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Types of Clinical Aggression

Human aggression constitutes a multidetermined act that results in physical or verbal injury to self, others, or objects. It appears in several forms and may be defensive, premeditated (e.g., predatory), or impulsive (e.g., nonpremeditated)

in nature. Defensive aggression is generally seen as dictated by particular external realities and within the normal range of human behavior. Premeditated and impulsive aggressive behaviors are commonly viewed as pathological. Specific acts of aggression may be situational, but the tendency to behave aggressively represents a behavioral trait. While the frequency of aggressive acts tends to decrease with advancing age, numerous studies document that the trait of aggressiveness begins early in life and continues through adulthood. Both impulsive and premeditated aggression represents the potential for significant physical and psychological harm to the individual, to those subjected to the effects and to society in general. However, a converging pattern of empirical data from a variety of studies consistently links impulsive, but not premeditated, aggression to biological, environmental, and pharmacological or psychological treatment response factors.

One guiding principle to the consideration of human aggression is that biological and psychological factors contribute significantly to this behavior. Biological factors contribute to aggressive behavior through reduced inhibitory, and/or increased facilitatory, neuronal inputs to behavior. Research in this area has found utmost support for the role of inhibitory behavioral inputs modulated by brain serotonin (5-HT) function. The role of various neurotransmitter systems in increasing facilitatory input for aggressive behavior has received less attention and, in contrast to 5-HT, the results have been somewhat inconsistent. On the other hand, psychotherapy outcome research has successfully focused attention in this general area, vis-a-vis the relationship between the impulsive aggressive individual and his/her external/internal environment as facilitatory in generating impulsive aggressive behavior. Here, the focus is on the hypothesis that vulnerable individuals manifest impulsive aggressive behavior in response to external/internal stimuli perceived as "provocative" or "aversive" in nature which lead to variable states of anger that drive susceptible individuals (e.g., individuals with reduced central 5-HT function) to exceed their "threshold" for effective behavioral inhibition so that an impulsive aggressive outburst is initiated. If so, treatment aimed at increasing central (5-HT mediated) behavioral inhibitory tone and reducing states of high anger (i.e., negative emotionality) should be an effective strategy in treating impulsive aggressive behavior in human subjects. To date, research has shown the potential efficacy of (1) pharmacological approaches to reducing impulsive aggressive outbursts and, (2) psychological approaches to reducing states of acute (and chronic) anger. To date, however, neither approach has been combined or compared in the same study.

Impulsive Aggression Expressed as a Dimension

Behavioral Genetics of Impulsive Aggression

Data from twin, adoption, and family studies suggest genetic influence on aggression. Heritability estimates for measures of aggression are moderately substantial in adults ranging from 44% to 72% and a recent meta-analysis confirmed the presence of a substantial genetic influence for aggression. Heritability estimates were most pronounced for aggression measures reflecting anger and hostility, or anger, impulsiveness, and irritability. It is noteworthy that these same phenomena are associated with the clinical profile of intermittent explosive disorder (IED).

Psychosocial/Environmental Correlates of Impulsive Aggression

The most important psychosocial factors involved in the development of aggression appear to be low socioeconomic status, ineffective parenting style, as well as physical punishment in childhood and exposure to aggression within and outside of the family. Notably, harsh discipline and child abuse (regardless of SES status) have been found to predict the development of impulsive, but not nonimpulsive, aggressive behavior in children. In one study, 41% of children abused in the first 5 years of their life became impulsively aggressive later in life, compared with 15% of nonabused children; in contrast, none of the nonimpul-sively aggressive subjects had a history of child abuse.

Neurochemical Correlates of Impulsive Aggression

Among all of the biological factors potentially involved in aggression, the most studied factors relate to brain neurochemistry, specifically monoamines such as serotonin (5-HT) and other centrally acting neurotransmitters (Brown et al. 1979; Coccaro and Siever 2005; Coccaro et al. 1989). Evidence of a role of brain 5-HT in human aggression is especially strong and points to an inverse relationship between brain 5-HT activity and aggression in animal models, nonhuman primates, and humans. In human studies, various measures reflecting central (as well as peripheral) 5-HT function have been shown to correlate inversely with life history, questionnaire, and laboratory measures of aggression. Most importantly, the type of aggression associated with reduced central 5-HT function appears to be impulsive, rather than nonimpulsive aggression (Linnoila et al. 1983). In human studies, there are selective cases where the relationship between 5-HT and aggression is positive in direction or does not exist at all. This may be due to the presence of other factors (e.g., diagnostic group; drug dependence; developmental stage) which may involve differential contributions from other neurotransmitter systems that also influence the tendency to react aggressively in social contexts. Limited evidence also supports a role for Non-5-HT brain systems and modulators in impulsive aggression. These findings suggest a permissive role for ► dopamine, ► norepinephrine, vasopressin, testosterone, and an inhibitory interaction between neuronal nitric oxide synthase and testosterone in rodents.

Functional Neuroanatomy of Aggression-Related Disorders in Humans

While IED is the only DSM-IV disorder (see later) for which aggression is the cardinal symptom, both borderline personality disorder (BPD) and antisocial personality disorder (AsPD) share a number of attributes associated with aggression as a dimension. At their most basic level, all three disorders are associated with increased anger and irritability as well as self- and other-directed aggression. All three diagnostic groups demonstrate a number of the deficits associated with the orbital ► medial prefrontal cortex (OMPFC)-amygdala tract including deficiencies of executive functions and socioemotional information processing. For IED, a series of PET studies on "impulsive aggressive" patients with both IED and BPD fail to parallel the increase in OMPFC metabolism by normal controls in response to acute administration of serotonin agonists, suggesting an important reduction in OMPFC function in impulsive aggressive individuals (New et al. 2002). Notably, however, chronic administration of a serotonin agonist over 12 weeks can both increase OMPFC metabolism and reduce impulsive aggressive behaviors. A study of temporal lobe epilepsy patients with and without IED, found that a subgroup of 20% of the IED patients (BPD status not assessed) had "severe" amygdala atrophy. In contrast to these studies, the only available imaging data from subjects with IED, demonstrate that IED subjects (even those without BPD or AsPD) have augmented Amygdala (AMYG), and reduced OMPFC, fMRI blood oxygenated level dependent (BOLD) signal activation to angery faces (Coccaro et al. 2007). In contrast to IED, there is a larger imaging literature among patients with BPD and AsPD. Structural MRI studies show only weak support for the existence of reduced frontal volumes for either disorder with equally equivocal support for morphological changes in the amygdala. In contrast, PET and fMRI studies have produced a fairly consistent pattern of altered corticolimbic activation for both disorders. Three PET studies have reported reduced metabolism in the frontal (e.g., OMPFC) cortex in BPD subjects. Both BPD and AsPD populations show decreased OMPFC activation during emotional information processing

(e.g., trauma scripts, a conditioned aversive stimulus) compared to control populations. Psychopaths also evidence less activation to abstract words in the right lateral frontal cortex. Both groups show increased amygdala activation to emotional stimuli; BPD subjects display enhanced amygdala activation to unpleasant pictures, as well as fearful and neutral words (viewed as negative by BPD subjects). While psychopaths showed increased amygdala activation when passively viewing negatively valenced pictures, amygdala activation for psychopaths may be attenuated/eliminated during emotional learning/conditioning tasks.

Recurrent, Problematic, Impulsive Aggressive Behavior as a Target for Study and Intervention: Intermittent Explosive Disorder

Although the term IED has only been in the DSM since the third edition (1980), the "construct" of a "disorder of impulsive aggression'' has been in the DSM since its inception in 1956. Currently, it describes individuals with recurrent, problematic episodes of aggression not accounted for by other medical or psychiatric factors (Coccaro et al. 2005). While DSM-IV does not specifically refer to the aggression in IED as impulsive in nature, premeditated aggression is typically a characteristic seen in antisocial personality disorder.

Clinical Description

Aggressive outbursts in IED have a rapid onset, often without a recognizable prodromal period. Episodes are typically short-lived (less than 30 min) and involve verbal assault, destructive and nondestructive property assault, or physical assault. Aggressive outbursts most commonly occur in response to a minor provocation by a close intimate or associate, and IED subjects may have less severe episodes of verbal and nondestructive property assault in between more severe assaultive/destructive episodes. The episodes are associated with substantial distress, impairment in social functioning, occupational difficulty, and legal or financial problems.

Epidemiology

In the largest epidemiological study to date, the lifetime prevalence of IED by "Narrow" DSM-IV criteria is estimated at 5.4% with 1-year prevalence estimated at 2.7% (Kessler et al. 2006).

Age of Onset and Demographics

IED appears as early as childhood and peaks in mid-adolescence, with a mean age of onset in three separate studies ranging from 13.5 to 18.3 years. The average duration of symptomatic IED ranges from 12 to 20 years to the whole lifetime. While initially thought to be more common in males, recent data suggest the gender difference in prevalence of IED may be closer to 1:1. Socio-demographic variables (e.g., sex, age, race, education, marital and occupational status, family income) do not appear to differ meaningfully as a function of IED status.

Laboratory Studies

To date, published data have reported IED subjects as having altered ► serotonin function compared with non-IED subjects or healthy controls. Other studies demonstrate a reduction in prolactin responses to ► fenflur-amine challenge, in the numbers of platelet 5-HT transporters in IED subjects compared with non-IED subjects. Two FDG PET studies report low FDG utilization after d,l-fenfluramine challenge in frontal areas of the brain and low FDG utilization after m-CPP challenge in the anterior cingulate in IED subjects compared with healthy controls. A ligand binding study of the 5-HT transporter also reports reduced low 5-HT transporter availability in the anterior cingulate in IED subjects versus healthy controls. Finally, fMRI study demonstrates increased activation of AMYG, and reduced activation of OMPFC, to angry faces, in IED subjects compared with healthy controls.

Family Study

Family history study of IED subjects demonstrates a significantly elevated morbid risk for IED in relatives of IED, compared with healthy controls, probands (0.26 vs. 0.08, p<0.01). Elevation in morbid risk for IED was not due to the presence of comorbid conditions among IED probands (e.g., history of suicide attempt, major depression, alcoholism, drug use disorder, etc.) and not due to elevations in morbid risk of other non-IED disorders in relatives (e.g., major depression, alcoholism, drug use disorders, anxiety disorder, and any other disorder).

Treatment of Impulsive Aggression and IED

Impulsive Aggression

Several psychopharmacologic agents appear to have effects on impulsive aggression. Classes of agents shown to have "antiaggressive" effects in ► double-blind, ► placebo-controlled trials of individuals with "primary" aggression (i.e., not secondary to psychosis, severe mood disorder, or organic brain syndromes) include mood stabilizers (e.g., ► lithium), 5-HT uptake inhibitors (e.g., fluoxetine) and, anticonvulsants (e.g., diphenylhydantoin, ► carba-mazepine). While norepinephrine beta-blockers (e.g.,

► propranolol, nadolol) have also been shown to reduce aggression, these agents have exclusively been tested in patient populations with "secondary" aggression (e.g., mental retardation, organic brain syndromes, etc.). Classes of agents which may have also "pro-aggressive" effects under some conditions include ► tricyclic antidepressants (e.g., ► am-itriptyline), ► benzodiazepines, and stimulant and hallucinatory drugs of abuse (e.g., amphetamines, ► cocaine,

► phencyclidine). Emerging evidence of differential psy-chopharmacology is of critical importance, and findings from the literature of double-blind, placebo-controlled, clinical trials suggest that antiaggressive efficacy is specific to impulsive, rather than nonimpulsive, aggression.

Intermittent Explosive Disorder: Effect of Psychopharmacologic Intervention

► Fluoxetine demonstrates clear antiaggressive efficacy for reducing impulsive aggressive behavior in IED subjects compared with placebo (Coccaro et al. 2009). Fluox-etine's antiaggressive effect is most clearly seen on verbal aggression and aggression against objects. Despite this effect, somewhat less than 50% of IED subjects treated with fluoxetine achieve remission. Gains made with flu-oxetine typically dissipate within 1 month after discontinuation but can be achieved again when the drug is reinstituted. Notably, fluoxetine has not been shown to increase aggression in IED subjects in placebo-controlled trials. Another placebo-controlled study of IED involving divalporex reported a favorable effect of this agent on overt aggression but only in IED subjects with comorbid cluster B personality disorder.

Intermittent Explosive Disorder: Effect of Psychosocial Intervention

While there are very few studies on the psychosocial treatment of impulsive aggression in adults, the efficacy of treatments that address the related constructs of anger dyscontrol and/or interpersonal aggression have been evaluated and suggest that relaxation training, interpersonal skill training, cognitive therapy, and multicompo-nent treatments all have moderate to large effects in the treatment of anger, and that the anger-reducing effects of anger treatment remain at follow-up. Of the different approaches for treating individuals with anger and aggression problems, cognitive restructuring, interpersonal skills training, multicomponent treatments, and relaxation skills had the strongest influence on aggression with effect sizes (Cohen's d) for the four types of treatment ranging from 1.06 to 1.87. Recently, a well-controlled study of cognitive behavior therapy in IED focusing on cognitive restructuring, relaxation and coping skills training has been published, demonstrating significant reduction in impulsive aggressive behavior and in hostile automatic thoughts (McCloskey et al. 2008). The antiaggressive response in this study was similar to that seen with fluoxetine, suggesting the possibility that the two interventions, together, may be very effective in treating the impulsive aggression seen in individuals with IED.

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