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Background: This review unpacks the emotional presentation of externalizing behaviors in attention deficit hyperactivity disorder (ADHD), by diving into the psychophysiology, neurophysiology, and neurogenetics in relation to executive function. The correlations among these three variables are identified, showing that standard assessments for ADHD leave out the emotional dysregulation element. This may lead to suboptimal management outcomes during the developmental progression into adolescence and adulthood. Summary: The emotional impulsivity manifestation in adolescence and adulthood related to the under-managed emotional dysregulation in childhood is found to be associated with subtle confounding impact of 5-HTTLPR (serotonin-transporter-linked promoter region) genotype. The genotype of interest affects the neurochemistry, neurophysiology, and psychophysiology of the cognition for executive function. The established practice of using methylphenidate in treating ADHD surprisingly has a neurogenetic effect in targeting the genotype of interest. Methylphenidate provides neuroprotective effects throughout the neurodevelopment timeline from childhood to adulthood. Key Messages: The emotional dysregulation element in ADHD which is often overlooked should be addressed to improve the prognostic outcomes in adolescence and adulthood.

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Objective: The study explored associations between personality traits, perceived stress and symptoms of depression in oncological patients characterized by the two variants of the serotonin transporter (5-HTTLPR) polymorphisms. Method: The sample was composed of 41 gynecological cancer patients who completed self-reported questionnaires including the NEO Five-Factor Inventory, the dimension of depression-dejection (D/D) of the Profile of Moods State and the Perceived Stress Scale (PSS). The polymerase chain reaction was also employed to identify genotypes in the serotonin (5HTT) polymorphism. Results: The one-way ANOVA test, across the 5-HTTLPR genotype groups, showed significant effects of the short variants on neuroticism (p=0.009) and of the long variant on agreeableness (p=0.022), as well as a tendency to a statistical significance of the l/l variant on consciousness (p=0.074). Bivariate correlations showed positive correlations of neuroticism with both psychopathological symptoms (D/D r=0.522; PSS r=0.586) in the combined group S, negative association of agreeableness with depression (D/D r=-0.613) and of consciousness with depression (D/D r=-0.750) and perceived stress (PSS r=-0.702) in the group of the long variant of 5-HT-TLPR genotype. Conclusions: Personalized medicine should consider the interaction between genotype and phenotype in reducing levels of clinical psychological distress, highlighting how psychotherapeutic processes should improve patients' quality of life.

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OBJECTIVE: Interaction between the nervous and immune systems may influence emotions, ultimately affecting human health. Cytokines may play a role in developing emotional dysregulation as in alexithymia, a personality construct characterized by the subclinical inability to identify and describe emotions, often associated with several psychiatric and psychosomatic disorders. The proinflammatory cytokine IL-18, with a recognized role in brain functions, may influence serotonin metabolism and appears to be associated with alexithymia. Healthy individuals carrying the long allele (L) of the serotonin transporter gene polymorphic region (5-HTTLPR), and thus having lower concentrations of serotonin in the synaptic cleft, show a greater tendency toward alexithymia, with some gender differences. To explore a potential physiological interaction between IL-18, serotonin neurotransmission, and alexithymia, we investigated whether IL-18 serum levels and 5-HTTLPR are linked to alexithymic traits in healthy subjects. METHODS: We measured IL-18 serum levels in 115 Italian-Caucasian healthy subjects genotyped for 5-HTTLPR allele variants, divided by gender and assessed for alexithymia scores using the 20-item Toronto Alexithymia Scale. RESULTS: IL-18 levels are significantly more elevated in individuals with the LL genotype (n = 25) than in carriers of the short allele (n = 90, p = 0.0073). Specifically, in LL males (n = 11), i.e., the group with the most relevant increase in IL-18, cytokine values positively correlated with difficulty identifying feelings, which is a component of alexithymia (r = 0.634, p = 0.036). CONCLUSIONS: These results indicate a possible novel interaction between IL-18 and the serotoninergic system to mediate emotional unawareness, suggesting putative biological predictors of emotional dysregulation, which in turn can act as a risk factor for a variety of medical conditions in susceptible subjects.

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Road traffic accidents are a serious public health issue, and real-life traffic offences are an excellent indicator of the behavioural tendencies of impulsivity and risk-taking. We have previously reported on short-term efficacy of a brief intervention in driving schools to reduce traffic risks (Paaver et al., Accid. Anal. Prev., 2013; 50, 430-437), and have now addressed the question of whether does the impact of the intervention last for a few years, and whether traffic behaviour and the intervention effect are associated with the serotonin transporter polymorphism (5-HTTLPR) genotype as the central serotonin system is strongly associated with impulse control. Participants of the study were 1866 novice car-drivers (mean age 23.0, SD = 7.2 years). Data on traffic violations were obtained four years after intervention from the police database and on traffic collisions from the national traffic insurance database. DNA samples were available for 767 participants and 5-HTTLPR genotypes were classified using the triallelic model. For the observation period after the intervention, speeding, drunk driving and involvement in traffic accidents were significantly lower in the intervention group. 5-HTTLPR genotype was associated with traffic behaviour: The S'-allele carriers had significantly lower odds for speeding offences and traffic accidents. The lower prevalence of S'-allele carriers among those who had committed speeding offences was statistically significant in females, while the lower prevalence of having been involved in a traffic accident was rather observed in males. Statistically significant intervention effects were observed only in the L'/L' homozygotes who had higher prevalence of traffic incidents. Conclusively, the brief intervention in traffic schools had a significant impact on traffic safety within subsequent four years, and traffic behaviour was associated with the serotonin transporter genotype. These findings suggest that subjects who are less likely to self-regulate their driving habits while gaining experience would benefit from training of impulsivity recognition.

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BACKGROUND AND OBJECTIVES: Prior studies have found that the serotonin transporter gene-linked polymorphic region (5-HTTLPR) interacts with trauma exposure to increase general risk for Posttraumatic Stress Disorder (PTSD). However, there is little knowledge about the effects of the interaction on distinct symptom clusters of PTSD. This study aimed to investigate the relation between the interaction of 5-HTTLPR and earthquake-related exposures and a contemporary phenotypic model of DSM-5 PTSD symptoms in a traumatised adult sample from China. DESIGN: A cross-sectional design with gene-environment interaction (G × E) approach was adopted. METHODS: Participants were 1131 survivors who experienced 2008 Wenchuan earthquake. PTSD symptoms were assessed with the PTSD Checklist for DSM-5 (PCL-5). The 5-HTTLPR polymorphism was genotyped with capillary electrophoresis (CE) in ABI 3730xl genetic Analyzer. RESULTS: Although there was no significant interaction between 5-HTTLPR and traumatic exposure on total PTSD symptoms, respondents with the LL genotype of 5-HTTLPR who were highly exposed to the earthquake experienced lower intrusion and avoidance symptoms than those with the S-allele carriers. CONCLUSIONS: The findings suggest that the 5-HTTLPR may have an important impact on the development of PTSD and add to the extant knowledge on understanding and treating of posttraumatic psychopathology.

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There is substantial evidence for the assumption that particularly heavy cannabis usett is associated with a variety of psychopathologic conditions. Little is known about the relationship between cannabis and anxiety. Prior studies have concluded that cannabis use alone is not sufficient for the development of long-term anxiety, and it has been suggested that cannabis is simply a risk factor that operates in conjunction with other risk factors. One such risk factor may be an individuals' genetic vulnerability. The present study examines the relationship between cannabis use and symptoms of anxiety by taking a developmental molecular-genetic perspective with a focus on a polymorphism involved in the regulation of serotonin. Specifically, we concentrated on changes in cannabis use and symptoms of anxiety over time and differences herein for individuals with and without the short allele of the 5-HTTLPR genotype. Data were from 1424 adolescents over a period of 5 years. We used different statistical analyses to test co-development of cannabis use and symptoms of anxiety throughout adolescence and the possible role of the 5-HTTLPR genotype in this process. Results from different analyses showed that cannabis use is associated with an increase in symptoms of anxiety, but only in carriers of the short allele of the 5-HTTLPR genotype, not in non-carriers. The findings of the present study show first evidence that the links between cannabis use and symptoms of anxiety are conditional on the individuals' genetic make-up.

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Suicidal behavior and self-mutilation can be regarded as the expression of self-directed aggression and both are common in prison populations. We investigated the influence of externalizing behaviors, depressive symptoms, childhood trauma, 5-HTTLPR variants on self-directed aggression (N = 145) in a group of 702 male Italian prisoners. Participants were comprehensively evaluated, including for psychiatric disorders, impulsive traits, lifetime aggressive behavior [Brown-Goodwin Lifetime History of Aggression (BGHA)], hostility, violent behavior during incarceration, depressive symptomatology [Hamilton Depression Rating Scale (HDRS)], childhood trauma [Childhood Trauma Questionnaire (CTQ)]. Logistic regression analysis showed false discovery rate corrected independent main effects of externalizing behaviors: BGHA (P = 0.001), violent behavior in jail (P = 0.007), extraversion (P = 0.015); HDRS (P = 0.0004), Axis I disorders (P = 0.015), CTQ (P = 0.004) and 5-HTTLPR genotype (P = 0.02). Carriers of 5-HTTLPR high (LA LA ), intermediate (LA LG , SLA ) activity variants were more likely to have exhibited self-directed aggression relative to the low activity (LG LG , SLG , SS) variant: high/low: odds ratio (OR) = 2.3, 95% confidence interval (CI) 1.27-4.68, P = 0.007; intermediate/low: OR = 1.96, 95% CI 1.09-3.68, P = 0.025. The CTQ main effect was driven by physical abuse. There was no interactive effect of 5-HTTLPR and CTQ. Secondary logistic regression analyses in (1) all suicide attempters (N = 88) and (2) all self-mutilators (N = 104), compared with controls showed that in both groups, childhood trauma (P = 0.008-0.01), depression (P = 0.0004-0.001) were strong predictors. BGHA, violent behavior in jail predicted self-mutilation (P = 0.002) but not suicide attempts (P = 0.1). This study was able to distinguish differing influences on self-directed aggression between groups of closely related predictor variables within the externalizing behavioral domain. 5-HTTLPR had an independent, variant dosage effect.

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Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype in predicting the emergence of post-traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5-HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5-HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or LG ) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (LA ). These data suggest that 5-HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress.

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We examined transgenerational effects of maternal childhood adversity on child temperament and a functional promoter polymorphism, 5-HTTLPR, in the serotonin-transporter gene (SLC6A4) as potential moderators of such maternal influences in 154 mother-child dyads, recruited into a longitudinal birth cohort study. We examined the interactive effects of maternal childhood experience using an integrated measure derived from Childhood Trauma Questionnaire (CTQ) and Parental Bonding Index (PBI). Triallelic genotyping of 5-HTTLPR was performed. A measure of 'negative emotionality/behavioural dysregulation' was derived from the Early Childhood Behaviour Questionnaire at 18 and 36 months. Negative emotionality/behavioural dysregulation was highly stable between 18 and 36 months and predicted psychosocial problems at 60 months. After controlling multiple demographics as well as both previous and concurrent maternal depression there was a significant interaction effect of maternal childhood adversity and offspring 5-HTTLPR genotype on child negative emotionality/behavioural dysregulation (ß = 1.03, t(11,115) = 2.71, P < .01). The results suggest a transgenerational effect of maternal developmental history on emotional function in the offspring, describing a pathway that likely contributes to the familial transmission of vulnerability for psychopathology.

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Strong evidence links the 5-HTTLPR genotype to the modulation of amygdala reactivity during fear conditioning, which is considered to convey the increased vulnerability for anxiety disorders in s-allele carriers. In addition to amygdala reactivity, the 5-HTTLPR has been shown to be related to alterations in structural and effective connectivity. The aim of this study was to investigate the effects of 5-HTTLPR genotype on amygdala reactivity and effective connectivity during fear conditioning, as well as structural connectivity [as measured by diffusion tensor imaging (DTI)]. To integrate different classification strategies, we used the bi-allelic (s-allele vs l/l-allele group) as well as the tri-allelic (low-functioning vs high-functioning) classification approach. S-allele carriers showed exaggerated amygdala reactivity and elevated amygdala-insula coupling during fear conditioning (CS + > CS-) compared with the l/l-allele group. In addition, DTI analysis showed increased fractional anisotropy values in s-allele carriers within the uncinate fasciculus. Using the tri-allelic classification approach, increased amygdala reactivity and amygdala insula coupling were observed in the low-functioning compared with the high-functioning group. No significant differences between the two groups were found in structural connectivity. The present results add to the current debate on the influence of the 5-HTTLPR on brain functioning. These differences between s-allele and l/l-allele carriers may contribute to altered vulnerability for psychiatric disorders.

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Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel-based morphometry and Freesurfer) in 138 healthy individuals categorized into 'no anxiety' and 'subclinical anxiety' groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours.

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OBJECTIVE: Several studies have implicated the 5-HTTLPR polymorphism in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. The aim of this study was to examine the association between polymorphism in the serotonin transporter gene and citalopram effectiveness in Iranian patients suffering from major depressive disorder (MDD). METHODS: The sample consisted of 104 patients, with Fars ethnic background, who were diagnosed according to DSM-IV-TR criteria. Beck Depression inventory was used to evaluate the severity of the symptoms during the follow-up, and to determine clinical response of the patients at 4th and 8th week, respectively. RESULTS: Our results showed a correlation between the genotype and response to antidepressant drug citalopram, (odds ratios for L/S and L/L were 3.90 (95 percent CI: 1.29- 11.80) and 1.90 (95 percent CI: 0.72-5.08), respectively). CONCLUSION: In conclusion, our results reveal that genetic variation of serotonin transporter is involved in clinical remission of major depressive episodes in Iranian patients after citalopram treatment.

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Evidence for the assumption that cannabis use is associated with depression and depressive symptoms is inconsistent and mostly weak. It is likely that the mixed results are due to the fact that prior studies ignored the moderating effects of an individual's genetic vulnerability. The present study takes a first step in scrutinizing the relationship between cannabis use and depressive symptoms by taking a developmental molecular-genetic perspective. Specifically, we concentrated on changes in cannabis use and depressive symptoms over time in a simultaneous manner and differences herein for individuals with and without the short allele of the 5-hydroxytryptamine (serotonin) transporter gene-linked polymorphic region (5-HTTLPR) genotype. Data were from 310 adolescents over a period of 4 years. We used a parallel-process growth model, which allows co-development of cannabis use and depressive symptoms throughout adolescence, and the possible role of the 5-HTTLPR genotype in this process. We used data from the younger siblings of these adolescents in an attempt to replicate potential findings. The parallel-process growth model shows that cannabis use increases the risk for an increase in depressive symptoms over time but only in the presence of the short allele of the 5-HTTLPR genotype. This effect remained significant after controlling for covariates. We did not find conclusive support for the idea that depressive symptoms affect cannabis use. These findings were replicated in the sample of the younger siblings. The findings of the present study show first evidence that the links between cannabis use and depressive symptoms are conditional on the individual's genetic makeup.

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