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Serotonin, the prefrontal cortex, and the amygdala interact with one another in the emergence of impulsive aggression. Which pharmacological and psychosocial treatments prove most effective?
While the causes of the aggression and violence that we encounter daily on our TV screens and newspapers are complex and multifactorial, many of our patients suffer from a more explicit difficulty in containing their aggressive impulses, particularly when frustrated or provoked. This results in interpersonal conflict, disruptive relationships, familial abuse and occupational failure. It is precisely this type of impulsive aggression that appears to have important neurobiological as well as psychosocial underpinnings. These patients with a "short fuse" have a limited capacity to suppress or delay the impulse to aggression when frustrated or provoked.
From an evolutionary perspective, aggression is a response to a potential threat or provocation across a variety of species and seems to be an inborn response tendency. Human beings in particular have evolved higher-order cortical centers that serve to suppress the emergence of more primitive forms of aggression when these are deemed inappropriate. To understand the neurobiological basis of aggression, an understanding of both the cortical inhibitory mechanisms and the more primitive limbic systems involved in the generation and modulation of aggression is required.
Thus, the prefrontal cortices, particularly the orbital prefrontal cortex and the ventral medial prefrontal cortex, play a key role in inhibiting limbic regions involved in the generation of the aggression. The anterior cingulate cortex may be involved in evaluating affectively charged stimuli, just as the amygdala responds to threat and provocative stimuli. These subcortical regions may then serve to signal other critical nodes, such as the hypothalamus, that modulate the body's hormonal internal milieu and cortical regions initiating motor action.
Impulsive aggression is a hallmark of several of the Axis II dramatic clusters or Cluster B diagnoses. The prototype of a personality disorder marked by impulsive aggression is borderline personality disorder (BPD), where impulsive aggression is coupled with a highly reactive and unstable affect modulation. Thus, patients with BPD will respond to disappointment and frustrations with intense emotions like rage, fear of abandonment and dysphoria. These affects then serve to trigger the generation of an impulsive, often aggressive, response to the provocation.
For example, a woman with BPD learns through a phone call of a mutual acquaintance that her boyfriend has slept with her best friend. She rips the phone cord from the wall, throws the phone against the wall, and then smashes a bottle and proceeds to cut herself with it, drawing blood. These actions exemplify aggression--both other-directed and self-directed acts--in response to a provocative event that touched on deeply experienced vulnerabilities around feelings of low self-esteem, envy and fears of abandonment.
Patients with narcissistic personality disorder may also act aggressively in an impulsive manner when feeling humiliated or "narcissistically injured." Finally, patients with antisocial personality disorder may act aggressively with little apparent remorse about their aggressive and antisocial behaviors, which may result in criminal activities.
While the propensity to impulsive aggression interacts with an exquisite affective sensitivity and lability in BPD, it can be associated with the shallow affect of histrionic personality disorder and psychopathic traits in antisocial personality disorder. Thus, the more affectively labile individual with BPD may be more likely to seek treatment, while individuals with antisocial personality disorder may more likely be seen in forensic settings due to their illegal behaviors.
The Serotonin System
The serotonin system has been the most extensively studied neuromodulator system in relation to impulsive aggression. Studies of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) suggested that people with major depressive disorder may demonstrate reduced concentrations of cerebrospinal fluid (CSF) 5-HIAA. A more careful study of this phenomena suggested a bimodal distribution in depressed patients, with violent suicidal acts associated with low CSF 5-HIAA and nonviolent attempts, such as overdoses, associated with a more "normal" mode of CSF 5-HIAA (Asberg et al., 1976). Subsequent studies demonstrated that low CSF 5-HIAA also occurred in criminal offenders and armed-forces personnel with a history of violence (Cocarro and Siever, 2002). Studies with serotonergic agonists such as d,l-fenfluramine, which causes the release of serotonin, blockade of reuptake and direct agonism of 5-HT2 receptors, resulted in blunted hormone responses in personality-disordered patients with impulsive aggression. In a study of male patients with clearly defined major affective disorder and/or personality disorder, patients with BPD evidenced blunted prolactin responses to fenfluramine, compared to responses of controls and another personality-disorder comparison group. The degree of impulsive aggression was inversely correlated with the prolactin response to fenfluramine (Coccaro et al., 1989). This measure provides a putative index of serotonergic responsiveness in the hypothalamus that might not reflect a more generalized serotonergic deficit. This result was replicated in a study of patients with impulsive-aggressive personality disorders using the agent d-fenfluramine (Coccaro et al., 1996a; Coccaro et al., 1996b) as well as in studies using the direct 5HT2C agonist metachlorophenylpiperazine (m-CPP) (Coccaro et al., 1997).
The serotonin system modulates activity of inhibitory areas in the prefrontal cortex and related areas such as the anterior cingulate cortex. Some of these areas have been documented to be important in the modulation of aggression. For example, the well-known story of Phineas Gage--dependable and hard-working railroad construction worker who became irascible and aggressive following an injury--is consistent with the role of the orbital frontal cortex and ventral medial frontal cortex in inhibiting the emergence of aggression and modulating social judgment.
A variety of case studies of patients with damaged orbital frontal cortex or frontal temporal dimensions with frontal and temporal hypoperfusion suggests that a damaged orbital frontal cortex can result in irritability and angry outbursts (New et al., 1998b). Furthermore, postnatal lesions of the prefrontal cortex, particularly in orbital regions, early in development may result in antisocial and aggressive behavior in adulthood (Bechara et al., 2001). A propensity to violent behavior has also been found in patients with temporal lobe tumors or lesions. Electrical stimulation of the amygdala has been associated with rage attacks, and a reduced ability to recognize a threat may be associated with bilateral amygdala lesions. These considerations suggest that impairment or reduction in prefrontal cortical inhibition of subcortex capacity or exaggerated responsiveness in excitatory circuits of subcortical areas such as the amygdala may be associated with aggression. Reduced prefrontal gray matter has been associated with autonomic deficits and aggression in patients with antisocial personality disorder (Raine et al., 2000). Decreased blood flow or glucose metabolism has been reported in the temporal and frontal cortex of violent offenders and psychiatric patients.
Given that serotonin can modulate prefrontal cortical activity, reduced serotonergic activity might be expected to result in reduced brain activity in critical cortical inhibitory regions such as the orbital frontal, ventral medial and anterior cingulate cortex. Impulsive-aggressive patients with personality disorders demonstrate blunted responses of orbital frontal, ventral medial and cingulate cortex of the glucose metabolic increases induced by acute pharmacologic administration of fenfluramine (Siever et al., 1999). This is a more direct test of serotonergic modulation of inhibitory regions of interest in the cortex than neuroendocrine responses. Reduced glucose metabolism was founded in the medial and orbital frontal cortex, the left-middle and superior temporal left gyrus, the left parietal lobe, and the left caudate in a later study of BPD marked by impulsive aggression (Soloff et al., 2000). The 5-HT2 agonist m-CPP induces metabolic increases in the orbital frontal and other prefrontal cortical regions, as well as other cortical and limbic regions. In personality-disordered patients marked by impulsive aggression, the metabolic responses to m-CPP were reduced in the orbital frontal and anterior cingulate cortices (New et al., 2002). Both the fenfluramine and m-CPP studies also suggested that correlations between prefrontal and amygdala activity found in normal controls were absent in the impulsive-aggressive patients, raising the possibility that a disconnection between inhibitory centers and limbic centers involved in the generation of aggression may be responsible for the disinhibition of aggression. This dysjunction may be related to underactivation of serotonin activity modulating the prefrontal cortex and/or overactivation of the limbic cortex.
Serotonin's effects on the prefrontal cortex may be mediated largely by 5-HT2A receptors, which enhance prefrontal activity through innervation of inhibitory interneurons. Thus, while responsiveness to m-CPP is reduced, suggesting reduced 5-HT2 responsiveness, it is also possible to directly examine the number of 5-HT2 binding sites. Platelet and postmortem studies suggest that the number of 5-HT2A receptors, which are the predominant neuronal 5-HT2 receptors in the cortex, are actually increased in platelets and postmortem brains of people who have attempted suicide (Mann et al., 1992; Pandey et al., 1990).
A recent preliminary study of 5-HT2 receptor binding in impulsive-aggressive personality-disordered patients in our laboratory suggested actual increases in 5-HT2 receptor binding, even in patients who previously demonstrated reduced responses to m-CPP (Siever et al., 2002). These results raise the possibility of a defect in transduction distal to the receptor and possibly compensatory upregulation of the 5-HT2 receptor. While the pathophysiology of this receptor system needs to be more fully characterized, it is clearly implicated in the external and directed aggression observed in personality-disordered patients as well as the self-directed violence seen in suicide attempters.
While the evidence is not as compelling for the role of catecholamines in aggression as for serotonin, a number of animal and clinical studies suggest that increased reactivity of the noradrenergic and dopaminergic system may facilitate aggressive behavior in humans. Reduced presynaptic concentrations of catecholamines, such as norepinephrine, coupled with supersensitive postsynaptic receptors, may be responsible for exaggerated irritability in response to stress. A report has suggested that there is a positive correlation between the growth hormone response to clonidine (Catapres) and irritability in personality-disordered and healthy volunteer subjects (Coccaro and Siever, 2002).
Vasopressin plays an important role in modulating memory and behavior. A positive correlation between CSF vasopressin and life history of aggression has been reported in personality-disordered subjects, which is consistent with animal studies that show a vasopressin antagonist reduced aggression (Coccaro et al., 1998). Opiate-binding protein has been associated with aggression in healthy male volunteers and metenkephalin levels have been associated with self-injurious behavior (Coccaro and Siever, 2002).
Steroids such as testosterone have been correlated with aggression in normal human subjects, as well as in psychiatric and criminal populations. Reduced cholesterol has been associated with aggressive behavior and suicide attempts. Primates randomized to low-cholesterol diets have also displayed increases in aggressive behavior. Therefore, it appears likely that aggression is moderated by a variety of neuromodulators, including monoamines, neuropeptides and neurosteriods.
Twin and adoption in family studies support heritability of aggression. Heritability estimates vary from 44% to 72% in adults (Bergeman and Seroczynski, 1998). While it is clear that there is no gene or gene coding for aggression, it is possible that polymorphisms in genes that regulate the activity of neuromodulators such as serotonin or genes for structural components of critical brain regions regulating aggression may contribute to individual differences in the susceptibility to aggressive behavior.
For example, a mutation of the monoamine oxidase-A gene was linked to impulsive violence in an extended family pedigree, and its genetic alteration was associated with altered catecholamine metabolism. While this is an unusual genetic variant, relatively common polymorphisms exist in relation to serotonin-related genes such as tryptophan hydroxylase (TPH), 5-HT1B receptor, 5-HT2A receptor and 5-HT1A receptor. An allele for TPH polymorphism has been associated with suicide attempts in violent offenders and with impulsive aggression in personality-disordered patients in some but not all studies (New et al., 1998a; Nielsen et al., 1998). More recent pilot studies suggest a relationship between alleles of the 5-HT1B receptor, which modulates pre-synaptic release of serotonin, as well as the 5-HT2A receptor, in relation to impulsive aggression and personality-disordered patients (New et al., 2002).
An increased understanding of the neurobiology of aggression has enabled the development of agents that may be ultimately successful in reducing a tendency to respond to frustration with irritable aggression. A number of uncontrolled studies and, more recently, double-blind, placebo-controlled trials have suggested that selective serotonin reuptake inhibitors may reduce irritability and aggression consistent with the hypothesis of reduced serotonergic activity in aggression (Coccaro and Kavoussi, 1997). Mood stabilizers that dampen limbic irritability may also be important in reducing the susceptibility to react to provocation or threatening stimuli by overactivation of limbic system structures such as the amygdala. Carbamazepine (Tegretol), diphenylhydantoin (Dilantin) and divalproex sodium (Depakote) have all yielded promising results, not only in open trials but in more recent placebo-controlled trials of patients with personality disorders or other psychiatric disorders with aggressive behavior (Coccaro and Siever, 2002).
Excessive dopaminergic activity might suggest that neuroleptic medications might be of help, and, indeed, atypical neuroleptics have been successful in reducing aggression and other symptoms of BPD, including a recent double-blind study of olanzapine (Zyprexa) (Zanarini and Frankenburg, 2001). Anti-adrenergic agents such as b-blockers have also been shown to reduce aggression in populations with brain injuries and dementia, presumably by dampening excessive noradrenergic activity (Ratey et al., 1992). Finally, there have been some reports of the use of the antiandrogens to more specifically reduce sexually related aggression (Coccaro and Siever, 2002).
An increased understanding of the neurobiology of impulsive aggression may ultimately help us to understand psychosocial treatments that are grounded in theoretical frameworks that include this diathesis as part of their formulation. Thus, the emotional dysregulation often resulting in impulsive, self-destructive behaviors becomes a target of the cognitive-behavioral technique, dialectical behavioral therapy, and the diathesis to aggressive behavior is part of psychoanalytic formulations of BPD (Kernberg, 1992). Cognitive-behavioral therapies strive to validate and understand the intense affects experienced by people with these personality disorders but provide alternative ways of channeling the impulses generated by these intense feelings away from self-injurious or aggressive behaviors toward more interpersonally effective coping strategies. Psychoanalytic therapies use exploration of unconscious conflict in here-and-now distortions of the transference to help shift deeply ingrained assumptions and strategies.
Often, medications used to reduce the diathesis to impulsive aggression may help facilitate the intrapsychic shifts that are the goals of these therapies. They are more useful in disorders such as BPD, where affects are intensely experienced and yearning for attachment is great. Impulsive aggression is found in antisocial personality disorder and is often accompanied by a psychopathy or emotional "agnosia" that makes it less amenable to psychiatric treatment, but responses have been observed in therapeutic communities or highly cohesive self-help groups. Thus, the promise that an increased understanding of the neurobiology of aggression holds for therapeutic and possibly future preventive treatment still remains to be realized, but current research is providing a promising foundation.
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