On Sat, 5 Apr 2008 01:47:51 -0800, "Superman Hughes Troll and s***
bag" <BillHughes@[EMAIL PROTECTED]
> wrote:
Neurobiology of Impulsive-Aggressive Personality-Disordered Patients
Larry J. Siever, M.D.
Dr. Siever is professor of psychiatry and director of the Outpatient
Psychiatry Division at Mount Sinai School of Medicine in New York. He
also directs the Mood and Personality Disorders Program in Mount
Sinai, a federally funded research program that investigates the
neurobiology of the schizophrenic spectrum personality disorders. Dr.
Siever serves as executive director of Mental Illness Research,
Education and Clinical Center at the Bronx VA Medical Center.
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
relation****ps, familial abuse and occupational failure. It is
precisely this type of impulsive aggression that appears to have
im****tant 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.
Personality Disorders
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 S*****onin System
The s*****onin system has been the most extensively studied
neuromodulator system in relation to impulsive aggression. Studies of
the s*****onin 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 s*****onergic agonists such as
d,l-fenfluramine, which causes the release of s*****onin, 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 s*****onergic responsiveness
in the hypothalamus that might not reflect a more generalized
s*****onergic 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 s*****onin 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 do***ented to be im****tant 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 tem****al dimensions with frontal and tem****al
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 tem****al 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 re****ted in the
tem****al and frontal cortex of violent offenders and psychiatric
patients.
Given that s*****onin can modulate prefrontal cortical activity,
reduced s*****onergic 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 s*****onergic 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 tem****al 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 s*****onin activity modulating the prefrontal
cortex and/or overactivation of the limbic cortex.
S*****onin'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.
Catecholamines
While the evidence is not as compelling for the role of catecholamines
in aggression as for s*****onin, 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 re****t 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).
Peptides
Vasopressin plays an im****tant role in modulating memory and behavior.
A positive correlation between CSF vasopressin and life history of
aggression has been re****ted 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.
Genetics
Twin and adoption in family studies sup****t 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
s*****onin 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 s*****onin-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
relation****p between alleles of the 5-HT1B receptor, which modulates
pre-synaptic release of s*****onin, as well as the 5-HT2A receptor, in
relation to impulsive aggression and personality-disordered patients
(New et al., 2002).
Treatment Implications
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
s*****onin reuptake inhibitors may reduce irritability and aggression
consistent with the hypothesis of reduced s*****onergic activity in
aggression (Coccaro and Kavoussi, 1997). Mood stabilizers that dampen
limbic irritability may also be im****tant 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 re****ts of the use of the antiandrogens to more specifically
reduce ***ually 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 ****ft deeply ingrained assumptions and
strategies.
Often, medications used to reduce the diathesis to impulsive
aggression may help facilitate the intrapsychic ****fts 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.
--
“A winner makes commitment. A loser makes promises.”
“The path of least resistance is the path of the loser.”
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