clinical responses. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
- "In an initial study carried out to determine which OCD patients respond best to quetiapine augmentation of SRIs, Denys et al. (2007a) found that lower doses of SRIs predicted a more robust response. Given an emerging literature on the demographic and clinical predictors of response to SRIs in OCD (Ravizza et al., 1995; Ackerman et al., 1996, 1999; Black et al., 1998, 1999; Mataix-Cols et al., 1999; Alonso et al., 2001; Erzegovesi et al., 2001; Stein et al., 2001; Denys et al., 2007b), it may be useful to explore whether such variables also predict response to antipsychotic augmentation of SRIs in OCD. A number of obsessive–compulsive symptom factors, for example, have been shown to predict poorer response to SRI treatment (Black et al., 1998; Mataix-Cols et al., 1999; Roseboom and Kalin 2000; Alonso et al., 2001; Erzegovesi et al., 2001; Stein et al., 2001). "
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ABSTRACT: Several studies have examined the predictors of treatment response in obsessive-compulsive disorder (OCD). Only limited information is available on the predictors of response to antipsychotic augmentation of serotonin reuptake inhibitors (SRIs). Data from placebo-controlled studies of augmentation with quetiapine were combined in a best subsets logistic regression to derive a predictive model for Yale-Brown Obsessive-Compulsive Scale (YBOCS) change and the YBOCS endpoint. Data from the YBOCS checklist and a variety of clinical and demographic variables previously shown to predict treatment outcome in OCD were analysed. In univariate analyses, the failure of fewer previous SRI trials was associated with the YBOCS response. In the multivariate model, for YBOCS change, 45% of the variance was attributed to the fact that patients had failed fewer previous SRI treatments, had higher baseline obsession scores, and ordering and arranging compulsions. For the YBOCS endpoint scores, 50% of the variance was attributed to the fact that patients had fewer failed SRI trials, higher baseline compulsion scores, and counting/ordering and arranging compulsions. These data indicate a number of predictors of response to augmentation of SRIs in treatment-refractory OCD. These include fewer previously failed SRI trials and generally higher overall baseline scores for obsessions and compulsions as well as counting/ordering and arranging compulsions. Other factors are, however, also likely to play an important role in predicting outcome.
Available from: Homero Vallada
- "Few studies have investigated serotonergic polymorphisms and SRI treatment responses
in OCD patients. Denys et al. (13)
reported that in paroxetine-treated patients, the majority of the responders were
homozygote for the G allele of the 1438 G/A polymorphism of the HTR2A gene. Cavallini et al. (14) found no
association between the Cys23Ser polymorphism of the HTR2C gene and a therapeutic
response to clomipramine. "
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ABSTRACT: Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers.
Patients with obsessive-compulsive disorder were classified as either responders or non-responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1Dβ gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene.
The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non-responders) than in the controls (p<0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p<0.01). The CC genotype of the serotonin receptor subtype 1Dβ G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p<0.01 and p<0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p<0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders.
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