Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder

Abstract

OBJECTIVES: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.METHODS: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.RESULTS: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.

Altered cognitive response to serotonin challenge as a candidate endophenotype for obsessive-compulsive disorder

“…It cannot be seen "by the unaided eye" and therefore requires technology to be accessed (Gottesman and Gould, 2003). While the original definition of 'endophenotypes' recognized that they could be elicited by a behavioural (Gottesman and Gould, 2003) or a pharmacological challenge such as one of the SRIs (Corregiari et al, 2012;Miller and Rockstroh, 2013), this latter strategy has been largely overlooked in OCD to date.…”

Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia

“…Women with bulimia nervosa who are GG homozygous at -1438G/A HTR2A (rs6311) have a blunted PRL response following m-CPP compared to controls (Bruce et al 2005). Corregiari et al (2012) measured G861C HTR1B (rs6296), T102C HTR2A (rs6313) and C516T HTR2A (rs6305) in patients with obsessive-compulsive disorders. Only patients who were CC homozygous at G681C HTR1B (rs6296) had a different PRL response to acute intravenous challenge with citalopram.…”

“…The human genes HTR1B and HTR6 are located on human chromosomes 6 (6q13) and 1 (1p35-p36) (Filip and Bader 2009). Several authors have studied the functional consequences of specific polymorphisms in HTR2A and HTR2C after challenging the system with (indirect) 5-HT agonists, such as meta-chlorophenylpiperazine (m-CPP), fenfluramine or citalopram and measuring the PRL response (K€ uhn et al 2002;Reist et al 2004;Bruce et al 2005;Corregiari et al 2012). K€ uhn et al (2002) observed that Cys23Ser HTR2C (rs6318) exhibits a slightly stronger, but not significantly different, PRL response to the m-CPP challenge.…”

SCL6A4 polymorphisms rs25533 and I425V: Association with obsessive–compulsive disorder and its treatment response in Iranian patients

“…1). According to the Y-BOCS score reduction at the beginning of the treatment compared to the score after 12 weeks, patients were divided into two groups: responders were patients who exhibited > 35% reduction in Y-BOCS scores after treatment with fluvoxamine; non-responders, patients that exhibited < 35% reduction in Y-BOCS scores [43,44]. We considered another group, refractory, patients who experienced various SSRI trials during their illness period but the severities of their symptoms did not change or even became worse [45].…”