Larry J. Siever, MD

If psychopharmacology sometimes feels like walking a fine line between undertreatment and overtreatment or between letting patients suffer and turning to medications as an "easy fix," then the psychopharmacology of personality disorders can feel like walking a tightrope without a net.

Unfortunately, the published literature is helpful only up to a point. There are not many peer-reviewed randomized controlled trials, given the prevalence and debilitating nature of some of the personality disorders. Studies have tended to be comparatively small and, especially in light of the chronic nature of much Axis II pathology, short in duration.

 Few, if any, trials have compared in size and scope to the large government- or industry-funded studies of the major mood and psychotic disorders.

The studies that have been published often have had high dropout rates, with positive results limited to certain domains and other areas of disturbance largely unimproved.

 There also has been a growing trend, perhaps caused by liability or institutional review board concerns, for treatment studies to include only patients who are comparatively stable and free of active suicidality. Few recent personality disorder drug studies have included, for example, the intermittently unsafe borderline patients often seen in clinical practice. This means that there are virtually no randomized clinical trials of increasingly popular agents like topiramate, lamotrigine, or the atypical antipsychotic in borderline or other personality disordered patients who are or recently have been actively suicidal.

Nevertheless, meaningful strides have been made over the past several years, with several novel agents demonstrating statistically significant results. Most promising are major discoveries relating to neurobiologic abnormalities and neurobiologic changes in response to provocation or treatment that have helped elucidate the constitutional factors that underlie personality disturbance.

 Much of this recent outcome and neurobiologic research has focused on aspects or dimensions of the Axis II disorders in addition to or instead of the categoric syndromes defined by the 

Personality disorders are phenotypic expressions of biologic vulnerabilities and arise from a combination of predisposing genotypes and experiential factors.

 These factors may consist of present-day life stressors and/or early abuse and neglect, the effects of all of which may be modulated by damage to the CNS as it develops during childhood and adulthood.

 Although the strong correlation between negative life experiences and personality disorders has become a cornerstone of our understanding of some Axis II pathology, it should be remembered that heredity also appears to play a crucial role in the pathogenesis of personality disorders.

A Norwegian twin study suggested that personality disorders are more strongly determined by genetics than are almost all the Axis I disorders.

 Moreover, the psychological damage caused by abuse and neglect may be modulated by deleterious effects on the "hard-wiring" of the CNS.

 It should not, therefore, be surprising that many patients with personality disorders exhibit structural and functional brain abnormalities, or that certain medications may be beneficial in these disorders.

By far the most studied personality disorder, borderline personality disorder (BPD), is also the only one to be the subject of an American Psychiatric Association practice guideline.

 Pioneering BPD studies that suggested the utility of neuroleptics and mood stabilizers, as well as the risks of benzodiazepines and tricyclic antidepressants, are by now well known.

 Early neurobiologic research implicated disturbances of the serotonin system in the suicidality and impulsive aggression characteristics of this population.

 Currently, the best validated medications for BPD may be the selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs), antipsychotics, and anticonvulsants.

In placebo-controlled trials, fluoxetine has been shown to be helpful with anger,

 irritability, aggression, and overall clinical status,

 although it did not appear to benefit patients receiving concurrent dialectical behavior therapy (DBT)

 and was less efficacious than olanzapine or the olanzapine-fluoxetine combination for depression and impulsivity-aggression.

 In a rare pharmacologic study using decreases in suicide attempts as the principal outcome measure, paroxetine was superior to placebo in a mixed sample of multiple attempters, the majority of whom had BPD.

 Both sertraline and citalopram were found to decrease the frequency of BPD-and of several other personality disorders-in patients entered into a randomized, non–placebo-controlled depression treatment study.

 Most recently, fluvoxamine was better than placebo for rapid mood shifts in BPD but not for impulsivity or aggression.

Exploration of serotonergic abnormalities has continued to dominate neurobiologic research into BPD and its component dimensions. Trait impulsivity in persons with personality disorders has been associated with blunted hormonal responses to the serotonergic probe ipsapirone.

 Positron emission tomography (PET) scans of patients who have personality disorders with impulsive aggression have shown blunted metabolic responses to fenfluramine in the orbitofrontal, adjacent ventromedial, and cingulate cortices.

 Fluoxetine treatment of BPD in a sample of patients with impulsive aggression was associated not only with clinical improvement but with PET findings of increased metabolic rate in the orbitofrontal cortex.

During the first wave of pharmacologic research in BPD, neuroleptics were among the most consistently efficacious agents, although follow-up studies to one famous set of trials failed to support haloperidol's overall usefulness.

 Two important studies demonstrated a decrease in suicide attempts or self-harm behaviors with depot neuroleptics.

 Unsurprisingly, atypical antipsychotics have supplanted neuroleptics in more recent research. Olanzapine has proved better than placebo on scales of anxiety, paranoia, anger/ hostility, and interpersonal sensitivity, although not depression

; andwhen added to DBTdepression, anxiety, and impulsive aggression.

 More recently, aripiprazole was found to be superior to placebo for depression, anxiety, anger, and most of the domains measured by the SCL-90-R.

 The (partial) efficacy of antipsychotics in BPD may reflect underlying causative abnormalities of the dopaminergic system.

Anticonvulsants have proved attractive to clinicians and researchers working with BPD because of the disorder's resemblance, in certain respects, to bipolar disorder, and because BPD patients' "anger attacks" sometimes seem seizure-like in their suddenness and irresistibility. Early encouraging results with carbamazepine10 were followed by a published trial in which the active drug showed no greater efficacy than placebo. 

 In a controlled study of the effect of divalproex on aggression, the intent-to-treat analysis failed to reveal any significant benefit, but subgroups with cluster B personality disorders

 showed improvements on various measures of anger, aggression, and overall clinical status. Divalproex has also been associated with amelioration of interpersonal sensitivity, anger/hostility, and aggression in BPD patients with comorbid bipolar II disorder.

Newly popular anticonvulsants for BPD include lamotrigine and topiramate, both of which have been associated with decreases in self-report measures of anger in BPD patients.

 A recent topiramate study is noteworthy among BPD drug trials for using an usually broad range of outcome measures. Significant treatment-associated improvements were noted in somatization, interpersonal sensitivity, anxiety, hostility, phobic anxiety, and global severity on the SCL-90-R; 4 of 8 scales of the Inventory of Interpersonal Problems; and all 8 scales of the SF-36 Health Survey, an instrument measuring health-related quality of life.

Innovative, recently studied agents to treat BPD include ethyl-eicosapentaenoic acid, which sometimes is used for bipolar and other mood disorders, and was found to be superior to placebo at reducing aggression and the severity of depressive symptoms in BPD.

 Two different doses of the -adrenergic agonist, clonidine, were given to BPD patients experiencing strong urges to engage in self-injurious behavior; both were associated with significant decreases in dissociative symptoms, suicidal ideation, and wishes to commit self-harm.

Intravenous naloxone, in the only published placebo-controlled trial of an opiate antagonist known to us, appeared to reduce dissociative symptoms but failed to show greater efficacy than placebo.

 Nevertheless, BPD treatments that mimic or block narcotic activity show some promise. Many BPD patients mutilate themselves or engage in other behaviors like bulimia and substance abuse that also may reflect abnormalities of the endogenous opiate system. BPD patients who self-mutilate have shown diminished pain sensitivity,

 which, in turn, has been correlated with dissociation.

 Interestingly, responders to therapy for BPD show normalization of previously impaired nociception.

 It may be that physical self-destructiveness, impulsivity, and dissociation in BPD represent the final pathways of various possible disturbances in the painprocessing system, and that medications that help offset these disturbances will provide substantial benefit.

As with schizophrenia, functional impairment in schizotypal personality disorder (SPD) may be due more to patients' social withdrawal and cognitive abnormalities than to their odd beliefs and perceptual experiences. Several early BPD pharmacologic studies included persons with SPD and found little difference in medication responsiveness between the 2 groups. Unfortunately, little randomized research has been undertaken in the intervening years. One exception is a placebo- controlled study using low-dose risperidone that found significant treatment-associated improvements in both positive and negative symptoms.

 Promising agents for schizophrenia-spectrum disorders include drugs that enhance executive function, for example, through potentiating effects on noradrenergic neurons with termini in the prefrontal cortex or through prefrontal D1 agonism.

Randomized studies in antisocial personality disorder have generally focused on forensic populations, often male prison inmates. Published research of this type has all but disappeared during the last 10 years, perhaps because of regulatory obstacles to enrolling prisoners in drug trials. In older studies, both lithium

 were found to be useful in decreasing aggression and/or rule infractions in incarcerated violent offenders.

Of all the interrelationships between Axis I and Axis II disorders, one of the most widely agreed on is the close resemblance between social anxiety disorder and avoidant personality disorder (APD).

 In a controlled trial, a monoamine oxidase inhibitor (MAOI) was shown to be useful for social anxiety and, perhaps more strongly, for maladaptive personality traits, with a twothirds reduction in the number of brofaromine-treated patients who met criteria for APD.

Despite the inconclusive evidence at present for the effectiveness of pharmacotherapy for the treatment of many personality disorders, patients with Axis II pathology, especially BPD, are among the most likely populations to be prescribed psychotropic drugs, often several simultaneously.

 The only combined therapy that has been tested in BPD, to our knowledge, is the olanzapine-fluoxetine combination, which was found not to be superior to olanzapine alone for depressive symptoms and impulsive aggression, although it did result in less weight gain.

In our experience, polypharmacy in BPD frequently occurs as the result of a cumulative process: medications with unclear benefits continue to be prescribed for fear of inducing a clinical deterioration in a worrisome patient, while more and more medications are added on because of persistent symptomatology. Clinicians treating patients with BPD and other personality disorders should be on guard against this unwitting polypharmacy, since it is of little empirically supported usefulness and may result in exposing a vulnerable population to dangerous iatrogenic complications.

One common approach to patients with personality disorders with comorbid mood or anxiety disorders can be summarized as, "medicate the Axis I symptoms and leave the Axis II problems for psychotherapy." In many clinicians' experience, however, including our own, pharmacologic treatments for mood or anxiety disorders tend to work less well in patients with severe personality disorders.

This is a controversial area, with some published research suggesting that Axis II pathology worsens the response to medication treatment of Axis I disorders and other studies suggesting that it does not. However, most of the relevant studies have excluded the sickest personality-disturbed patients (eg, ones who were suicidal), or else required that the Axis I disorder be the primary diagnosis, thereby excluding patients who were judged to be personality disturbed with a superimposed mood or anxiety disorder.

Much research remains to be done on personality disorder pharmacotherapy, especially neurobiologic explorations of underlying causes and risk factors. It is imperative that there be larger and longer randomized drug treatment trials, in both healthier and sicker populations, including studies in patients at risk for homicide or suicide. In view of the comparatively limited evidence for the efficacy of medications for Axis II pathology, as well as the marked placebo-responsiveness of some personality disordered patients, it seems both ethical and necessary for there to be further placebo-controlled trials, or at least trials with substantial placebo lead-in periods.

For clinicians treating patients with personality disorders, many medication options are available. In BPD, the bestsubstantiated choices include SSRIs/ SNRIs, anticonvulsants, and neuroleptics/atypical antipsychotics. Most of these drug classes have shown statistically significant benefits for aggression, anger, impulsivity, and/or affective lability, although results have been somewhat inconsistent.

There is evidence that atypical antipsychotics may be helpful for both positive and negative symptoms in SPD and that MAOIs may be a treatment for APD. Aggressiveness in antisocial personality disorder (ASPD) may be reduced by phenytoin or lithium, and it seems reasonable to infer that agents useful in treating aggressiveness in BPD may be useful in ASPD as well, especially given the high rates of comorbidity between the disorders.

It is worthwhile to bear in mind that the extreme, dysregulated emotions to which patients with personality disorder are prone are likely to influence their attitudes toward medications. Treaters should expect certain persons with personality disorders, especially those with BPD, to alternate between idealizing the miraculous potential of medications and devaluing them as not worth taking or even considering.

An important pitfall to avoid is fostering in Axis II patients an overly optimistic conviction that a medication "cure" is just around the corner and that it is just a matter of finding "the right drug." Although it is reasonable to encourage patients to participate in rational medication trials, treaters should simultaneously encourage them to participate in evidence-based psychotherapy and to make efforts to sustain their realworld functioning, regardless of whether or not a given medication trial is successful. At the present time, there is little evidence that the difficulties experienced by persons with personality disorders will go into remission as a result of pharmacotherapy. Fully effective medication treatments for these widespread and often crippling disorders must await further descriptive and empirical research.

Dr Triebwasser is a research fellow affiliated with the Bronx, NY, VA Medical Center and the Mount Sinai School of Medicine. He reports that he has no conflicts of interest concerning the subject matter of this article.

Dr Siever is the director of the Special Evaluation Program for Mood and Personality Disorders and is a professor of psychiatry at the Mount Sinai School of Medicine. He is also director of the Bronx VA Mental Illness Research, Education, and Clinical Center. He reports that he has no conflicts of interest concerning the subject matter of this article.

Aripiprazole (Abilify)
Brofaromine (Consonar)
Carbamazepine (Carbatrol, Tegretol, others)
Citalopram (Celexa)
Clonidine (Catapres)
Divalproex (Epival, Depakote)
Ethyl-eicosapentaenoic acid
Fenfluramine (Pondimin)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Haloperidol (Haldol)
Ipsapirone
Lamotrigine (Lamictal)
Lithium (Eskalith)
Naloxone (Narcan, Suboxone, Pentazocine)
Olanzapine (Zyprexa)
Paroxetine (Paxil)
Phenytoin (Dilantin)
Risperidone (Risperdal)
Sertraline (Zoloft)
Topiramate (Topamax)


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Articles

The prevalence and debilitating nature of some of the personality disorders has impeded the study of psychopharmacology in these conditions. However, important advances have been made in the last several years.

Pharmacology of Personality Disorders

Studies in humans and nonhuman primates have identified the prefrontal cortex as a structure that plays a central role in many aspects of cognition. Results from preclinical studies of prefrontal cortex dysfunction suggest that monoaminergic neurotransmitters exert a modulatory role on its intrinsic circuitry. Findings from several studies suggest that, in patients with schizophrenia and one of the schizophrenia spectrum disorders, cognitive impairments are associated with reduced stimulation of the prefrontal cortex dopamine (DA) receptors. However, mounting evidence suggests that dysregulation in other monoaminergic neurotransmitter systems might also be involved. After treatment with antipsychotic medication, functional deficits in social, occupational and independent living activities in patients with schizophrenia often persist--even in the presence of only residual psychotic symptoms. Since these functional deficits are believed to be strongly associated with the negative symptoms and cognitive deficits present in patients with schizophrenia, new psychopharmacological therapies are being developed to improve cognition in this disorder.

This overview will focus on monoaminergic neurotransmitters that hold promise as therapeutic interventions for the cognitive deficit in schizophrenia (Table).

Evidence from multiple studies suggests that dysregulation of DA plays a critical role in the pathophysiology of schizophrenia. An early hypothesis of this relationship (the "classical" DA hypothesis) postulated that hyperactivity of mesolimbic DA projections to subcortical areas results in positive symptoms (Carlsson and Lindqvist, 1963). More recently, it has been recognized that the impairment in several cognitive domains in patients with schizophrenia is the best predictor of their social and occupational reintegration.

A "revised" DA hypothesis (Davis et al., 1991; Weinberger, 1987) attributed the cognitive impairments and negative symptoms of schizophrenia to hypoactivity of mesocortical DA projections to D

 receptors in the prefrontal cortex. This hypothesis is supported by studies of nonhuman primates with reduced stimulation of prefrontal cortex D

 receptors that exhibited cognitive impairments similar to the ones observed in schizophrenia (Goldman-Rakic et al., 2000), as well as reports from genetic polymorphism studies of the DA-inactivating enzyme catechol-O-methyl-transferase (COMT). The Val/Val genotype of COMT, which is associated with more efficient metabolism of dopamine than Met/Val or Met/Met genotypes and, thus, reduced dopaminergic availability in prefrontal cortex D

 receptors, has been shown to correlate with poor performance on tests of executive function and working memory (Egan et al., 2001).

Furthermore, reports from functional imaging measurement studies of D

C]NNC 112 showed excessive expression of these receptors in the dorsolateral prefrontal cortex of drug-free patients with schizophrenia, which predicted poorer working memory performance (Abi-Dargham et al., 2002). The authors proposed that chronic deficit in presynaptic DA function in the dorsolateral prefrontal cortex may be the cause for both the D

 receptor upregulation and the impaired working memory performance reported in their study.

In humans, there is growing evidence that cognitive function improves after the use of dopamine agonists (Kimberg and D'Esposito, 2003). Recent cognitive enhancement studies reported amelioration of working memory (Carter et al., 1998; Stevens et al., 1998) and selective attention impairment (Carter et al., 1997), as well as increase in prefrontal cortex blood flow (Daniel et al., 1991) in patients with schizophrenia after the use of amphetamine. However, the magnitude of DA release and subsequent stimulation of striatal D

 receptors induced by amphetamine in these patients correlates with worsening of their psychotic symptoms (Breier et al., 1997).

In ongoing studies by our group, patients with schizotypal personality disorder, the prototypic disorder of the schizophrenia spectrum, who were given oral administration of 30 mg of a single dose of d-amphetamine showed improvement of visuospatial and auditory working memory (Mitropoulou et al., 2005). Moreover, this improvement occurred without secondary worsening of psychotic-like symptoms. This observation can be explained by the fact that while patients with schizophrenia and schizotypal personality disorder share a hypoactivity of DA receptors in the prefrontal cortex, patients with schizotypal personality disorder do not exhibit the striatal DA hyperactivity present in patients with schizophrenia (Siever et al., 1993). Thus, the study of patients with schizotypal personality disorder, in conjunction with the wealth of data already available regarding schizophrenia, offers a unique opportunity to identify modifying factors contributing to the more serious cognitive/social deficits of chronic schizophrenia in individuals who are relatively free of a history of long-term antipsychotic treatment, institutionalization and chronic psychosis.

Despite its potential benefit, there is presently no specific D

 agonist available for human use. Several pharmacologic agents with a high ratio of D

 activity are being evaluated for use as cognitive function enhancers in patients with schizophrenia. Pergolide (Permax) is an ergot derivative D

 receptors that has been utilized in Parkinson's disease (PD) (Fici et al., 1997). This compound was reported to improve visuospatial working memory in healthy individuals (Muller et al., 1998) as well as improve scores in tests measuring frontal function and memory in patients with PD (Kulisevsky et al., 2000) and visual memory and attention in patients with sleep disorders and attention-deficit/hyperactivity disorder (Walters et al., 2000).

Because of these findings, it is of interest to evaluate the effects of pergolide on working memory and attention in schizophrenia and the schizophrenia spectrum disorders. In ongoing studies, our group has demonstrated cognitive improvement in patients with schizotypal personality disorder tested after a four-week administration of escalating doses of pergolide. Specifically, participants demonstrated improvement in auditory working memory and information processing, reflecting an overall improvement in context-dependent working memory processing.

Dihydrexidine is another agent with a high ratio of D

 activity that has been extensively studied in animals and more recently in patients with PD (Blanchet et al., 1998). Since recent data demonstrate that atypical antipsychotics, such as clozapine (Clozaril), have D

 antagonist activity (Cussac et al., 2004), several ongoing studies are evaluating the use of D

 agonist agents as add-on therapy to atypical antipsychotics in patients with schizophrenia, in order to improve their cognitive deficit.

The noradrenaline system has been implicated in cognitive functions, such as memory, consolidation/learning (McDowell, 1996) and selective attention (Aston-Jones et al., 1999; Lange et al., 1992). The dorsal noradrenergic bundle is composed of axons of the locus ceruleus' noradrenergic cell bodies. This bundle innervates the prefrontal cortex, which has a high density of α

-adrenergic subtype receptors (Aoki et al., 1994).

Animal studies have shown that noradrenergic depletion of the prefrontal cortex, by means of surgical ablation, toxin exposure or aging, leads to spatial working memory deficits (Brozoski et al., 1979; Cai and Arnsten, 1997). These deficits are improved by clonidine (Catapres), an α

 adrenergic receptor agonist (Arnsten and Goldman-Rakic, 1985).

It has been proposed that moderate levels of norepinephrine enhance prefrontal cortex functions through actions at postsynaptic α

 adrenoceptors, while the release of high levels of norepinephrine activates a1 adrenoceptors, leading to cognitive dysfunction (Arnsten et al., 1999; Birnbaum et al., 1999; Mao et al., 1999). Guanfacine (Tenex), by enhancing signals at postsynaptic α

-adrenergic receptors, has been shown to improve working memory performance in animal models (Arnsten and Goldman-Rakic, 1985; Marjamaki et al., 1993; Schneider and Kovelowski, 1990; Uhlen et al., 1995) and healthy individuals (Jakala et al., 1999).

In our ongoing studies, participants with schizophrenia spectrum personality disorders, tested after four weeks of guanfacine administration, showed significant improvements in tests of cognitive processing (i.e., Paced Auditory Serial Addition Test [PASAT], Letter-Number Sequence and Trail-Making Test B [TMT-B]). These results, while preliminary, support the hypothesis that α

 adrenergic receptors are potential targets for cognitive enhancement in psychiatric disorders. Similarly, atomoxetine (Strattera), a norepinephrine reuptake inhibitor that indirectly increases DA concentration in the prefrontal cortex, is presently being tested as a potential therapy for the cognitive deficits of schizophrenia (Friedman et al., 2004).

Serotonin (5-HT) is implicated in the modulation of cognition, emotion and perception (Azmitia, 2001; Williams et al., 2002). Moreover, cognitive deficits and impulsivity in psychiatric disorders such as schizophrenia and depression have been correlated with dysregulation of this neurotransmitter system. The relationship between 5-HT and preservative behavior observed in schizophrenia was suggested by reports of cognitive inflexibility in animals after prefrontal 5-HT depletion with the use of the selective neurotoxin 5,7-DHT (Clarke et al., 2004).

At least 15 distinct 5-HT receptors have been identified. The preclinical and human literature are not in agreement as to whether it is activation or antagonism of the 5-HT

 receptor that enhances cognition (Roth et al., 2004). For example, both atypical antipsychotic drugs with 5-HT

 partial agonist action and antagonist action have been shown to enhance cognition (Newman-Tancredi et al., 1998). Additionally, tandospirone, a compound with 5-HT

 partial agonist action, has been shown to enhance verbal memory in schizophrenia (Sumiyoshi et al., 2001) and to impair explicit memory function in patients with dementia (Yasuno et al., 2003). (

Tandospirone is not approved for use in the United States--Ed.

) Furthermore, it has been hypothesized that compounds with a high degree of 5-HT

 agonist action, such as NAE-086, carry a significant risk of exacerbating symptoms in patients with schizophrenia (Renyi et al., 2001).

Multiple lines of evidence suggest that 5-HT

 antagonism improves cognition in schizophrenia. Most atypical antipsychotics have significant 5-HT

 antagonist actions and, while cognitive improvement was seen in patients with schizophrenia after the administration of mianserin, a drug with 5-HT

 antagonist activity (Poyurovsky et al., 2003), the reverse was observed in healthy volunteers after the administration of psilocybin, a 5-HT

Mianserin and psilocybin are not approved for use in the United States--Ed.

Moreover, worsening working memory was also reported in primates after the use of a 5-HT

 agonist (Williams et al., 2002). However, findings from immunocytochemical studies suggest that beneficial effects of 5-HT

 antagonism might be secondary to normalization of N-methyl-D-aspartate receptor functioning (Varty et al., 1999). Since most atypical antipsychotics have potent 5-HT

 antagonist activity, it is unlikely that the introduction of an agent with specific antagonist activity in this receptor will provide significant added cognitive improvement in patients with schizophrenia (Silver, 2003).

Additionally, reports from studies of selective serotonin reuptake inhibitor augmentation of atypical antipsychotics are contradictory. Although earlier studies have reported improvement in negative symptoms (Silver et al., 1995; Szegedi et al., 1995) and cognitive deficits (Lammers et al., 1999) in schizophrenia, a more recent study by Friedman et al. (2005) found that adding citalopram (Celexa) to atypical antipsychotics did not produce improvements in clinical symptoms or cognitive performance in these patients when compared with placebo treatment. Thus, further research on alternative serotonergic approaches for the treatment of cognitive deficits in schizophrenia is warranted.

Despite 50 years of pharmacological intervention, schizophrenia remains one of the top causes of disability across cultures (Murray and Lopez, 1997). Meta-analytic reviews clearly demonstrate a correlation between cognitive impairment and several domains of functional outcome (Green, 1996) and have led to the hypothesis that cognitive-enhancing treatments (Hyman and Fenton, 2003) in schizophrenia may result in improved functional outcomes. An important goal for future studies is the development of novel agents with specific activity on promising targets to enhance cognition in patients with schizophrenia.

Drs. Chemerinski and Siever have indicated they have nothing to disclose.

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Although several clinical studies suggest that cognitive impairments in schizophrenia are associated with reduced stimulation of dopamine receptors in the prefrontal cortex, mounting evidence suggests that other monoaminergic neurotransmitter systems may also be involved. We provide an overview of neurotransmitters that hold promise as therapeutic interventions for the cognitive deficit in schizophrenia.

Monoaminergic Treatment of Schizophrenia

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 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-HT

 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-HT

 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-HT

 receptors, which enhance prefrontal activity through innervation of inhibitory interneurons. Thus, while responsiveness to m-CPP is reduced, suggesting reduced 5-HT

 responsiveness, it is also possible to directly examine the number of 5-HT

 binding sites. Platelet and postmortem studies suggest that the number of 5-HT

 receptors, which are the predominant neuronal 5-HT

 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). 

 receptor binding in impulsive-aggressive personality-disordered patients in our laboratory suggested actual increases in 5-HT

 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-HT

 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-HT

 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-HT

 receptor, which modulates pre-synaptic release of serotonin, as well as the 5-HT

 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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Coccaro EF, Kavoussi RJ, Oakes M et al. (1996b), 5-HT

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?

Author | Larry J. Siever, MD

Articles

Pharmacology of Personality Disorders

Monoaminergic Treatment of Schizophrenia

Neurobiology of Impulsive-Aggressive Personality-Disordered Patients