Anita Benko

New Evidence for the Association of the Serotonin Transporter Gene (SLC6A4) Haplotypes, Threatening Life Events, and Depressive Phenotype

BACKGROUND Since the first report of the significant gene-environment interaction (G x E) in depression published by Caspi et al., the literature is considerably contradictory in this field. To clarify this question, we analyzed the interaction between the serotonin transporter gene (SLC6A4) and threatening life events (TLE) on Zung Self-Rating Depression Score (ZSDS). METHODS Five markers tagging the whole SLC6A4 gene (5-HTTLPR and 4 single nucleotide polymorphisms: rs2020942, rs140700, rs3798908, rs1042173) were genotyped in 567 nonclinical individuals. Generalized linear models were used to analyze single marker associations, and likelihood ratio tests and score tests were used for haplotype analysis. RESULTS Haplotype analysis revealed a significant global effect of haplotypes on ZSDS score in high TLE subgroup (p = .008). Besides the 5-HTTLPR, rs140700 tagging the middle region of the gene had significant effects. Subjects carrying the A allele of rs140700 scored lower on ZSDS independently of 5-HTTLPR carrier status. Explained variances for depressive phenotype were 1%, 4%, and 6% when 5-HTTLPR, 5-HTTLPR x TLE and 5-HTTLPR x rs140700 x TLE were included in the model, respectively. CONCLUSIONS Our results demonstrate heterogeneity of individuals carrying S alleles of 5-HTTLPR in association with high TLE providing possible explanation for the inconsistency of previous studies. In addition to the promoter, the middle region of the SLC6A4 gene carries the G x G x E interaction for mood, and this new model provided a higher explained variance. We report the first evidence for the significant effects of haplotypes of the SLC6A4 gene and threatening life events on depressive phenotype.

Significant association between the C(-1019)G functional polymorphism of the HTR1A gene and impulsivity.

Serotonin‐1A (5‐HT1A) receptors are known to play a role in impulsivity‐related behavior. The C(−1019)G functional polymorphism (rs6295) has been suggested to regulate the 5‐HT1A receptor gene (HTR1A) expression in presynaptic raphe neurons, namely, increased receptor concentration and reduced neuronal firing could be associated with the G allele. Previous studies indicate that this polymorphism is associated with aggression, suicide, and several psychiatric disorders, yet its association with impulsivity has rarely been investigated. We studied the relationship between impulsivity and the C(−1019)G polymorphism of the HTR1A in a population sample of 725 volunteers using the Impulsiveness subscale (IVE‐I) of the Eysenck Impulsiveness, Venturesomeness, and Empathy scale and also the Barratt Impulsiveness Scale (BIS‐11). Data were analyzed using analysis of variance with age and gender as covariates and Tukeys HSD post‐hoc test. Post‐hoc analysis revealed that the study had 0.958 power to detect 0.15 effect size. Significant differences between the C(−1019)G genotype groups (GG vs. GC vs. CC) were found. Subjects carrying GG genotype showed significantly higher impulsiveness scores compared to GC or CC carriers for the IVE‐I scale (P = 0.014), for the Motor (P = 0.021), Cognitive Impulsiveness (P = 0.002), and for the BIS total score (P = 0.008) but not for the Nonplanning Impulsiveness (P = 0.520) subscale of the BIS‐11. Our results suggest the involvement of the HTR1A in the continuum phenotype of impulsivity.

Increased wakefulness, motor activity and decreased theta activity after blockade of the 5-HT2B receptor by the subtype-selective antagonist SB-215505.

Serotonin‐2 receptor antagonists, like ritanserin, greatly enhance deep slow wave sleep (SWS‐2) and low‐frequency EEG power in humans and rodents. 5‐HT2A and 5‐HT2C receptors may be involved in these effects, but the role of the 5‐HT2B receptor is still unclear. To investigate the role of the 5‐HT2B receptor in regulation of the sleep–wake cycle, the subtype‐selective antagonist SB‐215505 (0.1, 0.3 and 1.0 mg kg−1 i.p.) was administered to Sprague–Dawley rats at light onset (beginning of passive phase). EEG, EMG and motor activity were recorded during the subsequent 8 h. SB‐215505 dose‐dependently increased wakefulness (W) at the expense of the intermediate stage of sleep, paradoxical sleep (PS) and SWS‐2 in the first hour. Parallel to increased W, significantly increased motor activity was found. Spectral analysis of the EEG in W showed a dose‐dependent decrease in power density in the 3–8 Hz frequency range (maximum effect at 6 Hz). In light slow wave sleep and SWS‐2, the drug reduced low‐frequency (<8 Hz) EEG power, suggesting decreased sleep intensity after SB‐215505 treatment. In PS, the drug dose‐dependently decreased EEG power solely in the theta (6–9 Hz) band, primarily affecting the peak power value (7 Hz). The well‐known SWS‐2 enhancing effect of 5‐HT2 receptor antagonists is mediated by 5‐HT2A and/or 5‐HT2C receptors. In contrast, blockade of 5‐HT2B receptors increases motor activity and W along with decreased theta activity during W and PS. Activation of 5‐HT2B receptors may contribute to initiation of sleep and to theta generation during W and PS under physiological conditions.

Partial lesion of the serotonergic system by a single dose of MDMA results in behavioural disinhibition and enhances acute MDMA-induced social behaviour on the social interaction test

The acute effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) on anxiety-related behaviours were studied using indices of social interaction in Dark Agouti (DA) both drug naive rats and those pretreated with MDMA (15 mg/kg i.p.) 3 weeks earlier. The functional neuroanatomy of these MDMA effects was visualised using 2-deoxyglucose imaging of local cerebral glucose use (LCMRglu), whilst MDMA-induced serotonergic neurotoxicity was measured by radioligand binding with [3H]paroxetine. Acute MDMA alone markedly decreased most typical elements of social interaction but increased adjacent lying, a behaviour that also contains social elements. In animals pre-exposed to MDMA, decreased [3H]paroxetine binding indicated serotonergic terminal depletion, and in these animals significant increases in locomotor activity, exploratory behaviour and aggressive behaviour were found. Both behavioural effects and also the metabolic activation induced by acute MDMA were potentiated in rats previously exposed to the drug. In conclusion, a single dose of MDMA caused marked changes in social behaviour acutely that might be interpreted either as a decrease or increase in anxiety. Three weeks after MDMA a behavioural disinhibition similar to psychomotor agitation, a symptom connected to depression or mania, and a sensitization to the acute effects of MDMA are apparent in both the behavioural and brain metabolic effects of the drug.

Acute and long-term effects of a single dose of MDMA on aggression in Dark Agouti rats.

MDMA causes selective depletion of serotonergic terminals in experimental animals and the consequent decrease in synaptic 5-HT may, inter alia, increase impulsivity. To study the effects of MDMA upon brain function, the behaviour of male Dark Agouti rats exposed to MDMA (15 mg/kg i.p.), two 5-HT1B agonists (CGS-12066A and CP-94,253, both 5 mg/kg i.p.) or saline were investigated in the resident-intruder test. Studies were performed in drug-naive rats and also in rats exposed to MDMA (15 mg/kg i.p.) 21 d earlier. In parallel experiments the functional neuroanatomy of MDMA effects were assessed using 2-deoxyglucose imaging of local cerebral metabolic rate of glucose utilization (LCMRGlu) and neurotoxicity was assessed by measuring [3H]paroxetine binding. There was no significant difference in aggressive behaviour (biting, boxing, wrestling and their latencies) between drug-naive rats and rats previously exposed to MDMA 21 d earlier, despite reduced social behaviour, decreased LCMRGlu in several brain areas involved in aggression, and reductions in paroxetine binding by 30-60% in the forebrain. CGS-12066A, CP-94,253 and acute MDMA produced marked decreases in aggressive behaviours, especially in biting, boxing and kicking found in drug-naive rats. In animals previously exposed to the drug, acute anti-aggressive effects of MDMA were, in general, preserved as were MDMA-induced increases in LCMRGlu. Our studies provide evidence that in the resident-intruder test, where social isolation is a requirement, aggressive behaviour and acute anti-aggressive effects of MDMA and 5-HT1B receptor agonists remain intact 3 wk after a single dose of the drug despite significant damage to the serotonergic system.

Seasonality and winter-type seasonal depression are associated with the rs731779 polymorphism of the serotonin-2A receptor gene

Seasonal Affective Disorder (SAD), seasonality and increased sensitivity to the fluctuation of seasons in biological and psychological parameters can manifest to varying degrees across a normal population. The serotonin-2A (5-HT2A) receptor gene has long been suggested as a candidate for the genetic basis of this phenomenon. We hypothesized that functional sequence variation in this gene could contribute to seasonality and the development of winter- and/or summer-type seasonal depression. Seasonality was measured by the self-rating Global Seasonality Score (GSS) of the Seasonal Pattern Assessment Questionnaire, and SAD by the Seasonal Health Questionnaire (SHQ). We analysed associations between GSS or SAD scores and 5-HTR2A receptor gene polymorphisms rs731779, rs985934 and rs6311, in 609 individuals. People carrying the GG genotype of rs731779 were six times more likely to manifest winter or summer SAD compared to GT or TT genotypes (OR = 6.47), and the chance of having winter-type SAD was almost nine-fold (OR = 8.7) with the GG genotype. GG subjects of rs731779 also scored significantly higher on the GSS scale compared to carriers of the T allele. In the haplotype analysis subjects carrying the G allele of rs731779 scored higher on the GSS scale, while the presence of the T allele leads to lower scores. These results suggest that variations in the 5-HTR2A gene play a significant role in the development of seasonality and especially in winter-type SAD. The fact that the above polymorphism showed association not only with clinical SAD but also seasonality symptoms in a general population provides evidence for the spectrum nature of this connection.

Association of depressive phenotype with affective family history is mediated by affective temperaments.

Increasing data support an association of cyclothymic temperament with bipolarity, but our knowledge about the relationship of affective temperaments (ATs) to depressive symptoms based on inheritance in a non-clinical population is limited. The aim of this article was to demonstrate how ATs and affective family history relate to the depressive symptoms in a general population. Subjects comprised 501 Hungarian adults who completed a background questionnaire, the TEMPS-A, the Zung Self-Rating Depression Scale (ZSDS) and the depression subscale of the Brief Symptom Inventory (BSI-D). Stepwise linear regression was performed to analyse the role of ATs and affective family history (AFH(0) and AFH(1)) in the variance of ZSDS and BSI-D scores. Cyclothymic, depressive and anxious temperaments have a significant role in the explained variance of depression scores, and they are all significantly related to AFH(1). Significant differences were found between AFH(1) and AFH(0) groups in ZSDS and BSI-D scores, and these effects were eliminated if ATs were entered as covariates. The probability of having any dominant temperament was more than two-fold in group AFH(1) compared with AFH(0) (OR=2.33). Our results suggest that a crucial part of inherited factors of depression is mediated by affective temperaments.

Genetic variants in the catechol-o-methyltransferase gene are associated with impulsivity and executive function: Relevance for major depression†‡

The catechol‐o‐methyltransferase (COMT) gene has been extensively investigated in depression with somewhat contradictory results but the role of impulsivity, as a possible intermediate phenotype in this disorder, has not been considered yet. In our study, four tagging SNPs in the COMT gene (rs933271, rs740603, rs4680, rs4646316) were genotyped in two independent population cohorts: Manchester (n = 1267) and Budapest (n = 942). First, we investigated the association between COMT genotypes, impulsivity, neuroticism and depression using haplotype trend regression, and constructed a model using structural equation modeling to investigate the interaction between these factors. Secondly, we tested the effect of executive function on this model in a smaller interviewed sample (n = 207). Our results demonstrated that COMT haplotypes were significantly associated with impulsivity in the combined cohort, showing the same direction of effects in both populations. The COMT effect on depressive symptoms (in subjects without history of depression) and on executive function (interviewed sample) showed the opposite pattern to impulsivity. Structural equation models demonstrated that COMT and impulsivity acted, both together (through neuroticism) and independently, to increase the risk of depression. In addition, better executive function also operated as a risk factor for depression, possibly though reduced ability to flexibly disengage negative emotions. In conclusion, variations in the COMT gene exert complex effects on susceptibility to depression involving various intermediate phenotypes, such as impulsivity and executive function. These findings emphasise that modeling of disease pathways at phenotypic level are valuable for identifying genetic risk factors.

The possible protective role of personality dimensions against premenstrual syndrome

Previous studies suggest that women with premenstrual syndrome (PMS) differ from those without PMS in personality dimensions, but it is not clear what role personality plays in the background of premenstrual symptomatology. Our purpose was to examine personality dimensions measured by the Tridimensional Character Inventory (TCI) in psychiatrically healthy women not suffering from premenstrual dysphoric disorder (PMDD) in relation to the severity of distressing and impairing mental and physical symptoms experienced in the late luteal phase of the menstrual cycle. Forty healthy women completed the prospective record of the Impact and Severity of Menstrual Symptoms (PRISM) calendar every evening through three consecutive menstrual cycles and were assigned into LPS (luteal phase symptom) vs. non-LPS groups. Our grouping did not reflect categorization according to the presence of PMS, since we investigated healthy women. Personality characteristics were evaluated using the TCI. LPS subjects scored significantly higher in subscales associated with novelty seeking (NS), self-directedness (S), cooperation (C) and self-transcendence (ST), and lower in the harm avoidance (HA) scale. Elevated scores of women with higher symptom severity in the late luteal phase in NS, S, ST and C scales and lower HA scores are in contrast with previous results on personality traits associated with PMS. However, we investigated psychiatrically healthy women. Therefore, our results suggest that this personality profile is a protective factor against developing serious psychiatric symptoms when experiencing a distressing and more marked symptomatology associated with the late luteal phase of the reproductive cycle.