neurotransmitter dysfunction in patients with borderline personality disorder

BORDERLINE PERSONALITY DISORDER 0193-953X/OO $15.00 + .OO

NEUROTRANSMITTER DYSFUNCTION IN PATIENTS

WITH BORDERLINE PERSONALITY DISORDER

Irene G. Gurvits, MD, Harold W. Koenigsberg, MD, and Larry J. Siever, MD

Borderline personality disorder (BPD) is a severe personality disorder characterized by potentially self-damaging impulsivity, inappropri- ate or uncontrolled anger, recurrent suicidal threats or gestures, physi- cally self-damaging acts, and disturbances in identity and interpersonal relations. It is associated with high levels of distress, significant impair- ment in social and occupational functioning, and a 10% lifetime risk for suicide. Approximately 2% of the population meets criteria for BPD. It is more often diagnosed in women and is more widespread among first- degree relatives of those with the disorder.

BPD and the other personality disorders have traditionally been understood in the context of psychodynamic, psychosocial, or behavioral approaches. Research over the past 2 decades has demonstrated the significance of biological factors and traumatic early life experiences that may have long-lasting biological sequelae. BPD is one of several disorders associated with a history of childhood physical or sexual trauma.23, 28, Also, several neurobiological correlates of BPD have been identified. Two potentially biologically mediated traits may contribute to BPD- affective instability and impulsive aggression. Although some studies have shown that BPD runs in twin studies suggest that BPD per se is not inherited, but its components, impulsive aggression and

From the Mount Sinai School of Medicine, New York (all authors); and the Bronx Veterans Affairs Medical Center, Bronx, New York (HWK, LJS)

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

VOLUME 23. NUMBER 1 * MARCH 2000 27

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affective instability, are partially heritable.77 Evidence from neurochemical assays, receptor-density studies, neuroendocrine-challenge para- digms, functional neuroimaging studies, and candidate-gene studies have converged to identify several neurotransmitter systems that may be associated with the neurobiology of BPD. This article examines the neurotransmitter systems associated with impulsive aggression and affective instability of BPD.

Impulsive aggression in patients with BPD is characterized by self- destructive acts, including suicidal and parasuicidal behavior, and out- wardly directed aggression. Affective instability is defined by DSM-IV as ”intense episodic dysphoria, irritability, or anxiety, usually lasting a few hours and only rarely more than a few days.”la Psychosocial cues, most typically frustrations, humiliations, losses, separations, and rejections, often trigger the affect swings in BPD. It may be useful to look separately at two components of affective instability, one encompassing the lability of affect, and the other, the reactivity to environmental cues. Affective instability may interfere with the ability to develop a stable perception of self or others and may result in difficulty in maintaining self-esteem. An interaction may exist between affective instability and poor impulse control, in which intense affective storms trigger impulsive behavior.

NEUROCHEMISTRY OF IMPULSIVE AGGRESSION

Serotonin

Dysfunction in the serotonin (5-HT) system has been associated with self-directed and non-self-directed impulsive aggression. Early evidence for this association emerged from studies of violent suicide at- tempters and of individuals who had committed violent acts. One of the first approaches to assess the activity of the serotonin 5-HT system was to measure the concentration of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the cerebrospinal fluid (CSF). In a study of violent offenders, Linnoila et a14‘j found that CSF 5-HIAA levels were significantly lower in violent offenders who committed impulsive crimes than in nonviolent offenders who committed premeditated crimes. Of- fenders who committed more than one violent crime had lower CSF 5- HIAA levels than offenders with only one violent crime. A decrease in CSF 5-HIAA level was also noted among people who had murdered their own children.45 In addition to violence against others, decreased concentrations of CSF 5-HIAA have been reported in suicidal patients regardless of their psychiatric diagnosis?, 69 Patients with histories of violent suicidal behavior had significantly lower CSF 5-HIAA concentrations than patients with more benign, non-self-destructive histories. Autopsy studies comparing the density of 5-HT2 receptors in the brains of 11 suicide victims and 11 matched controls showed a higher receptor density across all cortical layers in the prefrontal cortex (PFC) in suicide

NEUROTRANSMITTER DYSFUNCTION IN PATIENTS WITH BPD 29

victims, possibly reflecting reduced 5-HT release and increase of receptors?

Studies of the platelet 5-HT system may provide a window into brain 5-HT function because 5-HT2, and 5-HT transporter (SERT) sites in platelets and CNS seem to be identi~al.4~ Several studies have reported increases in platelet 5-HT binding associated with suicidality61a and self- reported aggres~ion.'~ In patients with personality disorder, the number of platelet SERT binding sites has been shown to vary inversely with self-m~tilation~~ and life history of aggre~si0n.l~

Pharmacologic studies with 5-HT-enhancing agents provide a means for more directly assessing the activity of neurotransmitter systems in vivo. Studies using fenfluramine, a 5-HT releasing agent and reuptake inhibitor, have been conducted to assess activity of the 5-HT system in patients with personality disorder. Prolactin is secreted in response to activation of 5-HT receptors by fenfluramine. The level of prolactin secretion following a fenfluramine challenge is a measure of the reactivity of the 5-HT system. Compared with patients with other personality disorders, patients with BPD show a blunted prolactin response to fenfluramine, suggesting reduced central 5-HT activity. When levels of impulsive aggression were measured across a group of personality-disordered patients, the degree of blunting of the prolactin response was directly correlated with the level of impulsive aggression.l', 14, 17* 60, 70

Studies of the 5-HT system have been carried out with more specific serotonergic agonists. These studies used direct 5-HT agonists (e.g., m- chlorophenylpiperazine [m-CPP]), 5-HT1, partial agonists (e.g., buspirone), and a more potent and selective 5-HT1, agonist, ipsapirone. In general, they support the theory of an inverse relationship between 5- HT activity and degree of aggression. For example, reduced prolactin responses were shown after administration of the postsynaptic 5-HT agonist m-CPP to a group of male patients with antisocial personality disorder and alcohol abuse compared with healthy control subjects. An inverse correlation between m-CPP and peak prolactin response to m- CPP (PRL[m-CPP]) was demonstrated across all An inverse correlation between PRL(m-CPP) and assaulti~eness~~ has been reported in male and female patients with personality disorders. Prolactin response to buspirone has been demonstrated to be inversely correlated to self-reported violence and irritability.12 A study of the 5-HT1, agonist ipsapirone using 31 human subjects with a range of aggressive behavior showed an inverse relationship between 5-HT function and aggression in individuals who showed a more aggressive response on the Point Subtraction Aggression Paradigm, a laboratory measure of aggre~sion.~~ These neuroendocrine responses are shown to be specifically associated with those criteria of BPD that reflect impulsive-aggressive traits, such as angry outbursts, impulsivity, and self-damaging acts, but they are not associated with interpersonal or affective related traits. The association between reduced 5-HT activity and aggression does not seem to be specific to BPD but rather to the impulsivity and aggression found in other personality disorders as well, such as antisocial personality disorder.

30 GURVITS et a1

Neuroimaging methods enable physicians to measure regional metabolic activity. The frontal cortex and temporal areas have extensive 5- HT enervation. Studies using positron-emission tomography scans have shown that individuals with aggressive behavior show decreased cere- bral glucose metabolism in the frontal orbital cortex63; surrounding cortical areas, such as middle frontal or inferior frontal cortex; and temporal 10bes.2~ Using neuroimaging technology, the responsiveness of the serotonergic system to agonists can be evaluated in regions of the cortex relevant to the initiation and control of behavior. This approach has the advantage over neuroendocrine response studies of assessing directly serotonergic modulation of the limbic system and cortex. In a study comparing healthy volunteers and moderately depressed patients with histories of personality disorders and suicidal behavior, fenfluramine was found to increase metabolic activity in the frontal and temporal lobes of healthy volunteers. Moderately depressed patients with personality disorders and histories of suicidal behavior were found to have decreased metabolic responsiveness to fenfluramine those regi0ns.4~ In a positron-emission tomography study of regional metabolic activity in response to a fenfluramine challenge in patients with a history of aggression or impulsivity versus healthy controls, controls showed increased metabolism in the orbital frontal and adjacent ventral medial frontal cortex, cingulate cortex, and inferior parietal cortex. Patients with impulsive aggression, on the other hand, showed a markedly blunted fenfluramine response in the orbital frontal, and adjacent ventral and cingulate cortex but not in the inferior parietal cortex.68a

Candidate gene strategies afford the possibility of identifying genetic variations that contribute to the formation of particular personality traits. Several polymorphisms in genes that code for proteins involved at various stages in 5-HT neurotransmission have been identified and include genes that code for tryptophan hydroxylase (TPH), the enzyme of the rate-limiting step in 5-HT synthesis, the SERT protein, and the 5- HT,, and 5-HT2, receptors. If particular 5-HT-related polymorphisms were found to be associated with impulsive aggression, this would add support to the role of the 5-HT system in contributing to this trait.*" 59

Several studies have examined polymorphism of the TPH gene, which has two alleles designated conventionally, Ls and The Ls allele is less prevalent than L, having a frequency of 0.40 in the white p~pu la t ion .~~ This polymorphism is not believed to influence 5-HT synthesis directly, so that any significant association between this polymorphism and behavior may be the result of linkage dysequilibrium between the polymorphism and variation in the coding or regulatory region of the TPH or possibly a neighboring gene.50 One study57 reported an association between the L allele of the TPH gene and violent suicide history, whereas another study58 found no association. A polymorphism involving two alleles, the G and C, which code for the same amino acid in the gene for the 5-HT1, receptor, has also been studied. The G allele has been associated with a history of suicide in a sample of white subjects with personality This finding is consistent with the observation of in-


creased aggression in mice lacking the 5-HT1, gene. A nonfunctional polymorphism involving two alleles of the 5-HT2, receptor, the 1 and 2 alleles, has also shown an association with impulsive aggression. The 1 allele was associated with self-mutilation in a sample of 137 personality- disordered patients and with suicide in a subgroup of 77 males in the sample.58 Although the candidate gene studies to date are suggestive of an association between 5-HT function and impulsive aggression, the genetic findings obtained thus far are not always consistent and are preliminary. Specific personality phenotypes are likely the product of multiple genes acting together (i.e., epistasis), or different combinations of genes may give rise to the same phenotype (i.e., heterogeneity). Newer and more sophisticated approaches are now being applied to the complex genetics of personality.1° Such methods may better establish connections between personality traits and specific neurotransmitter sys- t e m ~ . ~ ~

Arg i n i ne Vasopressin

Another neurotransmitter, vasopressin, has been associated with aggressive behavior. Animal studies have long suggested a positive relationship between CNS vasopressin level and aggression.21 Central arginine vasopressin (AVP) may directly correlate with levels of general aggression and aggression against other people in patients with personality disorders.16 This study found that CSF arginine vasopressin level was correlated directly with life history of general aggression and aggression against persons and inversely correlated with the prolactin response to fenfluramine. Also, central AVP may play a role in enhancing, whereas 5-HT plays a role in inhibiting, aggressive behavior in personality-disordered patients. Central AVP may influence human aggressive behavior by a mechanism independent of central 5-HT or by interacting with it.

NEUROCHEMISTRY OF AFFECTIVE INSTABILITY

Although the neurochemistry of affective instability is less understood than that of impulsive aggression, preclinical and clinical research suggests that dysregulations in cholinergic, noradrenergic (NE) or gamma-aminobutyric acid (GABA)-minergic systems may play an important role in affective instability. Also, the instability may result from unstable feedback regulatory systems at the level of neural networks, synaptic neurotransmission, or intracellular signal transduction.

Acetylcholine

Several lines of evidence point to the importance of cholinergic systems in affect regulation. Limbic structures that are implicated in

32 GURVITS et a1

emotion regulation, such as the amygdala, hippocampus, and cingulate cortex, have rich cholinergic enervation. High levels of choline acetyl- transferase are found in the primate amygdala and paralimbic areas. The nucleus basalis has dense reciprocal cholinergic connections to limbic and paralimbic structures and cortical efferents that could allow it to facilitate the affective modulation of complex behaviors.39 A diverse body of evidence associates acetylcholine with the major mood disorders. Cholinergic systems regulate rapid eye movement (REM) sleep, and REM sleep disturbances in turn are characteristic of major depression. Cholinomimetics produce changes in the hypothalamic-pituitary- adrenal axis that are similar to those seen in depression. These changes in hypothalamic-pituitary-adrenal axis are greater in patients with affective disorders than in normal Depressive symptoms can be produced by the administration of the centrally acting cholinomimetics.32 The administration of arecholine to depressed patients leads to an increase in depression, hostility, and anxiety.66 The infusion of physostigmine results in an increase in depressive symptoms in manic and hypomanic bipolar ~atients.3~ The behavioral and cardiovascular response to physostigmine in healthy male subjects correlated with high emotional lability, high irritability, feelings of stress, and low life contentment.22 Physostigmine infusions in healthy men resulted in anergia, exhaustion, decreased spontaneous activity, and diminished verbal fluency, without changes in cognition, attention, or mood.76 Additional studies demonstrated that physostigmine-induced and arecholine-induced depressed mood in depressed patients and in some remitted affective disorder patients and reduced manic symptoms.34 Procaine, a cholinergic agonist, selectively activates limbic 39 Infusions of procaine in healthy volunteers produced intense euphoria in one third of the subjects and intense fear in one Positron-emission tomography imaging of these subjects showed activation of the left amygdala that correlated with the affective response to procaine. These studies suggest that cholinergic dysregulation may play a role in the Axis I affective disorders.

More recently, studies of BPD patients have associated cholinergic mechanisms with affective instability. Patients with BPD show decreased and more variable REM latency1, 6, 52a and enhanced reduction in REM latency in response to cholinomimetics.6 In a study in which procaine was administered intravenously to 17 patients with BPD, 7 patients with affective disorder, and 7 healthy controls, a great variability in affective responses was noted.38 Mood elevation and hypomanic features were seen in some bipolar subjects. A high degree of dysphoria was induced in the patients with BPD. The cholinomimetic physostigmine was administered intravenously to 34 personality-disordered patients, including 10 subjects with BPD and 11 healthy controls.” The subjects with BPD responded to physostigmine but not to placebo, with an affective shift toward depression that was significantly greater than in controls. The depressive response to physostigmine was also more rapid among patients with BPD than controls (90% of controls took 75 minutes for the peak depressive response, whereas 50% of patients with BPD had their


maximal response within 20 min). The magnitude of the depressive response to physostigmine correlated significantly with the number of affective instability traits (i.e., affective instability per se, unstable rela- tionships, identity disturbance, and chronic feelings of emptiness and boredom) in the patient sample but not with impulsive-aggressive traits. The finding that physostigmine can rapidly perturb affect in patients with affective instability provides additional support to a role for cholinergic dysregulation in affective instability.

Norepinepherine

The NE neurotransmitter system modulates normal arousal and engagement with the environment. Novel or threatening stimuli increase the activity in the locus ceruleus, and this increase in primary NE activity is associated with irritable aggression in primate models.41, 44 Thus, increased NE activity may be associated with the heightened engagement with, and reactivity to, the environment seen in patients with BPD. A heightened reactivity to environmental stimuli could contribute to affective instability.

In a study of 11 healthy subjects administered oral doses of dextroamphetamine, dysphoric responses to amphetamine correlated with affective lability. To the extent that dextroamphetamine is a releaser or reuptake inhibitor of NE, this finding associates NE with affective instability. Alternative interpretations, however, are possible because dextroamphetamine is also a releaser or reuptake inhibitor of dopamine (DA) and, to a lesser degree, 5-HT. Personality-disordered patients with high levels of risk taking, irritability, and verbal aggression, all of which are influenced by the engagement with the environment, seem to have hyper-responsive NE The sensitivity of the NE system in particular can be assessed in vivo by measuring growth hormone response to clonidine. Clonidine, an a,-agonist, stimulates release of growth hormone (GH) by the hypothalamic-pituitary axis. By measuring the peak level of GH following a clonidine challenge, one can assay the responsiveness of post-synaptic az activity. An increased GH response to clonidine has been measured in subjects who are highly reactive to their environment, a feature that could contribute to affective instability.42a GH release in response to clonidine directly correlates with irritability in healthy controls and patients with BPD but not in depressed patients.I3 Another study16 reports a negative correlation between plasma 3-methoxy-4-hydroxyphenylglycol, an NE metabolite, and life history of aggression in personality-disordered patients. These apparently discrep- ant studies could be reconciled by postulating that irritability is associated with postsynaptic rather than presynaptic NE dysregulation. Thus, factors that could contribute to affective instability, such as heightened reactivity to the environment and irritability, have been associated with NE dysregulation.

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In addition, because NE activity is associated with alertness, attention to external stimuli, and extraversion, it may be connected with outward directed aggression. Decreased NE activity is associated with withdrawal from the environment, and increased NE activity is associated with heightened engagement and response to the environment. 5- HT hypofunction may be associated with self-directed or other-directed impulsive aggression. The interaction between 5-HT and NE systems may determine the nature of aggression in BPD. Low 5-HT activity together with high NE activity may predispose to impulsive aggression directed toward the outside world, whereas low 5-HT activity and low NE activity may lead to self-directed

Gamma-Aminobutyric Acid

Gamma-aminobutyric acid is a widely distributed neurotransmitter with inhibitory functions. It could serve as a "brake," damping rapid excursions of emotion. Decreased activity of the GABAminergic system could thus potentially result in affective instability. The amygdala, which is activated during the induction of strong affecP9 has particularly high levels of GABA, receptors. Moreover, lithium, valproate, and carbamazepine, which are all mood stabilizers that have been reported to stabi- lize mood in affectively labile personality-disordered patients and in bipolar patients, all seem to increase GABAminergic transmission.68 The GABAminergic system also interacts closely with the NE system, raising the possibility that an imbalance in the ratio of NE to GABAminergic activity may contribute to affective instability.

Disequilibrated Homeostatic Systems and Affective Instability

Although a simple increase or decrease of any of these neurotransmitter systems could account for affective instability, the dysregulation could be more complex, involving dynamic disequilibria in homeostatic systems. Neuroimaging studieszoa, 42, 357 52 have identified several closely interconnected structures that seem to have a role in affect regulation, including the subgenual cingulate, anterior insula, amygdala, hippocampus, thalamus, dorsal prefrontal cortex, dorsal anterior cingulate, and inferior parietal cortex. The dorsal structures, including the dorsal prefrontal cortex, dorsal anterior cingulate, posterior cingulate, and inferior parietal lobe, which subsume cognitive and attentional functions, may regulate ventral components of the emotion network, such as the subgenual cingulate, anterior insula, and hippocamp~s.~~ These structures are interconnected by multiple feedback loops and relative imbalances in the strengths of these interconnections could lead to undamped or negatively damped oscillatory states. Such strong excursions in the emotion regulating system could give rise to affective instability.


Homeostatic systems operate at the level of synaptic transmission. Here, presynaptic autoreceptors regulate the release of neurotransmitters as part of negative-feedback loops. Dysregulations at this level, in which the feedback signal is particularly weak, could lead to decreased responsivity to input signals and low signal to noise properties. This may be mechanism in some mood disorders. Conversely, increased responsivity to input signals leading to high signal to noise ratio could lead to intense affective excursions. This model has been hypothesized as a mechanism in posttraumatic stress disorder.s0 Similar synaptic feedback dysregulations may account for affectively unstable states.

Disturbances at the level of intracellar signal transmission could also lead to affective instability. Because bipolar disorder can manifest with affective instability, especially in its mixed states, and in its ul- trarapid cycling variants36 it may provide clues to the mechanism of affective instability. These intracellular signaling systems have been associated with bipolar disorder. Neurotransmitter activation of cell-surface receptors is transduced to intracellular chemical changes by various G- protein types that bind to the receptors and then activate intracellular second messengers, such as adenylate cyclase, phosphatidylinositol, protein kinase C, myristoylated alanine-rich C kinase substrate (MARCKS), and intracellular calcium. Abnormalities in levels of G-proteins have been identified in bipolar disorder. Also, mood stabilizers, such as lithium, valproate, and carbamezepine, affect G-protein, protein kinase C, MARCKS, and calcium activity.24 Avissar and Schreiber4 have proposed a dynamic model to account for the mood oscillations in patients with bipolar disorder based on the interaction of systems involved in the synthesis of protein kinase A and protein kinase C, which are in a dynamic equilibrium. At certain concentrations of the G-proteins and for certain kinetic constants for the various reactions, this system may oscillate between states as a negatively damped oscillator, subjecting the system to unstable and extreme excursions in state. Although developed to explain bipolar oscillations, with suitable parameters, such a model could account for affective instability in patients with the personality disorders.

DISCUSSION

Impulsive aggression and affective instability are two traits present in patients with BPD for which evidence associates disturbances with neurotransmitter function. Although each of these traits may contribute individually to certain personality disorders (e. g., impulsive aggression to antisocial personality disorder, or affective instability to histrionic personality disorder), their co-occurrence may particularly predispose to BPD. Certain life experiences, such as ongoing abuse or neglect during childhood, may need to be present in addition for these biological vulnerabilities to give rise to the full BPD syndrome.

Impulsive aggression and affective instability seem to account for

36 GURVITS et a1

many of the symptoms of BPD included in the DSM-IV diagnostic criteria. The impulsive-aggressive trait could give rise to the criteria symptoms of impulsivity in areas that are self-damaging and of suicidal or self-mutilating behavior. Affective instability seems to contribute not only to the criteria of affective instability per se but also to identity disturbance, chronic feelings of emptiness, and possibly unstable rela- tionships and fears of abandonment (Koenigsberg et al, under review).

The role of hyporesponsiveness of the 5-HT system in patients with impulsive aggression is supported by a convergent body of evidence, including well-replicated 5-HT-agonist response studies, receptor-assay research, plasma and CNS neurochemical assays, and neuroimaging findings. The candidate gene studies, although more tentative, provide additional support. The neurotransmitter AVP has been associated with aggressive behavior in subjects with personality disorders. NE may be associated with aggression, especially outward-directed aggression. Evidence shows that NE is associated with high responsivity to environmental cues and irritability, personality features that seem to be associated with affective instability. The cholinergic system, which has been associated with Axis I affective disorders, may also be involved in affective instability. Dysfunctions in the inhibitory GABAminergic system may also play a role in affective instability. Studies of bipolar disorder suggest that imbalances in components of second messenger systems may contribute to affective dysregulation. Such imbalances could play a role in affective instability in the personality disorders. Research into intracellular signaling mechanisms should be extended to the personality disorders to address this important question.

Dysregulations in single neurotransmitter systems may not be suf- ficient to account for the full expression of affective and impulsive symptoms in patients with BPD. Thus, the combination of low 5-HT activity and excessively high or low NE activity may be required for impulsive aggression. An imbalance between cholinergic and GABAmi- nergic or NE systems may be involved in affective instability. In addition to such imbalances in neurotransmitter activity, dysregulations in homeostatic systems may account for unstable oscillations that may gener- ate affective instability. This may occur at the level of neural networks, synaptic self-regulation, or intracellular signal transduction mechanisms.

Identification of specific neurotransmitter systems or second messenger disturbances that underlie the core symptoms of BPD can play an important role in the development of pharmacologic approaches to treatment. Additional studies are needed to formulate clear operational definitions of the key personality traits, such as impulsivity, aggression, and affective instability that are present in patients with BPD. The developing field of complex genetics has provided new methodologic approaches to psychiatric geneticdo that lend themselves to the personality disorders. Application of these approaches and functional neuroimaging methods to the personality disorders will help to not only identify the relevant neurotransmitter systems but also better understand how individual systems and functional brain regions may interact to predispose to the personality disorders.


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