تداوم رفتار ضد اجتماعی تهاجمی از کودکی تا بزرگسالی: سوال از تعریف فنوتیپ
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|37216||2009||11 صفحه PDF||سفارش دهید||محاسبه نشده|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : International Journal of Law and Psychiatry, Volume 32, Issue 4, July–August 2009, Pages 224–234
Abstract Aiming to clarify the adult phenotype of antisocial personality disorder (ASPD), the empirical literature on its childhood background among the disruptive behaviour disorders, such as attention deficit/hyperactivity disorder (AD/HD), oppositional defiant disorder (ODD), conduct disorder (CD), or hyperkinetic conduct disorder (HKCD), was reviewed according to the Robins and Guze criteria for nosological validity. At least half of hyperactive children develop ODD and about a third CD (i.e. AD/HD + CD or HKCD) before puberty. About half of children with this combined problem constellation develop antisocial personality disorder (ASPD) in adulthood. Family and adoption/twin studies indicate that AD/HD and CD share a high heritability and that, in addition, there may be specific environmental effects for criminal behaviours. “Zones of rarity” delineating the disorders from each other, or from the normal variation, have not been identified. Neurophysiology, brain imaging, neurochemistry, neurocognition, or molecular genetics have not provided “external validity” for any of the diagnostic categories used today. Deficient mental functions, such as inattention, poor executive functions, poor verbal learning, and impaired social interaction (empathy), seem to form unspecific susceptibility factors. As none of today's proposed syndromes (e.g. AD/HD or psychopathy) seems to describe a natural category, a dimensional behavioural phenotype reflecting aggressive antisocial behaviours assessed by numbers of behaviours, the severity of their consequences and how early is their age at onset, which will be closely related to childhood hyperactivity, would bring conceptual clarity, and may form the basis for further probing into mental, cognitive, biological and treatment-related co-varying features.
Introduction That problem behaviours in children may herald psychosocial problems in adult life is basically a universal insight and the mainstay of most educational efforts. The association has also been demonstrated in a number of longitudinal studies and forms the nucleus in phenotype definitions of adult impulsive behaviours, physical aggression, violation of societal norms, and deficient emotional reactions, that is antisocial personality disorder (ASPD, American Psychiatric Association (APA), 1994), dissocial personality disorder (ICD-10, World Health Organization, 1993) or psychopathy (Hare, 1980). Nevertheless, the nosological categories proposed to capture specificproblem constellations both overlap and are heterogeneously defined. Attention-Deficit Hyperactivity Disorder (AD/HD) is an umbrella term by definition consisting of three problem domains, inattention, hyperactivity and impulsivity, listed in two separate sets of criteria that may be met individually or together. Two persons who both have this diagnosis may theoretically not share a single criterion. The International Classification of Diseases, tenth edition (ICD-10, WHO, 1993) has based its corresponding definition on hyperactivity (Hyperkinetic Disorder), noting attention deficits as a common complication. If hyperkinesia is combined with outright antisocial behaviours, the diagnosis of hyperkinetic conduct disorder (HKCD) may be made. In the DSM-IV, Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) are instead treated as two separate disorders. Other diagnostic categories that have been implicated in the context of childhood aggressive behaviours are the autism spectrum disorders (ASD), describing deficits in social interaction or “empathy”, verbal and/or non-verbal communication and flexibility, and “paediatric mania” or bipolar disorder with irritable, elated mood swings. A brief overview of the current diagnostic definitions that may be related to early-onset antisocial behaviours provided by the DSM-IV and the ICD-10 is given in Table 1. Table 1. Currently used diagnostic definitions for childhood-onset behavioural disorders. Diagnostic categories Diagnostic code (DSM-IV and ICD-10) Age at onset Problem dimensions Definitional context (cf. temperament as patterns of reactions to stimuli/percepts) AD/HD 314.01 0 years Hyperkinesia Behaviours in face of situations demanding motor activity control F90.0 ASD 299.00 0 years Social interaction / Communication Behaviours, cognitions and emotions in relation to others F84.0, 5, 9 AD/HD 314.01 4 years Impulsivity Behaviours in conversations and queues F90.0 ODD 313.81 4 years Opposition Emotional expressions and behaviours in face of other people F91.3 AD/HD 314.00 ∼ 6 years Inattention Behaviours in face of situations demanding attention and executive functions (school work) F90.0 Mania 296.0× ? Agitation, irritability, elation, grandiosity Dysregulated behaviours related to unstable mood F30.1 CD 312.81 ∼ 4.5–5 years “Criminality” Behaviours in contradiction with norms and regulations F91.0–2 Table options Assessing the validity of diagnostic concepts in psychiatric nosology is a continuous process, where, in the absence of knowledge about specific aetiological factors, definitions have to be regarded as preliminary and subject to revision. A seminal paper by Robins and Guze (1970) argued that a valid classification should be based on systematic empirical studies rather than on “a priori principles”, according to five specific criteria (Table 2). We have reviewed the literature by these criteria in order to 1. assess the validity of current categorical diagnoses and 2. propose more specific clinical descriptions of the development of aggressive antisocial behaviours. Table 2. Criteria for diagnostic validity. According to Robins and Guze (1970) and Andreasen (1995) 1. Clinical description (including unique symptoms that do not occur in other disorders, sex, age, precipitating factors, response to various forms of treatment). 2. Laboratory studies identifying biological or other so called “markers” for the disorder. In addition, Andreasen proposed “external” validators from molecular genetics, molecular biology, neurochemistry, neuroanatomy, neurophysiology and cognitive neuroscience. 3. Delimitation from other disorders. 4. Follow-up studies showing a homotype progression, i.e. that the disorder remains stable over time. 5. Family studies showing higher familial aggregation as compared with control groups.
نتیجه گیری انگلیسی
Results 3.1. Criteria 3 and 4: Delineation and homotype progression Six studies on clinic-referred children and six population-based prospective, longitudinal studies following hyperactive children into adulthood were identified (Table 4). All these studies had included children according to behavioural criteria at base-line. Detailed figures for the follow-up of cases and controls in relation to our defined outcome parameters are given in the bottom row of the table with p-values for comparisons. Studies included in the meta-analyses are indicated in the table. The studies that were not included in the meta-analyses did not provide precise figures for cases versus controls or did not include certain measures, such as personality disorders, in their follow-ups. Hyperactive children were at significantly increased risk for ASPD, including CD. There were also more violent deaths in this group, but due to small numbers, the difference in risk (1.3% vs 0.3%) did not reach statistical significance. Diagnostic stability was surprisingly low, and only a small minority (6%) of formerly hyperactive children still met full criteria for AD/HD combined or hyperactive subtypes) at follow-up. In contrast, the prevalences of several other mental disorders were higher than that of AD/HD. Some conclusions may be drawn from the joint studies. ODD is very common in hyperactive children. Almost all children who develop CD have had ODD, while a subgroup of children with ODD develop CD. A central question is whether hyperactivity in itself, without early-onset CD, increases the risk for ASPD and criminality. To study this association would require studies that systematically identified all cases with pre-pubertal CD within their study groups. We did not find any such study. Often CD was not clearly assessed at inclusion, and children varying broadly in age were included. A seven-year old with hyperactivity but not CD will be at risk during the rest of his childhood to develop the combination. It is therefore not possible by today's literature to pin a risk increase for ASPD and criminality in adulthood on hyperactivity without early-onset CD, even if such an association may exist in real life. 3.2. Clinical description Diagnostic criteria describe behaviours in relation to specific situations (e.g. “home”, “school”) or to different challenges (e.g. “remaining seated when expected”, “to comply with adults' requests”) (Table 1). At first glance, there seems to be no direct content overlaps. Yet, as items across the categorical definitions are worded in relation to heterogeneous contexts, they may still refer to common, more “molar” or general deficits. For example, deficits in behavioural and emotional inhibition are central to AD/HD, ODD, and CD, and can also play a role in some autism spectrum disorder (ASD) criteria (such as problems in sustaining a mutual conversation with others) or symptoms of mania (disinhibited behaviours with negative consequences). Similarly, criteria referring to social interaction problems are found across all diagnostic categories (e.g. the AD/HD criterion; “often interrupts or intrudes on others”, or the HCD criterion; “socially disinhibited”, just as the at least four ODD and seven CD criteria that refer to interpersonal interaction, and the first group of ASD symptom criteria (DSM-IV)). 3.3. Age at onset Diagnostic criteria are worded in relation to developmental phases, and all definitions of ‘disorder’ or ‘deficit’ have to relate to an idea about ‘normal’ development. Hence, the pattern of overlap between problems depends on the age at which the cross-section is made. Assessment methods (e.g. questionnaires, symptom lists, standardized observational schemes, and neuropsychological tests) for the preschool period have become more available, which has started to bear fruit in birth cohort studies (Angold & Egger, 2007). Problems manifested early in development, already in the first years of life and at least well before puberty, may be more pivotal to the phenotype definitions, as studies across diagnostic categories have shown higher heritability and persistence over time for early-onset problems (Kim-Cohen et al., 2005 and Moffitt, 1993). The DSM-IV defines early-onset CD as onset before 10 years. Among children with AD/HD, studies have indicated that virtually all cases of CD develop before the age of 12 ( Biederman, Faraone, Milberger, Jetton, et al., 1996). Conversely, most cases of early-onset CD have been shown to arise in children with hyperactive, “undercontrolled temperaments” ( Lahey and Loeber, 1997 and Moffitt, 1990). Adolescent onset CD differs by being more related to peer groups, less hereditary and less persistent ( Moffitt & Henry, 1991). 3.4. Treatment response Response to treatment merits a review on its own, but let us here merely consider that at least four different types of pharmacological treatments have been studied and used to treat aspects of aggressive antisocial behaviours in children, adolescents, and adults, and that these may target specific neurobiological systems and problem types, which would make them candidates for phenotype markers. Psychostimulants are effective for hyperactivity (Biederman & Faraone, 2005), neuroleptics for aggression (Turgay, 2005), mood stabilizers for negative emotions in mood swings (Smith, Cornelius, Warnock, Bell, & Young, 2007), and, possibly, anti-depressants for impulsivity (Popper, 1997). Psychotherapeutic and educative efforts may target behaviour patterns, deficient cognitive abilities and/or hampered personality maturation. 3.5. Familial aggregation A unanimous literature describes a high familial aggregation of hyperactivity and AD/HD (e.g. Faraone, 2004). Twin studies have yielded a mean estimate of 76% for the share of variance attributable to genetic factors (Faraone et al., 2005), which is in line with findings from adoption studies (Sprich, Biederman, Crawford, Mundy, & Faraone, 2000). A substantial genetic overlap has been shown between AD/HD and ODD/CD (Nadder, Rutter, Silberg, Maes, & Eaves, 2002), and a recent twin study was interpreted as rejecting the hypothesis that they are three “independent” conditions (Rhee, Willcutt, Hartman, Pennington, & DeFries, 2008). Family studies, however, indicate that AD/HD with CD, just as CD on its own, carries an increased prevalence of CD and ASPD in relatives, while relatives to probands with AD/HD in the absence of CD (regardless of whether it is combined with ODD or not) do not have increased risk for criminality ( Faraone et al., 1997 and Faraone et al., 2000). It therefore seems probable that there is a basic susceptibility for hyperactivity, to which specific genetic and environmental susceptibility factors for the progression into CD or criminal behaviours may be added ( Maes, Silberg, Neale, & Eaves, 2007). Furthermore, there is increasing evidence that aggressive and non-aggressive antisocial behaviours can be etiologically differentiated, with the former being highly heritable (accounting for 65% of the variance, Burt, 2009). Genetic factors indeed seems to mediate the progression from early onset, persistent aggression and delinquency to a self-rated psychopathic personality in adolescence, while shared environmental factors are involved in the association to more general antisocial behaviour ( Forsman, Larsson, Andershed, & Lichtenstein, 2007). Among the facets of psychopathic personality, unique genetic effects were identified for the lack of emotional reactions and the antisocial behaviour, while the interpersonal dominance seeking was associated with both genetic and shared environmental factors ( Larsson, Andershed, & Lichtenstein, 2006). 3.6. “External” validators 3.6.1. Neurophysiology Gray's (1987) motivational theory suggests three interdependent brain systems, two linked to the balance between activation and inhibition (the behavioral activation system (BAS) and the behavioral inhibition system (BIS)), and the fight-flight-freezing system. Disinhibition purportedly results from an imbalance in BAS and BIS functioning, favouring behavioural activation. BIS activity has been measured by electrodermal responding, i.e. changes in the conductivity of the skin, which is increased by the sweating resulting from activation of the sympathetic autonomous nervous system (Fowles, 1988). A few studies in AD/HD have demonstrated attenuated electrodermal responses to stress (Iaboni, Douglas, & Ditto, 1997), while studies of antisocial subjects have more consistently shown reduced responses as compared to controls (Gatzke-Kopp, Raine, Loeber, Stouthamer-Loeber, & Steinhauer, 2002). Inhibition has also been assessed through neuroendocrine markers in response to stressors. Lower activity in the hypothalamic-pituitary-adrenal (HPA) axis in relation to stress has been reported both from groups with AD/HD and ODD/CD (e.g. Randazzo et al., 2008 and van Goozen et al., 2007). Beauchaine (2001) has suggested an additional emotion regulation deficit in aggressive CD, adding to the BIS and BAS model, and possibly expressed as an inadequate vagal modulation of cardiac output (Beauchaine, Gatzke-Kopp, & Mead, 2007). A large number of EEG studies have found subjects with AD/HD to be characterized by an overall “theta excess” and “alpha slowing” (Barry, Johnstone, & Clarke, 2003), but similar changes have been described in a very vast range of mental or neurological disorders (Hughes & John, 1999). In criminality, Raine (1997) summarized that there “have probably been hundreds of studies assessing EEGs in criminals, delinquents, psychopaths, and violent offenders” showing these kinds of unspecific patterns. A reduced amplitude of the event-related P3 (third positive) component potential (ERP), i.e. the wave of brain electrical activity emerging approximately 300 ms following a rare stimulus, has also been unspecifically implicated across a spectrum of disorders, such as alcohol dependence, illicit drug dependence, nicotine dependence, AD/HD, ODD, CD and ASPD (Iacono, Carlson, Malone, & McGue, 2002). 3.6.2. Brain imaging Brain imaging studies are structural, functional or both. Structural imaging is quantified for research purposes by measuring volumes, while functional imaging is measured by general (such as the blood flow or glucose metabolism) or specific (ligands for receptors or transmitter precursors) indicators of activity in specific regions of interest (ROIs). A quantitative review of structural studies on AD/HD (Valera, Faraone, Murray, & Seidman, 2007) based on more than 500 index children and young adolescents, and as many controls, showed significant volume reductions in the cerebellum, the callosal body, and the right caudate nucleus, and also for the total and right cerebral volume. A similar picture emerged in an MRI study of 24 adults with AD/HD (Seidman et al., 2006). Cortical reductions have also been longitudinally associated with persistence of AD/HD symptoms and poorer out-come (Shaw et al., 2006). Decreased or aberrant global and regional metabolism, especially in the striatum, has been a fairly consistent finding in studies of regional brain activity in AD/HD, while findings of changed activity in the prefrontal cortex have been less consistent (as reviewed in Bush, Valera, & Seidman, 2005). In spite of an extensive literature on the structural neural underpinnings of aggression in children (van Goozen et al., 2007), few studies have actually investigated children and adolescents defined as fulfilling criteria for CD. In Bussing, Grudnik, Mason, Wasiak, and Leonard (2002), a small community sample of children with AD/HD in the presence or absence of CD were assessed by MRI and compared to controls, but no significant differences were detected. One study of early-onset CD in combination with AD/HD, however, found significantly reduced right temporal lobe volumes and a tendency to reductions in the prefrontal areas, as compared to healthy controls (Kruesi, Casanova, Mannheim, & Johnson-Bilder, 2004). Another study of early-onset CD reported significantly reduced grey matter volumes in the bilateral anterior insular cortex and the left amygdala, which also correlated with dimensional measures of aggression and even more strongly with attention problems (Sterzer, Stadler, Poustka, & Kleinschmidt, 2007). In adults with different forms of antisocial behavior, the prefrontal cortex has been in focus for imaging studies ever since Damasio's re-rendering of the Phineas Gage case (Damasio, Grabowski, Frank, Galaburda, & Damasio, 1994). However, Harlow's original case report rather presents a case of progressive bacterial encephalitis with recurrent fits (including epileptic states) than a specific status post the injury so elegantly depicted in the computer simulated imagery from Damasio's paper. Significant prefrontal cortical volume loss was indeed demonstrated in 21 community-recruited adults with ASPD (Raine, Lencz, Bihrle, LaCasse, & Colletti, 2000), while Dolan, Deakin, Roberts, and Anderson (2002) found no significant frontal or temporal structural differences between a group of patients with high psychopathy scores and controls. Functional or structural changes in brain regions involved in the regulation of emotional behavior, such as the temporal lobes and the limbic system, have been recurrent in imaging studies of adults with antisocial behaviour disorders (Anckarsater, 2006). In adolescents with CD and AD/HD, aberrant functional reactions in the anterior cingulate cortex and the amygdala when processing negative affective stimuli, have also been observed (Stadler et al., 2007 and Sterzer et al., 2005). Specific methodological problems for imaging studies include heterogeneous assessment procedures and image evaluation techniques. Just for AD/HD, Valera et al. (2007) emphasized the tremendous variability in the placement of ROIs, with differences in size and definition across studies that make quantitative meta-analyses virtually impossible. Measures of activity are expressed as relative regional signals in comparison to other brain structures, such as the contralateral hemisphere, occipital cortex, or the cerebellum. This may have influenced results since, for example, the cerebellum is also involved across social and emotional reactions, and we therefore do not know whether reduced regional/cerebellar ratios are due to cerebellar hyperactivity rather than hypoactivity in the studied region ( Anckarsater, 2006). In common with other studies comparing possible external markers between cases with antisocial life histories and controls, confounding factors are virtually impossible to control for in imaging studies, as are the effects of publishing biases. 3.6.3. Neurocognition Clinical as well as community studies have found lower scores on intelligence tests in individuals with AD/HD as compared to control groups, particularly in verbal intelligence (e.g. Mariani and Barkley, 1997 and Peterson et al., 2001), and a community twin study found common genetic influences behind inattention and reading difficulties, but not hyperactivity (Willcutt, Pennington, Olson, & DeFries, 2007). The difference typically equals between a half and one standard deviation in intelligence quotients on the group level. Children and adolescents with ODD/CD have similar reductions in comparison to normal controls (Pennington, 2002), even after controlling for socio-economic and ethnic confounders (Moffitt, 2006). It is notably difficult to compare results on intelligence tests across populations, but it may be concluded that specific deficits or uneven profiles form more relevant models than general learning disabilities in the background to hyperactivity or antisocial behaviours. The central deficit behind the AD/HD symptom complex has been described as executive dysfunction, a broad construct referring to complex organizing of behaviour and various functions involved in the maintenance of behaviour on a goal set over time independently from external saliencies (Nigg, Willcutt, Doyle, & Sonuga-Barke, 2005). Among these functions, executive motor disinhibition (especially notable in the Stop task) has been most consistently associated with AD/HD (Lijffijt, Kenemans, Verbaten, & van Engeland, 2005), as children with AD/HD have significantly longer reaction times to an inhibition signal than controls. Even if numerous studies have reported on abnormal results for tests of executive functions in AD/HD, negative reports have not been uncommon (Willcutt, Doyle, Nigg, Faraone, & Pennington, 2005). Other functions, such as reaction time to response signals, have been even more deviant in AD/HD, and executive functions have been as deficient in other diagnostic categories, such as autism (Pennington & Ozonoff, 1996) and CD (Oosterlaan, Logan, & Sergeant, 1998). By simply reading the diagnostic criteria, it is, however, obvious that several AD/HD criteria describe what has been defined as executive functions (and the tests are designed to measure), i.e. a lack of focus, direction and consideration of consequences. Coghill, Nigg, Rothenberger, Sonuga-Barke, and Tannock (2005) suggested that inattention, but not hyperactivity/impulsivity, is associated with deficient executive functions and poor academic achievement, referring to clinical as well as community samples (e.g. Chhabildas, Pennington, & Willcutt, 2001), and that hyperactivity/impulsivity is more closely related to dysfunctions of reward mechanisms (e.g. Sonuga-Barke, Dalen, & Remington, 2003). Castellanos et al. (2006) reviewed the model presented by Zelazo and Mueller (2003) on the functional differentiations within frontal cortices. They distinguished between more purely cognitive, “cool” aspects of executive functions associated with the dorsolateral frontal cortex and “hot”, or affective, aspects, associated with the orbital and medial prefrontal cortex. In this model, ‘cool’ executive functions are elicited by relatively abstract, decontextualized problems, such as most of the tasks tested so far in AD/HD (e.g. working memory and tests requiring sustained attention and inhibitory activity). ‘Hot’ executive functions are required for problems that are characterized by high affective involvement or demand flexible or appropriate appraisals of the emotional significance of stimuli. For example, risky decision-making in the Iowa Gambling Task could be a ‘hot’ executive function (Kerr & Zelazo, 2004). Deficits on this test have also been associated with hyperactivity/impulsivity (Toplak, Jain, & Tannock, 2005) and with symptoms of opposition and conduct problems (Ernst et al., 2003), but not with symptoms of inattention. Children with AD/HD have also exhibited marked difficulties in decoding affective facial expressions, with a specific deficit in identifying anger and sadness (e.g. Pelc, Kornreich, Foisy, & Dan, 2006). The ‘hot’ executive functions thus resemble the functions ascribed to the limbic system, processing social stimuli by memories and emotions. Interestingly, clinical states associated with damage in the limbic system, in the non-dominant hemisphere or with reduced interhemispheric communication have shown common clinical features. Thus, problems with ‘hot’ executive functions, recognition of affects and visuospatial deficits may be found together (Raine et al., 2005). “Callous-unemotional” traits describe reduced emotional reactivity and are associated with antisocial behaviours (such as in the ASPD or psychopathy constructs) (Frick and Stuart, 2008 and Loney et al., 1998). Reductions of these functions also recur in the non-verbal learning disability (NVLD) syndrome described by Rourke (1987), which also includes a risk for aggressive behaviours. The specificity of these problems in relation to the verbal executive functions has been disputed (Moffitt et al., 2008), and, conceptually, these definitions also overlap with core dysfunctions in the autism spectrum, such as deficits in social interaction and non-verbal communication. Inter-hemispheric transfer is targeted in research on brain processes relevant for autism (Nydén, Carlsson, Carlsson, & Gillberg, 2004). Details of these parallels are, however, insufficiently known (Rogers, Viding, Blair, Frith, & Happé, 2006), and clinical experience describe autistic social difficulties as qualitatively distinct. In sum, two large aspects of neurocognition are often implicated as susceptibility factors for aggressive antisocial behaviour. One is related to problems with language, especially abstractions, deficient strategies, and the prefrontal cortex, the other to shallow affects, visuo-spatial problems, reduced emotional integration and non-verbal communication and the limbic circuitry, inter-hemispheric transfer and/or the non-dominant hemisphere. These broad domains recur across scientific models in relation to aggressive behaviours. Traditionally, verbal deficits have been proposed to be specific for CD (e.g. Caspi & Moffitt, 1995), but as spatial impairments have increasingly been brought in focus (e.g., Raine et al., 2005 and Speltz et al., 1999), it seems more reasonable to describe these as two large domains of mental functional deficits, whose relations to each other remain insufficiently known. 3.6.4. Neurochemistry Low serotonergic neurotransmission has been associated with emotionally driven, impulsive, destructive acts (e.g. Asberg et al., 1976, Brown et al., 1982 and Virkkunen et al., 1987) but not with instrumental violence (Gardner et al., 1990 and Lidberg et al., 1985). Kruesi, Swedo, Leonard, Rubinow, and Rapoport (1990) found that children with ODD/CD and/or AD/HD had lower concentrations of serotonin metabolites in the cerebrospinal fluid than children suffering from obsessive–compulsive disorder, and that these concentrations were inversely correlated with ratings of aggressive behaviours. At a two-year follow-up, the metabolite concentrations also predicted the severity of physical, aggressive behaviour and poor outcome (Kruesi et al., 1992). In contrast, Castellanos et al. (1994) found that the same metabolite concentrations were positively correlated with measures of aggression and impulsivity in a study of boys with AD/HD. Since this group was more hyperactive and less aggressive than the previous one, the authors speculated that serotonin measures may correlate with aggression only in groups of children with a core aggression problem. Lower cerebrospinal fluid concentrations of serotonin metabolites have also been reported in several studies of aggressive antisocial adults and youths with CD (Berman, Kavoussi, & Coccaro, 1997). The ratio between the dopamine and serotonin metabolites in the CSF, which reflects the serotonergic regulation of dopaminergic activity, was positively associated with aggression, AD/HD and CD in two separate studies of adult offenders (Soderstrom, Blennow, Sjodin, & Forsman, 2003). The dopamine systems play a central role in the regulation of attentional processes, psychomotor activity and reward-seeking behavior (e.g. Krause et al., 2000 and Spencer et al., 2002). Stimulants, such as methylphenidate, probably reduce AD/HD symptoms by increasing the release of dopamine and norepinephrine (Biederman, 2005). In addition to neurotransmitters, hormones have been studied as covariates to antisocial behaviours. Activated thyroid hormones (in relation to precursors) have been associated with AD/HD symptoms in clinical (Stein & Weiss, 2003) as well as community study groups (Alvarez-Pedrerol et al., 2007), and have been predictive of criminal recidivism in studies among both young lawbreakers (Levander, Mattsson, Schalling, & Dalteg, 1987) and adult criminals (Stalenheim, 2004). As depression has been associated with the inverse pattern, this may, however, not express a direct link but a lack of depressive reactivity among the more cold-hearted and thereby recidivism-prone subjects (Soderstrom & Forsman, 2004). Testosterone increases aggressive behaviours (Archer, 1991) and the mere prevalence of violence and criminality in young men as compared to elder men and women, and the increased aggression noticed in females in the prementrual phase (Dougherty, Bjork, Huang, & Moeller, 1997), makes testosterone a prime suspect in the quest for biological background factors to aggression. Testosterone has been related to delinquency, alcoholism and drug use among adults, as well as to conduct problems in childhood (e.g. Dabbs, Carr, Frady, & Riad, 1995). Effect sizes for these relations are typically small, but tend to be larger for males from lower socioeconomic backgrounds. Some studies also have failed to find any relationship between aggression and testosterone (e.g. van Bokhoven et al., 2006). 3.6.5. Molecular genetics In a comprehensive review of the search for molecular genetic markers for AD/HD, Bobb, Castellanos, Addington, and Rapoport (2005) concluded that of all publications on associations between AD/HD and specific gene variants, 36% were positive, 17% showed trends and 47% were negative. This was uncorrelated with sample size, but studies using dimensional measures, or case-control models, tended to report more positive findings than categorical or family based studies. It was also a clear trend that positive, dimensional, and case-control studies were published earlier than more recent negative replications using family-based models. Again, the publication bias is described as a major obstacle to understand and interpret the results, while underpowered samples and selected populations add to the weakness of possible interpretations. Linkage studies of AD/HD have identified specific chromosome regions that have also been implicated in aggressive behaviours (e.g. Kendler et al., 2006), leading to the possible conclusion that “AD/HD co-segregates with disruptive behaviours as a unique, phenotypically variable trait as evidenced by highly significant pair-wise linkages” (Jain et al., 2007). Findings for various definitions of CD or aggression have been inconsistent, but these studies have generally been based on study cohorts originally assembled to study other problem definitions, such as substance abuse (e.g. Stallings et al., 2005). In association studies, the most thoroughly investigated genes are those implicated in serotonergic and dopaminergic neurotransmission. Repeat polymorphisms, some of which have been shown to be functional, have been studied in relation to aggressive behaviours in the genes for the dopamine receptor 4, the dopamine transporter, the serotonin transporter, and the monoamine oxidase type A. The latter is especially interesting for disorders with a skewed sex ratio as it is located on the X chromosome. The gene for the serotonin receptor 2A contains several single nucleotide polymorphisms that have been studied in relation to psychiatry. Other genes that have been studied in relation to behavioural disorder include those coding for other enzymes and receptors involved in monoaminergic neurotransmission, sexual hormone metabolism, and a vast array of proteins involved in brain development. So far, no study has indicated any polymorphism or gene locus that may effect the variance in the phenotypical definitions described above by more than a minute effect (typically with odds ratios well below 2 or effect sizes maximally at a couple of percents, Kendler, 2005). During recent years, intense interest has been focused on interactions between specific genotypes and environmental factors as a possible key to disentangle the inconsistent findings from univariate association studies. The first paper to identify such effects was published in 2002 by Caspi and co-workers, who could show that maltreated boys with the high-activity polymorphism in the MAO-A gene were less likely to develop antisocial behaviours than maltreated boys with the low-activity polymorphism, while the polymorphism did not have any effect on the variation of antisocial behaviours in the population at large. This finding has been replicated in several independent studies (e.g. Foley et al., 2004 and Kim-Cohen et al., 2006), while others have been negative (e.g. Widom and Brzustowicz, 2006 and Young et al., 2006). A range of similar interactions have been proposed, e.g. that “maternal insensitivity” may lead to aggressive behaviours, specifically in the presence of the DRD4 seven repeat polymorphism (Bakermans-Kranenburg & van Ijzendoorn, 2006). The initial enthusiasm evoked by this line of reports of complex models has faltered as replications have proved as inconsistent as for univariate associations. Simulated analyses by categorical phenotypes and logistic regressions also repeatedly yield models with significant main effect of the environment, no significant main effect of the genotype, and significant G × E interactions, regardless of whether meaningful or nonsense data are used (Eaves, 2006). In the last few years, new approaches to psychiatric molecular genetics have been called for, focusing on molecular rearrangements and other modifications thought to influence the translation of the genes and thereby the functional activity of its enzymatic end product. Besides some studies of parental imprinting (Kent et al., 2008), convincing associations with behavioural features have not yet been presented for such “epigenetic” models.