International Journal of Law and Psychiatry 32 (2009) 235–243

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International Journal of Law and Psychiatry

The relation of ADHD and violent aggression: What can we learn fromepidemiological and genetic studies?

Wolfgang Retz ⁎, Michael RöslerInstitute for Forensic Psychology and Psychiatry, Neurocenter – Saarland University Hospital, Homburg/Saar, Germany

⁎ Corresponding author. Tel.: +49 6841 1626350; faxE-mail address: wolfgang.retz@uniklinik-saarland.de

0160-2527/$ – see front matter © 2009 Elsevier Ltd. Aldoi:10.1016/j.ijlp.2009.04.006

a b s t r a c t

a r t i c l e i n f o

Keywords:

ADHDViolenceGenesEnvironmentSerotoninPsychopathy

Disruptive behavior includes psychopathological and behavioral constructs like aggression, impulsivity,violence, antisociality and psychopathy and is often closely related with diagnostic categories like conductdisorder (CD), attention deficit disorder (ADHD) and antisocial personality disorder (ASP). There is now clearevidence that neurobiological and environmental factors contribute to these phenotypes. A mounting body ofevidence also suggests interactive effects of genetic and environmental risks.In this selective review we give an overview over epidemiological aspects of the relation between ADHD andantisocial behavior, including violent aggression and psychopathy. Moreover, we summarize recent findingsfrom molecular genetic studies and particularly discuss pleiotropic effects of a functional polymorphism ofthe serotonin transporter promoter gene (5HTTLPR) and childhood adversity on ADHD and violent behavior.The reported gene–environment interactions are not only informative for understanding the neurobiologicalunderpinnings of disruptive behavior, but also throw some light on the relation between ADHD and violentbehavior from a genetic perspective. The impact of genetic research on forensic psychiatry and futuredirections of neurobiological research are discussed.

© 2009 Elsevier Ltd. All rights reserved.

1. Introduction

Social maladaptive, disruptive behavior arises from several condi-tions including genetic disposition aswell as cultural and social factors,which are enforced on the background of the individual's experiences(Fig. 1). Important progress has been made in identifying genetic riskfactors that predispose to antisocial behavior (Raine, 1993; Volavka,2002). Also much progress has been made in uncovering psychosocialrisk factors for antisocial and violent behavior (Farrington, 2000;McCord, 2001). The discussion in the past regarding the role of“nature” and “nurture” has been now followed by research on inter-action between genetic and environmental influences on the devel-opment of disruptive behavior (Raine, 2002).

Beside research on the influence of genes and environment withdisruptive behavior, investigations concerning the association withpsychiatric disorders provide an additional source to elucidate theneurobiological and environmental underpinnings of aggression,violence and antisociality. Among other psychiatric disorders likeschizophrenia, suicidal depression and cluster B personality disorders,attention deficit/hyperactivity disorder (ADHD) is of particularinterest in this context, because it is characterized by psychopatho-logical complex of attentional problems, motor overactivity andimpulsivity, which is per se closely linked to behavioral problems. In

: +49 6841 1626335.(W. Retz).

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addition, this disorder starts early in life and, therefore, is suggested tohave high impact of an individual's socialization.

In this report we summarize some work concerning geneticinfluences on ADHD and violent behavior with a focus on genesinvolved in the regulation of serotonergic neurotransmission. Thiswork also turns towards the question of gene–environment interac-tions in the etiology of ADHD and violent aggression and sheds somelight on the relation of violence and ADHD from a genetic perspective.

1.1. Genetics of antisocial behavior

Despite the heterogeneity of definitions and classifications usedand the difficulties regarding operationalization and assessment ofantisocial behavior phenotypes, there is clear evidence from twin,adoption and molecular genetic studies to support the notion thatthere are genetic influences on antisocial and aggressive behavior(Raine, 1993). It has to be emphasized that the variability of findingsregarding the magnitude of environmental and genetic contribution ishigh. This variability is not only attributable to differences betweenthe investigated populations, but also to the difficulties in the mea-surement of disruptive disorders or antisocial behavior. The composi-tion of well observable behavioral (e.g. violence, verbal aggression)and psychopathological features (e.g. unemotionality, hostility)differs profoundly between the investigated phenotypes. Moreover,there is often a fluent passage between phenotypes which should bedelineated. For instance, an aggressive act might present features of

Fig. 1.Model of the development of disruptive behavior. Positive and negative, pervasive and situative environmental factors modulate genetic disposition for disruptive behavior interms of e.g. social maladaptation, aggression and violence. Genetic susceptibility genes include genes involved in monoaminergic neurotransmission: catecholamine-O-methyl-transferase (COMT), monoamine oxidase A (MAOA), serotonin transporter (5-HTT), tryptophane hydroxylase 2 (TPH2) and neuronal nitric oxide synthetase (NOS1). This model alsoincludes putative interactions between genetic and environmental factors.

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proactive and reactive aggression that might provide problemsregarding unequivocal classification.

In a meta-analysis of 51 twin and adoption studies Rhee andWaldman (2002) estimated moderate genetic (additive 32%, non-additive 9%) and environmental influences (shared 16%, non-shared43%) on antisocial behavior. More specifically, moderate heritabilityhas been also found for violent behavior (Cloninger & Gottesman,1987; Rushton, 1996). Twin- and adoption studies also provideinformation which go beyond pure quantification of genetic andenvironmental effects. One example is the evaluation of genderdifferences. It has been shown that the magnitude of environmentaland genetic influences on antisocial behavior is equal for males andfemales (Rhee & Waldman, 2002; Widom & Ames, 1988), but also aslightly higher genetic load in males was found (Miles & Carey, 1997).Given the higher prevalence of antisocial behavior in males thanfemales and the little or absent difference in the magnitude of geneticeffect on antisocial behavior, different genes or environmental factorsor both might be important within each sex.

Another important issue are developmental changes of the geneticand environmental impact on antisocial behavior phenotypes. AlthoughRhee and Waldman (2002) found a decrease of familial genetic andenvironmental factors and an increase of non-familial factors fromchildhood to adulthood, the direction of difference regardingheritabilityvaries across studies (DiLalla & Gottesman, 1989; Miles & Carey, 1997).These discrepancies might be partially due to confounding methods ofmeasurement of behavioral phenotypes, but also to various subtypes ofindividuals with different life-course patterns of antisociality (e.g. life-course persistent vs. adolescence-limited; Moffitt, 2003).

But not only differentiation of developmental subtypes, but alsomore detailed psychopathological characterization of antisocialbehavior reveals additional information from twin- and adoptionstudies. Examples for this are the finding that continuous aggressivebut not non-aggressive antisocial behavior is largely geneticallymediated (Eley, Lichtenstein, & Moffitt, 2003) or that antisocialbehavior is more heritable in children with thanwithout concomitantcallous-unemotional personality traits (Viding, Jones, Frick, Moffitt, &Plomin, 2008). It could also be demonstrated that the importance ofgenetic and environmental influences varies regarding subgroups ofindividuals with antisocial behavior, if measures of attention deficitdisorder, conduct and oppositional disorder and other psychopatho-

logical features were used for latent class analysis (Silberg et al., 1996),suggesting heterogeneity of antisocial behavior and emphasizing theneed for multivariate approaches for studying phenotypes relatedwith antisociality.

Further, adoption studies provide substantial evidence thatenvironmental and genetic risks interact. For example in a Swedishstudy 40% of adoptees were criminal when both genetic and postnatalenvironmental risks were present, but only 12.1% and 6.7% werecriminal in presence of either genetic or environmental risks,respectively (Cloninger, Sigvardsson, Bohman, & von Knorring,1982). These results suggest a non-additive but interactive effect ofgenetic and environmental risks for antisocial behavior.

Molecular genetic linkage and association studies have now justbegun to reveal the architecture of antisocial behavior more in detail.Results from few linkage studies regarding conduct disorder andantisociality performed so far are not consistent (Dick et al., 2004,2008; Kendler et al., 2006; Stallings et al., 2005). Association studieshave mainly focused on risk genes which are involved in the regulationof monoaminergic neurotransmission. They include catecholaminergicand serotonergic genes, but also genes which have been related toaggressive and violent behavior due to animal models, like the nitricoxide synthase (NOS-I) gene (Reif et al., 2009). For example, dopaminereceptorD2 (DRD2) anddopamine receptorD4 (DRD4) genevariants andinteraction between them are associated with conduct disorder andantisocial behavior (Beaver et al., 2007; Congdon, Lesch, & Canli, 2008).Also the catechol-o-methyltransferase (COMT) genehas been associatedwith increased aggressive behavior, at least in several samples ofpsychiatric patients (Volavka, Bilder, & Nolan, 2004). Most evidenceregardinggenetic regulation of antisocial behaviorhas been collected forserotonergic genes and will be outlined below.

Although suggested from epidemiological genetic investigations, thestudy of gene–environment interactions is still quite new in the field ofneuroscience (Caspi & Moffitt, 2006). Several lines of investigationsprovide increasing evidence that the effect of environmental pathogenson the development of mental disorders or behavioral traits includingantisocial behavior is conditional on the individual's genotype. Thesecomprise experiments with animalmodels, which allow to control bothgenetic and environmental conditions and studies that compare humangenotype groups on their response to environment.Moreover, theuse ofneuroimaging or neurophysiological techniques allows identifying

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functional and anatomical networks, which are involved in the responseto environmental stimuli in experimental settings. For example, it couldbe shown that amygdala volume andprefrontal and amygdala activationin response of emotional stimuli is mediated by the MAO-A genotype(Meyer-Lindenberg et al., 2006). Thus, combination of epidemiologicalgenetics with neuroscientific techniques allows progressing insight inthe mechanisms of the genetic control of environmental effects inmental disorders or antisocial behavior.

2. ADHD and antisocial behavior

Attention deficit-/hyperactivity disorder (ADHD) is a highlyheritable, disruptive condition with childhood onset and about 50%persistence in adulthood (Biederman & Faraone, 2005). ADHD isassociated with risks regarding daily functioning (Barkley, 2002). Thenumber of jobs in a given time period is increased as well asseparation and divorce rates. Many adults with ADHD have difficultieswith bad parenting. The risk of accidents at home, school, and voca-tional affairs and during leisure is much higher than in controls. Evenin cases of severe injury due to an accident ADHD is significantlyoverrepresented (Kaya et al., 2008). The risk of violations of the roadtraffic rules in adults with ADHD ismuch higher. According to a reviewby Jerome, Habinski, and Segal (2006) speeding, driving underalcohol, driving without licence and a much higher prevalence ofaccidents are the most frequent problems in ADHD populations whencomparing with individuals without ADHD.

According to recent epidemiologic research the transnationalprevalence of ADHD in adults was 3.7% (Fayyad et al., 2007). In theUSA a prevalence of 4.4% (Kessler et al., 2006) and in Germany aprevalence of 3.1% was found, respectively. In contrast, in offenderpopulations the prevalence of adult ADHD varies between 4% and 72%(Vermeiren, 2003). The majority of studies found prevalence ratesbetween 14% and 19%. In a German study with 129 male adolescentand young adult incarcerated subjects the prevalence of ADHDaccording to DSM-IV was 45% (Retz, Retz-Junginger, Hengesch et al.,2004; Rösler et al., 2004). Also among female detainees the rate ofADHD is higher compared to normal population (10%; Rösler, Retz,Yaqoobi, Burg, & Retz-Junginger, 2009). The high variety of findingsconcerning prevalence rates of ADHD in offender populations mightbe due to differences between the samples investigated, differentcriminal law systems, differences regarding the mean age of studypopulations and diagnostic procedures. Nevertheless, there is muchevidence that ADHD is increased in forensic populations.

Conduct disorder (CD) – and early-onset (before age 10 years) CDin particular – is highly prevalent in ADHD children (Angold, Costello,& Erkanli, 1999; Loeber, Green, Keenan, & Lahey, 1995). There is acontroversial discussion regarding the problem whether ADHD,comorbid CD or both conditions predict antisociality and criminalbehaviour in adults with ADHD. From a genetic perspective it has beenargued that ADHD with comorbid CD might be a more severe variantof ADHD and not distinct disorders (Dick, Viken, Kaprio, Pulkkinen, &Rose, 2005; Nadder, Rutter, Silberg, Maes, & Eaves, 2002; Thapar,Harrington, & McGuffin, 2001). Babinski, Hartsough, and Lambert(1999) found that conduct problems and hyperactivity/impulsivitybut not inattention contributed to the risk of criminal involvement in agroup of male offenders with recidivistic crimes. On the other hand,themajority of studies suggested that CD and not ADHD predicts adultantisociality (Lahey, Loeber, Burke, & Applegate, 2005; Satterfieldet al., 2007). Since the diagnostic criteria for CD do not refer topsychopathological symptoms, but exclusively to disruptive behaviorincluding criminal acts, it seems a truism to predict antisociality andcriminality in adulthood by “criminal” conduct in childhood andadolescence and does not elucidate the specific role of comorbidADHD for the development of delinquent behavior. Other studies,however, consistently emerged ADHD as a moderator of conductproblems in children. It seems that the decision over antisocial

outcome of ADHD children is given early. Numerous studies haveshown that children with both CD and ADHD, as compared withchildren with conduct problems alone, tend to have an earlier onsetand a more stable course of antisocial behavior (Loeber et al., 1995;Moffitt, 1990). As a result of such findings, the presence or absence ofADHD has become one key component of children's CD that is early“delinquent” behavior (Moffitt, 2003).

3. ADHD, antisocial personality disorder (ASP) and psychopathy

Follow-up studies with ADHD children revealed high rates ofAntisocial Personality Disorder (ASP) in later life (Barkley, Fischer,Smallish, & Fletcher, 2004; Mannuzza, Klein, Bessler, Malloy, &LaPadula, 1998; Satterfield & Schell, 1997; Weiss, Hechtman, Milroy,& Perlman,1985). They exceed by far an expected rate of accidental co-occurrence of both disorders of 0.06%, given an estimated prevalenceof adult ADHD of about 3% and a prevalence for ASP from populationbased epidemiological studies of about 2%. Interestingly, a highproportion of ADHD children without CD at time of inclusion in theNew York follow up studies (Mannuzza, Klein, Bessler, Malloy, &LaPadula, 1993) were diagnosed with ASP in later life, suggesting thatearly onset CD is not a necessary condition for later ASP. Moreover,Satterfield et al. (2007) published the results of a 30-year prospectivefollow-up study of hyperactive boys with conduct disorder and foundthat there was a steady decline in offence rates with increasing age.Thus, conduct problems which occur together with ADHD duringchildhood and adolescence may persist in adulthood as ASP and seemto be followed by decline of both, ADHD and antisociality. It shouldbe considered that ASP in context with ADHD might represent aspecial subtype of ASP, but more studies are needed to confirm thishypothesis.

The concept of psychopathy (Hare, 1996) refers to a core populationof ASP individuals and goes beyond bare description of antisocialbehavior. Psychopathy according to Hare comprises traits dealing withinterpersonal and affective deficits (e.g. shallow affect, superficialcharm, manipulativeness, lack of empathy) and symptoms relating toantisocial behavior (e.g. criminal versatility, juvenile delinquency). Thisconstruct goes back to the beginning of the 19th century when Prichard(1835) described the psychopathology of “moral insanity”. Psychopathyis associatedwith poor treatment response and the forensic prognosis isunfavourable in almost all cases. The total score of the PsychopathyChecklist (PCL; Hare et al., 1990) is a valid risk factor indicating criminaloffences and in particular violent behavior. Psychopaths are a smallpopulation but they account for an excess quantity of felony crimes andfor criminal recidivism. An association between ADHD and thepsychopathy concept could be assumed since there is certain overlapbetween the DSM-IV items referring to the syndromatic complex ofhyperactive–impulsive features inADHDand thePCL factor focussingonpoor behaviour control and impulsivity. However, if the hypothesisis true that ASP in combination with ADHD represents a subtypewith more favourable prognosis, it should be able to differentiatethese individuals from psychopaths in terms of psychopathology andoutcome.

In order to elucidate the relation between ADHD and psychopathy,we conducted a study with 230 incarcerated male subjects. All hadcommitted felony crimes andwere incarcerated for more than 2 years.ADHD syndrome and psychopathy scores were established by meansof the ADHD self report scale (Rösler et al., 2006) and the PCL-SV,respectively. We found a rank correlation of 0.2 between PCL-SV andADHD-SR mean scores, which was statistically significant (p≤0.01),but clinically not meaningful. In order to investigate possibleassociations between features of psychopathy and diagnostic ADHDcriteria we performed a factor-analysis. We expected to find factors ofcommon psychopathology in the case of an association betweenADHD and psychopathy. A seven factors model accounted for 60% ofthe variance. No factor comprised items from both concepts, but there

Fig. 2. Non-violent, reactive and proactive violent behavior in offenders with childhoodADHD (partially remitted), persistent ADHD and without ADHD. (according to Retz &Rösler, 2007) Statistics: χ2=21.0, p=.000, Odds ratio (reactive vs. proactive violencein ADHD): 2.7; 95% CI: 1.5–107.9).

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were 3 pure ADHD and 4 pure psychopathy factors (Retz & Rösler,2007). It is apparent from this finding that there is no associationbetween diagnostic items of ADHD with those of psychopathy in thesample under investigation, suggesting different pathways of anti-social behavior in psychopaths and ADHD subjects. In accordancewiththis finding Fowler and colleagues recently reported elevated totalpsychopathy and emotional-dysfunction scores according to norms inADHD adolescents, but none scored in the clinical range of psycho-pathy (Fowler et al., 2009). More specifically, Eisenbarth et al. couldshow an increase of behavioral features of psychopathy in adult ADHDpatients, but a reduction of emotional features like coldheartednessand stress immunity compared to controls (Eisenbarth et al., 2008).

4. ADHD and aggression

Aggressive behavior is a common phenomenon accompanyingchildhood ADHD (Barkley, 1998; Hinshaw, 1992). Considering hetero-geneity of aggression and violence which is often associated withdelinquent behavior, a sensible construct has been created inhypothesizing a dichotomy between a reactive–impulsive–hostile–affective subtype and a proactive-controlled-instrumental-predatorysubtype of aggressive and violent behavior (Vitiello & Stoff, 1997). Inchildren with conduct problems, it has been shown that ADHD is amoderator of reactive but not proactive aggression (Waschbusch &Willoughby, 2007). In addition, Bennett, Pitale, Vora, and Rheingold(2004) showed that reactive antisocial behavior was more closelyrelated to ADHD than proactive antisocial behavior in 8 to 15 year oldchildren and that the relation between ADHD symptoms andproactive antisocial behavior increased from middle childhood toadolescence. Association of ADHD with reactive aggression seemsplausible with regard to the characteristic psychopathology of ADHD.Reactive aggression is not planned but always spontaneous, a reactionto a provocation or a conflict. Reactive aggression is driven by affectiveoutbursts. It is short-lived and has no finalistic target except thereduction of tension and agitation. Usually reactive violence is notrationale but impulsive. There is no systematic or instrumentalcharacter of aggressive actions. In so far, there are some similaritiesto the hyperactive–impulsive psychopathology of ADHD.

Following the hypothesis that reactive, but not proactive aggres-sion is associated with ADHD in adult offenders, we performed a pilotstudy with 66 males from a forensic population with and withoutADHD, which has been previously described (Reif et al., 2007; Retzet al., 2008). We found a strong association between the presence ofADHD and reactive violent aggression (χ2=21.0, p=.000, OR: 2.7;95% C.I: 1.5–107.9, Retz & Rösler, 2007). In contrast, proactive violentaggression was found predominately in absence of ADHD (Fig. 2).These results corroborate the findings in ADHD children and have tobe further elaborated.

Concerning the epidemiological findings mentioned above, thepathways from childhood ADHD to functional disabilities andantisocial behavior in adulthood are summarized in Fig. 3.

5. ADHD, serotonergic genes and environment

Genetic epidemiological studies indicate heritability of ADHD up to90% (Thapar, Holmes, Poulton, & Harrington, 1999). Up to now, only afew genome-wide linkage studies have been performed, indicating thatseveral chromosomal regions are implicated in ADHD.Moreover, a largenumber of association studies have been realized, inspired by highevidence of monoaminergic dysfunction in ADHD (Pliszka, McCracken,& Maas, 1996). Replicated and in pooled analyses confirmed findingssuggest significant association of ADHD with the dopamine D4 and D5receptor genes and the dopamineDAT1 transporter gene (Faraone et al.,2005). In addition, there is a mounting body of evidence suggesting anassociation of ADHD with genes involved in the regulation of sero-tonergic transmission. Independent replicated associations have been

reported regarding ADHD and the serotonin transporter gene (5HTtransporter linked polymorphic region, 5HTTLPR). Association of thelong (L) 5-HTTLPR allele and the long/long (LL)-genotype, respectively,has been demonstrated by different groups using population-based andfamily-based case control studies (Beitchman et al., 2003; Manor et al.,2001; Seeger, Schloss, & Schmidt, 2001; Zoroglu et al., 2002) andquantitative trait loci approaches (Retz, Thome, Blocher, Baader, &Rösler, 2002; Curran, Purcell, Craig, Asherson, & Sham, 2005). Kent et al.(2002) reported a small but significant associationwhen they analysedpooled data from three studies, but only a statistical trend in their ownstudy, but there are also studieswhichdidnot corroborate thesefindings(Langley et al., 2003).

Although genetic epidemiological and molecular genetic studiesclearly indicate a crucial impact of genes in the etiology of ADHD,heritable factors only partially explain the pathogenesis of thisdisorder. The work of Rutter and colleagues emphasized the role ofpsychosocial environmental factors including family conflict, socialclass, family size, maternal psychopathology, and paternal criminalityfor the risk for child psychopathology (Rutter, 1999). These findingswere confirmed in recent studies particularly with regard to ADHD,which could also show, that males are more vulnerable to environ-mental adversity than female subjects (Biederman et al., 1995,Biederman, Faraone, & Monuteaux, 2002). Additionally, recent studiessuggest that association of 5-HTTLPR with behavioural phenotypesand certain disease states may depend on environmental influencesand individual life-history experiences (Barr et al., 2003; Caspi et al.,2003; Fox et al., 2005; Sjöberg et al., 2005). They also indicate thatgenetic regulation of serotonergic neurotransmissionmay be sensitiveto environmental influences (Bennett et al., 2002; Manuck, Flory,Ferrell, & Muldoon, 2004).

Recently, we have reported the association of the 5HTTLPRLL-genotypewith childhood ADHD symptoms and persistent ADHD in aforensic population (Retz et al., 2008). The results confirmed priorfindings of an association of the ADHD phenotypewith the long allele ofthe 5-HTTLPR (Retz et al., 2002) and a significant impact of adversechildhood environment on childhood ADHD symptomatology, whichhas been suggested in several studies before (Biederman et al., 1995,2002). It was also shown that interaction between the 5-HTTLPR andenvironmental conditions has a significant influence on ADHDsymptomatology (Fig. 4a). In this study, carriers of the LL-genotypehad a higher risk for presentingmoreADHD symptoms,when childhoodpsychosocial adversity was low. There was only little increase of ADHDpsychopathology in these individuals under unfavourable environmen-tal conditions. By contrast, carriers of at least one S-allele were muchmore responsive to adverse environment regarding the development of

Fig. 3. Pathways from ADHD to delinquent behavior. ADHD (mainly combined and hyperactive/impulsive subtype) are frequently associated with early-onset and to a much lesserextent to adolescent-onset conduct disorder (CD). Individuals with ADHD + CD are likely to develop Antisocial Personality Disorder (ASP) combined with ADHD (also partiallyremitted subtype). This developmental subtype of ASP is only weakly related to psychopathic personality traits (according to Hare) and more frequently associated with reactive–impulsive than with premeditated–proactive violent aggression. “Pure” ADHD (without CD) also leads to social problems and is associated with rule braking behavior like trafficviolations, but the rate of violent aggression and general delinquency is not elevated. Substance use disorders (SUD) are important moderators for antisocial behavior related toADHD. The percentage values refer to the total population of persons with ADHD.

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ADHD symptomatology. The results suggested that the 5-HTTLPRmediated risk for ADHD is moderated by environmental adversity andthat the impact of environment depends on an individual's geneticbackground. This finding is in agreement with experiments with 5-HTTknock-out mice, which exhibit an increased stress-responsive pheno-type (Murphy et al., 2001). They also corroborate the findings of Caspiet al. (2003), whowere able to demonstrate that the relation of stressfullife-events on affective disturbances is moderated by the 5-HTTLPRgenotype with highest vulnerability in carriers of the SS-genotype.Similar findingswere reported byWilhelm et al. (2006). Under the lightof these studies the LL-genotype does not simply increase the risk forADHD psychopathology, at least under favourable environmental con-ditions, but seems to have protective effects against adverse environ-mental influences on serotonergic brain function.

6. Violence, serotonergic genes and environment

So far, genetic studies in humans concerning aggressive behaviorhave mainly focused genes involved in the regulation of serotonergicneurotransmission. Indeed, since socio-psychological research under-scores the relation between cognition, emotion, and aggression, itappears reasonable that neural circuitries that affect emotional states,like the central serotonergic system, also affect the predispositiontowards aggressive behaviors. Serotonergic susceptibility genes forhuman aggression include the monoamino-oxidase A (MAOA) gene,the serotonin transporter promoter gene (5HTTLPR), the tryptophanehydroxylase 2 (TPH2) gene and the serotonin receptor 1a and 1b(5HTR1a and 5HTLPR1b) genes (Papova, 2006).

In the last years molecular genetic studies provided also evidencesuggesting interactive effects of biological and social factors ondisruptive behavior. Gene–environment interactions in the develop-ment of aggressive behavior were demonstrated for childhoodmaltreatment and the MAOA gene (Caspi et al., 2002; Foley et al.,

2004; Huang et al., 2004). Data from the Dunedin longitudinal study(Caspi et al., 2002) suggested that childhood maltreatment is a riskfactor for conduct disorder, antisocial personality disorder and violentbehavior. High MAO-A activity, i.e. long MAOA alleles, protectedagainst the development of violent behavior in the presence ofchildhood maltreatment, whereas short MAOA alleles predisposedtowards violent behavior, at least in case of exposure to childhoodmaltreatment. Likewise, low-activity MAOA alleles could be foundmore often in conduct disorder exclusively in the presence of adversechildhood environment (Foley et al., 2004). Nilsson et al. (2006)reported that the short MAOA allele interacted with adversepsychosocial risk factors during adolescence to result in criminalbehavior in general, but also specifically with violence in a Swedishpopulation. Conflicting with some of these findings, short MAOAalleles in turn appeared to be associated with a history of childhoodabuse and with higher impulsivity measures, but not with Brown-Goodwin Aggression Scale scores (Huang et al., 2004). Other studiesfailed to replicate the findings of the Dunedin study and an associationof the MAOA genotype with conduct problems (Haberstick et al.,2005; Young et al., 2006), or found genetic and environmentalinfluences, but no interactive effects (Reif et al., 2007). According to ameta-analysis of 5 studies, the association between maltreatment andantisocial behavior was found significantly stronger in male carriersof the short MAOA allele (Kim-Cohen et al., 2006) suggesting thatthe MAOA gene influences vulnerability to environmental stress inchildhood.

So far, only a few studies have concerned a possible relationbetween the 5-HT transporter promoter gene polymorphism andviolence. The 5HTTLPR genotype has been shown to be associated withNeuroticism (Lesch et al., 1996), especially in patients with cluster Cpersonality disorders (Jacob et al., 2004) and particular aspects ofnegative emotionality like hostility and agreeableness (Lesch &Merschdorf, 2000). Zalsman et al. (2005) and coworkers have

Table 1Influence of childhood psychosocial adversity and 5HTTLPR genotype on risk for ADHDand violent behavior in an offender population (according to Reif et al., 2007 and Retzet al., 2008).

Childhood psychosocial adversity

Low High

5HTTLPR genotype LL ADHD ↑ ADHD ↑↑Violence ↓↓ Violence ↓

SL/SS ADHD ↓↓ ADHD ↑↑Violence ↓ Violence ↑↑

Fig. 4. (a) Influence of the 5-HTTLPR genotype (LL vs. SS/SL) on the prevalence of ADHDismodulated by psychosocial adversity during childhood (high vs. low CAEI) (Retz et al.,2008). (b) Influence of the 5-HTTLPR genotype (LL vs. SS/SL) on the prevalence ofviolent behavior is modulated by childhood psychosocial adversity (high vs. low) (Reifet al., 2007). CAEI: Childhood Adverse Environment Index.

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reported a significant difference in violence measures in suicidalpatients carrying the L/L and L/s genotypes. In a study regardinghomicidal behavior in schizophrenics, no association was observedwith the 5-HT transporter promoter gene polymorphism (Kotler et al.,1999). In heroin addicts, the s/s genotype was associated with violentoffence, but not Buss-Durkee Hostility Inventory scores (Gerra et al.,2004). Additional data also pointed towards an association of the s/sgenotype with violent crime (Liao, Hong, Shih, & Tsai, 2004), and astudy from our group demonstrated that the s allele was foundsignificantly more often in violent crime offenders especially whenADHD psychopathology was present, explaining 5% of the geneticvariance of violent behavior (Retz, Retz-Junginger, Supprian, Thome, &Rösler, 2004). Further, Beitchman et al. (2006) reported associationbetween 5HTTLPR genotype and childhood aggression.

Investigating the influence of both, childhood psychosocial adversityand 5HTTLPR genotype, on the appearance of violent aggression in adultoffenders, Reif et al. (2007) recently showed that homozygotes for the5HTTLPR L-allele were generally less likely to develop later-life violentbehavior, while carriers of at least one S-allele were influenced byenvironmental factors (Fig. 4b). The results of this study suggest that thispolymorphism might have a role in balancing aggressive behaviors indiffering societies. Corresponding to this finding, in rhesus monkeysadverse early environment interacted with the monkey analogue of the5HTTLPR in exactly the samemanner as in the present study (Barr et al.,2003), further arguing for the notion that this polymorphismmodulatesthe response towards adverse environments.

7. Violence, ADHD, 5HTTLPR and environment

The reported results of studies concerning association of the5HTTLPR genotype and childhood psychosocial adversity with ADHDand violent behavior reported here not only support the notion of gene–environment interactions in the etiology of these phenotypes, but alsothrow some light on the relation of ADHD and violent behavior onthe background of genetic and psychosocial risk factors shared by bothphenotypes. It has been shown that the risk for ADHD was generallyhigh in carriers of the 5-HTTLPR LL-genotype and independentfrom psychosocial influences, whereas the prevalence of habitualviolent behavior in these individuals was low. In contrast, carriers ofthe 5-HTTLPR SS/SL-genotype had a low risk for both ADHD and violentbehavior in absence of psychosocial adversity, but the risk for ADHD andviolent behavior increased markedly, if psychosocial adversity was high(Table 1). It has to be concluded, that violent behavior is not inevitablyassociatedwith ADHD, but co-occurrence depends on particular geneticand environmental constellations. This finding is in good agreementwith epidemiological studies, which have reported an association ofADHD with disruptive behavior including impulsive aggression andantisociality, but not with instrumental violence and psychopathyaccording to the concept of Hare.

In general, the results of the studies reported here support thenotion, that common genetic polymorphisms like 5HTTLPR mighthave pleiotropic effects on several phenotypes, which are substan-tially influenced by environmental conditions. Presuming interactionsof genetic and environmental factors on several levels – gene–gene,gene–environment, environment–phenotype etc. – it becomesobvious that genes do not linearly influence human behavior. Forexample, Cadoret et al. (2003) failed to detect a main effect between5HTTLPR and aggressivity, CD or ADHD, but association of the 5HTTLPRS-allele with externalizing behavior was found when confoundingvariables like sex and parental antisociality were taken into account.Therefore, it is necessary to assess pleiotropic genetic polymorphismslike 5HTTLPR for differential influence on males and females and indifferent co-occuring phenotypes regarding different environmental –psychosocial and biological – conditions.

8. Implications for forensic psychiatry – general conclusions

Studies on interactive effects of genes, environment and pheno-types are an important issue of research in forensic psychiatry withrespect to the ongoing discussion about the freedom of will and thebiological determination of human behavior. The findings in this fieldshow that disruptive and criminal behaviors are not sufficientlypredictable by genetic or environmental factors alone. Considering theenormous variety of potential interactions between biological andenvironmental factors, it has to be concluded that genetic factors donot narrow human behavior, but increase its degree of freedom.Advantageous environmental conditions might give some protectionagainst genetic risks, and conversely, particular genetic constellationsmight have some protective effects against environmental adversity.Thus, the genetic background likely stabilizes the individual's social-ization by giving a frame, in which environmental factors shape the

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personality and behavioral styles rather than predict behavior. Itshould be emphasized that genes do not directly code for aggression,violence or delinquent behavior. They do not directly determinateconcrete behavior. Rather, allelic variation is responsible for individualdifferences in neural functioning, resulting in a disposition for violentaggression or delinquent behavior. They do not specify behaviordirectly but rather encode molecular products that build and governthe functioning of the brain through which behavior is expressed. Thegenes' effects are not deterministic but probabilistic and leave a widemargin for self-ruled decisions. Therefore, knowledge of geneticeffects on human behavior in general and of specific genetic variantsin particular is only a weak argument in the discussion about biologicdetermination of human behavior to assume irresponsibility for anyindividual's misconduct.

In this context it is also important to note that complex behavioralphenotypes like antisociality and violent aggression cannot be attrib-uted to a single gene. They are likely to involve a number of genes andthe interplay between them. Moreover, genetic heterogeneity of thesecomplex phenotypes has to be considered, suggesting that differentgenetic constellationsmight contribute to similar phenotypes, at least ininteraction with environmental factors. Therefore, it is not unexpectedthat single genetic or environmental factors have only small effects onthe variance of behavioral phenotypes in genetic association studies.Even statistically significant associations of genetic variations withbehavioral phenotypes explained only a short proportion of behavioralgenotypes throughoutall studies.Also the combinationwithother genesand non-genetic variables does not significantly improve this situation.Therefore, expectations or apprehensions genetic analyses might behelpful regarding the prediction of an individual's future behavior seemto be unrealistic.

Genes are clearly only a part of the story. In order to discover thekey processes involved in the development of antisocial andaggressive behavior, it will be necessary to focus research further onthe interplay between genetic and environmental influences. Sincegenes do not directly determine violent behavior, it is important toinvestigate the mechanisms regarding genetic effects on cognitive andemotional brain function. The combination of brain-imaging techni-ques with genetic data is an important step forward to do this(Dreßing, Sartorius, & Meyer-Lindenberg, 2008). On a molecular level,epigenetic researchwill help to explain how environmental factors getinfluence on the gene expression during critical periods throughoutthe lifecycle (McEwen, 2008; Robinson, Fernald, & Clayton, 2008).

Moreover, there is an essential need for a better differentiation ofthe behavioral phenotypes in terms of psychopathological featuresand comorbid disorders. It is necessary to consider the distinction ofpremeditated, predatory and impulsive, reactive violence and the roleof psychopathic personality features. Also developmental subtypes ofantisocial behavior, e.g. life-course persistent vs. adolescence-limited,and age of onset should be considered in future studies.

There is also no doubt, that underlying psychiatric disorders likeADHD, but also substance use disorders or psychoses have an importantimpact on biological and environmental framework of disruptivebehavior. Only with multivariate approaches, which include distinctphenotypes associated with antisociality like ADHD, conduct disorder,antisocial personality disorder, psychopathy and others, we will be ableto generate clearer hypotheses regarding the pathways from genes toneural processes and behavior, which might in turn also offer newoptions to influence disruptive behavior and enables therapeuticapproaches and prevention of disruptive behavior.

Regarding the impact on the role of themental health professional inthe legal system or legal policies two major aspects should beconsidered. First, the complex interdependencies between environmentand genetic factors make it obvious that a linear deduction of individualbehavior from the presence of single gene or a set of risk genes isdefinitely impossible. Genes do not directly determine behavior, but byinteractingwith environment, theymight enhance environmental risks,

but also prevent the individual from negative environmental impact.Thus, gene–environment interactions expand the scope for individualself-ruled behavior and do not narrow it. Mental health experts have tobe aware of the general role of genetic factors on personality traits andbehavioral styles and the progress in molecular genetics that has madegenetic influence on behavior more specific and identifiable. However,they should also keep in mind the limited predictive value of geneticanalyses concerning an individual's concrete future action. Associationsbetween particular genes and defiant behavior – even if statisticallysignificant in group comparisons – do not prove causation of behavior.They statistically explain only a small proportion of the behavioralphenotype, and they are not specific for any particular behavior.Therefore, genetic tests for responsibility or prognosis are still utopian.Second, the more general question has to be discussed whetheridentification of risk genes for violent aggression necessarily leads tothe conclusion that offenders carrying such risk genes have to beconsidered as impaired in their accountability and criminal responsi-bility (Bernet, Vnencak-Jones, Farahany, & Montgomery, 2007; Blair,2008). The fact that we have now started to identify specific risk genesand to show specific neuronal network activation with functionalimaging techniques (Dreßing et al., 2008) does not apply really newaspects to the fundamental question of the human's responsibility,which is a principle cornerstone of our legal system. The definition ofresponsibility and the decision about what to do with criminal people –to leave them unpunished, to detain them or to treat them – arenormative acts which do not automatically result from our knowledgeabout the etiology of criminal behavior. Answers to the question, whichconclusions we should draw from the fact that genes and environmenthave impact on human behavior and whether offenders should betreated or detained in forensic psychiatric hospitals or prisons cannot begiven by neuroscientists or mental health professionals alone, but onlyby a discourse together with representatives of legal professions,criminologists, sociologists, philosophers and politicians. However, it isnecessary to communicate and explain the results of neuroscientificresearch and their correct interpretation to all those who participate inthis discussion.

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