This is an ongoing assignment and will be worked on each week. This is what is required this week. I also picked to focus on Borderline Personality for my topic.Select the topic for your Critical Revi

REVIEW ARTICLE Possible role of a dysregulation of the endogenous opioid system in antisocial personality disorder Borwin Bandelow* and Dirk Wedekind Department of Psychiatry and Psychotherapy, University of Göttingen, Germany Around half the inmates in prison institutions have antisocial personality disorder (ASPD). A recent theory has proposed that a dysfunction of the endogenous opioid system (EOS) underlies the neurobiology of borderline personality disorder (BPD). In the present theoretical paper, based on a comprehensive database and hand search of the relevant literature, this hypothesis is extended to ASPD, which may be the pre- dominant expression of EOS dysfunction in men, while the same pathology underlies BPD in women. According to evidence from human and animal studies, the problematic behaviours of persons with antisocial, callous, or psychopathic traits may be seen as desperate, uncon- scious attempts to stimulate their deﬁcient EOS, which plays a key role in brain reward circuits. If the needs of this system are not being met, the affected persons experience dysphoric mood, discomfort, or irritability, and strive to increase binding of endogenous opioids to receptors by using the rewarding effects of aggression by exertion of physical or manipulative power on others, by abusing alcohol or sub- stances that have the reward system as target, by creating an“endorphin rush”by self-harm, by increasing the frequency of their sexual con- tacts, or by impulsive actions and sensation seeking. Symptoms associated with ASPD can be treated with opioid antagonists like naltrexone, naloxone, or nalmefene. Copyright © 2015 John Wiley & Sons, Ltd.

key words—antisocial personality disorder; borderline personality disorder; endogenous opioid system; reward system INTRODUCTION Antisocial personality disorder (ASPD) is characterized by hostility, aggression, callousness, lack of remorse, deceitfulness, manipulativeness, irresponsibility, im- pulsivity, and risk-taking. It is estimated that around half the inmates in prisons (Fazel and Danesh, 2002) and forensic psychiatric institutions (Coidet al., 1999; de Ruiter and Greeven, 2000) have ASPD.

Recently, we have formulated a theory that border- line personality disorder (BPD) may originate from a dysfunction of the endogenous opioid system (EOS) (Bandelowet al., 2010). In an attempt to extend our theory to patients with ASPD, we are reviewing the evidence for a role of a dysfunctional opioid system in ASPD. First, we will give a short overview of the “EOS theory of BPD”and current theories on the neurobiology of antisocial behaviour, followed by a short description of the brain reward system. Then, we will gather arguments supporting the theory of adysfunctional EOS in ASPD. Then, we will argue that ASPD and BPD have many symptoms and features in common, and these similarities may have their basis in a common underlying EOS dysfunction. In the last part, we will discuss the role of attention-deﬁcit/ hyperactivity disorder (ADHD), which may also be caused by an EOS deﬁciency, as a harbinger of both ASPD and BPD.

A comprehensive literature search was performed by using PubMed and ISI Web of Science Databases and additional hand search.

Some of theﬁndings discussed in this article have been described in patients deﬁned as having“psychop- athy”rather than ASPD. Psychopathy (Cleckley, 1941) is not identical with the DSM-5 deﬁnition of ASPD and is usually operationalized by means of the Psychopathy Checklist—Revised (PCL-R) (Hare, 2003). There has been some debate whether these two constructs should be differentiated (Hare and Neumann, 2010; Antonet al., 2012; Lynam and Vachon, 2012). However, the descriptions in the PCL-R and in the DSM-5“diagnostic criteria”,“diag- nostic features,”and“associated features”of ASPD (APA, 2013) make it difﬁcult to separate these *Correspondence to: B. Bandelow, Department of Psychiatry and Psycho- therapy, University of Göttingen, von-Siebold-Str. 5, D-37075 Göttingen, Germany. Tel: +49-551-3966610; Fax: +49-551-3966597 E-mail:

human psychopharmacology Hum. Psychopharmacol Clin Exp2015; 30: 393–415 Published online 7 August 2015 in Wiley Online Library (wileyonlinelibrary.com)DOI: 10.1002/hup.2497 constructs on grounds of symptomatology. The deﬁni- tion of ICD-10 dissocial personality disorder is con- ceptually even closer to psychopathy (Ogloff, 2006).

Therefore, we did not make a strict distinction between antisociality and psychopathy.

The EOS theory of BPD According to this“EOS theory of BPD,”availability of endogenous opioids or changes in the sensitivity of opioid receptors constitute part of the pathophysiology of BPD. Dysphoric mood and feelings of emptiness may be expressions of decreased EOS activity, which the affected patients try to compensate by EOS- stimulating actions. The self-destructive behaviours of BPD patients may be explained by unconscious and uncontrollable attempts to stimulate their EOS, regardless of the possible harmful consequences. Fre- quent and risky sexual activities, efforts to avoid aban- donment, and attention seeking may be interpreted as attempts to take advantage of the reinforcing effects of human attachment facilitated by the EOS. BPD pa- tients have a tendency to abuse substances that target μ-opioid receptors. Self-harm, reduced food intake, sensation seeking, and aggressive behaviour may be interpreted as desperate attempts to put the organism into an artiﬁcial“survival mode,”in order to mobilize every last reserve of the EOS. Evidence for the EOS theory is further based on the successfulμ-opioid antagonist treatment of BPD-associated symptoms, such as sub- stance abuse, self-harm, anorexia, depersonalization, and compulsive sexual behaviour. The theory is sup- ported by positron emission tomography (PET)ﬁndings:

Prossinet al.(2010) found evidence of EOS malfunction in BPD patients in a PET study. Moreover, in subjects with Cluster B personality disorder (mostly with BPD), patients showing self-injury had signiﬁcantly lower levels ofβ-endorphin and met-enkephalin in their cere- brospinalﬂuid (CSF) than individuals without self-injury (Stanleyet al., 2010). However, a dysregulation ofμ- opioid receptor binding was also found in PET studies in patients with depression (Kennedyet al., 2006).

THE NEUROBIOLOGY OF ANTISOCIAL BEHAVIOUR Numerous studies have been performed to identify the neurobiological substrates of antisocial behaviour, psy- chopathy, or callous/unemotional traits. Antisociality has been associated with hormone disturbances, for example, reduced cortisol levels and increased testosterone levels (van Honk and Schutter, 2006; Yildirim and Derksen, 2012). Neurotransmitter studies have examined an asso- ciation of the monoamine oxidase A gene and aggression(Buckholtz and Meyer-Lindenberg, 2008; Gunteret al., 2010). Other lines of evidence suggest a role for seroto- nin dysfunction (Beauchaineet al., 2009; Gunteret al., 2010). However, serotonergic antidepressants, such as selective serotonin reuptake inhibitors, have only a moderate inﬂuence on few symptoms of ASPD, and from these unspeciﬁc effects it cannot be concluded that a dysregulation of serotonin systems is a central cause of the disorder. Antisocial individuals do not have a tendency to overdose serotonergic drugs or to buy them on the black market; in contrary, their compliance with prescribed serotonergic agents is poor. Dopamine is another neurotransmitter that is likely to be involved in antisocial behaviour. Drugs abused by ASPD patients increase dopamine in the nucleus accumbens (NAcc) (Brewer and Potenza, 2008). Some patients with Parkinson’s disease, in particular those taking dopamine agonists, show impulse control disor- ders that resemble pathological behaviours of ASPD and BPD patients, including gambling, hypersexuality, compulsive spending/shopping, or binge eating (Weintraubet al., 2010; Hassanet al., 2011). Besides these lines of indirect evidence, a few studies directly demonstrate dopamine dysfunction in antisocial indi- viduals. CSF levels of the dopamine metabolite HVA were found to be related to impulsive behaviour in patients with psychopathy (Soderstromet al., 2001).

In genetic studies, polymorphisms affecting dopamine receptors have been associated with antisocial spec- trum disorders (Reeseet al., 2010).

However, if a dopamine dysfunction would play a ma- jor role in ASPD, the administration of dopamine antag- onists should substantially alter the symptomatology of the disorder, but antipsychotics showed only limited ef- fects on a few symptoms of ASPD (Khalifaet al., 2010).

If dopaminergic overstimulation would be the primary cause of ASPD, patients would likely try to purchase do- pamine antagonists illegally and would take overdoses of these agents. In addition, dopamine agonists are not used as addiction drugs, and from what we know from Parkinson patients, these drugs would have an opposite effect by inducing addiction-like behaviour.

On the other hand, patients with ASPD show a strong preference for drugs that stimulate the EOS, such as heroin, morphine, or amphetamines. Therefore, it seems warranted to test the hypothesis that the pri- mary dysfunction in ASPD is located in the EOS.

Brain reward circuits Primary rewards, including food, water, and sex, are essential for the survival of the species. For many years, the mesolimbic dopamine pathway from the ventral teg- mental area (VTA) to the NAcc was considered as the 394b. bandelow and d. wedekind Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup central mechanism for reward processing. Olds and Milner (1954) discovered this system by using micro- electrodes that could be self-stimulated by rats. The re- searchers found that rodents would press the lever almost up to 5000 times an hour and would even tolerate pain for an opportunity to press the lever.

Reward anticipation is followed by dopamine re- lease in the NAcc (Knutsonet al., 2001). Natural rewards and drugs of abuse are associated with synap- tic alterations of the mesolimbic dopamine system (Baik, 2013). Dopamine antagonists reduce these re- warding properties (Wise, 2004). However, accumu- lating evidence argues against a primary role of dopamine in reward processes. Today, it is assumed that the brain reward circuit is not only based on the VTA–NAcc pathway but constitutes a complex net- work that integrates a number of other brain regions, in which opioid peptides and receptors are expressed (Figure 1), placing the EOS in a key position in reward processing (Le Merreret al., 2009). Reward has two components: the preparatory aspects, incentive sa- lience (“wanting”) and a hedonic reaction (“liking”).While dopamine is believed to be responsible for in- centive salience processing, EOS stimulation mediates the hedonic aspects of natural rewards (Barbano and Cador, 2007; Berridge and Aldridge, 2008).

The endogenous opioids (Pert and Snyder, 1973; Hugheset al., 1975) consist of three classes, the endor- phins (includingβ-endorphin), the pentapeptide enkephalins, and the dynorphins. They activateμ-,δ-, andκ-opioid and nociceptin receptors.β-Endorphin shows strong afﬁnity forμandδreceptors, while the enkephalins bind to theδ-receptor and the dynorphins to theκ-receptor (Roth-Deriet al., 2008; Machin and Dunbar, 2011). Re- warding and addictive properties of endorphins are similar to those displayed by morphine (van Ree, 1979).

β-Endorphinic cell bodies end in various regions, in- cluding the VTA and the NAcc (Le Merreret al., 2009).

There, opioids increase dopamine release by inhibition ofγ-aminobutyric acid (GABA) release (Johnson and North, 1992; De Vries and Shippenberg, 2002; Roth- Deriet al., 2008). There is also a reverse interaction:

intracranial application of dopamine into the NAcc increasesβ-endorphin levels (Roth-Deriet al., 2003).

Figure 1. Brain structures that are involved in reward mechanisms. In all these regions, endogenous opioid peptides and receptors are expressed (Kelley, 2004; Roth-Deriet al., 2008; Le Merreret al., 2009; Der-Avakian and Markou, 2012; Dichteret al., 2012; Koob, 2013). BNST, bed nucleus of the stria terminalis; VTA, ventral tegmental area; PAG, periaquaeductal grey 395 the eos in antisocial personality disorder Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup Release of endogenous opioids is involved in the regulation of positive emotion in humans (Koepp et al., 2009).β-Endorphin is also released during stress situations (Roth-Deriet al., 2008). In an animalﬁght- ing for its life and bleeding from wounds,β-endorphin helps it to survive by inducing euphoria and analgesia.

Endorphin release plays a role in releasing pain in se- verely hurt accident victims, in long-distance running, or during childbirth, as well as in positive experiences like sexual activities (Goldfarb and Jamurtas, 1997; Ravertet al., 2004; Esch and Stefano, 2005; Boecker et al., 2008). Starvation sensitizes the body to reward, which can be reversed by intraventricular administra- tion of the opioid antagonist naltrexone (Carr, 1996).

In contrast to the positive effects of endorphins, stimulation ofκ-opioid receptors, for example, by dynorphins, can induce dysphoria (Walshet al., 2001).

Besides opioids and dopamine, other neurotransmit- ters like serotonin and the inhibitory neurotransmitter GABA are involved in the biology of reward (Stein and Belluzzi, 1986).

The EOS in ASPD In the following section, we will discuss how the symptoms and behaviours of ASPD can be explained by a dysfunction of the EOS as the primary distur- bance. In Table 1, an overview of the neurobiological ﬁndings supporting the EOS theory is displayed, sorted by the symptom clusters that are characteristic for ASPD.

Antagonism.Aggressive behaviour.In many species (e.g. lions), aggressive behaviour is necessary to ac- cess resources such as food, mates, and territory. An evolutionary theory assumes that two million years ago, the hominides turned from vegetarianism to meat eating because of the better energy balance associated with meat eating. It has been supposed that the killing of prey was accompanied by a release in the reward system in order to reinforce the preservation of the spe- cies during evolution (Elbertet al., 2010). Consistent with this theory, a certain“lust to kill”may still play a role today (as demonstrated by the fascination for hunting and sports like wrestling or boxing in men) and may be particularly strong in some antisocial indi- viduals. It seems conceivable that ASPD individuals tend to create an artiﬁcial survival situation by starting aﬁght in order to stimulate their deﬁcient EOS.

In animal models, it has been shown that aggression (e.g. biting a male intruder) is reinforcing (de Almeida and Miczek, 2002; Fishet al., 2002). Dopamine block- ade in the NAcc attenuates aggressive reactions in animals (Couppis and Kennedy, 2008).β-Endorphin-deﬁcient mice show higher aggression score levels than wild-type mice (Vaanholtet al., 2003), and ag- gressive mouse strains have low endorphin levels (Tordjmanet al., 2003).

In humans, kleptomania, which was interpreted as some form of antisocial behaviour or as a behavioural ad- diction, can be treated with opioid antagonists (Table 2).

A number of human brain imaging studies have ex- amined the association of aggressive/antisocial behav- iour and reward centres in the striatum. Tiihonenet al.

(1995) found that violent alcohol-dependent patients had increased densities of dopamine transporters in the striatum when compared with control subjects in a single photon emission tomography (SPECT) study.

In a structural magnetic resonance imaging study, Schifferet al.(2011) found that violent offenders had larger volumes in the NAcc and the caudate head than non-offenders. In a functional magnetic resonance imaging (fMRI) study in adolescents presenting with ADHD, oppositional deﬁant disorder (ODD), or conduct disorder (CD), which may be predecessors of ASPD, cues to respond for rewards activated the NAcc (Bjorket al., 2010). In an fMRI study, adolescents with aggressive CD were scanned while watching pictures showing other people experiencing pain (Decetyet al., 2009). In contrast to controls, adoles- cents with CD showed a signal increase bilaterally in the striatum, but also in the amygdala, medial orbitofrontal cortex, and temporal pole. However, in another study, criminal psychopaths showed signiﬁ- cantly less affect-related activity in the ventral striatum and other brain regions when compared with criminal non-psychopaths and non-criminal control participants (Kiehlet al., 2001). In an fMRI comparison of psycho- pathic and non-psychopathic prison inmates, signiﬁ- cantly different correlations between ventral striatum activity and psychopathy severity within each group were observed (Pujaraet al., 2013). A study using PET and blood oxygen level-dependent fMRI found that “antisocial traits”were associated with NAcc dopamine release and reward anticipation-related neural activity in response to pharmacological and monetary rewards, re- spectively (Buckholtzet al., 2010). However, this study was not performed in patients with ASPD but in a sample of community volunteers. In another fMRI study with healthy individuals, high psychopathy scores also correlated positively with recruitment of ventral striatum and anterior cingulate cortex during reward instrumental anticipation (Bjorket al., 2012).

However, brain imaging studies in ASPD do not only show abnormalities in reward centres but also in many other brain regions (see Section on Similarities in Brain Imaging Findings). 396b. bandelow and d. wedekind Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup Table 1. Correspondence of symptoms in ASPD and BPD, according to DSM-5 diagnostic criteria (DC), diagnostic features (DF), associated features supporting diagnosis (AF), or evidence from the literature FeaturesASPD BPD Other neurobiological ﬁndings supporting the EOS theory DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in ASPD DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in BPD Antagonism (hostility) Failure to conform to social norms, unlawful behaviours, or acts that are grounds for arrestYes Larger volumes in the NAcc in violent offenders (Schiffer et al., 2011)BPD present in 55% of prison inmates (Blacket al., 2007)Aggression is reinforcing in animals (de Almeida and Miczek, 2002; Fishet al., 2002); dopamine blockade in the NAcc attenuates aggression (Couppis and Kennedy, 2008);β- endorphin-deﬁcient mice show higher aggression scores (Vaanholtet al., 2003) Deceitfulness, repeated lying, use of aliases, or conning others for personal proﬁtor pleasureYes Antisocial traits in healthy volunteers associated with dopamine release in NAcc (Buckholtz et al., 2010) Lack of remorse Yes Psychopathy traits in healthy volunteers correlated with ventral striatum and ACC activation in fMRI (Bjorket al., 2012) Irritability, aggressiveness, or repeated physicalﬁghts or assaultsYes Yes Evidence of CD with onset before age 15 yearsYesStrong association between CD and BPD (Howardet al., 2012; Freestone et al., 2013) Disinhibition Impulsivity or failure to plan aheadYes CSF levels of the dopamine metabolite HVA related to impulsive behaviour in psychopathy (Soderstromet al., 2001)Yes Impulsivity decreased after administration of amphetamine or methylphenidate in rodents (van Gaalenet al., 2006) and healthy volunteers (de Wit et al., 2002). Impulsiveness traits were associated with higherμ-receptor concentrations and higher stress-induced EOS activation (Loveet al., 2009) Impulsive decision- making, the tendency to choose a small immediate reward instead of a large delayed reward, was found in substance abusers with a comorbid diagnosis of ASPD (Petry, 2002) Reckless disregard for safety of self or othersYes Yes Increasedβ-endorphin immunoreactivity (Hennig et al., 1994). Healthy sensation-seeking individuals showed increased response to opioid treatment (Zacny, 2010) (Continues) 397 the eos in antisocial personality disorder Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup Table 1. (Continued) FeaturesASPD BPD Other neurobiological ﬁndings supporting the EOS theory DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in ASPD DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in BPD Impulsive/risky sexual behaviour or history of many sexual partnersYes Among sexual offenders, the rate of ASPD is high (Jumperet al., 2012), especially among sadistic sexual offenders (Berger et al., 1999) and multiple sexual murderers (Hill et al., 2007)Yes High rate of BPD among prostitutes (Brodyet al., 2005), sexual offenders (Curtin and Niveau, 1998), and sexual murderers (Hill et al., 2007)Sexual activity mediated by the EOS (Esch and Stefano, 2005) Addiction-like sexual behaviour can been treated with naltrexone (Table 2) Irresponsibility, failure to sustain consistent work behaviour, or honourﬁnancial obligationsYesYes BPD patients hold lower-skilled jobs (Peltopuroet al., 2014) Disability payments by 60% of BPD patients (Zanarini et al., 2008) Excessive spending of moneyYes 11% ASPD among compulsive buyers (Schlosseret al., 1994)Yes Substance abuse Yes High rate of abuse of drugs targeting the EOS in ASPD (Westermeyer and Thuras, 2005; Chapman and Cellucci, 2007)Yes 75% of BPD patients have abuse of drugs (Hatzitaskoset al., 1999); BPD is mainly associated with abuse of substances that directly target the EOS (Carpenteret al., 2015); 45% of heroin addicts suffer from BPD (Darke et al., 2005)Alcohol and drugs target EOS (Le Merreret al., 2009; Koob, 2013; Nutt, 2014); genetic link (Malone et al., 2004; Brewer and Potenza, 2008) Alcohol and drug abuse can be treated with naltrexone (Table 2) Pathological gambling Yes 29–40% of gamblers have (Blandet al., 1993)Association between gambling and antisocial tendencies (Mishraet al. , 2011); genetic link between gambling and antisocial behaviour (Slutskeet al., 2001)Yes 16% of gamblers had BPD (Fernandez- Montalvo and Echeburua, 2004)Endorphin levels increased during gambling (Shinohara et al., 1999); less endorphin release after amphetamine (Rabineret al., 2014) Gambling can be treated with naltrexone (Table 2) Eating disorders (binge eating/bulimia)Association between bulimia nervosa and ASPD (Rossiteret al., 1993; Zapolskiet al., 2010)Y e s Endogenous opioids are mobilized in fooddeprivation in rats (Marrazzi and Luby, 1986) β-endorphin is elevated during fasting (Komaki et al., 1990) Eating disorders can be treated opioid antagonists (Table 2) (Continues) 398b. bandelow and d. wedekind Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup Features ASPD BPD Other neurobiological ﬁndings supporting the EOS theory DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in ASPD DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in BPD Negative affectivity Boredom proneness Yes Callous–unemotional traits in adolescents associated with less reward responsivity and sensation seeking (Marini and Stickle, 2010)YesEndorphins maintain a basal level of positive affect in mice (Narayananet al., 2004) Chronic feeling of emptinessYesVentral striatum activity decreased in depression (Keedwellet al., 2005) Dysphoria Yes YesStimulation/overactivity ofκ- opioid receptors can induce dysphoria (Kumoret al., 1986; Walshet al., 2001) Suicidal behaviour Increased suicide rate in ASPD (Veronaet al., 2001; Rothet al., 2011)Yes Affective instability Depressive symptoms in 23–30% (Robins, 1966); however, affective instability more typical for ASPD than for BPD (Pariset al., 2013)Yes Self-harm Increased rate of self- mutilation (Virkkunen, 1976; Sendula-Jengicet al., 2004; Alpay Ateset al., 2011) (Winchel and Stanley, 1991)Yes Patients report relief, pleasure, or“kick” during self-injury (Kleindienstet al., 2008) (Bohuset al., 2000)Self-harm in mentally retarded subjects can be treated with naltrexone (Table 2) Bonding problems Efforts to avoid abandonmentPathological jealousy frequently found in ASPD (Storeyet al., 2009)YesEOS plays a central role in sociality (Pankseppet al., 1978; Machin and Dunbar, 2011). In animals, separation distress can be alleviated by morphine and potentiated by naloxone (Kalinet al., 1995). Deﬁcits in attachment behaviour in μ-knockout mice (Moles et al., 2004). In primates, a variation at theμ-opioid receptor gene modulates attachment (Barret al., 2008); in healthy individuals, social rejection/ attachment is associated withμ-opioid receptor availability (Hsuet al., 2013). In humans, romantic love is associated with an activation of the right VTA (Aronet al., 2005) Unstable relationships Yes Yes Anxiety,psychosis, dissociation Anxiety Yes Comorbid anxiety disorder in 50% (Hodginset al., 2010)Yes– Stress-related paranoid ideationTransient and stress-related paranoid symptoms (Yochelson and Samenow, 1976; Lykken, 1995); higherYes– (Continues) 399 the eos in antisocial personality disorder Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup Manipulativeness.Antisocial and psychopathic indi- viduals try to dominate others not only by using phys- ical but also by psychological force. They often have the ability to exert mental power even from a lowest possible position (e.g. by splitting the staff team in a prison or a forensic hospital). Typical behaviours are deceitfulness, manipulativeness, conning others, or lying just for pleasure, even when they do not have a personal proﬁt from their dishonesty and when it is safer to say the truth. These behaviours seem addiction-like, as they are relatively punishment- insensitive. They aim at immediate reward and not on acting with foresight. Therefore, an association be- tween manipulativeness and EOS dysfunction seems plausible, although it will be difﬁcult toﬁnd empirical data for conﬁrming this link.

Disinhibition.Impulsivity.Antisocial-personality dis- order patients show impulsivity, intolerance for reinforcement delay, failure to plan ahead, and frustra- tion intolerance. They tend to follow the“pleasure principle”in their excessive reward seeking, for exam- ple, by stealing a desired object instead of saving money for buying it or by quitting a job prematurely when they do not see immediate success. In order to receive instant satisfaction, they disregard social con- ventions and seem to be unable to learn from punish- ments. These characteristics may also be explained by an urge to stimulate the EOS, which then takes priority over the“social fear system”that tries to warn of the deleterious social consequences of unlawful behaviour.

Impulsive decision-making, the tendency to choose a small immediate reward instead of a large delayed re- ward, was found in substance abusers with a comorbid diagnosis of ASPD (Petry, 2002). This behaviour was shown to decrease after administration of amphet- amine or methylphenidate in rodents (van Gaalen et al., 2006), healthy volunteers (de Witet al., 2002), or children with ADHD (Shielset al., 2009). Among other receptor mechanisms, these stimulants act on the brain opioid system (Wileyet al., 2009; Zhu et al., 2011; Guterstamet al., 2012). In healthy volun- teers, impulsiveness traits were associated with higher μ-receptor concentrations and higher stress-induced EOS activation (Loveet al., 2009). Theseﬁndings can be interpreted as indirect evidence for the involve- ment of the EOS in impulsivity.

Sensation seeking.Sensation-seeking behaviours such as reckless driving are characteristic for ASPD (Zapolskiet al., 2010; Huanget al., 2011). Surviving a dangerous situation unharmed may result in euphoric Table 1. (Continued) FeaturesASPD BPD Other neurobiological ﬁndings supporting the EOS theory DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in ASPD DC DF AFFrequency of symptom according to literatureEvidence for involvement of the EOS in BPD psychosis score in comorbid ASPD/BPD patients than in ASPD alone (Freestone et al., 2013) Dissociative symptoms50.4% dissociation in ASPD (Semizet al., 2007)Yes Dissociation can be treated with opioid antagonists (Table 2) Neurobiologicalﬁndings supporting the EOS theory. Yes = symptom is listed in DSM-5. ASPD, antisocial personality disorder; BPD, borderline personality disorder; EOS, endogenous opioid system; NAcc, nucleus accumbens; fMRI, functional magnetic resonance imaging.

400b. bandelow and d. wedekind Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup feelings (this also applies to only virtually dangerous situations, such as riding on a roller coaster). This phe- nomenon may be explained by special properties of the reward system: dopamine neurons increase theirﬁring when a punishment is expected but does not occur (Martin-Soelchet al., 2001; Schultz, 2002; Shizgal and Arvanitogiannis, 2003). In bungee jumpers, in- creasedβ-endorphin immunoreactivity was observed after the jump (Henniget al., 1994). Healthy individ- uals scoring high on sensation seeking showed an increased subjective response to treatment with an opioid (Zacny, 2010). Thus, risk-taking behaviour of ASPD patients is probably driven by the (unconscious) urge to stimulate the EOS to compensate a pathologi- cal downregulation.

Risky sexual behaviour.Some individuals with ASPD tend to have numerous brief, superﬁcial, and often risky sexual contacts, regardless of the negativeconsequences, such as unwanted pregnancy, alimony payments, infections, or a bad reputation. Among sex- ual offenders, the rate of persons with ASPD is very high (Jumperet al., 2012), especially among sadistic sexual offenders (Bergeret al., 1999) and multiple sex- ual murderers (Hillet al., 2007). Sexual offenders with ASPD have a high recidivism rate.

The inability to control sexual drive may also be an expression of an understimulated EOS. One important function of the EOS is to reinforce individuals for sex- ual activity. However, the biochemistry of love and sexual attraction is also mediated by other neurotrans- mitters, such as dopamine, vasopressin, and oxytocin (Pfauset al., 1990; Odent, 1999; Esch and Stefano, 2005). Addiction-like sexual behaviour has been treated with naltrexone (Table 2).

Substance and alcohol abuse.Perhaps the most con- vincing evidence supporting a dysregulation of the Table 2. Treatment studies of ASPD-associated and BPD-associated symptoms with opioid antagonists Syndromes Treatment Study type ReferencesGlobal improvement Heroin addiction Naltrexone Systematic review of DBPC studies Adiet al.(2007) + Amphetamine addiction Naltrexone DBPC Jayaram-Lindstromet al.(2008) + Alcohol addiction Naltrexone Meta-analysis of DBPC studies Streeton and Whelan (2001) + Nalmefene DBPC Antonet al.(2004) Nalmefene DBPC Masonet al.(1999) + Naltrexone; NalmefeneDBPC Drobeset al.(2004) + Nalmefene Review Keating (2013) + Pathological gambling Naltrexone DBPC Kimet al.(2001) + Naltrexone DBPC Grantet al.(2008) + Nalmefene DBPC Grantet al.(2006) + nalmefene DBPC Grantet al.(2010) Naltrexone Open Kim and Grant (2001) + Compulsive buying Naltrexone Case series Bullock and Koran (2003) + Kleptomania Naltrexone DBPC Grantet al.(2009) + Naltrexone Open study Grant and Kim (2002) + Naltrexone Case report Orihuela-Floreset al.(2010) Kleptomania and compulsive sexual behaviour Naltrexone Case report Grant and Kim (2001) + Compulsive sexual behaviour Naltrexone Case reports Raymondet al.(2002) + Naltrexone Case report Bostwick and Bucci (2008) + Sexual overstimulation in sexual offenders Naltrexone Open study Ryback (2004) + Anorexia/bulimia nervosa Naltrexone DBPC Marrazziet al.(1995) + Naltrexone DBPC Husemanet al.(1990) + Naltrexone DBPC Mitchellet al.(1989) Naltrexone Open study Jonas and Gold (1986) + Naltrexone Case report Chatooret al.(1994) + Self-injury In mentally retarded subjects Naltrexone Review of DBPC studies Symonset al.(2004) + Various diagnoses Naltrexone Open study Rothet al.(1996) + In BPD Naltrexone Case series Sonneet al.(1996) + In BPD Naltrexone Case report McGee (1997) + Dissociation In BPD Naltrexone Open study Bohuset al.(1999) + In BPD Naltrexone DBPC cross-over Schmahlet al.(2012) In BPD Naloxone DBPC Philipsenet al.(2004) In PTSD and other disorders Naltrexone Open study Pape and Woller (2014) + ASPD, antisocial personality disorder; BPD, borderline personality disorder; PTSD, posttraumatic stress disorder; DBPC, double-blind, placebo-controlled.

+/ , global improvement/superiority to placebo shown/not shown. 401 the eos in antisocial personality disorder Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup EOS derives from the high rate of substance abuse in ASPD (Westermeyer and Thuras, 2005; Chapman and Cellucci, 2007). Heroin and other“hard”drugs are frequently consumed by ASPD patients, despite of the harmful consequences (Darkeet al., 2004).

Many patients have polysubstance dependency (Hatzitaskoset al., 1999), and death due to accidental overdose is not rare (Kjelsberget al., 1995).

Although alcohol, heroin, cocaine, amphetamines, cannabis, and nicotine have different primary targets, that is, GABAergic, dopaminergic, or glutamatergic systems (Kelley and Berridge, 2002; Ikemoto and Wise, 2004), they all directly or indirectly stimulate dopamine transmission in the NAcc (Nestler, 2005) and activate the EOS (Le Merreret al., 2009; Koob, 2013; Nutt, 2014) (Figure 1). Heroin targetsμ-opioid receptors. Cocaine inﬂuences the EOS (Zubietaet al., 1996; Gorelicket al., 2005). Its reinforcing effects can be blocked by naltrexone (Roth-Deriet al., 2008). Amphetamines modulate the dopaminergic re- ward system and cause endorphin release (Guterstam et al., 2012). Benzodiazepines, which are often overdosed by patients with ASPD, augment the inhib- itory activity of GABA, which modulates the EOS and mesocorticolimbic dopamine neurotransmission (Ishikawaet al., 2008; Enginet al., 2014). Alcohol elicits endorphin release via GABA Areceptors within reward circuits (Enoch, 2008; Steffensenet al., 2009). Abstinent alcoholic patients displayed an in- crease inμ-opioid receptors in the ventral striatum (Heinzet al., 2005). Opiate and alcohol dependency can be treated with opioid antagonists (Table 1).

The high comorbidity between ASPD and substance or alcohol abuse suggests that these disorders share susceptibility genes (Maloneet al., 2004). In search of the genetic basis of substance abuse, candidate genes (μ,κ, and prodynorphin genes) were found that are associated with the EOS (Brewer and Potenza, 2008; Yuferovet al., 2010).

Non-substance-related addictions Non-substance-related addictions, including gambling, kleptomania, or compulsive sexual behaviour, are also common in ASPD. They seem to have a genetic basis (Slutskeet al., 2001; Kreeket al., 2005; Mishraet al., 2011) and have been linked to a dysregulation in the EOS (Brewer and Potenza, 2008). These disorders have been successfully treated with opioid antagonists (Table 1). During gambling,β-endorphin plasma level increase has been demonstrated (Shinoharaet al., 1999). After an amphetamine challenge, pathological gamblers released less endorphins than non-gamblers and reported less euphoria (Rabineret al., 2014).Mesolimbic dopamine release was correlated with symptom severity in pathological gambling (Joutsa et al., 2012). In an fMRI study, blocking of opioid function with naloxone while subjects performed a gambling task resulted in a reduction of pleasure rat- ings for reward outcomes, accompanied by a reduction of activity in the anterior cingulate cortex. Moreover, under naloxone, negative outcome was rated as more unpleasant (Petrovicet al., 2008).

Negative affectivity.Dysphoric mood.Whereas real depression seems to be rare in sufferers from ASPD, affective instability (e.g. dysphoria, irritability, and feelings of emptiness or tediousness) is common. De- spite the opinion that persons with ASPD are immune to suicidal risk, they have a suicide completion rate of 4–5%, which is not much less than in BPD (Verona et al., 2001; Rothet al., 2011).

The sudden and unpredictable mood changes of in- dividuals with ASPD could be explained by rises and falls in endogenous opioid levels. Feelings of empti- ness may be triggered by a reduced hedonic tone caused by subsensitivity ofμ-opioid receptors or, as an alternative hypothesis, an overactivity of the κ-opioid receptor system, which is associated with dysphoria (Kumoret al., 1986; Schlaepferet al., 1998). Studies with mice deﬁcient in dopamine recep- tors suggest that endogenous opioid peptides have the function of maintaining a basal level of positive affect (Narayananet al., 2004).

Bonding problems.Fear of abandonment.Although individuals with ASPD often change their partners, they also tend to show pathological jealousy and threaten to hurt or kill their disloyal partners. Stalking as an expression of pathological jealousy is frequently reported in persons with psychopathy or ASPD (Storey et al. , 2009).

The EOS plays a central role in sociality (Panksepp et al., 1978; Machin and Dunbar, 2011). In primates and other animals, separation distress vocalizations can be alleviated by morphine and potentiated by nal- oxone (e.g. Kalinet al., 1995).μ-Knockout mice are characterized by deﬁcits in attachment behaviour (Moleset al., 2004). In primates, a variation at the μ-opioid receptor gene (OPRM 1) modulates attach- ment (Barret al., 2008).

In healthy volunteers, social rejection/acceptance was linked with changes inμ-opioid receptor availabil- ity in brain reward circuits (Hsuet al., 2013). In humans, romantic love is associated with an activation of the right VTA (Aronet al., 2005). There is a partic- ularly high density of opioid receptors in the 402b. bandelow and d. wedekind Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup orbitofrontal cortex (Powellet al., 2010; Lewiset al., 2011). It may therefore be hypothesized that the difﬁ- culties of ASPD patients in forming stable social bonds are due to a reduced opioidergic tone. When deeply in love, we suspend critical judgments towards our partner, which is probably a natural phenomenon designed to facilitate human bonding (“love is blind”).

Increased activity in the VTA in romantic love was mirrored by a decrease in activity of cortical zones that are responsible for negative feelings or critical judge- ment (Zeki, 2007). This mechanism may also explain why some antisocial individuals are able to easily at- tract partners despite their often difﬁcult behaviours.

Moreover, men incarcerated for heinous crimes are of- tenﬂooded with letters with marriage proposals from female admirers.

Self-harm.Self-mutilation is quite frequent in ASPD (Virkkunen, 1976; Sendula-Jengicet al., 2004; Alpay Ateset al., 2011). In addition, the tendency of antiso- cials to be involved inﬁghts shows that they are not as afraid of injuries as healthy persons are. Moreover, tattoos and piercings, which were very common among antisocial individuals (Inch and Huws, 1993) long before they became a mass phenomenon (Virkkunen, 1976), may also be interpreted as some form of self-injury.

We had hypothesized that patients with BPD hurt themselves in order to put their body into an artiﬁcial “survival mode,”thus taking advantage of the associ- ated“endorphin rush”(Bandelowet al., 2010; see also Bresin and Gordon, 2013). A complex dysfunction of the opioid system may explain why self-harming indi- viduals report euphoria and no pain when they cut their arms, while healthy persons would only feel pain (Kleindienstet al., 2008). In an MRI study, it was found that antinociceptive mechanisms in patients with BPD were associated with an increased pain-induced response in the dorsolateral prefrontal cortex and lower activity in the anterior cingulate and the amygdala (Schmahlet al., 2006). In self-injuring individuals, pain was associated with reward, as could be demon- strated by a greater correlation between blood oxygen- ation level-dependent response signal and“relief”than in control subjects in brain areas associated with reward/pain and addiction (Osuchet al., 2014). Self- injury in subjects with mental retardation is probably due to a disturbance of endorphin production and can be treated with opioid antagonists (Table 2). In a case series, buprenorphine, a potentμ-opioid partial agonist andκ-opioid antagonist, was beneﬁcial in individuals with self-injury (Norelliet al., 2013).Antagonizing ASPD symptoms with opioid antagonists The EOS theory is further supported by the positive effects of opioid antagonists, including naltrexone, naloxone, and nalmefene, on addiction and other symptoms commonly found in ASPD (Table 2). These drugs block opioid receptors but do not have an intrin- sic effect. However, there are no controlled studies investigating the effects of opioid antagonists in pure ASPD samples.

How can opioid antagonists improve ASPD- associated symptomatology? First, we can assume an acute effect. For example, by binding to opioid recep- tors, the reinforcing positive effect of heroin is blocked by the antagonist. Second, the antagonists may have long-term effects, which consist of an upregulation of opioid receptor sensitivity. After long-term treatment of heroin addiction with naltrexone, resuming heroin intake at the previously used dose could result in a fatal overdose because of a normalization of a pathological subsensitivity of opioid receptors by naltrexone. Alter- natively, naltrexone, by blockingκ-opioid receptors, may act by suppressing dysphoric and dissociative states.

However, the positive effects of opioid antagonists seem to be paradoxical, as one would expect anhe- donic feelings resulting from opioid receptor blockade.

Yet, patients treated with naltrexone for self-injury do not report anhedonia or increased feelings of empti- ness. In clinical studies, depression was reported as a side effect but did not occur more frequently than in the placebo arms (Naltrexone package insert).

THE“SOCIAL FEAR SYSTEM” Callous–unemotional traits with lack of guilt and em- pathy are characteristic for ASPD. Although this as- sumption is speculative, it can be postulated that the brain possesses a“social fear system,”which is able to analyse social situations and to cause fear or un- pleasant feelings when negative consequences of anti- social behaviour are anticipated. This network is the counterpart of the reward system—in analogy to Freud’s model of the“Id”and the“Superego.”While the reward system is rather archaic and only focused on the satisfaction of primary needs such as sex and food, the social fear network seems to be on a higher intellectual level and is more developed in humans than in animals. In this network, a complex set of laws and rules that control social interaction has to be stored and managed. In contexts, in which the desire to satisfy primary drives is in conﬂict with social rules, it is able to balance decisions—it warns us not to have 403 the eos in antisocial personality disorder Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup sex on the street, steal food from children, or beat our parents. It is likely that this system is located in the frontal lobe (Figure 1). The lateral and medial regions of the prefrontal cortex are centrally involved in con- trolling and correcting punishment-related behaviour (Rolls and Grabenhorst, 2008), emotion regulation (Blair, 2008), compassion, and sensitivity to others’ emotional states (Schirmeret al., 2008) and lack of in- sight (Barrashet al., 2000).

Antisocial behaviour may result from a failure of the social fear network to inhibit centres of the brain, which control the satisfaction of primary drives and aggression. It was hypothesized that a prefrontal- limbic circuit, which includes the orbitofrontal cortex, the anterior cingulate, and the amygdala, is disinhibited in aggressive behaviour (Davidsonet al., 2000; Patrick, 2008; Siever, 2008). Massive brain damage in the frontal lobe, including the orbitofrontal cortex, caused by tumour or trauma may result in“ac- quired”antisocial behaviour (Damasioet al., 1994; Grafmanet al., 1996). However, in typical cases of ASPD, neuroanatomical changes are only subtle and only detected when a larger group of ASPD patients is compared statistically with healthy controls. By using brain imaging techniques, structural and func- tional deﬁcits in subjects with antisocial behaviour were found mainly in the orbitofrontal and ventrome- dial prefrontal cortex, the anterior cingulate cortex, the insula, and the limbic system (including the amyg- dala), but also in other regions of the brain. However, it is not yet well understood how these variousﬁndings relate to the complex organization of cortical networks in antisocial behaviour.

In contrast to antisocial individuals, patients with social phobia are oversensitive to the negative conse- quences of antisocial behaviour. In an fMRI compari- son of psychopaths, social phobics and healthy controls, the psychopaths lacked activation of the orbitofrontal cortex, the insula, and the anterior cingu- late, while social phobics showed increased activity in the amygdala and orbitofrontal cortex in response to a social stimulus (Veitet al., 2002).

ARE BPD AND ASPD DISTINCT DISORDERS?

The DSM (APA, 2013) deﬁnitions of BPD and ASPD suggest clear-cut differences between these disorders.

However, ASPD and BPD have a number of similari- ties in symptoms, which is reﬂected by a high comor- bidity rate (Zimmermanet al., 2005; Freestoneet al., 2013). Moreover, they show parallels in prevalence, risk factors, course, and response to treatment. Only about oneﬁfth of ASPD patients are women, and oneﬁfth of BPD patients are men, while both disorders have comparable prevalence rates. Therefore, it has been suggested that the two disorders reﬂect outcomes of a single aetiology shaped by gender (Paris, 1997; Beauchaineet al., 2009), although this link has been questioned (Pariset al., 2013). In the following sec- tion, we will show that the striking similarities of both disorders in symptomatology, aetiology, heritability, course, and treatment response suggest that BPD and ASPD have a common origin, an EOS deﬁciency.

Similarities in symptomatology The similarities in symptomatology are listed in Table 1. Some of these similarities are reﬂected in the“diagnostic criteria”(DC); others are“diagnostic features ”(DF) or“associated features supporting diag- nosis”(AF) of the DSM-5. Some of the similar symp- toms are not listed in the DC, DF, or AF of the DSM, such as“unlawful behaviour”in BPD. In these cases, we tried to provide evidence from the literature in the table to show whether this symptom is a relevant fea- ture in ASPD or BPD.

Antagonism.Anger, violence, or recurrent physical ﬁghts are also common in BPD. Among violent of- fenders, 47% of men and 21% of women have ASPD (Fazel and Danesh, 2002). In BPD, we see a mirror im- age: in a study of prison inmates, BPD was present in 55% of the women and 27% of men (Blacket al., 2007). The lower crime rate in women with BPD com- pared with men with ASPD can simply be explained by the general tendency that women commit fewer crimes—only 13% of jail inmates are women (Minton, 2013). Neurobiological accounts for these differences have been formulated. For example, polymorphisms of MAO Agenes, which are located on the X chromo- some, could explain sex differences in aggression (Brunneret al., 1993; Caspiet al., 2002; Meyer- Lindenberget al., 2006). Neuroimaging studies found structural differences in the orbitofrontal gray as a pos- sible explanation for sex differences in ASPD (Raine et al., 2011). However, also gonadal hormones may account for sex differences in the expression of a puta- tive EOS dysfunction (Machin and Dunbar, 2011).

Testosterone improves the analgesic effects of endoge- nous opioids. It reduces the sensitivity for punishment while enhancing the sensitivity for reward (van Honk and Schutter, 2006). A link between circulating testos- terone and antisocial behaviour was reported (Yildirim and Derksen, 2012). The role of oestrogen is variable; it can act as an opioid antagonist (Zubietaet al., 2002; Bodnar, 2007). 404b. bandelow and d. wedekind Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup Disinhibition.Both disorders are characterized by im- pulsivity (Petry, 2002; Lawrenceet al., 2010). Impul- sivity in ASPD men seems to be more likely to be expressed through exploitation or injury of others, whereas impulsivity in women with BPD seems to be reﬂected in self-destructive behaviours. Because of their inability to plan ahead and to sustain consistent work behaviour, patients with these disorders often show low education levels and a higher rate of unem- ployment (Pajeret al., 2006). Like in ASPD, BPD patients often show sensation-seeking behaviour and reckless disregard for safety of self or others (Sansone et al., 2010). BPD and ASPD are common among female and male prostitutes and sexual offenders (Curtin and Niveau, 1998). Impulsive or high-risk sexual activities are characteristic for both BPD and ASPD patients. Drug and alcohol abuse was reported by 37–76% of BPD and 74–95% of ASPD patients (Hatzitaskoset al., 1999; Öhlinet al., 2011). In partic- ular, among opioid-dependent individuals, the rate of ASPD (71%) and BPD (64%) is high (Darkeet al., 2004). BPD is mainly associated with abuse of sub- stances that directly target the EOS (Carpenteret al., 2015). Impulse control disorders like pathological gambling or compulsive buying are characteristic for both disorders (Schlosseret al., 1994; Muelleret al., 2009). Although eating disorders are not explicitly listed in the DSM-5 criteria, they are found in 54% of patients with BPD (Zanariniet al., 2010). This symptom does not seem to play a major role in men with ASPD, but antisocial tendencies are common in patients with eating disorders (Rossiteret al., 1993; Zapolskiet al., 2010).

Negative affectivity.The suicide completion rates in ASPD and BPD are comparable (Paris and Zweig- Frank, 2001; Zanariniet al., 2005; Brodskyet al., 2006). While self-harm is generally seen as a typical BPD symptom and rarely listed as an ASPD feature, it is not uncommon in ASPD.

Bonding problems.Frantic efforts to avoid abandon- ment are a DSM-5 feature of BPD and not listed in the ASPD criteria. However, also antisocial persons are known to react desperately and jealously when abandoned by their partners.

Anxiety, psychosis, and dissociation.Comorbid anxi- ety disorders are not only found in BPD but also in 50% of ASPD patients (Hodginset al., 2010). BPD symptoms like depersonalization or rare subdelusional paranoid symptoms may also occur in ASPD (Yochelson and Samenow, 1976; Lykken, 1995; Freestoneet al.,2013). Dissociation, a typical BPD symptom, which is responsive to opioid antagonist treatment, is also not rare in ASPD (Semizet al., 2007).

Similarities in aetiology Similar to BPD, the origin of ASPD has been attrib- uted to an interaction of environmental and genetic factors. Increased rates of childhood trauma, including physical and sexual abuse, are seen in both ASPD and BPD (Pariset al., 1994; Koppet al., 2009). However, studies investigating childhood trauma may be subject to systematic distortions, as patients with both disor- ders tend to devalue their parents. Family, twin and adoption studies have been used to disentangle environmental and genetic factors (Bandelowet al., 2005). In twin studies, 35 –69% of the variance in BPD symptoms was attributable to additive genetic effects (Livesleyet al., 1993; Torgersenet al., 2000; Distelet al., 2008; Torgersenet al., 2008; Amad et al., 2014). Similarly, in twin studies of ASPD, herita- ble factors account for approximately 50% of the vari- ance (Rhee and Waldman, 2002; Maeset al., 2007; Vidinget al., 2008; Ferguson, 2010). Shared genetic and environmental risk factors for BPD and ASPD are greater than for other personality disorders (Torgersen et al., 2008), which is likely because of shared vulnera- bility for impulsivity (Nestadtet al., 1994).

If BPD and ASPD are sex-related expressions of a common inherited neurobiological factor, the male ﬁrst-degree relatives of individuals with BPD should be more likely to have ASPD, and vice versa.Genetic studies have not tested this hypothesis explicitly by differentiating by gender but have shown that individ- uals with BPD or ASPD had signiﬁcantly greater rates of the other disorder in theirﬁrst-degree relatives (Zanariniet al., 1988; Goldmanet al., 1993; Zanarini et al., 2004).

Similarities in neuropsychology In BPD, various impairments in neuropsychological functions have been found, including executive, memory, attention, or language functions (LeGris and van Reekum, 2006; Dell’Ossoet al., 2010). However, the studies produced equivocal conclusions (Kunert et al., 2003; Ruocco, 2005; Haaland and Landro, 2009). Likewise, in ASPD, multiple neurocognitive domains such as executive functions have been found to be disturbed, but the changes were subtle and not speciﬁc (Morgan and Lilienfeld, 2000; Dolan, 2012).

Thus, as there is no consistent pattern of neuropsycho- logical dysfunctions neither for BPD nor ASPD, it would be premature to conclude that the two disorders share a common neuropsychological disturbance. 405 the eos in antisocial personality disorder Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup Similarities in brain imagingﬁndings Structural and functional brain imaging studies have found some similarities between ASPD and BPD. For example, in both disorders, reduced volumes (Raine et al., 2000; Laaksoet al., 2002; Tebartz van Elst et al., 2003; Raineet al., 2011; Gregoryet al., 2012) or reduced regional bloodﬂow (Kuruogluet al., 1996; Goethalset al., 2005) were found in the prefron- tal cortex. However, altogether, brain imagingﬁndings in ASPD and in BPD are far from showing a consistent picture (Koenigset al., 2011; Glenn and Yang, 2012), as abnormalities in ASPD were observed in many different brain regions such as the orbitofrontal cortex (Raineet al., 2011), the ventromedial prefrontal cortex (Herperset al., 2013), the anterior cingulate cortex (Vollmet al., 2010), the temporal lobe (Goethals et al., 2005; Gregoryet al., 2012), the putamen (Barkatakiet al., 2006), the corpus callosum (Raine et al., 2003), the thalamus (Kumariet al., 2013), or the hippocampus (Raineet al., 2004). Likewise, for BPD, abnormalities were seen in the orbitofrontal cor- tex (Tebartz van Elstet al., 2003; Chanenet al., 2008; Soloffet al., 2012), the anterior cingulate cortex (De La Fuenteet al., 1997; Tebartz van Elstet al., 2003), the caudate (De La Fuenteet al., 1997), the amygdala (Tebartz van Elstet al., 2003; Wenigeret al., 2009; Herperset al., 2013), the hippocampus (Brambilla et al., 2004; Wenigeret al., 2009), the parietal lobe, and the precuneus (Tanget al., 2013). Some of these studies may be preliminary due to their small sample sizes. The diversity of theseﬁndings does not allow drawing conclusions that support the EOS theory.

Similarities in treatment response Patients and treatment providers are often struggling desperately with treatment resistance in BPD and ASPD. Treatment with dialectical behaviour therapy has shown some promising results in BPD (Bloom et al., 2012). However, only improvements of some symptom complexes can be achieved, while complete remission is rare (Binkset al., 2006b; Stofferset al., 2012). Also, only certain symptoms of BPD can be treated with psychopharmacological agents (Binks et al., 2006a; Stofferset al., 2010). Likewise, drug therapy of ASPD has very limited effects (Khalifa et al., 2010), and psychological treatments show al- most no efﬁcacy. The psychological intervention that seemed to work best in ASPD was“contingency man- agement”for drug-addicted patients, in which clean urine specimens are rewarded with money vouchers (Gibbonet al., 2010)—a treatment that directly targets the reward system.Similarities in course Antisocial personality disorder and BPD are also alike regarding the course of illness. During childhood, many ASPD and BPD patients had ADHD. Both disor- ders are worst between the 20s and 30s and then grad- ually improve (Pariset al., 1987; Blacket al., 1995; Zanariniet al., 2011). Such mitigation of symptoms is not seen in other personality disorders (Paris, 2003).

In summary, the striking similarities in symptom- atology, aetiology, heritability, course, and treatment response strongly suggest that BPD and ASPD have a common origin, and the differences between them are mostly shaped by gender differences—in general, aggression and substance abuse are more common in men, while depression and self-injury are more com- mon in women. These differences may be due to hor- monal differences. Female rodents were consistently shown to express signiﬁcantly lessμ- andδ-opioid re- ceptors in the cortex and the brainstem in comparison with males (Loydet al., 2008; Williamset al., 2011).

ATTENTION-DEFICIT/HYPERACTIVITY DISOR- DER AS A HARBINGER FOR ASPD OR BPD When an EOS disturbance is characteristic for both ASPD and BPD, it seems logical that this common neurobiological alteration with probable genetic back- ground was already present during childhood. ADHD may be a harbinger of later ASPD or BPD.

An elevated rate of childhood or adult ADHD was found in prison populations (Cahillet al., 2012).

ADHD is comorbid with CD or ODD in over half of the cases (Connoret al., 2010). In prospective follow-up studies, up to 58% of children with ADHD showed delinquent behaviour or ASPD later in life (Mofﬁtt and Silva, 1988; Mannuzzaet al., 2002; Biedermanet al., 2012). Likewise, up to 60% of patients with BPD were found to have a history of ADHD during childhood (Fossatiet al., 2002; Davids and Gastpar, 2005; Burke and Stepp, 2012). This asso- ciation between early ADHD and later ASPD or BPD has also been corroborated in genetic studies (Distel et al., 2011; Beaveret al., 2012).

Attention deﬁcit, hyperactivity, and impulsivity, the dominant symptoms of ADHD, can be treated with methylphenidate, dextroamphetamine, and atomoxetine.

These stimulants act on different neurotransmitter sys- tems but have in common that they all act also on the EOS (de Witet al., 2002; Pietraset al., 2003; Creighton et al., 2004; Faraone and Buitelaar, 2010). Similarly, many other ADHD symptoms can also be explained by an EOS deﬁciency. During the lifespan of ADHD 406b. bandelow and d. wedekind Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup patients, symptomatology changes. Whereas hyperac- tivity decreases, impulsivity remains, and EOS- associated features like antisocial behaviour, substance abuse, and eating disorders become more dominant with increasing age (Biedermanet al., 2010; Biederman et al., 2012). In summary, an EOS dysfunction may be the common neurobiological factor causing not only BPD in adult women and ASPD in adult men but also ADHD in children. However, this hypothesized link to ADHD needs to be conﬁrmed by additional research.

DISCUSSION In an earlier article, we have posed that the disabling symptoms of patients with BPD can be best explained by a malfunction of the EOS (Bandelowet al., 2010).

Now, we extend this theory to ASPD. The EOS theory assumes that both disorders derive from a common un- derlying neurobiological dysfunction, which consists of a subsensitivity of endogenous opioid receptors and/or a reduced availability of endogenous opioids.

The hypothesis further supposes that ASPD is the pre- dominant expression of this malfunction in males, whereas BPD is the female form of the disorder. Child- hood ADHD may be an early expression of this EOS dysfunction. It may be discussed that ADHD, ASPD, and BPD are manifestations of an“EOS deﬁciency syndrome”rather than being developmental or person- ality disorders.

All individuals want to stimulate their reward sys- tem, but healthy humans impose certain ethical limits on themselves and prefer to satisfy their instinctual needs such as sex and food in a controlled way, in order not to break social rules or to avoid dangerous encounters.

Gray proposed the existence of two systems: the behavioural activation system (BAS), which initiates goal-directed behaviour in response to reward, while the behavioural inhibition system (BIS) serves to avoid aversive stimuli or punishment (Gray, 1987). Quay (1993) proposed that the excessive BAS activity seen in antisocial youth results in a reward-dominant re- sponse style that predominates over the BIS and leads to persistent approach or reward-seeking behaviours.

Others proposed that antisocial behaviour instead re- ﬂects an underactive reward system that facilitates sen- sation seeking (Cloninger, 1987; Zuckerman, 1996).

Blum has coined the term“reward deﬁciency syn- drome”for the association of aggressive behaviour in ASPD, CD, ADHD, impulsivity, aberrant sexual behaviour, gambling, eating disorders, and substance abuse, and linked this syndrome mainly to a genetic dysfunction of dopamine receptors (Blumet al.,2012). At present, it seems more likely that a dysfunc- tional EOS plays a key role in this syndrome. If the needs of the EOS-controlled reward system are threat- ened or are not being met, individuals experience discomfort, dysphoric mood, irritability, feeling of emptiness, and anxiety, and tend to compensate this deﬁciency by displaying problematic addictive, aggressive, or impulsive behaviours, which are poten- tially dangerous or socially undesirable.

The reward system seems to be antagonized by a pu- tative“social fear system,”which is on a higher cogni- tive level than the EOS and is designed to warn us that we should not behave impulsively or impudently. The prefrontal cortex, in which the social fear system may be located, is rich in opioid receptors (Powellet al., 2010; Lewiset al., 2011). The EOS on one side and the“social fear system”on the other counteract each other in order to keep satisfaction of primary drives and social consideration in balance. However, it is still unclear whether the imbalance between these systems found in antisocials results from an ineffective social fear system, a dysregulated EOS, or a combination of both. The numerous neuroanatomical deﬁcits found in the orbitofrontal cortex and other brain regions in persons with antisocial, callous, or psychopathic traits have to be integrated into the EOS theory.

The lack of remorse and compassion in antisocial in- dividuals could be explained by an underdeveloped sensitivity for emotions and social cues, due to a weak social fear system. However, is it really true that anti- socials have a“big black hole”in their brain where normal persons have a social fear network? In con- trary, clinicians often observe that individuals with ASPD or psychopathy have a“supernatural”ability to reveal the desires, weaknesses, and inner secrets of their counterparts, indicating that their skills to read other people’s minds are not at all diminished. This hy- pothesis is difﬁcult to test. In tasks related to cognitive empathy, superior performance was found in psycho- paths in some studies (Dolan and Fullam, 2004; Book et al., 2007; Hansenet al., 2008), but in others, normal or deﬁcient ability to recognize emotion was reported (Brook and Kosson, 2013; Brooket al., 2013). Supe- rior cognitive empathy in psychopathy may be limited only to a subset of individuals with this condition, the “successful psychopaths.”Nevertheless, per deﬁnition, antisocials and psychopaths may be manipulative, deceitful, fraudulent, charming, glib, seductive, and ingratiating. These traits require a well-functioning de- tection system for social cues. The problem is that the affected persons do not use the acquired information for mutually positive social interactions but misuse their increased sensitivity for exploiting, conning, or 407 the eos in antisocial personality disorder Copyright © 2015 John Wiley & Sons, Ltd.Hum. Psychopharmacol Clin Exp2015;30: 393–415 DOI: 10.1002/hup humiliating others, in order to obtain personal proﬁt (e.g. money and sex) or psychological force (e.g. sta- tus, inﬂuence, and supremacy). Moreover, by doing this, they seem to put the emphasis on immediate satis- faction of their needs while disregarding the beneﬁts of long-lasting, reliable social relations. Altogether, it seems not unlikely that antisocial behaviour can be ex- plained solely by an EOS deﬁciency without requiring a disturbed social fear system.

The EOS theory may also explain the high crime re- lapse rate in ASPD. As the EOS is an overpowering brain structure due to its role as a survival system, it is more difﬁcult for subjects with ASPD to control their emotions than for individuals without such a dis- turbance. This also has implications for ethical consid- erations regarding the criminal liability of the affected persons.

If the EOS theory receives more support from new neurobiologicalﬁndings in the future, chances for im- provement of treatments for ASPD may emerge.

Future research should focus on double-blind studies with opioid antagonists like naltrexone, naloxone, or nalmefene. These drugs can have immediate effects by blocking rewarding effects of pathological behav- iours and chronic effects by normalizing the decreased sensitivity of opioid receptors. However, they do not have intrinsic effects on the receptors and do not ele- vate a reduced hedonistic tone. Therefore, the develop- ment of partial agonists/antagonists that have intrinsic activity at endogenous opioid receptors without caus- ing addiction would be more promising. For example, in animal studies, the non-opioid, unnatural isomer (+)-naloxone, by blocking the toll-like receptor 4, sup- pressed opioid-induced conditioned place preference (Hutchinsonet al., 2012). Thus, the rewarding stimula- tion by opioids could be disentangled from the devel- opment of addiction. Combining this drug with an opioid like morphine could theoretically relieve the endorphin deﬁcit in individuals with BPD or ASPD, without the costs of dependency.

Limitations The EOS theory has a number of limitations. Direct measurements of endogenous opioids in plasma or the CSF would be inconclusive, as these hormones do not easily pass the blood–brain barrier. However, opioid antagonists can be used to indirectly measure endorphin release by observing the changes that occur when opioid receptors are blocked. Another limitation of the EOS theory is that opioid receptors have not yet been studied in clinical samples of antisocials using brain imaging techniques. Today, PET imaging ofμ-, δ-, andκ-opioid receptors is possible in the brain,and radioligands are currently under development for SPECT studies of opioid receptors, making it possible to detect functional abnormalities (Lever, 2007; Hirvonenet al., 2009).

It may be argued that it is too simple to attribute the complex psychopathology of ASPD or BPD to just one neurotransmitter system. Future research should focus on the complex links of the EOS/reward system to other brain systems, including serotonergic path- ways. If BPD and ASPD are sex-dependent manifesta- tions of the same neurobiological dysfunction, research should also focus on the possible role of sex hormones or gender-speciﬁc candidate genes. Re- search will also have to elucidate why ASPD and BPD symptomatology is worst between the 20s and 30s and then gradually improves, which makes it un- likely that the neurobiological changes are of neurode- generative nature.

CONFLICT OF INTEREST In the last 3 years and in the near future, Dr Bandelow has been/will be on the speakers’/advisory board for AstraZeneca, Glaxo, Janssen, Lilly, Lundbeck, Ono, Otsuka, Pﬁzer, and Servier. Dr Wedekind was on the speakers’board of AstraZeneca, Essex Pharma, Lundbeck, Wyeth, and Servier.

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