Bárbara Arias

5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study.

In the context of a long term follow-up study, we analysed the possible implication of the 5-HTTLPR polymorphism at the serotonin transporter gene in clinical response and remission of major depressive patients treated with citalopram. The sample consisted of 131 patients, all of Spanish origin, diagnosed according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale (HDRS) was used to evaluate severity of the symptoms during the follow-up and to determine clinical response and remission condition of the patients at 4th and 12th week, respectively. Our results showed that S/S genotype of the 5-HTTLPR polymorphism was associated with the non-Remission condition at 12th week (χ2 = 8.7, P = 0.013). Moreover, homozygous for the allele S presented three times more risk for non reaching remission of depressive episode after citalopram treatment than patients with any other 5-HTTLPR genotype combination (χ2: 7.29, P = 0.006; OR = 3.23 [95%CI: 1.24–8.5]). In conclusion, our results show that genetic variation of serotonin transporter is involved in clinical remission of major depressive episodes after twelve weeks of citalopram treatment.

Evidence for a combined genetic effect of the 5-HT1A receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT1A receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram. We had previously reported an association between variation on the SERT gene (SLC6A4) and clinical remission after citalopram treatment. In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated. The sample consisted of 130 patients, all of Spanish origin, who were diagnosed as having a current major depressive episode according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale was used to assess severity of symptoms at the beginning and during the follow-up to determine the outcome and remission status at week 12. Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype. Data were analysed adjusting for the effect of poor metabolizers in clinical response. No independent effect was found for the 5-HT1A receptor gene in relation to clinical outcome or remission after citalopram treatment. However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02]. When considering the remission status, an increase of patients carrying the risk genotype combination (S/S-G/G) was found among those subjects who did not reach remission (Fisher’s exact test = 0.009). Our results suggest that the combined effect of the serotonin transporter and the 5-HT1A receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.

Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences

BACKGROUND The well-established relationship between childhood adversity and psychosis is likely to involve other factors such as genetic variants that can help us to understand why not everyone exposed to adverse events develops psychotic symptoms later in life. AIMS We investigated the influence of childhood abuse and neglect on positive and negative psychotic-like experiences in adulthood and the potential moderating effect of the BDNF-Val66Met polymorphism. METHOD Psychotic-like experiences and childhood adversity were assessed in 533 individuals from the general population. RESULTS Childhood abuse showed a strong independent effect on the positive dimension of psychotic-like experiences (β = 0.16, s.e. = 0.05, P = 0.002). Furthermore, this association was moderated by the BDNF-Val66Met polymorphism (β = 0.27, s.e. = 0.10, P = 0.004). CONCLUSIONS Individuals exposed to childhood abuse are more likely to report positive psychotic-like experiences. Met carriers reported more positive psychotic-like experiences when exposed to childhood abuse than did individuals carrying the Val/Val genotype. Therefore, the observed gene-environment interaction effect may be partially responsible for individual variation in response to childhood abuse.

Variability in the 5-HT 2A receptor gene is associated with seasonal pattern in major depression

The 102-T/C polymorphism of the 5-HT2A receptor gene was analysed in 159 patients with major depression and 164 unrelated and healthy controls using a case-control design. Allele and genotype frequencies did not differ between cases and controls. No differences according to sex, age of onset, melancholia, suicidal behaviour or family history of psychiatric illness were found. However, genotype distributions significantly differed between patients with seasonal pattern in their episodes (MDS) and patients with no seasonal pattern (N-MDS) (χ2 = 10.63; P = 0.004). A seasonal pattern was 7.57 times more frequent in 102C-allele carriers than in 102T homozygous (95.1% of patients MDS carried 102C-allele vs 72% of patients N-MDS (χ2 = 9.45, df=1, P = 0.002; OR = 7.57 (95% CI: 1.65–48.08)). These results suggest that variation in the 5-HT2A receptor gene may play a role in the development of major depression with seasonal pattern and support the existence of a genetic and etiological heterogeneity underlying the diagnosis of major depression.

Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT 1A receptor gene as putative risk factors in major depression

Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT 1A receptor gene as putative risk factors in major depression

Putative role of the COMT gene polymorphism (Val158Met) on verbal working memory functioning in a healthy population.

Working memory has been described as a neurocognitive probe of prefrontal brain functioning. Genetic variability related with catechol‐O‐methyltransferase (COMT) gene (Val158Met polymorphism) has received increasing attention as a possible modulator of working memory tasks in both schizophrenic patients and healthy subjects, although inconsistencies across studies have been found. This may be related to the existence of different working memory components, processes and modalities, which may have different sensitivities to subtle changes in dopamine levels and, therefore, the effect of the underlying COMT Val158Met genetic variability. To test this out a large sample of 521 healthy individuals from the general population were tested on the WCST and three working memory tasks that cover the assessment of verbal and spatial working modalities as well as different components and processes (Letter and Number Sequencing, CPT‐IP, Backwards Visual Span). All individuals were genotyped for the rs4680 (Val158Met) polymorphism at the COMT gene. Met carriers showed near‐significant better performance in the LNS compared with Val/Val individuals (F = 3.9, df = 1, P = 0.046). Moreover, the analysis for linear trend found that Met allele carriers showed significantly better performance than Val/Val individuals (B = 0.58 P = 0.031), although evidence for a linear trend was not found. None of the WCST indices differed among genotypes. Consistent with the hypothesis that Val158Met polymorphism (COMT gene) might account for individual differences on dopamine‐dependent prefrontally related neurocognitive functions, the Letter‐Number Sequencing task, which requires not only maintenance but also active manipulation of information seemed to be more sensitive to the disadvantageous Val/Val genotype in a large non‐clinical sample.

Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes

To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol‐O‐methyltransferase) gene.

The role of genetic variability in the SLC6A4, BDNF and GABRA6 genes in anxiety-related traits

Arias B, Aguilera M, Moya J, Sáiz PA, Villa H, Ibáñez MI, García‐Portillo MP, Bobes J, Ortet G, Fañanás L. The role of genetic variability in the SLC6A4, BDNF and GABRA6 genes in anxiety‐related traits.

Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: data from an association study.

OBJECTIVE To investigate the association between dopaminergic polymorphisms [DRD2 -141C Ins/Del, DRD3 Ser9Gly, and SLC6A3 VNTR] and schizophrenia. METHODS Two hundred and eighty-eight outpatients with schizophrenia (DSM-IV criteria) [mean age (SD)=36.4 (12.4), 60.1% males] and 421 unrelated healthy controls [mean age (SD)=40.6 (11.3), 51.3% males] from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS There was a significant difference in genotype distribution for the DRD2 -141C Ins/Del polymorphism [(chi(2) (2)=12.35, corrected p=0.012]. The -141C Del allele was more common in patients than in controls [0.19 vs. 0.13; chi(2) (1)=9.14, corrected p=0.018, OR (95% CI)=1.57 (1.17-2.10)]. Genotype and allele distributions for DRD3 Ser9Gly and SLC6A3 VNTR polymorphisms were similar in both groups. However, there was tentative evidence of an interaction effect between DRD3 Ser9Gly and SLC6A3 VNTR [Wald=9.56 (4), p=0.049]. Compared to the SLC6A3 10/10 genotype category, the risk of schizophrenia was halved among those with 9/10 [OR=0.51 (95% CI=0.30-0.89), p=0.017]. This protective effect was only present in combination with DRD3 Ser/Ser genotype because of the significant interaction between 9/10 and both Ser/Gly [OR=2.45 (95% CI=1.16-5.17), p=0.019] and Gly/Gly [OR=3.80 (95% CI=1.24-11.63), p=0.019]. CONCLUSIONS This study provides evidence that a genetic variant in the DRD2 gene and possible interaction between DRD3 and SLC6A3 genes are associated with schizophrenia. These findings warrant examination in replication studies.

Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression

In the present study, genetic variation of the 5-HT5A receptor was analyzed in patients affected by affective disorders and healthy controls. The sample consisted of 181 patients with major depression, 88 patients with bipolar affective disorder (BP) and 157 unrelated controls (C), all of Spanish origin. Two polymorphisms (-19G/C and 12A/T) in the 5-HT5A receptor gene were analyzed by polymerase chain reaction amplification and subsequent enzyme digestion. No genotype, allele or haplotype differences were found when we compared patients and controls. When clinical variables were considered as possible tools for detecting genetic heterogeneity, no differences were found. Our results suggest that the polymorphisms analyzed in the 5-HT5A receptor gene do not play a major role in the pathogenesis of affective disorders.