CLINICS 2012;67(4):335-340 HTR2A gene T102C polymorphism in both patient groups (responders and non-responders), whereas it was present in one-third of the CN (p,0.001). The T allele was more frequent among patients than among controls (p,0.01). These findings suggest that the presence of at least one T allele could be an OCD risk factor. The 102TT genotype was more frequent among patients than among controls (28.3% vs. 20.3%, respectively), but this difference was not statistically sig- nificant after a chi-square partition (p = 0.39). The study may be underpowered to confirm an excess of 102TT homozygous among the patients. The fact that the HTR2A T102C polymorphism was not in HWE in the patients group may be a concern. If deviations from HWE are present in the control population, then one or more of the model assump- tions may have been violated or that a genotyping error has occurred. During our experiment, the genotyping process was repeated when a disagreement arose between the independently trained research technicians who interpreted the data. However, a known homozygous sample was not used as a control, which would have guaranteed the genotyping accuracy. Notably, the CN is in HWE (p = 0.78). Therefore, a genotyping error appears unlikely. In the present study, the patient samples may not need to be in HWE because the patients were not randomly selected from the population (15). In other words, a deviation from HWE in the case subjects may indicate an association of a locus with OCD (16,17). Another reason for the lack of HWE could be ethnic differences between the subjects and consequent sample stratification. As noted, this reason could be the case in the current study because we did not control for ethnic back- ground. Interestingly, the HTR2A T102C polymorphism lacked HWE, and this polymorphism was associated with the disorder, suggesting that the association may be real. Another novel finding was that an excess of CC homozygosity and the C allele of C516T polymorphism of the HTR2A gene was observed among the non-responders. This finding may indicate that having at least one T allele could be a factor that indicates SRI responsiveness during OCD treatment. Notably, our previous study found no differences in the allele and genotype frequencies between OCD patients and the control groups for the T102C HTR2A gene polymorphism (18). Those results suggested that the C516T variant of the HTR2A gene may be a genetic risk factor for OCD. Another study by our group found no association between the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of HTR1B, the T102C (rs6113) and C516T (rs6305) polymorphisms of HTR2A and the clomipra- mine response in OCD patients (19). In the present study, these divergences may be caused by differences in sample characteristics with the refractory patients in the RT group and the highly responsive patients in the RP group. Finally, CC homozygosity for the HTR1B gene G681C polymorphism showed another relevant finding regarding the relationship between the endocrine response to citalo- pram and the investigated groups, despite a low tendency toward gene frequency discrepancies between responders and non-responders (p = 0.054). This genotype was present in only 6 of the 32 non-responders and was absent from the responders. The effect of this genotype on the hormonal response to IV citalopram, an indirect measure of serotonin functioning, is notable. The subgroup of the controls with the CC genotype (n = 2) showed the highest prolactin and 339 5-HT polymorphisms and response to SSRIs in OCD Corregiari FM et al. cortisol response after a citalopram infusion and presented the highest platelet-rich plasma serotonin concentration. In contrast, OCD patients with the same genotype (n = 6), all of whom were non-responders, presented the lowest cortisol responses and serotonin concentrations (not statistically significant with regard to other subgroups except for the Controls-CC genotype). The difference in magnitude is surprising (prolactin response: CN-CC = 558.01¡80.12%; NR-CC = 74.68¡49.13%; cortisol response: CN-CC = 317.48 ¡206.23%; NR-CC = 20.53¡26.63%; p,0.001 after a Bon- ferroni correction for both comparisons). Interestingly, when we analyzed the frequency of the HTR1B CC homoz- ygosity alone in the OCD group, there was an excess of this genotype among the non-responders (p = 0.018; 6 of 32 NRs; 0 of 27 RPs; see Table 2). These data should be interpreted cautiously because of the small subgroup size. Nevertheless, we hypothesized what could account for this genotype-group interaction and lead to a robust cortisol response to citalopram in the CC-Control subgroup and response in the CC-non responders subgroup. The 5-HT1Db receptor is localized chiefly in the 5-HT terminals in which its stimulation inhibits the release of 5-HT. Therefore, the 5-HT1Db receptor may be less active in the CC homozygous members of the CN, allowing a more intense post-synaptic serotonergic stimulation after citalopram infusion. The 5- HT1Db receptor is also expressed, however, in the terminals of nonserotonergic neurons, exerting heteroregulation of neurotransmitter release and a postsynaptic receptor. The latter occurs mainly in the basal ganglia. Chronic SRI administration desensitizes the 5-HT1Db receptors (20). This phenomenon, together with the desensitization of the somatodendritic 5-HT1A receptor (21), leads to progressive enhancement of 5-HT neurotransmission, correlating with a therapeutic response (22). Therefore, in CC homozygous patients, the observed blunted response could be related to the chronic SRI exposure. We infer that a higher acute serotonin response after SRI treatment could lead to more intense adaptation after chronic SRI exposure and conse- quently to a blunted cortisol response after a single dose of citalopram. Accordingly, disrupted 5-HT1Db acute regula- tion may cause other mechanisms to overcome an increased serotonin transmission (e.g., post-synaptic receptor down- regulation or decreased serotonin synthesis), which may lead to an over-adaptation to chronic SRI exposure and decreased SRI effectiveness. These hypotheses could be evaluated in future studies. As acknowledged, it may be premature to determine the validity of the association of therapeutic response and genetic polymorphisms because, as an alternative inter- pretation, they may be in linkage disequilibrium with other proximal polymorphisms that could affect the therapeutic response. Another limitation of this study was that the groups were unmatched for ethnic origin. In populations of highly mixed ethnicity, such as the Brazilian population, phenotyping expressions of ethnicity, such as skin, hair and eye pigmentation, is not viable (23,24). The sample size may be the main methodological limitation of this study. Because this was an exploratory study, we did not calculate the sample power a priori and instead studied all of the available subjects. It is worthwhile to note the unique features of this sample. OCD patients were selected by their long-term therapeutic responses; some of the resistant patients have been in treatment for decades. Moreover, in