84 | THE NEUROBIOLOGY OF PERSONALITY DISORDERS: THE SHIFT TO DSM-5
M. MERCEDES PEREZ-RODRIGUEZ, ANTONIA S. NEW, AND LARRY J. SIEVER
Investigations into the neurobiology of psychiatric disorder increasingly focus on dimensions or domains of psychopathology across diagnoses (as exemplified by the Research Domain Criteria initiative [RDoC]; Insel et al., 2010) and their underlying circuitry problems. Neuropeptides and neurotransmitters then modulate these critical circuits. Gene by environment interactions are a focus for investigating these domains.
Although the study of personality disorder had traditionally been the province of psychoanalytic or behavioral models, there is an emerging neurobiology of personality disorders grounded in altered neurocircuitry associated with individual differences and dimensions such as affective dysregulation (affective instability and negative affectivity), disinhibited aggression, anxiety/avoidance, cognitive/perceptual dysregulation, and social detachment/isolation. Thus, these new directions in psychiatry neurobiological research converge with efforts to identify the neural basis of stable traits in the personality disorders. The Five Factor Model of personality has identified core traits, such as neuroticism, which are stable and quite heritable. Extremes of these traits, expressed in the symptom dimensions, crystallize to the prototypic personality disorders as, for example, borderline personality disorder with affective instability, disinhibition/aggression, and social cognitive/interpersonal impairment. Schizotypal personality disorder is comprised of social isolation/detachment and cognitive/perceptual disorganization. Avoidant personality disorder is characterized by detachment and negative affectivity, whereas obsessive compulsive personality disorder is characterized by negative affectivity and conscientiousness. The cluster of traits that place an individual at risk for the development of a personality disorder also places him or her at risk for other psychiatric illnesses, such as depression and anxiety disorders particularly, accounting for the high rate of co-morbidity with personality disorders. Neurocircuits implicated in the affective instability (negative affectivity) and disinhibition of borderline personality disorder are related to limbic structures such as amygdala and insula as regulated by prefrontal regions including the orbitofrontal cortex (OFC). The cognitive disorganization of schizotypal personality disorder may be related to alterations in the dorsal lateral prefrontal cortex and temporal cortex, whereas deficiencies in ventral striatum dopamine systems may be related to the detachment/anhedonia. The biological underpinnings of avoidant and obsessive compulsive personality disorders are less well understood and because there is not a substantial body of research on these disorders, they are not reviewed in detail in this chapter.
The study of the neurobiology of personality disorders provides a gateway to understanding relationships between brain and behavior building on individual variation in anxiety threshold, affective regulation, social cognition, and inhibition/aggression, and thereby can help us understand the circuitry underlying these critical domains. These specific circuits are modulated by neurotransmitters such as serotonin or norepinephrine for prefrontal cortex, neuropeptides particularly for limbic regions, and these modulators tune the sensitivity and response characteristics of these circuits. The study of the genetics of personality disorders can identify critical genes that regulate the structure of these circuits and their connectivity as well as the modulators that regulate them. Because personality disorders evolve from the interaction of genetics and environment throughout the course of development, understanding the neurobiology of these disorders allows for the characterization of gene by environment interactions as well as the mechanisms by which these interactions unfold in the course of development. Environmental influences also may influence the expression of the genome through epigenetic factors and these are beginning to be investigated in the personality disorders. Finally, through identifying genetic variation and their epigenetic regulation as well as functional aspects of specific neurocircuitry, the molecular mechanisms underlying these differences in personality disorders can be characterized.
CATEGORIES VERSUS DIMENSIONS
IN PERSONALITY DISORDERS
Both dimensional and categorical approaches can be used to assess and diagnose personality disorders. There has been controversy about which approach is more valid and a hybrid system utilizing both was proposed for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (Rationale for the Proposed Changes to the Personality Disorders Classification in DSM-5: http://www.dsm5.org/ProposedRevision/Pages/proposedrevision.aspx?rid=17#). The final approved version of DSM-5 will maintain the categorical model and criteria for the 10 DSM-IV personality disorders, and will include the newly proposed trait-specific classification system in a separate area of Section 3.
There has been skepticism about the categorical nature of personality disorders (Eaton et al., 2011; Widiger et al., 2009) based in part on the high levels of co-morbidity among personality disorders and between personality disorders and psychiatric diagnoses categorized in DSM-IV on Axis I. This has led a number of investigators to favor a dimensional model based on elements of the Five Factor Model scales (Costa and Widiger, 2002). Other approaches incorporating a dimensional model include large-scale twin studies, which have supported a different model for personality disorders, suggesting four factors: internalizing, externalizing, anhedonic/introversion, and cognitive/relational disturbance (Kendler et al., 2011a; Roysamb et al., 2011); however, according to this model, the division between Axis I and II in DSM IV is called into question. For example, antisocial personality disorder is more closely linked to Axis I substance abuse disorders, and dysthymia is more closely linked to such disorders as avoidant and dependent personality disorders.
Some have argued that the best way to address the dimensions versus categories controversy for personality disorders classification is to adopt a hybrid dimensional-categorical model (Trull et al., 2011).
Borderline personality disorder (New et al., 2008b), ASPD (Patrick et al., 2009), and STPD (Siever and Davis, 2004) have been studied most comprehensively from a neurobiological vantage point and have the largest empirical evidence of clinical utility and validity among PDs (Skodol et al., 2011). In this chapter, rather than reviewing all of the DSM-IV PDs, we review findings in these three PDs.
Research on the metastructure of comorbidity among common mental disorders suggests that mental disorders can be considered indicators of latent dimensional propensities to two types of psychopathology: internalizing or externalizing (Hasin and Kilcoyne, 2012; Krueger, 1999; Krueger et al., 2002). The externalizing dimension is characterized by antisocial personality disorder and alcohol, nicotine, and drug dependence. The internalizing dimension includes two subdimensions, one involving distress (major depression, dysthymia, generalized anxiety) and the other involving fear (panic, social phobia, specific phobia) (Hasin and Kilcoyne, 2012).
BORDERLINE PERSONALITY DISORDER
The DSM-IV characterizes BPD as a pervasive pattern of instability of interpersonal relationships, self-image, and affects, and marked impulsivity beginning by early adulthood and present in a variety of contexts, as indicated by at least five of nine criteria: (1) frantic efforts to avoid real or imagined abandonment; (2) a pattern of unstable and intense interpersonal relationships characterized by alternating between extremes of idealization and devaluation; (3) identity disturbance: markedly and persistently unstable self-image or sense of self; (4) impulsivity in at least two areas that are potentially self-damaging (e.g., spending, sex, substance abuse, reckless driving, binge eating); (5) recurrent suicidal behavior, gestures, or threats, or self-mutilating behavior; (6) affective instability resulting from a marked reactivity of mood (e.g., intense episodic dysphoria, irritability, or anxiety usually lasting a few hours and only rarely more than a few days); (7) chronic feelings of emptiness; (8) inappropriate, intense anger or difficulty controlling anger (e.g., frequent displays of temper, constant anger, recurrent physical fights); and (9) transient, stress-related paranoid ideation or severe dissociative symptoms (APA, 2000). DSM-5 will maintain the same diagnostic criteria, and will include the newly proposed trait-specific classification system in a separate area of Section 3. In Section 3 of the DSM-5, the diagnosis of BPD is characterized by impairments in personality (self and interpersonal) functioning and the presence of pathological personality traits, including negative affectivity (characterized by emotional lability, anxiousness, separation insecurity, and depressivity), disinhibition (characterized by impulsivity and risk-taking), and antagonism (characterized by hostility).
The proposed traits included in Section 3 of the DSM-5 are based on the Five Factor Model (FFM) of personality (Costa and Widiger, 2002), and arise from the psychology literature. The relation between FFM traits and DSM-IV PDs is supported by considerable data (Samuel and Widiger, 2008). The traits that characterize BPD according to Section 3 of the DSM-5 (negative affectivity, disinhibition, and antagonism) are closely related to the core BPD traits of impulsive aggression and affective dysregulation, which are supported by validating data (Siever and Weinstein, 2009).
EPIDEMIOLOGY
The prevalence of BPD as defined in DSM-IV ranges between 0.5% and 5.9% in epidemiological studies of adults in the general US population (Grant et al., 2008; Leichsenring et al., 2011), making it as prevalent as schizophrenia and bipolar I disorder. This represents a wide range of prevalence, which may reflect the different approaches employed in the studies, although the largest sample of subjects interviewed directly from a community sample reports a lifetime prevalence of 5.9% (Grant et al., 2008). Torgersen et al. (2001) calculated a median prevalence of 1.35%, pooling results from 10 studies. Although earlier research supported a higher prevalence of BPD among women, as reflected in the 3:1 female to male ratio reported in the DSM-IV-TR (APA, 2000), more recent data suggest that there are no sex differences in the prevalence of BPD (Grant et al., 2008).
Borderline personality disorder seems to be less stable over time than expected for personality disorders, with high rates of remission reported in follow-up studies (Skodol et al., 2005; Zanarini et al., 2006) and an inverse relationship between age and prevalence of BPD in the general population (Grant et al., 2008).
COMORBIDITY, ILLNESS BURDEN, AND TREATMENT UTILIZATION
Borderline personality disorder is highly comorbid with both Axis I and II disorders (Grant et al., 2008; Lenzenweger et al., 2007; Skodol et al., 2005): 84.5% of patients with BPD met criteria for one or more 12-month Axis I disorders, most frequently mood disorders, anxiety disorders, and substance use disorders (Grant et al., 2008; Lenzenweger et al., 2007; Skodol et al., 2005). There appear to be gender differences with regard to Axis I comorbidity, with men having higher rates of substance abuse, whereas women are more likely to suffer eating, mood, anxiety, and posttraumatic stress disorders (Grant et al., 2008; Sansone and Sansone, 2011). About one-third of patients with BPD meet criteria for posttraumatic stress disorder (PTSD) during their lifetime (Grant et al., 2008): 73.9% patients with BPD meet criteria for another lifetime Axis II disorder, most frequently schizotypal, narcissistic, and obsessive compulsive PDs (Grant et al., 2008). Men with BPD are more likely than women to have antisocial personality traits (Grant et al., 2008; Sansone and Sansone, 2011). This high comorbidity rates may reflect a common vulnerability for Axis I and II disorders within the externalizing spectrum (Kendler, Aggen et al., 2011).
Individuals with BPD are higher users of mental health resources than patients with major depression (Bender et al., 2006), and they are overrepresented in clinical populations, with a prevalence of greater than 9% of all psychiatric outpatients (Zimmerman et al., 2005).
Borderline personality disorder is associated with severe and persistent functional impairment (Grant et al., 2008; Lenzenweger et al., 2007; Skodol et al., 2005; Skodol et al., 2005). Most—but not all—subjects with BPD have worsening levels of functioning over time, and never regain their initial level of functioning (Zanarini et al., 2006). They also have a high risk of suicide, with a mortality rate around 8% to 10% (Oldham, 2006).
THE ROLE OF TRAUMA
Patients with BPD report many childhood adverse events (e.g., trauma, neglect) and more negative life events than patients with other personality disorders (Bierer et al., 2003; Golier et al., 2003; Yen et al., 2002). However, no strong association between these experiences and the development of psychopathological changes in adulthood has been found (Fossati et al., 1999; Leichsenring et al., 2011). It appears that the interaction between biological (e.g., temperamental) and psychosocial factors (e.g., adverse childhood events) is likely what underlies the development of BPD (Wagner et al., 2009; Wagner et al., 2010).
PATHOPHYSIOLOGY
The neurobiological factors contributing to the genesis of BPD may be conceptualized in relation to core traits of the disorder (affective instability and impulsive aggression).
THE AFFECTIVE DYSREGULATION AND IMPULSIVE AGGRESSION DIMENSIONS
There is considerable support for the model of reduced medial prefrontal modulation of limbic structures (especially the amygdala), which appear to be hyperactive in patients with BPD, and results in dysregulation of emotions and aggression (Bohus et al., 2004; Mauchnik and Schmahl, 2010; New et al., 2012; New et al., 2008a).
One of the most consistent findings in patients with BPD compared with healthy individuals is a decrease in volume (especially gray matter volume) particularly in the anterior cingulate gyrus (ACG) (Hazlett et al., 2005; Minzenberg et al., 2008; Soloff et al., 2008; Tebartz van Elst et al., 2003), which may be especially pronounced in men with BPD (Soloff et al., 2008; Vollm et al., 2009). Other structural abnormalities in BPD include volume reduction in hippocampus (Brambilla et al., 2004; Irle et al., 2005; Nunes et al., 2009; Ruocco et al., 2012; Tebartz van Elst et al., 2003; Zetzsche et al., 2007), orbitofrontal cortex (OFC) (Tebartz van Elst et al., 2003), and amygdala (Nunes et al., 2009; Ruocco et al., 2012; Tebartz van Elst et al., 2007). However, some, but not all studies (de-Almeida et al., 2012) have raised the possibility that the smaller volumes in BPD may relate to comorbidity with PTSD or history of serious trauma for hippocampal volume (Nunes et al., 2009; Schmahl et al., 2009; Weniger et al., 2009) and the effect of comorbid MDD for amygdala volume remains unclear (Zetzsche et al., 2006).
Diffusion tensor imaging (DTI) studies examining white matter tract integrity suggest that there may be decreased fractional anisotropy (a measure of tract coherence) in the OFC in BPD (Grant et al., 2007) and diminished interhemispheric structural connectivity between both dorsal ACGs in BPD (Rusch et al., 2010).
In adolescent BPD, like adult BPD patients, ACG (Goodman et al., 2010; Whittle et al., 2009) and OFC gray matter volumes (Brunner et al., 2010; Chanen et al., 2008) are reduced compared with age-matched controls. One study showed that ACG volume correlated negatively with number of suicide attempts and BPD symptom severity, but not depressive symptoms (Goodman et al., 2010), suggesting that this volume reduction in ACG is related specifically to BPD pathology. This evidence of structural changes in ACG and nearby OFC is consistent with a model of a disruption in frontolimbic circuitry in BPD. This circuit has been studied with functional neuroimaging.
Multiple studies have reported decreased activation of prefrontal areas involved in emotion control in BPD. Early PET imaging studies showed decreased activity of OFC and ACG in BPD compared with controls (Goyer et al., 1994; Leyton et al., 2001; New et al., 2002; Siever et al., 1999; Soloff et al., 2000). A more recent PET study of laboratory-induced aggression using the Point Subtraction Aggression Paradigm found that BPD patients with impulsive aggression showed increased relative glucose metabolic rate in OFC and amygdala in response to provocation, but not in more dorsal brain regions associated with cognitive control of aggression (New et al., 2009). In contrast, during aggression provocation, healthy individuals showed increased relative glucose metabolic response in dorsal regions of prefrontal cortex, involved in top-down cognitive control of aggression, and, more broadly, of emotion (New et al., 2009). Poor connectivity between OFC and amygdala has also been reported in association with aggression (New et al., 2007).
Most functional magnetic resonance imaging (fMRI) studies using emotional stimuli have shown similar results of decreased prefrontal activation in BPD, with some exceptions (Minzenberg et al., 2007; Schmahl et al., 2006; Schnell et al., 2007). Most studies in BPD have shown less activation (or more deactivation) of frontal areas involved in top-down control of emotions, including OFC and ACG, in BPD compared to healthy controls in response to emotional probes (Koenigsberg et al., 2009b; Minzenberg et al., 2007; Schmahl et al., 2003; Silbersweig et al., 2007; Wingenfeld et al., 2009), although some studies showed heightened prefrontal activation to emotional pictures in BPD (Minzenberg et al., 2007; Schnell et al., 2007) and to unresolved conflicts (Beblo et al., 2006).
Because of its role in emotion encoding and regulation, the amygdala is another region of interest for the study of affective dysregulation in BPD. Several but not all structural studies of BPD have shown volume reduction in the amygdala (Nunes et al., 2009; Tebartz van Elst et al., 2007).
Functional neuroimaging studies also point to abnormalities in the amygdala in BPD patients. Several studies have shown increased amygdala activation to emotional probes (e.g., emotional pictures and faces) (Beblo et al., 2006; Donegan et al., 2003; Koenigsberg et al., 2009b; Schulze et al., 2011). However, the amygdala appears to become deactivated in response to painful stimuli in BPD (Kraus et al., 2009; Niedtfeld et al., 2010; Schmahl et al., 2006), although one study suggests that this finding may be specific to BPD patients with comorbid PTSD (Kraus et al., 2009).
In summary, it seems that in BPD patients, prefrontal brain regions that normally put the brakes on expressions of emotions and more broadly of aggression (e.g., the OFC and ACG) may fail to become activated during emotional provocation, whereas the amygdala appears to hyperrespond to emotional probes.
However, it is important to note that many of the circuits implicated in BPD (including a model of decreased ACG/OFC response with an associated hyperresponse of amygdala) appear to be implicated in other psychiatric disorders, including MDD (Davidson et al., 2003), bipolar disorder (Blumberg et al., 2003), and PTSD (Shin et al., 1999), indicating potential lack of specificity.
Several laboratory psychophysiological tasks also point to abnormal emotional processing in BPD. A study by Hazlett et al. (2007) showed that patients with BPD exhibited larger startle eye blink during unpleasant but not neutral words, interpreted as an abnormality in the processing of unpleasant stimuli.
Studies on the serotonergic system suggest that the putative imbalance between prefrontal regulatory control and limbic responsivity described in the preceding may relate to impaired serotonergic facilitation of “top-down” control. Early cerebrospinal fluid studies on serotonin metabolites found low cerebrospinal fluid 5-hydroxyindolacetic acid in individuals with a history of suicide attempts (Asberg and Traskman, 1981; Asberg et al., 1976) or impulsive aggressive behavior (Coccaro, 1989). Since then, numerous studies have investigated the role of serotonin in BPD. Studies employing a wide variety of methods have replicated decreases in serotonergic responsiveness in disorders characterized by impulsive aggression, such as BPD (Coccaro et al., 1989; Dougherty et al., 1999; O’Keane et al., 1992), including neuroimaging using pharmacological probes of serotonin (Leyton et al., 2001; New et al., 2002; New et al., 2004; Siever et al., 1999; Soloff et al., 2000). Recently, patients with personality disorders and impulsive aggression showed reduced serotonin transporter availability, as measured by the PET ligand, [11C]McN 5652, in the ACG compared with healthy subjects (Frankle et al., 2005). Moreover, metabolic activity in OFC and ACG in impulsive aggressive individuals is enhanced with fluoxetine treatment (New et al., 2004).
In summary, abnormalities in the serotonergic system may underlie the putative imbalance between prefrontal regulatory influences and limbic responsivity.
GENETICS OF IMPULSIVE AGGRESSION AND
AFFECTIVE DYSREGULATION
Twin studies of BPD show substantial heritability scores of 0.65 to 0.76 (Distel et al., 2008; New et al., 2008a; Torgersen et al., 2000). A moderate heritability has been reported for dimensional BPD traits (Torgersen et al., 2008). However, there is considerable disagreement about what specific underlying trait or traits predispose to BPD. Some studies have suggested that one highly heritable factor underlies the symptom domains in BPD (Kendler et al., 2011a) and this factor is closely related to affective instability. This same study also describes strong genetic correlations between BPD traits and elements of the five factor personality components, especially neuroticism, and inversely with conscientiousness and agreeableness. Other studies have suggested that the Five Factor Model has more convergent and discriminant validity than the DSM-IV diagnostic criteria for BPD (Samuel and Widiger, 2010) based largely on the superior convergence between self-report and other assessment modalities (e.g., interview, informant interview). The particularly poor ability of BPD patients to describe their own symptoms based on poor ability to mentalize may underlie some of the confusion in the field. The proper approach to describing the underlying neurobiology of BPD symptoms is an active area of investigation and is among the goals of the RDoC’s effort through the NIMH. This is important not only for elucidating what underlies BPD and whether new therapeutics might be developed with better neurobiological understanding of this illness, but it also is important because BPD features predispose individuals to other serious disorders, especially treatment-refractory depression (Kornstein and Schneider, 2001).
Candidate genes for impulsive aggression and emotional dysregulation include those that regulate the activity of neuromodulators, such as serotonin and catecholamines, as well as neuropeptides (Siever, 2008; Siever and Weinstein, 2009).
NEUROPEPTIDE MODEL
Neuropeptides are another recent area of interest in BPD. oxytocin has anxiolytic and prosocial effects (Macdonald and Macdonald, 2010), and it reduces amygdala activation in response to a variety of emotional stimuli in healthy individuals (Meyer-Lindenberg, 2008). However, there have been very few studies in BPD and none involving brain imaging. The two empirical studies of oxytocin administration in BPD have shown that oxytocin modestly decreased the subjective anxiety resulting from the Trier Social Stress Test in BPD (Simeon et al., 2011), but it decreased the level of cooperative behavior in BPD (Bartz et al., 2011). We have found that a polymorphism of oxytocin is associated with anger dyscontrol in BPD patients (Siever et al., unpublished data). This association is increased by trauma.
Opioids are also involved in social attachment. One recent imaging study measured μ-opioid receptor binding, by using the µ-opiate ligand [11C] carfentanil, in patients with BPD during induction of neutral and sad sustained emotional states (Prossin et al., 2010). They found greater baseline μ-opioid receptor availability in BPD, interpreted as a deficit in endogenous circulating opioids. Their results also suggest that BPD patients enhance endogenous opiate availability more than controls during sad mood induction, which might reflect a compensatory response and is consistent with lower levels of endogenous opioids in self-injurers (Stanley and Siever, 2010; Stanley et al., 2009). We have found that polymorphisms of the μ-opioid receptor may be associated with affective instability and BPD (Siever et al., unpublished data). These associations also seem exacerbated by trauma, underscoring the interactive effects of genetics and environment.
One theory about self-cutting, a behavior common in BPD, is that it represents a method of releasing endogenous opioids, to compensate for an intrinsic opioid deficit (New and Stanley, 2010; Stanley and Siever, 2010). The interpersonal difficulty that is central to borderline pathology might also be linked to a deficit in endogenous opiates.
A FOCUS ON FUNCTIONAL NEUROIMAGING OF INTERPERSONAL PROCESSES
Very little empirical work has been done on factors underlying interpersonal disruptions in BPD. Several studies have focused on recognition of facial emotional expression in BPD. Borderline personality disorder patients appear to have a heightened ability to identify emotional expressions correctly compared with healthy controls; however, they tend to interpret neutral faces as more angry than controls do (Donegan et al., 2003; Lynch et al., 2006; Wagner and Linehan, 1999). The data suggest that ambiguous stimuli or contexts including time constraints particularly trigger dysfunctional emotional processing in BPD (Dyck et al., 2009). Difficulties in interpreting social affective stimuli also seem to arise when BPD patients are presented stimuli from multiple sensory modalities (Minzenberg et al., 2006).
Even fewer studies have examined more complex social tasks in BPD. One study using a Theory of Mind task during brain imaging found that BPD patients had less activity in superior temporal areas than controls during a task that involved inferring what someone in a picture was feeling, and they had increased activation of anterior insula during a task probing their own responses to emotional pictures (Dziobek et al., 2011). This supports the disturbances of “self” and “other” described in BPD psychopathology (Bender and Skodol, 2007).
A seminal study of complex social interactions showed that BPD patients had difficulty maintaining cooperation in a version of the Trust game (King-CaKing-Casas et al., 2008). Behaviorally, BPD patients were unable to maintain cooperation, and were impaired in their ability to “repair broken cooperation” when their partner offered a “coaxing” bid. Neurally, healthy individuals activated anterior insula in relation to cooperative “offers” from their partner, whereas BPD patients activated the insula (a brain region predominantly involved in interoception and to a degree social cognition) in relationship to how much the patient him- or herself offered to the other. In a similar version of the Trust game, BPD subjects responded with greater self-criticism when given adverse monetary offers from a putative partner (Franzen et al., 2010).
BRAIN IMAGING OF DELIBERATE
EMOTION REGULATION IN BORDERLINE PERSONALITY DISORDER
Because psychotherapeutic strategies that enhance emotion regulation skills have proven effective in BPD, another area of growing interest involves the investigation of regional brain activity in response to deliberate emotion regulation (Koenigsberg et al., 2009a; Lang et al., 2012; Schulze et al., 2011). There has also been interest in whether changes in neurocircuitry in response to successful psychotherapeutic treatment can be detected in BPD (Lai et al., 2007). One very small study showed that in dialectical behavior therapy responders, there was a decrease in amygdala activation measured with fMRI in response to emotional stimuli (Goodman et al., unpublished data).
ANTISOCIAL PERSONALITY DISORDER
The DSM-IV characterizes antisocial personality disorder (ASPD) as a pervasive pattern of disregard for and violation of the rights of others that has been occurring since the age of 15 years, as indicated by at least three of seven criteria: (1) failure to conform to social norms with respect to lawful behaviors as indicated by repeatedly performing acts that are grounds for arrest; (2) deceitfulness, as indicated by repeated lying, use of aliases, or conning others for personal profit or pleasure; (3) impulsivity or failure to plan ahead; (4) irritability and aggressiveness, as indicated by repeated physical fights or assaults; (5) reckless disregard for safety of self or others; (6) consistent irresponsibility, as indicated by repeated failure to sustain consistent work behavior or honor financial obligations; (7) lack of remorse, as indicated by being indifferent to or rationalizing having hurt, mistreated, or stolen from another (APA, 2000). DSM-5 will maintain the same diagnostic criteria, and will include the newly proposed trait-specific classification system in a separate area of Section 3. In Section 3 of the DSM-5, the diagnosis of ASPD is characterized by impairments in personality (self and interpersonal) functioning and the presence of pathological personality traits, including disinhibition (characterized by irresponsibility, impulsivity, and risk-taking) and antagonism (characterized by manipulativeness, deceitfulness, callousness, and hostility).
Antisocial personality disorder is distinct from psychopathy, a construct characterized by pronounced problems in emotional processing (reduced guilt, empathy, and attachment to significant others; callous and unemotional traits) and increased risk for displaying antisocial behavior (Cleckley, 1941; Hare, 2003). The DSM-IV definition of ASPD has been criticized for focusing on the behavioral outcome such as criminality, and ignoring the core personality features such as affective deficits. Despite its association with ASPD, psychopathy is a distinct disorder: Whereas most of those who are diagnosed with psychopathy will also meet criteria for antisocial personality disorder, only about 10% of those with antisocial personality disorder meet criteria for psychopathy (NCCM) 2010; Table 84.1).
Another essential difference between ASPD and psychopathy is the type of aggression characteristic of each disorder. Two types of aggression have been described, which are given various names in the literature (e.g., proactive or instrumental vs. reactive; premeditated vs. impulsive; predatory vs. defensive). These two types differentiate aggressive behavior that is controlled/planned and serves an instrumental, goal-directed end (i.e., a planned robbery to obtain the victim’s money) versus aggressive behavior that is more retaliatory/impulsive (i.e., road rage), occurs in response to a threat or perceived threat and is associated with negative affect (i.e., hostility or anger; Dolan, 2010; Ostrov and Houston, 2008). Reactive aggression has been associated with a lack of impulse control (e.g., in ASPD, intermittent explosive disorder and BPD), whereas instrumental aggression has been uniquely linked to psychopathic features (Blair, 2010; Dolan, 2010; Ostrov and Houston, 2008).
TABLE 84.1. Items in the Hare Psychopathy Checklist-Revised
| FACTOR 1: INTERPERSONAL/AFFECTIVE |
FACTOR 2: SOCIAL DEVIANCE |
| 1. Glibness/superficial charm | 3. Need for stimulation/proneness to boredom |
| 2. Grandiose sense of self-worth | 9. Parasitic lifestyle |
| 4. Pathological lying | 10. Poor behavioral controls |
| 5. Conning/manipulative | 12. Early behavioral problems |
| 6. Lack of remorse or guilt | 13. Lack of realistic long-term goals |
| 7. Shallow affect | 14. Impulsivity |
| 8. Callous/lack of empathy | 15. Irresponsibility |
| 16. Failure to accept responsibility for own actions | 18. Juvenile delinquency |
| Additional items | 19. Revocation of conditional release |
| 11. Promiscuous sexual behaviour | 20. Criminal versatility |
| 17. Many short-term marital relationships |
EPIDEMIOLOGY
The 12-month prevalence of antisocial personality disorder (ASPD) was recently estimated to be 3.6% in a nationally representative general population survey (Grant et al., 2004). Antisocial personality disorder is more common in men, who are also more likely to have a persistent course of antisocial behavior when compared with women (NCCM, 2010).
Antisocial personality disorder is associated with a high risk of disorders within the externalizing spectrum, mainly alcohol, nicotine, and drug dependence (Hasin and Kilcoyne, 2012; Hasin et al., 2011). It has been postulated that this high comorbidity suggests common underlying biological contributors (Krueger et al., 2002).
Antisocial personality disorder is also frequently comorbid with other cluster B PDs. This is thought to result from both common genetic and environmental influences. Research suggests that, etiologically, ASPD and BPD are more closely related to each other than to the other cluster B disorders, with both ASPD and BPD showing a second genetic and non-shared environmental factor above and beyond the genetic factor influencing all cluster B disorders (Torgersen et al., 2008).
DEVELOPMENT AND CHILDHOOD ANTECEDENTS
Longitudinal, epidemiological studies have identified several risk factors for antisocial behavior, including maltreatment, harsh and coercive discipline, smoking during pregnancy, divorce, teen parenthood, peer deviance, parental psychopathology (including depression, antisocial behavior, and alcohol use problems), and social disadvantage (including poverty and neighborhood disadvantage; Jaffee et al., 2012), with varying support for causal effects.
Antisocial symptoms with onset in childhood often persist into adulthood and are associated with decreased functioning in educational, employment, interpersonal, and physical health domains (Jaffee et al., 2012).
THE DIMENSION OF IMPULSIVE AGGRESSION IN ANTISOCIAL PERSONALITY DISORDER
AND PSYCHOPATHY
Impulsive aggression is believed to be the core dimension underlying ASPD, and is also seen in all the Axis II cluster B PDs, most typically in BPD. The present review will focus on the pathophysiology of impulsive aggression.
REACTIVE AGGRESSION
Reactive aggression is common in ASPD (Blair, 2010; Dolan, 2010; Ostrov and Houston, 2008).
Animal research suggests that reactive aggression is part of a gradated response to threat: Distant threats induce freezing, closer threats induce flight, and very close threats in which escape is impossible induce reactive aggression. This progressive response to threat is mediated by a threat system that involves the amygdala, the hypothalamus, and the periaqueductal gray. It is believed that this system is regulated by medial, orbital, and inferior frontal cortices (Blair, 2007, 2010). According to this threat system, those individuals at increased risk of showing reactive aggression should show heightened amygdala responses to emotionally provocative stimuli and reduced frontal emotional regulatory activity (Blair, 2010).
INSTRUMENTAL AGGRESSION
Instrumental aggression is characteristic of psychopathy (Blair, 2010; Dolan, 2010; Ostrov and Houston, 2008). Instrumental aggression is hypothesized to be mediated by the motor cortex and the caudate, like any other form of motor response (Blair, 2007). An individual can choose among several available choices of motor response (e.g., instrumental aggression vs. more prosocial behaviors) based on the costs and benefits associated with each choice. For most individuals, the costs of instrumental aggression (e.g., harm to the victim or oneself, risk of punishment) outweigh the benefits, and more prosocial behaviors are chosen instead of instrumental aggression. However, it is believed that individuals with psychopathy initiate instrumental aggression because of dysfunctional representation of the costs of the behavior, related to amygdala and orbitofrontal cortex (OFC) dysfunction (Blair, 2010).
The amygdala is critical for stimulus reinforcement learning and feeding reinforcement expectancy information forward to the OFC to allow good decision making. Because of the hypothesized dysfunction in amygdala and OFC, individuals with psychopathic traits have difficulty socializing (related to dysfunction in stimulus reinforcement learning) and make poor decisions (because of the OFC dysfunction). According to this model, individuals with psychopathic traits should show reduced amygdala and OFC responses to emotional provocation and during emotion-based decision-making tasks (Blair, 2007, 2010).
Research suggests that healthy individuals are predisposed to find distress cues from others aversive and that we learn to avoid behaviors associated with distress cues (i.e., acts that harm others), which is critical for the development of morality. Distress cues from the victim are believed to act as an inhibitor of aggression (Blair, 1995), but this inhibitory mechanism appears to be defective in psychopathy (Blair, 2007).
NEUROIMAGING OF AGGRESSION IN ANTISOCIAL PERSONALITY DISORDER
AND PSYCHOPATHY
Although the data strongly support a disruption of amygdala and prefrontal cortex functioning—specifically, in the OFC, ACG, and dorsolateral prefrontal cortex—in individuals with psychopathic traits and/or antisocial behavior, the data for ASPD itself is less conclusive (Nordstrom et al., 2011; Yang and Raine, 2009). This may be because of the heterogeneity of the ASPD diagnosis itself and of the samples and control groups analyzed (e.g., different demographic groups, psychiatric comorbidities). The majority of the studies and metaanalyses focus on broadly defined antisocial constructs, including individuals with ASPD with or without psychopathy, psychopathy with or without ASPD, antisocial behavior, conduct disorder, oppositional defiant disorder, disruptive behavior disorder, criminals, violent offenders, or aggressive individuals (Yang and Raine, 2009). There is a paucity of studies focusing on ASPD specifically, and even fewer studies assessing the effect of comorbid psychopathy on neuroimaging findings in ASPD subjects (Boccardi et al., 2010; Gregory et al., 2012; Tiihonen et al., 2008).
Structural Findings in Antisocial
Personality Disorder
Prefrontal abnormalities
Laakso et al. (2002) observed reductions in volume of the dorsolateral, medial frontal, and orbitofrontal cortices in subjects with ASPD. However, after controlling for substance use and education, they concluded that the observed volume deficits were related more to alcoholism or differences in education rather than the diagnosis of ASPD.
Other authors did find reduced prefrontal volumes in ASPD, even after controlling for the effects of substance use (Dolan, 2010; Raine et al., 2000, 2003; Tiihonen et al., 2008). Raine et al. (2010) observed that individuals with cavum septum pellucidum (CSP), a marker of limbic neural maldevelopment, had significantly higher levels of antisocial personality, psychopathy, arrests, and convictions compared with controls, even after controlling for the effects of potential confounders including prior trauma exposure, head injury, demographic factors, or comorbid psychiatric conditions.
Other abnormalities
Antisocial personality disorder subjects have been reported to have smaller temporal lobes (Barkataki et al., 2006; Dolan et al., 2002), smaller whole brain volumes (Barkataki et al., 2006), larger putamen volumes (Barkataki et al., 2006), larger occipital (Tiihonen et al., 2008) and parietal lobes (Tiihonen et al., 2008), larger cerebellum volumes (Tiihonen et al., 2008), decreased volumes in specific areas of the cingulate cortex, insula, and postcentral gyri (Tiihonen et al., 2008), and cortical thinning in medial frontal cortices (Narayan et al., 2007). Raine et al. (2003) found that psychopathic, antisocial subjects had a longer, thinner corpus callosum with overall increased volume compared with healthy controls.
However, other studies (Gregory et al., 2012) found no differences in gray matter volumes between offenders with ASPD without psychopathy and healthy controls.
Functional Neuroimaging in Antisocial Personality Disorder
Most of the few functional neuroimaging studies with subjects diagnosed with ASPD suggest a dysfunction in brain regions involved in emotional processing and learning (Dolan, 2010). The first functional neuroimaging study in ASPD showed that, compared with healthy controls, subjects with BPD or ASPD activated different neural networks during response inhibition in a go/no-go task (Vollm et al., 2004). Although controls mainly activated the prefrontal cortex—specifically the right dorsolateral and the left OFC—during response inhibition, BPD and ASPD patients showed a more bilateral and extended pattern of activation across the medial, superior and inferior frontal gyri extending to the ACG (Vollm et al., 2004).
Some of the studies suggest that at least part of the neural abnormalities found in ASPD subjects may not be specific to this disorder, but rather associated with aggressive traits that are associated with a tendency to violent behavior. For example, Barkataki et al. (2008) found that both violent ASPD subjects and violent schizophrenia patients, but not nonviolent schizophrenia patients showed reduced thalamic activity, in association with modulation of inhibition in a go/no-go task. However, another study by the same group suggests that, although there are neural alterations related to violence found both in violent schizophrenic and violent ASPD patients in occipital and temporal regions, there are interesting differences specific to ASPD and schizophrenia, respectively. Specifically, they found that the violent ASPD subjects showed attenuated thalamic–striatal activity during later periods in a “threat of electric shock” task—whereas in the violent schizophrenic subjects there was hyperactivation in the same areas (Kumari et al., 2009). This suggests that, although there is a shared biological deficit, violent behaviors may arise from different mechanisms according to the specific disorder.
NEUROCOGNITIVE FUNCTION AND AGGRESSION IN ANTISOCIAL PERSONALITY DISORDER AND PSYCHOPATHY
Previous research investigating whether subjects with ASPD have impaired cognitive functioning has yielded inconsistent findings (Crowell et al., 2003; Morgan and Lilienfeld, 2000). Although some authors have found a broad range of deficits in planning ability and set shifting, response inhibition and visual memory, likely mediated by dorsolateral prefrontal cortex and ventromedial prefrontal cortex function in subjects with ASPD (Dolan and Park, 2002), others have only found circumscribed deficits in processing speed (Barkataki et al., 2005) or response inhibition (Barkataki et al., 2008) in ASPD subjects. Moreover, a metaanalysis of 39 studies including 4,589 participants found that, although antisocial behaviors in general were significantly associated with a large effect size for executive dysfunction, the effect size for executive function deficits among subjects with ASPD was statistically significant but negligible (Morgan and Lilienfeld, 2000), and others could find no differences in executive function between ASPD and healthy or psychiatric controls (Crowell et al., 2003). It should be noted that some authors have studied ASPD samples with high rates of psychopathy. Therefore, it is impossible to tease apart the contributions of psychopathy and ASPD respectively to the deficits reported. For example, Dinn et al. (2000) studied 12 ASPD patients, 11 of whom fulfilled criteria for psychopathy. They found that ASPD subjects showed greater deficits on measures of orbitofrontal dysfunction, but not on classical measures of executive function, in comparison with controls (Dinn and Harris, 2000).
Psychopathy has also been associated with executive function deficits as reported in the metaanalysis described in the preceding (Morgan and Lilienfeld, 2000). However, a more recent study found that among offenders with ASPD there was no significant association between executive function impairment and scores on a measure of psychopathy (Dolan, 2011).
GENETIC VULNERABILITY OF AGGRESSION AND ANTISOCIAL PERSONALITY DISORDER
Family, twin, and adoption studies suggest that antisocial spectrum disorders and psychopathy are heritable, with heritability ranging from 0% to 80% in individual studies, and estimated at around half of the variance in most studies and a metaanalysis of antisocial behavior (Rhee and Waldman, 2002; Viding et al., 2008), and even higher when studying externalizing disorders more broadly (Gunter et al., 2010; Krueger et al., 2002) or for certain subtypes, such as those with callous/unemotional traits (Viding et al., 2008).
In the last decade, considerable scientific energy has been focused on identifying specific genetic factors involved in the development of aggressive behavior, as a trait observed in antisocial spectrum disorders and psychopathy. However, despite the great advances in the field, behavioral genetics has yet to elucidate specific genetic pathways that lead to the genesis of the disorders, or develop molecular genetic tests that may inform diagnosis or treatment (Gunter et al., 2010). Association studies on single candidate genes have not yielded any loci with a major effect size. It has been suggested that examining gene by environmental interactions, performing detailed whole genome association studies, functional imaging studies of genetic variants, and examining the role of epigenetics may provide valuable new targets for research (Craig and Halton, 2009).
One of the challenges of the existing research is the heterogeneity of the phenotypes analyzed in different studies, including individuals with ASPD with or without psychopathy, psychopathy with or without ASPD, antisocial behavior, conduct disorder, oppositional defiant disorder, disruptive behavior disorder, criminals, violent offenders, or aggressive individuals, with only a handful of studies focusing on ASPD specifically (Gunter et al., 2010).
Genome-Wide Linkage and Association Studies
Several genome-wide linkage and association studies have suggested possible genomic locations in chromosomes 1, 2, 3, 4, 9, 11, 12, 13, 14, 17, 19, and 20 for antisocial spectrum disorders, but must be interpreted with caution because very few findings reach genome-wide significance, and even fewer have been replicated (Gunter et al., 2010). These studies have focused on diverse phenotypes, including conduct disorder with or without substance use disorders or attention deficit hyperactivity disorder (ADHD), suicidal behavior as a marker of impulsive aggression, or personality traits of psychoticism and neuroticism (Gunter et al., 2010). Of note, only one of these studies specifically included subjects with a diagnosis of ASPD, and found several regions of interest in the genome (Ehlers et al., 2008). An interesting question for future studies would be to assess whether other constructs (including dimensional personality approaches) may be closer correlates of the underlying genetic factors than the construct of ASPD itself as currently described in the DSM-IV (APA, 2000).
Candidate Genes
The most widely studied genes in antisocial spectrum disorders have been those related to serotonergic and dopaminergic systems, including catechol-O-methyl transferase (COMT), monoamine oxidase A (MAOA), dopamine beta hydroxylase (DBH), tryptophan hydroxylase 1 and 2 (TPH 1 and 2), dopamine receptor D2 (DRD2), dopamine receptor D4 (DRD4), serotonin receptor 1B (5HTR1B), serotonin receptor 2A (5HTR2A), serotonin transporter (5HTT), and dopamine transporter (DAT). Other targets include androgen receptors (AR), based on the gender differences in frequencies of antisocial spectrum disorders, and novel sites such as SNAP25, which was identified as a region of interest in genome-wide studies (Gunter et al., 2010). Currently, the strongest evidence available points to the MAOA and 5HTT genes in antisocial spectrum disorders (Gunter et al., 2010).
In the decade since the seminal study by Caspi et al. (2002) suggesting that MAO genotypes can moderate children’s sensitivity to environmental insults, the analysis of gene–environment interaction has received much attention. Some but not all studies have replicated gene–environment interactions in antisocial spectrum disorders (Gunter et al., 2010).
Other interesting avenues of research are those of analysis of gene expression and epigenetic modification of gene expression via methylation and histone modification, but data on the antisocial spectrum are still very scarce (Gunter et al., 2010). Only one study so far has analyzed the impact of epigenetic mechanisms on the development of ASPD symptoms. Beach et al. observed that the degree of methylation at 5HTT mediated the impact of childhood sex abuse on symptoms of ASPD (Beach et al., 2011).
In summary, there is compelling evidence that genes involved in the serotonergic system are implicated in impulsive aggression.
SUMMARY AND FUTURE DIRECTIONS
The ASPD diagnosis comprises a heterogeneous population, limiting neurobiological research efforts. However, considerable progress has been made in the understanding of impulsive aggression, a core dimension of antisocial spectrum disorders and psychopathy, including the roles of the prefrontal cortex, the amygdala, and neurocognitive deficits. The strongest genetic evidence points to the MAOA and 5HTT genes, and promising new approaches include genome wide analyses, epigenetics, gene expression, and neuroimaging genetics.
Using an interdisciplinary research team and a systems approach to the biology of complex illnesses such as antisocial spectrum disorders and psychopathy may help to shed light on the interplay among genetic factors, neural networks, and behavior (Gunter et al., 2010).
SCHIZOTYPAL PERSONALITY DISORDER
Schizotypal personality disorder (STPD), the prototypic schizophrenia personality disorder, is part of the schizophrenia spectrum disorders, characterized by the presence of attenuated symptoms typically present in chronic schizophrenia. The investigation of STPD offers an opportunity to elucidate the pathophysiological mechanisms giving rise to schizophrenia, in a less impaired and less heavily medicated population.
Schizotypal personality disorder is defined by DSM-IV-TR as “a pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships, as well as by cognitive or perceptual distortions and eccentricities of behavior, beginning by early adulthood and present in a variety of contexts,” and requires five or more of the following criteria: (1) ideas of reference (excluding delusions of reference); (2) odd beliefs or magical thinking that influences behavior and is inconsistent with subcultural norms (e.g., superstitiousness, belief in clairvoyance, telepathy, or “sixth sense”; in children and adolescents, bizarre fantasies or preoccupations); (3) unusual perceptual experiences, including bodily illusions; (4) odd thinking and speech (e.g., vague, circumstantial, metaphorical, overelaborate, or stereotyped); (5) suspiciousness or paranoid ideation; (6) Inappropriate or constricted affect; (7) behavior or appearance that is odd, eccentric, or peculiar; (8) lack of close friends or confidants other than first-degree relatives; and (9) excessive social anxiety that does not diminish with familiarity and tends to be associated with paranoid fears rather than negative judgments about self (APA, 2000). DSM-5 will maintain the same diagnostic criteria, and will include the newly proposed trait-specific classification system in a separate area of Section 3. In Section 3 of DSM-5, STPD is characterized by impairments in personality (self and interpersonal) functioning and the presence of pathological personality traits, including psychoticism, detachment, and negative affectivity (http://www.dsm5.org/proposedrevision/Pages/proposedrevision.aspx?rid=15#).
EPIDEMIOLOGY
The median prevalence of STPD had been estimated at 0.7% in the general population (Torgersen et al., 2001); however, recently a lifetime prevalence of 3.9% was reported in a large, nationally representative US community sample (Pulay et al., 2009). Schizotypal personality disorder is more frequent among males than females (Pulay et al., 2009).
More than 80% of those with STPD also suffer other comorbid personality disorders, especially BPD (Pulay et al., 2009) and narcissistic PD (Pulay et al., 2009). Lifetime comorbidity with Axis I disorders is high as well: 67% of individuals with STPD have at least one mood disorder, greater than 70% have at least one anxiety disorder, and greater than 65% have a substance use disorder (Pulay et al., 2009).
Schizotypal personality disorder is one of the DSM-IV PDs most strongly associated with reduced functioning (Pulay et al., 2009) with significantly worse levels of impairment than among patients with other PDs or major depressive disorder (Skodol et al., 2002).
PUTATIVE ETIOLOGIC FACTORS AND PATHOPHYSIOLOGY
The neurobiological factors underlying the genesis of STPD may be conceptualized in relation to each of the core traits of the disorder (psychotic-like symptoms and cognitive organization disturbances). In this way, disturbances in cognitive organization and information processing may contribute to the detachment, desynchrony with the environment, and cognitive/perceptual distortions of STPD and other schizophrenia spectrum personality disorders (Siever and Weinstein, 2009).
PSYCHOTICISM DIMENSION
Psychotic-like symptomatology is characteristic of STPD patients. Like in schizophrenia, increased dopaminergic neurotransmission is associated with more prominent psychotic symptoms, and the dimension of psychotic-like perceptual distortions has been correlated with measures of dopaminergic activity. The fact that STPD patients have less prominent psychotic symptoms than patients with schizophrenia is believed to be caused by better buffered subcortical dopaminergic activity (Siever and Davis, 2004; Siever and Weinstein, 2009). The results of functional and structural imaging and neuroendocrine challenge studies support this hypothesis. This better buffering system may result in less responsiveness to stress by subcortical dopaminergic systems, which may protect against psychosis (Mitropoulou et al., 2004; Siever and Davis, 2004; Siever and Weinstein, 2009).
It has been suggested that dopaminergic activity can be relatively increased or decreased, depending on the predominance of psychosis-like (hypervigilance and stereotypic cognitions/behaviors) or deficit-like (deficits in working memory, cognitive processing, and hedonic tone) symptoms (Siever and Davis, 2004).
Dopaminergic candidate genes including the dopamine D4 receptor and the dopamine β-hydroxylase gene have been found to be associated with psychosis-like symptomatology (Siever and Davis, 2004; Siever and Weinstein, 2009).
In summary, STPD patients share some of the dopaminergic abnormalities underlying psychotic-like symptoms found in schizophrenia, but in a more attenuated form, likely because of better buffered subcortical dopaminergic activity.
COGNITIVE IMPAIRMENT DIMENSION/DEFICIT SYMPTOMS
Research data suggest that patients with STPD suffer cognitive impairment, likely related to structural brain abnormalities, especially in the temporal cortex, similar to those seen in patients with schizophrenia. Despite these similarities, STPD patients differ from schizophrenia patients in that they have less impaired executive function—likely owing to greater reserves in prefrontal function (Siever and Davis, 2004; Siever and Weinstein, 2009).
Specifically, patients with STPD have increased ventricular volumes, and frontotemporal volume reductions similar but milder than those seen in schizophrenic patients, with sparing of some key regions (Hazlett et al., 2008).
Specific cognitive dimensions found to be impaired in STPD include attention, visual and auditory working memory, verbal learning and memory, and STPD individuals perform poorly on executive function tasks. However, the more generalized intellectual deficits found in schizophrenia are not observed in STPD (McClure et al., 2007; Siever and Weinstein, 2009).
These cognitive deficits may contribute to the impairments in social rapport and inability to read social cues seen in STPD patients. Actually, deficits in working memory have been correlated with interpersonal impairment (Mitropoulou et al., 2005).
Decreased dopaminergic and noradrenergic activity in the prefrontal cortex may contribute to the cognitive impairment in STPD. This is consistent with functional studies showing decreases in frontal activation during executive functioning tasks in STPD subjects. However, unlike schizophrenic patients and normal subjects, STPD subjects appear to activate other compensatory regions during executive function tasks (Koenigsberg et al., 2005).
Working memory has been shown to improve after pharmacological interventions with guanfacine, an alpha2 adrenergic agonist, and pergolide, a D1/D2 agonist (McClure et al., 2007, 2010).
Schizotypal personality disorder subjects also suffer deficits in information processing, reflected in physiological impairments seen in the schizophrenia spectrum. These include deficits in prepulse inhibition (PPI) of the acoustic startle response, the startle blink paradigm, the P50 evoked potential paradigm, or smooth pursuit eye movement among others (see Siever and Davis, 2004, for a review).
In summary, STPD subjects show cognitive and physiological impairments that seem to be partially caused by reduced prefrontal dopaminergic function and that can be partly reversed with dopamine agonists and partially compensated by activation in other brain areas not used by healthy controls.
GENETIC VULNERABILITY
Schizotypal personality disorder is partly heritable (Kendler et al., 2006), and its genetic factors overlap with those for schizophrenia and other schizophrenia spectrum disorders (Fanous et al., 2007; Siever, 2005). It has been suggested that positive and negative symptoms of STPD represent two distinct heritable dimensions. Thus, in disorders of the schizophrenia spectrum, a set of genetic factors expressed as social and cognitive deficits (spectrum phenotype) might be transmitted independently from a second genetic factor set related to psychosis (psychotic phenotype) (Siever and Davis, 2004).
A polymorphism of catechol-o-methyl-transferase (COMT), which metabolizes dopamine and regulates its activity in the frontal cortex, has been associated with working memory deficits and other cognitive deficits both in schizophrenic and schizotypal subjects (Ma et al., 2007; Smyrnis et al., 2007).
A recent study on a risk for psychosis haplotype of the proline dehydrogenase gene found that, in healthy controls, the psychosis variant was associated with PPI and verbal memory deficits as well as higher anxiety and schizotypal personality traits (Roussos et al., 2009).
In a large cohort of young healthy individuals, Stefanis et al. showed an association between common variants in G-protein signaling 4 (RGS4) and d-amino acid oxidase (DAAO) genes with negative schizotypal personality traits; dysbindin (DTNBP1) variants were associated with positive and paranoid schizotypy measures (Stefanis et al., 2007, 2008).
Finally, preliminary results from our group using the custom Consortium on the Genetics of Schizophrenia (COGS) 1,536-SNP chip found a strong association between polymorphisms in ERBB4, NRG1 and genes involved in glutamate, dopamine, GABA and serotonin receptors signaling, as well as cell signal transduction, with categorical clinical diagnosis (STPD vs. healthy controls) and dimensional quantitative phenotypes of STPD, including cognitive impairment, interpersonal deficits, and paranoia (Siever and Roussos, unpublished data).
In summary, several genetic variants have been associated with STPD traits and/or dimensional quantitative phenotypes of STPD, including cognitive impairment symptoms, opening promising avenues for research and pharmacological targets.
CONCLUSIONS
Increasing evidence suggests that several of the personality disorders that have been most studied including BPD, STPD, and ASPD have distinct neurobiological substrates that emerge from genetic susceptibilities, that are beginning to be identified, interacting with the environment. These categorical personality disorders can also be mapped into dimensions that extend across personality disorders and may even extend into normal personality.
A better understanding of the neurocircuitry underlying the personality disorders and their modulation by neuropeptides and neurotransmitters may help us intervene pharmacologically and even provide a base for predictors of outcome and a mechanism of action in the brain for psychosocial treatments for these disorders.
DISCLOSURES
Dr. Perez has no conflicts of interests to disclose. She is funded by the Department of Veterans Affairs (VISN3) Mental Illness Research, Education, and Clinical Center (MIRECC).
Dr. Siever has no conflicts of interest to disclose. His salary comes from the Peters VA and Mt. Sinai Medical school.
Dr. New has no conflicts of interest to disclose. Her salary comes from the James J Peters VA and Mount Sinai School of Medicine.
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