Elevated levels of serotonin 5-HT2A receptors in the orbitofrontal cortex of antisocial individuals.

Antisocial behavior (ASB) is characterized by frequent violations of the rights and properties of others, as well as aggressive conduct. While ample evidence points to a critical role of serotonin in the emotional modulation of social responses, the implication of this neurotransmitter in ASB is unclear. Here, we performed the first-ever postmortem analysis of serotonergic markers in the orbitofrontal cortex (OFC) of male subjects with ASB (n = 9). We focused on this brain region, given its well-recognized role in social response and ASB pathophysiology. Given that all individuals also had a substance use disorder (SUD) diagnosis, two age-matched control groups were used: SUD only and unaffected controls. Tissues were processed for immunoblotting analyses on eight key serotonergic targets: tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of brain serotonin synthesis; serotonin transporter (SERT), the primary carrier for serotonin uptake; monoamine oxidase A (MAOA), the primary enzyme for serotonin catabolism; and five serotonin receptors previously shown to influence social behavior: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4. Our analyses documented a significant increase in 5-HT2A receptor levels in the ASB + SUD group compared to SUD-only controls. Furthermore, TPH2 levels were significantly reduced in the SUD group (including SUD only and ASB + SUD) compared to unaffected controls. No difference was detected in the expression of any other serotonergic target. These results are in keeping with previous evidence showing high 5-HT2A receptor binding in the OFC of pathologically aggressive individuals and point to this molecule as a potential target for ASB treatment.

Catechol-O-methyltransferase activity in individuals with substance use disorders: a case control study.

BACKGROUND: Impulsivity and substance use disorders (SUD) have been both associated with changes in dopaminergic processes. In this study, we intended to evaluate the dopaminergic function in imprisoned SUD offenders through the determination of s-COMT activity. METHODS: The study included 46 male individuals from a Portuguese penal institution. The participants were assessed through a battery of standardised instruments: Psychopathy Checklist-Revised (PCL-R), Barratt Impulsivity Scale Version 11 (BIS-11), and the European version of the Addiction Severity Index (EuropASI). In addition, s-COMT erythrocyte activity was evaluated. RESULTS: Overall, 73.9% (n = 34) of the individuals had Antisocial personality disorder (ASPD) and 58.7% (n = 27) presented SUD. We evidenced, for the first time, that, in individuals with SUD, s-COMT activity was correlated with the severity of drug dependence (EuropASI) (p = 0.009), and with BIS-11 factors self-control (p < 0.0001) and non-planning (p = 0.002). CONCLUSIONS: This study opens new perspectives regarding the pharmacological intervention on substance dependence through the interference on dopamine pathways.

COMT Val/Met and Psychopathic Traits in Children and Adolescents: A Systematic Review and New Evidence of a Developmental Trajectory toward Psychopathy.

Psychopathic traits in youth may lead to adult criminal behaviors/psychopathy. The Val158Met polymorphism of catechol-O-methyltransferase (COMT) may influence the risk for psychopathy-related behaviors, while acting as a biomarker for predicting treatment response to dopaminergic medications. The literature shows inconsistent findings, making the interpretation of COMT's role difficult. The aims of this article are (i) to conduct a systematic review to analyze the effects of COMT Val158Met on psychopathic traits in children and adolescents, and (ii) to present new evidence on the developmental trajectory of the association of Val158Met and youth psychopathic traits. For the systematic review, a literature search was conducted using PubMed, EMBASE, OVID Medline and PsychINFO with the search terms for psychopathic traits, Val158Met and age of interest. In our genotype study, the COMT Val158Met genotype of 293 youth with European ancestry was analyzed in association with the psychopathy-related behavior scores from the Child Behavior Checklist and the Psychopathy Screening Device. To examine the potential influence of developmental changes, the sample was split into at or above and below age 13, and analyses were performed in males and females separately. The literature search yielded twenty-eight articles to be included in the systematic review, which demonstrated mixed results on the association depending on environmental factors, sex ratios, age groups and behavioral disorder diagnoses. The results from our genotype study revealed that Met homozygous youth in the below age 13 group and conversely Val carrier youth in the above age 13 group were more likely to display psychopathic traits. To our knowledge, this is the first study to systematically review the effects of COMT Val158Met on psychopathic traits in childhood and adolescence, and to provide new evidence on the changing effects of Val158Met on psychopathy-related behaviors with development. Elucidating the role of the COMT genotype in conjunction with the child versus adolescent stage of development for psychopathic traits may help predict treatment response, and may lead to early intervention and prevention strategies.

Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [(11)C] Harmine Positron Emission Tomography Study.

Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [(11)C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=-0.50 to -0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.

Alpha-amylase reactivity in relation to psychopathic traits in adults.

Recent investigations of the psychobiology of stress in antisocial youth have benefited from a multi-system measurement model. The inclusion of salivary alpha-amylase (sAA), a surrogate marker of autonomic/sympathetic nervous system (ANS) activity, in addition to salivary cortisol, a biomarker of the hypothalamic-pituitary-adrenal (HPA) axis functioning, has helped define a more complete picture of individual differences and potential dysfunction in the stress response system of these individuals. To the authors' knowledge, no studies have examined sAA in relation to antisocial behavior in adults or in relation to psychopathic traits specifically. In the present study, we examined sAA, in addition to salivary cortisol, in a relatively large sample (n=158) of adult males (M age=36.81, range=22-67 years; 44% African-American, 34% Caucasian, 16% Hispanic) recruited from temporary employment agencies with varying levels of psychopathic traits. Males scoring highest in psychopathy were found to have attenuated sAA reactivity to social stress compared to those scoring lower in psychopathy. No differential relationships with the different factors of psychopathy were observed. In contrast to studies of antisocial youth, there were no interactions between sAA and cortisol levels in relation to psychopathy, but there was a significant interaction between pre-stressor levels of sAA and cortisol. Findings reveal potential regulatory deficits in the fast-acting, 'fight or flight', component of the stress response in adult males with psychopathic traits, as well as abnormalities in how this system may interact with the HPA axis.

Monoamine oxidase A regulates antisocial personality in whites with no history of physical abuse.

OBJECTIVE: Preclinical and human family studies clearly link monoamine oxidase A (MAOA) to aggression and antisocial personality (ASP). The 30-base pair variable number tandem repeat in the MAOA promoter regulates MAOA levels, but its effects on ASP in humans are unclear. METHODS: We evaluated the association of the variable number tandem repeat of the MAOA promoter with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ASP disorder (ASPD) traits in a community sample of 435 participants from the Hopkins Epidemiology of Personality Disorders Study. RESULTS: We did not find an association between the activity of the MAOA allele and ASPD traits; however, among whites, when subjects with a history of childhood physical abuse were excluded, the remaining subjects with low-activity alleles had ASPD trait counts that were 41% greater than those with high-activity alleles (P < .05). CONCLUSION: The high-activity MAOA allele is protective against ASP among whites with no history of physical abuse, lending support to a link between MAOA expression and antisocial behavior.

Harsh discipline, childhood sexual assault, and MAOA genotype: an investigation of main and interactive effects on diverse clinical externalizing outcomes.

We studied the impact of MAOA genotype, childhood sexual assault, and harsh discipline on clinical externalizing symptoms (substance problems, adult antisocial behavior, and conduct disorder). Participants were 841 individual twins from the Minnesota Twin Family Study assessed through age 25. MAOA genotype was not associated with differences in any phenotype, nor was there a significant interaction between MAOA and harsh discipline for any phenotype or a significant interaction between MAOA and childhood sexual assault for substance problems. We found evidence that childhood sexual assault interacted with MAOA genotype to predict antisocial behavior and conduct disorder symptoms. Individuals with the low MAOA activity genotype who reported childhood sexual assault had more symptoms than individuals with either the high MAOA activity genotype and/or no history of childhood sexual assault. These findings suggest that the previously reported interaction between MAOA and childhood maltreatment may be specific to the antisocial subset of externalizing disorders.

MAOA methylation is associated with nicotine and alcohol dependence in women.

In recent years, the role of epigenetic phenomenon, such as methylation, in mediating vulnerability to behavioral illness has become increasingly appreciated. One prominent locus at which epigenetic phenomena are thought to be in play is the monoamine oxidase A (MAOA) locus. In order to examine the role of methylation at this locus, we performed quantitative methylation analysis across the promoter region of this gene in lymphoblast lines derived from 191 subjects participating in the Iowa Adoption Studies (IAS). We analyzed the resulting data with respect to genotype and lifetime symptom counts for the more common major behavioral disorders in the IAS, antisocial personality disorder (ASPD), and substance use disorders (alcohol (AD) and nicotine dependence (ND)). We found that methylation status was significantly associated with lifetime symptom counts for ND (P < 0.001) and AD (P < 0.008) in women, but not men. Furthermore, a trend was found for women homozygous for the 3,3 allele to have a higher degree of overall methylation than women homozygous for the 4,4 allele (P < 0.10). We conclude that methylation of MAOA may play a significant role in common psychiatric illness and that further examination of epigenetic processes at this locus is in order.

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence.

To identify sequence variants in genes that may have roles in neuronal responses to alcohol, we resequenced the 5' region of tyrosine kinase B neurotrophin receptor gene (NTRK2) and determined linkage disequilibrium (LD) values, haplotype structure, and performed association analyses using 43 single nucleotide polymorphisms (SNPs) covering the entire NTRK2 region in a Finnish Caucasian sample of 229 alcohol-dependent subjects with antisocial personality disorder (ASPD) and 287 healthy controls. Individually, three SNPs were associated with alcohol dependence and alcohol abuse (AD) (P-value from 0.0019 to 0.0059, significance level was set at P

Adolescent girls and criminal activity: role of MAOA-LPR genotype and psychosocial factors.

Recent findings among boys show that interactions between a polymorphism in the monoamine oxidase A gene promoter region (MAOA-LPR) and psychosocial factors predict criminal activity. The objective of this study was to investigate whether this finding could be extended to adolescent girls. One hundred nineteen female adolescents were recruited among respondents to a cross-sectional study of the total population of 16- and 19-year old girls. These girls constituted a randomly selected sub-sample from groups representing different degrees of risk behavior. The subjects filled in a questionnaire and were interviewed and genotyped with regard to MAOA-LPR. The results indicate that the long, (4-repeat) allele confer an increased risk for criminal behavior in the presence of psychosocial risk. Among girls without social risk, MAOA-LPR genotype was of no importance for criminal behavior. The present results suggest that previous observations on adolescent males, which demonstrate that the short MAOA-LPR genotype and psychosocial adversity interact to predict criminal activity, may not be applicable to females.

Childhood maltreatment, subsequent antisocial behavior, and the role of monoamine oxidase A genotype.

BACKGROUND: A functional promoter polymorphism in monoamine oxidase A (MAOA) has been implicated as a moderating factor in the relationship between childhood maltreatment and later adolescent and adult antisocial behavior. Despite wide interest in this hypothesis, results remain mixed from the few attempts at replication. METHODS: Regression-based analyses were conducted to test for a genotype-environment interaction using self-reported physical abuse and MAOA genotype to predict later antisocial behavior and arrests for violence by participants in the National Youth Survey Family Study. We also examined the interaction using a measure of violent victimization. The analysis sample included 277 Caucasian male respondents, aged 11-15 in 1976, who provided buccal swab DNA samples and who were successfully genotyped for the variable number tandem repeat (VNTR) in the MAOA promoter using polymerase chain reaction. RESULTS: Maltreatment by a parent during adolescence was a risk factor for adolescent and adult antisocial and violence related behavioral problems. Tests for the main effect of MAOA and a MAOA-maltreatment interaction were nonsignificant. Similar results were obtained using the measure of adolescent violent victimization. CONCLUSIONS: Findings from this general population sample could not confirm the hypothesis that MAOA moderates the relationship between adolescent maltreatment and adolescent or adult antisocial behavior.

MAOA and the "cycle of violence:" childhood abuse and neglect, MAOA genotype, and risk for violent and antisocial behavior.

BACKGROUND: Two recent studies with white males have shown that genotypes associated with high levels of monamine oxidase A (MAOA) protect against the impact of childhood maltreatment and adversity on the development of antisocial behavior and conduct disorder. METHODS: Participants in a prospective cohort design study involving court substantiated cases of child abuse and neglect and a matched comparison group were followed up into adulthood and interviewed (N = 802). Eighty-two percent consented to provide blood and 631 gave permission for DNA extraction and analyses. A composite index of violent and antisocial behavior (VASB) was created based on arrest, self-report, and diagnostic information. RESULTS: No main effect was found for the relationship between MAOA genotype and VASB. Genotypes associated with high levels of MAOA activity buffered abused and neglected whites from increased risk of becoming violent and/or antisocial in later life. This protective effect was not found for non-white abused and neglected individuals. CONCLUSIONS: Possible explanations for this differential effect for whites and non-whites include differences in contextual factors (e.g., environmental stressors) and a question of the suitability of using the MAOA promoter VNTR polymorphism as a proxy for MAOA levels in non-white populations.

MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis.

Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.

Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity.

BACKGROUND: A number of important sociological, psychological, and biological predictors of adolescent criminal behavior have been identified during the most recent decades. The aim of this study was to replicate recent findings that interactions between a polymorphism in the monoamine oxidase A (MAO-A) gene promoter region and psychosocial factors might predict male adolescent criminal activity. METHODS: A cross-sectional study with a randomized sample from the total population of 16- and 19-year-olds from the county of Västmanland, Sweden. Eighty-one male adolescents, who volunteered to participate, were randomly selected from groups representing different degrees of deviant risk behavior. RESULTS: The present study strongly supports the notion that carrying the 3-repeat allele of the MAO-A-gene promoter increases the risk of male adolescent criminal behavior, when interacting with psychosocial factors. No effects at all of the MAO-A genotype on adolescent criminal activity were found when MAO-A genotype was considered alone (i.e., without its psychosocial context). The explained variance of the bio-psychosocial model (controlling for MAO-A) in this study exceeded the psychosocial model by 12%. CONCLUSIONS: The findings support the notion that genotype and psychosocial factors interact to precipitate male adolescent criminal behavior.

The role of monoamine oxidase A, MAOA, in the aetiology of antisocial behaviour: the importance of gene-environment interactions.

Reports from both human studies and animal models suggest that MAOA may have a key role in aggression. Differences in the copy number of a repeat motif in the promoter of MAOA appear to regulate its activity. We review the evidence that suggests activity levels of this enzyme may play a key role in modulating antisocial/aggressive behavioural outcomes. Two common alleles in the human population have been identified which confer either high or low transcriptional functionality. The gene is X-linked and males can, therefore, be typed as 'low' or 'high' types. A key feature that has emerged from both our own studies and replicated recently by others, is that high activity variants of the gene appear to confer a protective influence against maltreatment, such that maltreated males with a high-MAOA activity genotype were less likely to develop antisocial problems, an observation that may explain part of the variability in developmental outcomes associated with maltreatment.

Monoamine oxidase A (MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment.

There is a robust relationship between the experience of maltreatment in childhood and later antisocial behaviors amongst adolescents and adults. Animal and human studies suggest that variation in monoamine oxidase A (MAOA) genotype may moderate the effects of maltreatment. Self-reported conduct problems and criminal convictions amongst sibling-pairs from the National Longitudinal Study of Adolescent Health were tested for association with reports of maltreatment before and after the age of 12. MAOA promoter polymorphisms were tested for possible moderation effects. Maltreatment predicted conduct problems and criminal convictions. MAOA genotype did not have a significant moderating effect in any of the six analyses that were conducted. We did not replicate a previous report that MAOA polymorphisms moderated the relationship between maltreatment and conduct problems. There was, however, a non-significant trend in the predicted direction. Additional studies will be needed before firm conclusions can be drawn about this hypothesized genotype-environment interaction.

Neither antisocial personality disorder nor antisocial alcoholism is associated with the MAO-A gene in Han Chinese males.

BACKGROUND: Recent studies on the genetics of alcoholism have suggested an association between antisocial alcoholism and the MAO-A gene. However, previous studies have failed to include subjects with antisocial personality disorder without alcoholism even though there is a high comorbidity between antisocial personality disorder and alcoholism. Consequently, the finding of an association between the MAO-A gene and alcoholism or antisocial personality disorder seems tenuous. In Taiwan, about 70% of the Han Chinese population have the ADH2*2 allele and 50% show ALDH2*1/*2 or ALDH2*2/*2 genotypes, which offer protection against drinking behavior and the risk of developing alcoholism. Thus, it is possible to recruit individuals with antisocial personality disorder but without alcoholism in Taiwan. Therefore, association studies of alcoholism or antisocial personality disorder in Chinese may be more reliable if pure antisocial alcoholics, pure antisocial personality disorders, and normal controls as MAO-A gene are examined. METHODS: In this study, the associations among antisocial alcoholism, antisocial personality disorder, and the uVNTR and EcoRV polymorphisms of the MAO-A gene, both individually and as a haplotype, were investigated among male adults recruited from jails in Taipei. A total of 129 Chinese Han males were studied, including 41 with antisocial personality disorder with alcoholism, 50 with antisocial personality disorder but without alcoholism, and 38 without either disorder as a jail control group. The diagnoses of alcohol dependence and antisocial personality disorder were made according to DSM-IV criteria. In addition, 77 normal controls were collected from the community. RESULTS: Strong linkage disequilibrium was found for the uVNTR and EcoRV variants of MAO-A gene in each study group. CONCLUSIONS: No significant association was observed between these two polymorphisms and antisocial personality disorder with alcoholism, either individually or for the haplotype, or for antisocial personality disorder without alcoholism. Thus, neither antisocial alcoholism nor antisocial personality disorder was associated with the genetic variants of MAO-A gene.

No association between a polymorphism in the promoter region of the MAOA gene with antisocial personality traits in alcoholics.

AIMS: We analysed the MAOAuVNTR functional polymorphism in the promoter region of the X-chromosomal monoamine oxidase A (MAOA) gene. Genotypes with three-repeat alleles were reported to be associated with antisocial as well as impulsive traits. METHODS: The repeat number (3-5) of the MAOA polymorphism was determined in 169 male alcoholic subjects and 72 controls of German descent. Behavioural and personality traits were evaluated using the Brown-Goodwin Assessment for History of Lifetime Aggression, the Buss Durkee Hostility Inventory, as well as the Barrat Impulsiveness Score. A median split in Brown-Goodwin, Buss Durkee Irritability, Buss Durkee Assault and Barrat Impulsiveness Score was conducted. RESULTS: High scores were found, i.e. 47.9% in Brown-Goodwin, 65.7% in Buss Durkee Irritability, 63.3% in Buss Durkee Assault and 59.8% in Barrat Impulsiveness Scale, indicating high impulsiveness, irritability and antisocial behaviour. Based on the results of these questionnaires, we detected no significant differences between the frequency of the three-repeat allele and high or low scores in alcoholics and controls. CONCLUSIONS: Taken together, these findings suggest that the three-repeat allele of the MAOAuVNTR 30-bp polymorphism is not associated with impulsive and aggressive personality traits.

Role of genotype in the cycle of violence in maltreated children.

We studied a large sample of male children from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not. A functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. These findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provide epidemiological evidence that genotypes can moderate children's sensitivity to environmental insults.