Raffaella Calati

Serotonin Transporter Gene Variants and Behavior: A Comprehensive Review

The serotonin system modulates affective, cognitive and behavioral processes. A key molecular structure of this system, the serotonin transporter (SERT) gene, has been associated with many human behaviors, both normal and pathological. This article aim is a comprehensive overview of the human behavioral features influenced by SERT gene variants and to suggest some comprehensive hypotheses. In particular, the SERTPR insertion/deletion polymorphism has been related to hippocampal volume and amygdala response and it has been found to influence anxiety-related personality traits and anxiety disorders; in mood disorders it showed some influences on age at onset, periodicity, illness recurrence, rapid cycling, antidepressants response and depressive reaction to stressful life events. Psychosomatic disorders, suicide, alcoholism, smoking, eating disorders, attention deficit hyperactivity disorders and autism have been also found to be related to SERTPR variants. SERT gene variants seem therefore to modulate a wide range of aspects in both normal and affected individuals, many of which are possibly due to indirect correlations between such human features.

Depressive symptomatology is influenced by chronotypes

BACKGROUND Rhythm disturbances are a frequent clinical manifestation of depression. In recent years a possible relationship between depression and chronotypes has emerged. Specifically eveningness has been proposed as vulnerability factor. The aim of this study was to describe sleep features of depressed patients according to chronotypes and to explore possible associations with the clinical features of depressive episodes. METHODS 100 patients diagnosed with Major Depressive Disorder according to the Mini International Neuropsychiatric Interview (MINI) were included (age: 34+/-11.74, range: 18-60 years; female/male:79/21). At admission the Hamilton Rating Scale for Depression (HRSD) was administered. Patients were also administered the Morningness-Eveningness Questionnaire (MEQ), the Epworth Sleepiness Scale, the Athens Insomnia Scale and the Pittsburgh Sleep Quality Index. RESULTS According to MEQ scores patients were classified in three groups: a) eveningness (n=18), b) neither (n=61) and c) morningness type (n=21). The age was different among chronotypes, being morningness-type patients older. The eveningness-type group showed higher scores in suicidal thoughts, more impaired work and activities, higher paranoid symptoms, higher scores on the anxiety cluster (HRSD), while the morningness-type group showed lower proportion of melancholic symptoms (MINI). We did not find association between sleep parameters and specific chronotypes. LIMITATIONS The relatively small sample size and the concurrent assessment of chronotypes and depression may have biased our findings. CONCLUSIONS Our data suggest the idea that chronotypes have an impact on depressive episodes features, with higher severity for the eveningness-type.

Personality and attempted suicide. Analysis of anger, aggression and impulsivity

Suicide is one of the leading causes of death worldwide, mortality from suicide being approximately 2%. Attempted suicide appears to be a major risk factor for suicide completion. Anger, aggression and impulsivity are personality traits associated with suicide attempt. In this study we analysed a part of a previously reported sample in order to test anger, impulsivity and temperament/character scales as predictors of aggression and self-aggression in suicide attempters and to compare anger- and aggression-related traits between impulsive and premeditated suicide attempts as well as between violent and non-violent suicide methods. One-hundred-eleven consecutively admitted inpatients with a lifetime history of attempted suicide were assessed for anger (State-Trait Anger Expression Inventory, STAXI), aggression (Questionnaire for Measuring Factors of Aggression, FAF) and temperament/character (Temperament and Character Inventory, TCI). Higher aggression scores, as measured by FAF, were predicted by being male, meeting criteria for borderline personality disorder and having higher angry temperament scores as assessed by STAXI; low cooperativeness was also associated with aggression but not after controlling for STAXI scales. TCI dimensions associated with self-aggression were high harm avoidance, high impulsivity and low self-directedness; state anger, inwardly directed anger and inhibition of aggression were also predictors of self-aggression. In conclusion, impulsivity and harm avoidance have emerged as temperament dimensions independently associated with self-aggressive tendencies in personality. Such interactions could explain the correlation between temperament and suicidality but further research is needed. Anger and self-directedness appear to have some effects on suicide attempt.

Pharmacogenetics of antidepressant response

Personalized medicine - the adaptation of therapies based on an individuals genetic and molecular profile - is one of the most promising aspects of modern medicine. The identification of the relation between genotype and drug response, including both the therapeutic effect and side effect profile, is expected to deeply affect medical practice. In this paper, we review the current knowledge about the genes related to antidepressant treatment response and provide methodologic proposals for future studies. We have mainly focused on genes associated with pharmacodynamics, for which a list of promising genes has been identified despite some inconsistency across studies. We have also synthesized the main results for pharmacokinetic genes, although so far they seem less relevant than those for pharmaco dynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.

Temperament and Character in Mood Disorders: Influence of DRD4, SERTPR, TPH and MAO-A Polymorphisms

Gene variants exert a complex range of effects on human normal and abnormal behavior. We previously reported the effect of gene variants in serotoninergic and dopaminergic pathways, in a range of clinical features in mood disorders, such as symptomathology, periodicity, social adjustment and treatment response. In this paper we hypothesized that the same gene variants could influence temperamental traits in mood disorders patients. We focused on genes of the serotoninergic and dopaminergic systems (dopamine receptor D4 gene, DRD4; serotonin transporter gene, promoter region SERTPR; tryptophan hydroxylase gene, TPH; monoamine oxidase A gene, MAO-A). Two hundred and seven euthymic subjects, affected by major depressive disorder (n = 73) and bipolar disorder (n = 134) were assessed by the Cloninger’s Temperament and Character Inventory (TCI) and typed using PCR-based analyses. Possible stratification factors such as demographic, clinical and other temperamental factors were also taken into account. We observed that homozygosity for the short SERTPR allele was associated with low novelty-seeking scores (p = 0.006) and genotypes containing the DRD4 long allele were marginally associated with low harm avoidance (p = 0.05). Finally, the long MAO-A allele was associated with decreased persistence scores among females (p = 0.006). Our observation of a pattern of influence on temperamental dimension exerted by serotonergic and dopaminergic genes suggests that the contribution of these polymorphisms to the clinical presentation of mood disorders could be mediated by an influence on personality differences.

Catechol-o-methyltransferase gene modulation on suicidal behavior and personality traits: review, meta-analysis and association study

Suicide is one of the leading causes of death among young adults. Both genetic and personality factors plausibly have a role on suicidal behavior. We focused on the catechol-O-methyltransferase gene (COMT) and we performed: a review of studies investigating the association between COMT and both suicidal behavior and personality; a meta-analysis of studies investigating the association between suicidal behavior and COMT rs4680 polymorphism; an association study investigating the link between seven COMT polymorphisms (rs737865, rs5844402, rs5993883, rs4680, rs4633, rs165599 and rs9332377) and both personality traits and suicidal behavior. For the review and the meta-analysis we performed an electronic search to identify studies focused on the association between COMT and both suicidal behavior and personality. The sample of the association study was composed of three groups: 289 German healthy controls, 111 German suicide attempters and 70 Italian mood disorder patients. From the review, the meta-analysis and the association study no relationship emerged between COMT and suicidal behavior. Nevertheless, from both review and association study several links were found between COMT and personality traits. In particular, in the association study we found a significant correlation between rs4633 and Reward Dependence (Temperament and Character Inventory). As secondary results we found an association between rs737865 and Angry Reaction (State-Trait Anger Expression Inventory) and between rs9332377 and Irritability (Questionnaire for Measuring Factors of Aggression). Our findings suggested that COMT variants may not be directly implicated in suicidal behavior, however evidence of a COMT role in the modulation of personality traits has been found.

The 5-HTTLPR polymorphism and eating disorders: a meta-analysis.

OBJECTIVE Eating disorders are influenced by both environmental factors and genes. The 5-HTTLPR polymorphism of serotonin transporter gene has been suggested as a good candidate. This meta-analysis was undertaken: (1) to investigate the association between 5-HTTLPR and eating disorders considered as a whole, including anorexia (AN), bulimia (BN), and binge eating disorder (BED); (2) to extend recently reported findings on the association between 5-HTTLPR and AN-BN. METHOD PubMed, ISI, and PsycINFO databases were searched for studies published until October 2009. Fifteen studies have been included. Data were analyzed with the Cochrane Collaboration Review Manager Software. Quality of studies and publication bias were assessed. RESULTS An association between S allele and eating disorders, in particular AN, has been found. DISCUSSION To be carrier of the 5-HTTLPR S allele seem to represent a risk factor for eating disorders, especially for AN. However, considering the reported high between-study heterogeneity, future studies should focus on more homogeneous endophenotype.

Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes are not associated with response and remission in a sample of depressive patients

Cytochrome P450 genes are involved in the metabolism of antidepressants and could influence treatment response. The aim of this study was to investigate the role of allelic variations of the cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes in antidepressant treatment response and remission rates. Two hundred and seventy-eight patients affected by major depression, responders (N = 81) and nonresponders (N=197) to at least one adequate antidepressant treatment, were recruited with a multicentre design for resistant depression and genotyped for all relevant variations. None of the considered metabolic profiles (e.g. poor, intermediate, extensive and ultrarapid metabolizers) was found to be associated with either response or remission rates. In conclusion, the investigated cytochrome genes do not seem to play a major role in antidepressant response in the present sample of depressive patients. Nevertheless, methodological and sample size limitations of this study do not allow definitive conclusions.

Switching antidepressant class does not improve response or remission in treatment-resistant depression.

Objective: The management of treatment-resistant depression is a much debated issue. In particular, the evidence supporting the commonly suggested sequential use of antidepressants from 2 different pharmacological classes is weak. This retrospective study was undertaken to investigate whether there is a better response in nonresponders switched to a different class of antidepressants (across-class) compared with nonresponders switched to an antidepressant from the same class (within-class). Methods: Three hundred forty patients with primary major depressive disorder were recruited in the context of a European multicenter project. Subjects whose current depressive episode had failed to respond to a first antidepressant trial of adequate dose and duration were included. Results: There was no significant difference in response or remission rates between the across-class and within-class groups after controlling for possible confounders. Conclusions: In depressed nonresponders to a previous antidepressant treatment, switching to a different class of antidepressants was not associated with a better response or remission rate.

The 5-HTTLPR polymorphism and posttraumatic stress disorder: a meta-analysis.

Environmental and genetic factors contribute to the development of posttraumatic stress disorder (PTSD). Variation in the 5-HTTLPR polymorphism of the serotonin transporter gene has been hypothesized to affect risk for PTSD. With the aim of investigating this association, we conducted a meta-analysis to shed light on prior controversial results and increase statistical power to detect smaller effect sizes. PubMed and ISI databases were searched for studies published until December 2012. Twelve studies have been included, all based on trauma-exposed samples. Data were analyzed with Cochrane Collaboration Review Manager Software (Version 5). Quality and publication bias were assessed. Metaregressions were performed using Comprehensive Meta-Analysis software, Version 2. Taking into account all studies, no association was found between 5-HTTLPR and PTSD (p = .10), with evidence of between-study heterogeneity, which could be partly explained by gender differences. In sensitivity analyses, we found an association between SS genotype and PTSD in high trauma-exposed participants (p < .001). To be a carrier of the SS genotype seems to represent a risk factor for PTSD in high trauma exposure. Further studies focusing on Gene × Environment interactions are needed to better understand the role of this polymorphism in PTSD.