Interpersonal Dimension of BPD - Neuropeptide Model (Oxy,Vp,Opd,NK1).pdf

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Reviews and Overviews

24 ajp.psychiatryonline.org Am J Psychiatry 167:1, January 2010

(Am J Psychiatry 2010; 167:2439)

as well as a sense o well-being suggests that these systems

may be implicated in borderline personality disorder and

are thereore potentially promising targets or treatment.

Indeed, Insel (3) speculates about whether social attach-

ment is an addictive disorder in discussing Paul MacLeans

notion that substance abuse represents an eort to replace

opioids ordinarily provided by social attachments. Given

that social attachments are quite problematic in border-

line personality disorder, the neuropeptides may be in-

volved. In this article, we present relevant preclinical and

clinical data in support o a possible role o neuropeptides

in this disorder.

We propose models emphasizing the dysregulation

o neuropeptidesin particular, the opioidsin distur-

bance o homeostatic maintenance o well-being and in-

terpersonal connection. To date, our understanding o the

neurobiology o borderline personality disorder is limited

and the ecacy o pharmacological interventions or the

disorder is disappointing. We hope to stimulate research

into the neurobiology o interpersonal sensitivity in the

context o borderline personality disorder and to open

new avenues o investigation that may provide promise

or more eective treatments o this serious disorder.

Phenomenology of BorderlinePersonality Disorder

Biological and environmental contributions to the de-

velopment o borderline personality disorder are com-

plex, with no single uniying etiological theory (4, 5). Rath-

er, a number o theoretical models have been proposed,

each emphasizing a dimension o the disorder (4, 6, 79).

Three main symptom clusters or dimensions have been

Borderline personality disorder is a complex disor-der associated with substantial morbidity, mortality, and

public health costs. Prominent symptoms include suicidal

behavior, nonsuicidal sel-injury, aggressive outbursts,

and emotional reactivity, all o which typically maniest

in an interpersonal context (1). For several years, there

has been an ongoing discussion about whether impulsive

aggression or aective dysregulation is at the core o the

disorder. While these actors are important in borderline

personality disorder, it is the exquisite interpersonal sen-

sitivity that requently triggers both dysregulated aect

and impulsive behaviors, which suggests that this sensi-

tivity perhaps rests at the core o the disorder and may in

turn drive impulsivity and dysregulated aect. Consistent

with this conceptualization, Gunderson (2) suggests that

disturbances in the interpersonal realm may serve as a po-

tential endophenotype or identiying genetic vulnerabili-

ties in borderline personality disorder, but little research

has been done on the neurobiological substrates o the

interpersonal sensitivity o the disorder.

It is noteworthy that many symptoms in the interper-

sonal domain o borderline personality disorder are actu-

ally maniestations o intrapersonal diculties (e.g., di-

culty being alone and misperception o the intentions o

others as malevolent), and this dimension could perhaps

be reconceptualized as intrapersonal dysunction. We

suggest that an internal eeling o well-being, stability, and

sel-regulation in borderline personality disorder is tenu-

ous and may rely heavily on a sense o interpersonal con-

tact and connectedness. This vulnerability may be related

to an underlying dysregulation o neuropeptides. The criti-

cal role o neuropeptides, including the opioids, oxytocin,

and vasopressin, in the regulation o aliative behaviors

Barbara Stanley, Ph.D.

Larry J. Siever, M.D.

Borderline personality disorder is charac-

terized by aective instability, impulsivity,

identity diusion, and interpersonal dys-

unction. Perceived rejection and loss o-

ten serve as triggers to impulsive, suicidal,

and sel-injurious behavior, aective re-

activity, and angry outbursts, suggesting

that the attachment and aliative system

may be implicated in the disorder. Neu-

ropeptides, including the opioids, oxyto-

cin, and vasopressin, serve a crucial role

in the regulation o aliative behaviors

and thus may be altered in borderline

personality disorder. While clinical data

are limited, the authors propose alterna-

tive neuropeptide models o borderline

personality disorder and review relevant

preclinical research supporting the role

o altered neuropeptide unction in this

disorder in the hope o stimulating more

basic research and the development o

new treatment approaches.

The Interpersonal Dimension of Borderline Personality

Disorder: Toward a Neuropeptide Model

This article is the subject o a CME course (p. 113).


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STANLEY AND SIEVER

Am J Psychiatry 167:1, January 2010 ajp.psychiatryonline.org 25

with Gundersons proposed endophenotype o disturbed

relatedness (2, 30). Although common conceptions o the

interpersonal diculties o borderline personality disor-

der ocus on external relationships and DSM-IV denes

the interpersonal diculties o the disorder as a pattern

o unstable and intense interpersonal relationships char-

acterized by alternating between extremes o idealiza-

tion and devaluation, the symptoms that cluster on thisdimension in actor analyses are unstable relationships,

identity disturbance, chronic eelings o emptiness, and

stress-related paranoid ideation (typically, rejection-re-

lated paranoid eelings) (31). All but the rst actor relate

to internal states and sel-regulation and have an impact

on relatedness. Identity diusion can also lead to extreme

vulnerability to real or perceived loss o important rela-

tionships (21) and overreliance on others to experience a

coherent sense o sel. This perspective is consistent with

an object relations theory o borderline personality disor-

der (26) as well as Bender and Skodols conceptualization

proposing that lack o sel-integration is at the core o thedisorder (27).

As previously noted, the interpersonal diculties o

borderline personality disorder appear to be responsible

or much o the distress these individuals experience in

daily lie. Loneliness, perceived rejection, and disruptions

in relationships are precipitants to suicide attempts (1,

32), nonsuicidal sel-injury, and substance use (33), while

the anxious-preoccupied insecure attachment style in

borderline personality disorder is associated with longer

psychiatric hospitalizations (34).

Healthy individuals develop a stable sense o well-being

and sel-esteem in the context o nurturing and soothinginterpersonal relationships over the course o develop-

ment. This stable sense o well-being and sel-esteem de-

pends on both the interpersonal environment and the in-

nate capacity to internalize these soothing relationships.

Because o their exquisite sensitivity to separation and

interpersonal vicissitudes, individuals with borderline

personality disorder seem to experience their sel-esteem

as dependent on the availability o important others.

When these important gures are unavailable or reject-

ing, these individuals can experience a plummeting loss

o well-being with accompanying eelings o abandon-

ment. The behaviors that resultsuicidal expressions,

emotional outbursts, and clinginessappear manipula-

tive and excessive, but to the person with borderline per-

sonality disorder they may be survival tactics to maintain

sel-esteem, given that their sense and integrity o sel rely

to a large extent on others. It is easier to understand the

excessive clinginess, demandingness, and panic at the

thought o abandonment in the individual with border-

line personality disorder i one considers that preserving

interpersonal connectedness serves not only to preserve

a key relationship but also, perhaps more importantly, to

provide a sense o cohesiveness o sel. Indeed, this may

be a key to understanding the ear o abandonment, pan-

identied (7): 1) behavioral dysregulation, characterized

by impulsive aggression (4, 8, 1016), nonsuicidal sel-

injury and suicidal behavior (6), substance abuse, reck-

lessness, impulsive spending, and inappropriate displays

o anger; 2) aect dysregulation (1719), characterized by

emotional lability, intense negative emotional reactions

(e.g., shame), diculty recovering rom disturbing triggers

(even seemingly modest ones), and pervasive dysphoria(4, 6, 9, 17, 18); and 3) disturbances in interpersonal relat-

edness, characterized by turbulent relationships and ear

o perceived or real abandonment. Neither behavioral nor

aect dysregulation is unique to borderline personality

disorder. Behavioral problems are prominent in antisocial

personality disorder (15, 16) and intermittent explosive

disorder. Aective reactivity (19) and dysphoria occur in

axis I mood disorders, particularly bipolar disorder. How-

ever, unlike bipolar disorder, the aective experience o

chronic emptiness (9) seems to be unique to borderline

personality disorder.

The third dimension o borderline symptomatology,disturbance in interpersonal relatedness, serves to dier-

entiate this disorder rom axis I and other axis II disorders.

Gunderson et al. (20) ound that two interpersonal criteria,

avoidance o abandonment and unstable relationships,

dierentiated borderline rom other personality disorders.

As noted above, symptoms in this domain maniest both

intra- and interpersonally, and this too is unique to bor-

derline personality disorder (21).

Neurobiological studies have begun to examine this in-

teraction (2125). In the intrapersonal domain, cognitive

distortions include misperceiving others intentions, clas-

siying people in extremes as good and bad (26, 27),misperceiving abandonment threats, attributing malevo-

lent intentions to others where none exist, and inability to

understand the mental state o others (i.e., mentalization)

(28). Interpersonal maniestations typically include exces-

sive dependency and turbulent relationships. However,

these symptoms too can be viewed as maniestations o

diculties in the intrapersonal domain: others may be

needed or sel-denition and soothing, and thus needi-

ness and hypervigilance to real or perceived abandon-

ment can be readily understood.

Interpersonal Dysfunction as a CoreComponent of Borderline PersonalityDisorder

Maniestations o behavioral and aect dysregulation

in borderline personality disorder can be viewed in the

context o a disrupted sense o sel in relation to others.

According to Fonagy and Bateman (29), the inability to

make sense o sel and others is at the core o the disor-

der and is a result o disrupted attachment in early de-

velopment, which may depend in part on the developing

childs capacities and vulnerabilities as well as environ-

mental infuences. This conceptualization is consistent


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TOWARD A NEUROPEPTIDE MODEL OF BORDERLINE PERSONALITY DISORDER


ute to much o the relational turmoil o borderline person-

ality disorder, they do not easily account or the eelings

o inner deadness or panicky aloneness these individuals

eel when they are separated rom the important gures in

their lie, the repeated sel-injurious behaviors when their

relationships are disrupted, and their reliance on others to

maintain a stable sense o sel-esteem.

In the third paradigm, there are specic neurobiologicalsystems (35), including neuropeptides such as the opioids

and oxytocin, that are implicated in aliative and interper-

sonal behaviors. Dysregulation o these peptides may spe-

cically contribute to the disturbed aliative behaviors by

intensiying the stress o separation, rendering the mainte-

nance o sel-esteem and a eeling o well-being more prob-

lematic, and diminishing the capacity to trust and respond

appropriately to others, thus driving sel-destructive behav-

iors that may provide relie rom pain. In conjunction with

neurological substrates already implicated in the impulsive

aggression and aective dysregulation o borderline per-

sonality disorder, these dysregulations may more directlyaect the capacity to maintain interpersonal relationships.

Considering these alternative paradigms, we propose

a model o borderline personality disorder that incorpo-

rates vulnerability or dysregulation o the opioid system.

We posit low basal opioid levels in this disorder, with a

compensatory supersensitivity om-opioid receptors such

that transient increases in opioids ollowing painul stim-

uli lead to heightened responses (21, 36). Low basal opioid

levels are refected clinically in a sense o inner dead-

ness, chronic dysphoria, and lack o a sense o well-be-

ing, all characteristics o borderline personality disorder,

while stimulation o the opioid system (e.g., nonsuicidalsel-injurious behavior) can result in heightened relie o

pain and restoration o a sense o well-being. This model

is consistent with observations o reduced b-endorphin

and met-enkephalin levels in CSF under basal conditions

in individuals with cluster B personality disorders and a

history o sel-injury (36, 37); increased pain threshold ol-

lowing painul stressors in borderline personality disorder

(38, 39); some therapeutic eect o naltrexone, an opioid

antagonist, or sel-injurious behavior (37); and the clini-

cal observation that individuals with borderline personal-

ity disorder tend to overuse opiate pain medications and

report a sense o well-being when taking these medica-

tions. While opiates alleviate subjective distress associated

with reduced endogenous basal opioid levels, naltrexone

dampens the reward o sel-injurious behavior by block-

ing opioid receptors. However, this approach does not ad-

dress the putative baseline decits in opioids.

In this model, dysregulation o oxytocin may distort the

reading o social cues, appropriate establishment o trust,

and capacity or attachment, and vasopressin may in part

regulate aggression in the context o intimate relation-

ships. Other neuropeptides outside the purview o this

article, such as neuropeptide Y and neurokinin 1, mediate

emotional responses to stress mediated by the amygdala,

icky avoidance o being alone, problems with trust in inti-

mate relationships, biases in social judgment, and conse-

quent turbulent relationships and sel-injurious behavior

in borderline personality disorder.

The opioids have been implicated in eelings o soothing

or pleasure as well as in the distress o social separation and

exclusion, and oxytocin has been implicated in the estab-

lishment o trust and aliative behaviors. Thus, dysregu-lation o neuropeptides such as opioids and oxytocin may

contribute to decits in the maintenance o well-being,

heightened separation distress, and mistrust in borderline

personality disorder. Although we ocus here on the inter-

personal dimension o borderline personality disorder, dys-

regulation o neuropeptides may also underlie many o the

behavioral and aective symptoms o the disorder.

Models of Interpersonal Dysfunctionin Borderline Personality Disorder

The interpersonal dysunction typically seen in this pa-tient group can be conceptualized within one o several

paradigms: 1) as distinct rom neurobiology and concep-

tualized purely in psychological or developmental terms;

2) as an emergent phenomenon stemming rom the in-

terpersonal consequences o impulsive aggression and/

or aective instability; and 3) as a problem arising rom

neurobiological vulnerabilities that lead to interpersonal

sensitivity, partially distinguishable rom those implicated

in impulsive aggression and aective instability and mani-

est most robustly in the interpersonal domain.

In the rst model, neurobiological actors are concep-

tualized as relatively nonspecic and less important, withinterpersonal disturbances developing in the context o

dysunctional attachment interactions. Specic stressors

include neglect, abuse, and other trauma as well as repeat-

ed experiences o eeling invalidated. In such a model, neu-

robiological actors may be considered in terms o a black

boxthat is, nonspecic mechanisms. We will argue that

the neurobiological underpinnings related to the interper-

sonal dysunction may be explicable in established neuro-

biological systems related to aliation and aect regula-

tion that shape the trajectory o interpersonal development

in the context o the specic interpersonal environment.

In the second, interpersonal dysunction emerges as a

consequence o the more undamental disturbances o

aect regulation and impulse dyscontrol (4, 2225). Thus,

individuals with borderline personality disorder are less

able to modulate their emotions in the context o inter-

personal relationships, so their well-being is experienced

as dependent on the availability o important others. They

are more likely to become disappointed, eel abandoned,

or become enraged in their key relationships. Because

they have a low threshold or impulsive behaviors, these

emotions are translated into action, including outwardly

aggressive or sel-destructive behaviors that disrupt these

relationships. While these dynamics may indeed contrib-


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STANLEY AND SIEVER


Opioids, Emotions, and Social Behavior

One hypothesis that provides an explanatory model or

the relationship between opioids and emotions posits the

mediation o social exclusion, separation, and abandon-

ment, particularly in the context o reactions to perceivedrejection, by the same opioid system that modulates phys-

ical pain (51). The experience o pain can be divided into

painul sensation and painul aect (51, 52). Painul aect

appears to be encoded primarily in the anterior cingulate

cortex but not in the somatosensory cortex (53). Thus, so-

cial exclusion is posited as triggering painul aective eel-

ings without accompanying physical pain.

Brain opioids appear to mediate social aect, particular-

ly social exclusion and separation in the context o social

attachments (54). Puppies, young guinea pigs, and chicks

emit distress vocalizations in the context o social separa-

tion and isolation. These vocalizations can be reduced ateradministration o opioids, such as oxymorphone. Nalox-

one, a m-opioid receptor antagonist, blocks the suppres-

sion o distress vocalizations produced by oxymorphone

and increases vocalizations several hours later, suggesting

a withdrawal eect. Also, administration o low doses o

morphine reduces the tendency o animals to spend time

close to other members o their species and increases play,

especially in socially isolated animals. It is hypothesized

that early in the developing brain, opioid systems medi-

ate eelings o soothing and pleasure during early nurtur-

ance and later reinorce relie o emotional distress in the

context o reunion ater separation in meaningul attach-

ments. Low doses o morphine increase play, whereas opi-

oid blockade with naloxone reduces play, which suggests

that opioid reduction is associated with reduced pleasure

and interaction in vigorous social relationships (55). In-

terestingly, naloxone has also been ound to acilitate in-

creased sexual behavior in some species (56).

With respect to emotional expression, the activation o

m-opioid receptor-mediated neurotransmission has been

shown to suppress ear and stress responses to noxious

or threatening stimuli and mother-inant separation (57,

58). The m-opioid receptors also contribute to regulation

o emotional memory (59). These animal studies invite

driving aective sensitivity (Figure 1). In this overview, we

review relevant preclinical data on neuropeptides such

as oxytocin, vasopressin, and opioids, preclinical models

o separation distress and social bonding, human studies

o these neuropeptides and their associated physiology,

clinical studies o sel-injurious behavior in borderline

personality disorder, and naltrexone trial data. We then

elaborate our specic model and conclude by oeringsuggestions or new research to address the hypotheses

and treatment strategies discussed.

The Opioids and Borderline PersonalityDisorder

Neuropharmacology and Neurophysiology o the

Opioid System

The opioid system modulates responses to acute

and chronic stressul and noxious stimuli that induce

physical, emotional, or social pain. Endogenous opi-oids include the endorphins, enkephalin, dynorphin,

and nociceptin/orphanin FQ agonists. These act on G-

protein-coupled receptor subtypes, including m-opioid

receptors, which respond preerentially to morphine;

kappa opioid receptors, which respond preerentially

to ketocyclazocine; delta receptors; and ORL-1 opioid-

like receptor binding sites (40). b-Endorphin and met-

enkephalin are agonists at m-opioid receptors and are

related to stress-induced analgesia and thermal pain

perception (4143). Met-enkephalin is also involved in

saliency, reward, and motivational behavior (44, 45). m-

Opioid receptors are widely distributed throughout the

human CNS, with a particularly dense distribution in

the basal ganglia, cortical structures, thalamic nuclei,

spinal cord, and specic nuclei in the brainstem (46);

high levels o binding o this receptor are ound in the

basolateral amygdala, nucleus accumbens, hypothala-

mus, thalamus, ventral tegmental area, and caudate

putamen. A variety o stressors activate b-endorphins in

rodents (47), and repeated restraint stress reduces opi-

oid receptor density (48). Furthermore, opioid activity

activates hypothalamic-pituitary-adrenal (HPA) axis ac-

tivity, up-regulating corticotropin-releasing actor and

pro-opiomelanocortin mRNA (49, 50). m-Opioid recep-

tors in periaqueductal gray matter mediate the antino-

ciceptive eects o opioids. Thus, the m-opioid receptor

system appears to be particularly relevant or the social

and aective regulation associated with borderline per-

sonality disorder. The central mediating role o opioids

in separation distress, relie and pleasure on reunion,

sel-soothing, and the pain o social exclusion and re-

jection suggests that this system is a likely candidate

or contributing to the interpersonal vulnerabilities and

intrapersonal pain o borderline personality disorder. In

the ollowing sections, we review emerging evidence re-

garding this system in borderline personality disorder.

FIGURE 1. Neuropeptide Modulation of Cortical and LimbicFunction

Interpersonal / Affiliation Systems

Opioids

Oxytocin

Vasopressin

Brain

Circuitry

Neuromodulators

(Neuropeptides)

Neuropeptide Y

Neurokinin 1Amygdala/Insula

Responsiveness

Limbic

Orbitofrontal/Cingulate

Cortex Processing

Cortical


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that naloxone or naltrexone is useul in diminishing

nonsuicidal sel-injury (76, 77). In a related study ocusing

on dissociation, another prominent borderline symptom,

Bohus et al. (78) ound naltrexone to be eective in

diminishing dissociation and tonic mobility in borderline

personality disorder.

One study suggested that paroxetine, a selective sero-

tonin reuptake inhibitor, induced an antinociceptive e-ect (79). This antinociception was signicantly inhibited

by naloxone, suggesting the involvement o opioidergic

mechanisms. Specically, a decrease in negative aect, an

increase in positive aect, and an increase in dissociative

symptoms were reported. Interestingly, it has been noted

in clinical observation that nonsuicidal sel-injury in bor-

derline personality disorder is oten ollowed by mood en-

hancement. Simeon et al. (80) suggested that sel-injury

could act as sel-healing through restoration o positive

aect, however brie. This demonstrates the interaction

between the serotonergic and opioid systems in the brain.

It would be o interest to evaluate the association o sel-injury with opioid release using negative aect provoca-

tion positron emission tomography imaging paradigms.

In summary, multiple lines o evidence suggest that en-

dogenous opioids are involved in the pathogenesis o

nonsuicidal sel-injury.

m-Opioid Imaging Studies in Borderline Personality

Disorder

Although ew studies have been conducted using m-

opioid imaging in borderline personality disorder, the ex-

isting investigations point to dysunction in the disorder.

In a study comparing women with borderline personalitydisorder and healthy comparison women (81), sustained

neutral and sadness states were induced by recall o a

previously experienced event, and displacement o the

m-opioid receptor selective radiotracer [11C]carentanil

was measured during these states. Women with border-

line personality disorder demonstrated greater m-opioid

binding in the orbital rontal cortex, the caudate nucleus,

and the nucleus accumbens as well as the let amygdala.

During the sadness induction, these women maniested

increased opioid release in the right pregenual anterior

cingulate, the let orbitorontal cortex, the let ventral

pallidum, the let amygdala, and the let inerior tempo-ral cortex but greater deactivation in the let accumbens,

the hypothalamus, and the right hippocampus. These re-

sults suggest increased baseline m-opioid receptor bind-

ing and increased sadness-induced opioid release in the

orbitorontal cortex, the caudate, and the accumbens.

Paralleling our proposed model o exaggerated response

to painul stimuli, increased responsiveness to sadness is

consistent with the emotional dysregulation o borderline

personality disorder and exaggerated responses to nega-

tive experiences or emotions. This is an innovative and

important study, but the results must be considered pre-

liminary given the small sample size. Naturalistic interac-

comparable human studies to identiy more specically

the interpersonal stressors in which opioids play a medi-

ating role.

Human studies have shown that regional activation

o m-opioid neurotransmission is centrally implicated

in the suppression o the aective qualities o a pain

stressor and in the negative internal aective states

induced by that challenge (60, 61). One study demon-strated dynamic changes in m-opioid neurotransmission

in response to an experimentally induced negative a-

ective state (62). The direction and localization o these

responses conrm the role om-opioid receptors in the

regulation o aective experiences in humans. Since the

experience o borderline personality disorder is char-

acterized by recurrent stress-induced negative aects,

reduced opioid levels may play an important part in

enhancing these characteristic negative emotions. It is

worth noting that endogenous opioids may mediate the

mood-enhancing eect o exercise (60, 61). More speci-

ic mapping o the negative aective states modulated bythe opioids is indicated in human studies, ideally in an

interactional setting.

Opioid Dysunction and Borderline Personality

Disorder

Borderline personality disorder and physical pain.

Aective dysregulation and sel-injurious behaviorkey

characteristics o borderline personality disorderappear

to be associated with lower pain perception. Experimental

studies have shown lower pain sensitivity in this patient

group (63, 64), as well as signicant positive correlations

between pain tolerance thresholds, aversive inner tension,and dissociation (65). Psychophysiological research has

shown no decits in the sensory-discriminative aspects

o pain processing in borderline personality disorder

(38). However, unctional imaging research suggests

that alterations in activation patterns o brain regions

associated with the aective-motivational aspects o

pain processing are associated with the pain perception

alterations seen in these patients (39). These studies

require replication with larger samples.

Borderline symptoms and endogenous opioids.

Endogenous opioids have been implicated in nonsuicidal

sel-injury, a behavior that occurs requently in the contexto borderline personality disorder (66, 67) and dissociation.

Evidence or such a role is based on the partial success

o opioid antagonist treatment to ameliorate sel-injury

(68, 69), as well as on reports o altered pain sensitivity

during episodes o sel-injurious behavior (7073) and

ndings o altered endogenous opioid levels in individuals

with histories o sel-injury (36, 74, 75). Stanley et al. (36)

demonstrated that sel-injurers with cluster B personality

disorders, predominantly borderline personality disorder,

have lower CSF levels o endogenous opioids, in particular

b-endorphin and met-enkephalin, compared to those

without sel-injury. Furthermore, several studies ound


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STANLEY AND SIEVER


the orbital rontal cortex, so opioid release would act on

supersensitive receptors in these regions. This up-regu-

lation is consistent with regulation om-opioid receptors

by opioid agonism-antagonism (87, 88). Reduced basal

opioids may contribute to the chronic dysphoria and lack

tional paradigms might represent a promising next step in

assessing opioid activity in an interpersonal context.

Individual Dierences in Opioid Activity

Individual dierences in the opioids are grounded in

a genetic basis, which includes genetic variation in the

opioid receptors as well as opioid release. Against this ge-

netic background, stress, induction o negative aect, andstates o acute separation may actively infuence opioid

concentrations, and developmental dierences in rearing

may alter the opioid system set-point.

Genetic Studies o the m-Opioid Receptor, Attachment

Behavior, and Borderline Personality Disorder

Recent genetic studies suggest that the m-opioid recep-

tor gene is associated with attachment abnormalities and

borderline personality disorder. Polymorphisms in the

m-opioid receptor gene in humans (OPRM1 AII8G) and

rhesus macaques (OPRM, C77G) result in amino acid

substitutions in the N-terminal arm o the receptor, lead-

ing to increased anity or b-endorphin in vitro (47, 82)and gain o unction in vivo (83, 84), as exemplied in in-

creased alcohol-induced stimulation, an in vivo behavior

mediated by endogenous opioids.

In rhesus macaques, the OPRM1 77G allele is associ-

ated with higher levels o attachment during early inancy,

which suggests increased reward during maternal contact

but greater persistence o separation distress (85). The

prevalence o this allele is also increased in opioid ad-

dicts. Another single-nucleotide polymorphism (SNP) o

OPRM1 (rs510769) may be increased in individuals with

borderline personality disorder (86) and is associated with

aective lability. Interestingly, this SNP accounts or sig-nicant variance in prerontal activation in relation to an

aggression provocation task imaged by fuorodeoxyglu-

cose positron emission tomography (L.J. Siever et al., un-

published data). Two SNPs o the opioid delta 1 receptor

gene are associated with identity disturbance (86). These

data, while quite preliminary, raise the possibility that ge-

netic variability in the opioid receptors may aect aec-

tive stability, attachment, and coherence o sel-concept.

Further investigation o these polymorphisms in larger

samples and their relation to unctional imaging would

help to elucidate these relationships.

Model o Opioid Dysunction in BorderlinePersonality Disorder

We propose a model o reduced basal opioid activity in

critical limbic circuitry, including the cingulate cortex and

the amygdala, in individuals with borderline personality

disorder. Observations o reduced CSF concentrations o

b-endorphin and met-enkephalin in patients with bor-

derline personality disorder with sel-injury, as well as evi-

dence o reduced release in the anterior cingulate cortex,

are suggestive o this possibility. m-Opioid receptors, con-

versely, are hypothesized to be up-regulated secondary to

reduced basal opioids in the amygdala, the striatum, and

FIGURE 2. Model of Opioid Dysfunction and Buprenor-phine Treatment in Borderline Personality Disordera

Net Effect

Borderline Personality Disorder

Painful Stimulus(high stimulated activity )


(low basal activity)

Healthy Comparison Subjects


with buprenorphine (b)

partial agonist

(low basal activity)

b

b

b

b

b


with buprenorphine (b)

partial agonist

(high stimulated activity )

Basal

Opiates

Opioid

Receptors

b

A

E

D

C

B

(from B)

(from D)

a Basal opioid levels in borderline personality disorder are hypoth-esized to be reduced in output, while receptors are increased in

number, so that during unstimulated conditions, borderline pa-tients experience dysphoria associated with reduced tonic opioidactivity. When stress or pain causes an increase in release of opi-oids, there is an increased opioid signal and relief from dysphoria.Treatment with buprenorphine, a partial agonist, would increasebasal opioid signal under baseline conditions of low tonic activ-ity and antagonize opioid receptors under conditions of increasedoutput (e.g., self-injurious behavior).


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havioral repertoires. Oxytocin can inhibit HPA axis activ-

ity stimulated by stress in women who are lactating (98).

Breasteeding can attenuate the response to stress, sug-

gesting a possible mediating role o oxytocin (98, 99). In

general, stimulation o the nipple, as well as social contact,

increases oxytocin release and also attenuates HPA axis re-

activity (100). In a placebo-controlled double-blind study,

healthy men exposed to the Trier Social Stress Test, a labo-ratory procedure that induces a moderate amount o stress

in a social setting, received intranasal oxytocin or placebo

beore the induced stress, with or without social support

rom a riend. Both social support and oxytocin dimin-

ished the stress response, and the combination o the two

resulted in a lower cortisol response (98). Distinct popula-

tions o neurons in the amygdala are activated by oxytocin

and arginine vasopressin receptor stimulation, and they

modulate integration o excitatory data rom the amygdala

and the cerebral cortex in opposite manners (96).

Oxytocin, Afliation, and Bonding

Preclinical studies demonstrate oxytocins crucial role

in bonding. Oxytocin receptors are richer in the monoga-

mous prairie voles than in mountain voles, which do not

orm stable monogamous relationships (101). Oxytocin

receptor levels in the central nucleus o the amygdala are

signicantly higher in rats exhibiting maternal behaviors,

including licking, grooming, and nursing o pups, than in

those with low levels o these behaviors (91). In humans,

oxytocin is a critical mediator o social connectedness

and bonding in the context o romantic attachments,

enduring monogamous partnerships, and maternal be-

havior. For example, in romantically unattached young

adults, oxytocin is associated with sel-report measures

o bonding to parents and inversely related to psycholog-

ical distress (92). Since receptors or oxytocin are more

abundant in the reward centers o prairie voles, which

orm enduring monogamous relationships, it has been

hypothesized that oxytocin plays a similar role in adult

human romantic attachments (102, 103). While studies

o oxytocin and monogamous behavior in humans have

not been conducted to date, one study ound that in co-

habiting couples, greater partner support is associated

with higher plasma oxytocin in both men and women

beore and ater a period o warm partner contact (93).

In humans, oxytocin concentrations during early preg-nancy and during the immediate postpartum period are

associated with maternal bonding behaviors, includ-

ing gaze, vocalizations, positive aect, and aectionate

touch, as well as thoughts related to attachment and

requent monitoring o the inant (104). Furthermore,

oxytocin mediates attachment behavior over the course

o development, with lower urinary concentrations o

oxytocin ound in maltreated children (105) and in adult

males with a history o early separation (106), as well as

in the CSF o adult emales with a history o childhood

abuse (107). However, these ew studies are based on ret-

o a sense o well-being as well as the diculties in sel-

soothing associated with borderline personality disorder.

On the other hand, painul stimuli may result in opioid re-

lease in the ace o more sensitive opioid receptors, thus

accounting or observations o a greater pain threshold

or a lower pain sensitivity in the disorder. Sel-injurious

behavior similarly may induce opioid release, stimulating

supersensitive opioid receptors and providing a possiblemechanism or the sense o well-being and rush oten

experienced ollowing sel-cutting or other orms o sel-

injury. Drugs that may be abused or prescribed or pain

control may enhance basal opioid levels and down-regu-

late m-opioid receptors (see Figure 2).

Lower opioid activity may be a unction o genetic ac-

tors, environmental actors, or, very likely, a combination

o the two. Genetic studies o polymorphism in the opioid

receptor suggest abnormalities in eating disorders, which

are also associated with impulsive behavior, binge eating,

and eelings o dysphoria and satiation. Preliminary data

cited earlier suggest that, indeed, there are alterations inopioid receptor genes, including the m-opioid receptor

(OPRM1), associated with aective instability and sensi-

tivity to abandonment (86).

Oxytocin and Borderline PersonalityDisorder

Neuroanatomy and Neuropharmacology o the

Oxytocin System

Oxytocin plays a critical role in maternal behavior,

partnering, and a variety o other prosocial behaviors. It

is synthesized in magnocellular neurons o the paraven-tricular and supraoptic nuclei o the hypothalamus (89)

and then transported to the posterior pituitary, where it

is released (90). Oxytocin receptors are especially abun-

dant in brain areas involved in social behaviors, including

the bed nucleus o the stria terminalis, the hypothalamic

paraventricular nucleus, the central nucleus o the amyg-

dala, the ventral tegmental area, and the lateral septum

(91). In rodent mothers, suckling, as well as visual, audi-

tory, and olactory cues related to their inants, enhances

maternal care behavior in part by increasing expression o

oxytocin receptors in these regions (91). In humans, oxy-

tocin is central to aliative behaviors, including bondingwith parents or romantic partners (92, 93). It also plays

a key role in emotion regulation and stability. Oxytocin

modulates the ormation o memories, particularly social

and spatial memory, as well as responses to emotional la-

tent stimuli, such as acial expressions. Oxytocin is thus

involved in reading states in other individuals (i.e., men-

talizing) (94). However, there has been limited study o the

aliative role o oxytocin.

Oxytocin and Stress

Oxytocin serves to diminish the stress response (9597).

Lesions o the medial preoptic area eradicate maternal be-


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STANLEY AND SIEVER


Oxytocin Dysunction in Borderline Personality

Disorder

Oxytocin is implicated in prosocial behavior, evalu-

ation o others, and ascertainment o others internal

states. To the extent that individuals with borderline per-

sonality disorder have diculty in consciously register-

ing the internal states o others, dysunction in oxytocin

activity may impair their capacity to evaluate others stateo mind rom social cues. While limited data are available

regarding the biologic activity o oxytocin in borderline

personality disorder and its eects, preliminary data sug-

gest that oxytocin reduces stress-induced increases in

cortisol in the Trier Social Stress Test (113) and skews re-

sponses o patients with borderline personality disorder

in a cooperation paradigm (114). In the latter study, bor-

derline patients and healthy comparison subjects played

an assurance game emphasizing trust in which the pay-

o is highest or both players i they cooperate, but i the

partner is mistrustul it pays more to deect. In this task, a

variant o the prisoners dilemma game, with a player anda conederate, participants played the assurance game

45 minutes ater randomized administration o intrana-

sal oxytocin or placebo. Paradoxically, while comparison

subjects tended to cooperate more ater administration

o oxytocin when the partner was hypothetically coopera-

tive, patients did not; they deected more ater receiving

oxytocin when paired with the hypothetical cooperative

partner. In contrast, they deected less than compari-

son subjects ater receiving oxytocin when the partner

is hypothesized to deect. Thus, in healthy comparison

subjects, the oxytocin appeared to tune their response to

more closely match the speculated intent o their partner,while in the patients with borderline personality disorder,

oxytocin seemed to do the converse. These data could

be interpreted in the ollowing manner. Individuals with

borderline personality disorder may view deection by

their partner as a threat, so they appeal to the partner by

cooperating, while partner cooperation may signal that

there is no threat, oering them the opportunity to gain

points or themselves. This interpretation suggests that

individuals with borderline personality disorder may view

relationships as competitive struggles rather than as col-

laborative ventures. However, this is a preliminary study

with a modest sample size, so urther research is needed.In a laboratory study using a social exchange game in

which cooperation benets two individuals playing the

game, King-Casas et al. (115) ound that individuals with

borderline personality disorder experienced diculty

maintaining cooperation and repairing relationships ater

cooperation was broken. Neurally, activity in the anterior

insula, a region known to respond to norm violations, dis-

tinguished healthy participants rom those with border-

line personality disorder, with healthy individuals show-

ing a strong linear relationship between anterior insula

response and both magnitude o monetary oer received

rom their partner (input) and the amount o money re-

rospective data, such as history o trauma, and the valid-

ity o one o the studies (105) has been questioned (108).

Thereore, additional studies, particularly with prospec-

tive designs, are needed to establish the role o oxytocin

in a developmental context.

Oxytocin and Trust

Intranasal administration o oxytocin has been shownin human studies to signicantly enhance trust (109,

110). This increase in trust augments social interactions

and is based on an increased willingness to accept social

risks but not a more generalized increment in readiness

to bear risks o all types. This has been demonstrated in a

double-blind study design using a trust game in which a

participant-investor can transer money to a trustee and

the latter has a choice o sharing the increase generated

by the transer or not. Oxytocin enhances prosocial be-

havior by infuencing the willingness to share in the ace

o social risks, biasing individuals to increase approach

and trust in others (110). One mechanism by which oxy-tocin may increase prosocial behavior is through infu-

encing aective experiences o others. In a conditioning

paradigm, dierential negative aective ratings o aces

can be induced by aversive conditioning compared to

a nonconditioning intervention, and this dierential

negative evaluation can be reversed by treatment with

oxytocin. This eect has been associated with an attenu-

ation o activation in the anterior cingulate cortex and

the anterior medial temporal cortex (111). Aversive con-

ditioning increased activation in the extended amygdala,

including the anterior medial temporal cortex just ante-

rior to the amygdala, but this eect was not seen in anoxytocin-treated group. Furthermore, activation o the

right amygdala is greater or aces with a direct gaze as

opposed to an averted gaze in a ear conditioning para-

digm, consistent with the social relevance or valence o

these aces.

Oxytocin can improve the ability to iner the mental

state o others (94), as assessed by a test o inerring the

internal state o others rom aces with aective acial ex-

pressive dierences. Oxytocin also improves perormance

on this task compared with placebo, particularly with

more challenging discriminations.

Oxytocin not only infuences the recognition o aec-

tive cues but also modulates the encoding o positive so-

cial interactions into memory. For example, in a double-

blind randomized placebo-controlled between-subjects

trial (112), healthy males received oxytocin or placebo

and then viewed 36 happy, angry, or neutral human aces;

they were asked the ollowing day whether they remem-

bered or knew previously seen aces. Those who re-

ceived oxytocin were more likely to remember or at least

recognize as amiliar previously seen happy aces com-

pared with angry and neutral aces, which suggests that

oxytocin infuences the ongoing representation o posi-

tive social interactions.


9/16



vous system, including a variety o limbic and subcorti-

cal structures.

Vasopressin and Social Behavior

The AVPR1A receptor plays a major role in the modu-

lation o social behavior within the vasopressin system; it

determines monogamous partner preerence, nurturance

o ospring, and selective aggression toward male com-petitors (117). In mammals, vasopressin is more involved

in male behaviors than in emale behaviors, which are

modulated through oxytocin (117).

Vasopressin also promotes behaviors that are adaptive

or monogamous relationships, including paternal care o

ospring, protection o mate, and selective preerence or

a mate in male voles, but vasopressin does not have this

role in nonmonogamous species. Vasopressin has a circa-

dian rhythm o release, with peak release during the day,

and it appears to have an inhibitory role in corticotropin-

releasing hormone and ACTH secretion (118).

Vasopressin also plays a critical role in aggression, pri-

marily aggression between males in monogamous spe-

cies, such as prairie voles. Vasopressin may be particularly

critical in regulating the aggression in the context o peer

bonding, so that higher levels o aggression are displayed

toward unamiliar males o the species. Increased inter-

actions with athers o newborn mice are associated with

higher levels o aggression than mice receiving less pater-

nal interaction (119).

Increasing vasopressin 1A receptors in nonmonoga-

mous vole species acilitates the ormation o selective

expression or a mate, which suggests that this receptor

plays an important role in modulating social behavior

(120). Indeed, the vasopressin 1A receptor gene is highly

polymorphic, such that variability in microsatellite-like

elements that control expression dierences are associ-

ated with dierences in social behavior in the laboratory

setting (121). Increased binding o this receptor may be

enhanced by repeated aggressive encounters in domi-

nant hamsters (122), depending on the species. Agonists

and antagonists o this receptor can modulate the ex-

pression o aggression (116). Treatment with fuoxetine

diminishes oensive aggression in part by blocking the

activity o the arginine vasopressin system, which sug-

gests that serotonin antagonizes the aggression-enhanc-

ing eects o vasopressin (123). Vasopressin inusionsenhance pair bonding by acilitating partner preerences

(124). Antagonists inhibit such preerences. This acilita-

tion, however, does not occur in nonmonogamous spe-

cies o the vole. Increasing vasopressin can induce pa-

ternal behavior in the nonmonogamous and aggressive

meadow vole (125).

Finally, like oxytocin, vasopressin plays a role in social

recognition, as vasopressin 1A and 1B receptor knockout

mice may have impaired social recognition (126) and an-

tagonists o vasopressin in normal rats impair social rec-

ognition (116).

paid to their partner (output). In contrast, activity in the

anterior insula o individuals with borderline personality

disorder was related only to the magnitude o payment

and not to oers o payment.

Given the specic role o oxytocin in trust and in read-

ing others internal statesprecisely qualities that may be

distorted in people with borderline personality disorder

urther investigations into this neuropeptide system usinggames that involve separation are warranted. In previous

studies, participants could not view the acial expressions

o their partners in computerized exercises, so the inter-

personal context was not accurately replicated. Innovative

strategies involving two partners and using real-time a-

ective interactions and observation o eects would ur-

ther elucidate the role o oxytocin in borderline personal-

ity disorder.

Individual Dierences in Oxytocin Activity

Levels o both oxytocin release and oxytocin recep-

tors are genetically regulated, and several alleles or the

oxytocin receptor have been identied. Early stress can

interere with the developing neuropeptide system and

alter oxytocin receptor binding (103), also modulating its

activity.

Oxytocin, Genetics, and Borderline Personality

Disorder

Several polymorphisms have been identied in oxyto-

cin genes and have been associated variously with eating

disorders and other psychopathology. However, little re-

search on oxytocin genes has been conducted in relation

to borderline personality disorder. In the only analysis to

date on personality disorders, one o our SNPs or oxy-tocin tasks (rs877172) was signicantly associated with

inappropriate intense anger in individuals with personal-

ity disorders (86). These preliminary results raise the pos-

sibility that there may be genetic dierences in oxytocin

expression in such patients, but this remains to be deni-

tively demonstrated.

The Vasopressin System andBorderline Personality Disorder

Neuroanatomy and Neuropharmacology o the

Vasopressin SystemArginine vasopressin, which is also implicated in social

behavior, is synthesized in the hypothalamus supraop-

tic nucleus and paraventricular nuclei in magnocellular

cells whose axons then extend to the posterior pituitary,

rom which the vasopressin is released into the blood-

stream when appropriately stimulated. Parvocellular

neurons also may contain vasopressin. The arginine va-

sopressin gene is on chromosome 20 and is evolutionari-

ly conserved. There are three major receptor subtypes or

vasopressin: the AVPR1A, AVPR1B, and AVPR2 receptors

(116). AVPR1A transcripts are ound widely in the ner-


10/16

STANLEY AND SIEVER


(127), which suggests that these two systems may inter-

act reciprocally to modulate aggression. Individuals with

borderline personality disorder who have reduced seroto-

nergic activity may have increased vasopressin concentra-

tions associated with aggression toward peers, consistent

with their lowered threshold or anger and aggression. Va-

sopressin thus may mediate the enhanced irritability and

aggression o these individuals in the context o close in-terpersonal relationships.

Implications for Research andTreatment

Research Implications

Despite the potential promise o understanding the

neurobiological basis o the interpersonal sensitivities and

vulnerability in borderline personality disorder, there has

been surprisingly little investigation in this area. There is

still a dearth o psychopharmacologic and psychosocialtreatment options with high ecacy or this disorder. A

better understanding o the substrates o the relational in-

stability o borderline personality disorder might enhance

our treatment options. Neuromodulators such as the neu-

ropeptides that have been shown to be involved in alia-

tive and relational behaviors could be studied in natural-

istic paradigms in interpersonal settings and in response

to specic behavioral tasks that involve perception o trust

and cooperation versus confict. In addition to document-

ing the role o neuropeptides such as oxytocin or opioids,

the eects o the administration o neuropeptides such as

oxytocin and buprenorphine can also be observed in bothnaturalistic and laboratory behavioral paradigms. Oxyto-

cin and synthetic oxytocin endogens, such as carbetocin

(140, 141), have been administered or labor induction and

postpartum hemorrhage and can be administered in the

context o paradigms involving aliation and trust. Vaso-

pressin and its synthetic analogue terlipressin (142) have

been administered or septic shock and could be used or

laboratory tasks and behavioral imaging paradigms involv-

ing elicitation o aggression. Buprenorphine, an opioid ag-

onist, is a candidate or naturalistic provocation paradigms

involving interpersonal interaction, sel-regulation, and

aective regulation. Neuroimaging studies can evaluateregional activation patterns related to interpersonal vicis-

situdes and aliative behaviors, especially in the context

o paradigms using neuropeptide administration or natu-

ralistic measures in neuropeptide activity. In these ways,

individual dierences in neuropeptide activity and eect

on relevant brain circuitry can be documented.

Naturalistic studies involving measurements o neuro-

peptides as well as administration o neuropeptides and

their analogues are particularly important because they

may help in the development o a more specic under-

standing o the mechanisms o these neuropeptides. For

example, studies o opioid release in relation to negative

Vasopressin and Aggressive Behavior

In contrast to the wealth o preclinical data regard-

ing vasopressin, there is a dearth o human studies. CSF

vasopressin concentration is positively correlated with

a history o disinhibited aggression, including temper

tantrums and physical aggression in patients with inter-

mittent explosive disorder, many o whom have comor-

bid borderline personality disorder (127). However, one

study ound no dierences in CSF vasopressin between

violent oenders and comparison subjects (128), which

raises the possibility that the vasopressin increases may

be particularly associated with aggression in an interper-

sonal context in those who are interpersonally sensitive

and not in antisocial individuals lacking interpersonal

sensitivity. Reduced concentrations o antibodies to va-

sopressin are more common in individuals with conduct

disorder (129), which also supports the relationship be-

tween vasopressin and interpersonal aggression. Further

studies show that administration o intranasal vasopres-

sin increases the perception o threat in response to neu-

tral stimuli (130), which is consistent with the tendency o

patients with borderline personality disorder to interpret

neutral aces as potentially threatening (131), while ele-

vations in vasopressin have been associated with depres-

sion and anxiety (116).

Individual Dierences in Vasopressin Activity

Genetic polymorphisms have been identied in AVPR1A

and have been ound to modulate human social behavior

and physiology, specically prosocial or altruistic decision

making (132, 133), prepulse inhibition (134), pair bond-

ing (135), and onset o sexual behavior (136). In humans,developmental infuences on vasopressin and its receptor

have not been clearly documented, but early social expe-

rience (137), manipulations o oxytocin (138), and early

maternal separation (139) appear to modulate vasopres-

sin through epigenetic mechanisms, gene expression, and

regulation o peptide release.

Model o Oxytocin and Vasopressin Activity in


Since oxytocin is involved in aliation and trust, it

would be tempting to propose a simplistic model o oxy-

tocin deciency in borderline personality disorder. Whileoxytocin did appear to reduce stress in a pilot study o the

Trier Social Stress Test, its eects on a cooperation para-

digm are more complex, which suggests that oxytocin

actually makes patients with borderline personality dis-

order hypersensitive to social stimuli, such that increased

tuning in to others motivations is actually aversive. This

possibility needs to be tested across a variety o labora-

tory paradigms.

Vasopressin in CSF is correlated with aggression in in-

dividuals with personality disorders, while vasopressin

concentrations are inversely associated with prolactin re-

sponses to enfuramine, an index o serotonergic capacity


11/16



borderline personality disorder, and which disturbances

are more directly attributable to the disorder.

It is also noteworthy that the ndings on neuropeptides

must ultimately be placed in the context o other known risk

processes or borderline personality disorder. For example,

research is needed to compare the strength o any neuro-

peptide associations with borderline personality disorder

with the strength o associations with other known risk ac-tors. Further research should also determine whether the

eects o neuropeptides on borderline personality disorder

are related to or depend on other risk actors. This type o

inormation will help to determine whether it is worthwhile

to pursue a neuropeptide-based treatment approach.

Treatment Implications

Eects o treatment, both psychosocial and psychophar-

macologic, can be observed in naturally occurring or pro-

voked variations in the neuropeptides o interest as well as

in response to exogenous neuropeptide administration.

A variety o psychosocial treatment options have demon-strated some ecacy in borderline personality disorder

dialectical behavioral therapy (144), cognitive therapy,

transerence-based therapy (145), mentalization therapy

(146), and schema-ocused therapy (147, 148)although

these treatments have typically shown ecacy or single

symptoms. For example, dialectical behavior therapy re-

duces suicidal behavior and nonsuicidal sel-injury, and

transerence-ocused therapy shows ecacy or refec-

tive unctioning but not suicidal behavior or sel-injury.

Psychopharmacologic interventions may be useul in tar-

geting dimensional vulnerabilities, including impulsive

aggression, aective lability, and potentially even the in-terpersonal turmoil o borderline personality disorder, and

thus they may have a broad-based impact on the disorder.

Successul treatments may modulate or normalize eects

o these neuropeptides on behavior and subjective state

so that provocation studies could be done beore and ater

treatment. Agents that modulate these systems may also

be used or longer-term treatment. For example, buprenor-

phine, an opioid partial agonist, is a promising candidate

and might be used to enhance basal opioid activity, yet

because o its partial agonist properties, it may also serve

to block increased endogenous opioid activity. Intranasal

oxytocin may serve to enhance trust in certain paradigms,although, as preliminary data suggest, in some contexts it

might serve to enhance social sensitivity to the point where

it leads to aversive behaviors. Vasopressin has been impli-

cated in aggression, aliation, pair bonding, anxiety regu-

lation, and social recognition (116, 149, 150). Vasopressin

(V1A receptor) antagonism can reduce amygdala activa-

tion (151). Vasopressin antagonists have been considered

or treatment o major depressive disorder (152) and may

be helpul in borderline personality disorder. Clearly, ur-

ther research is indicated to clariy optimal strategies ei-

ther to manipulate neuropeptide concentrations or to use

them as potential markers o benecial treatment eects.

aect and stress implicate these systems in the dysregula-

tion o negative aect in borderline personality disorder

(81). Results o oxytocin administration in the context o

a trust paradigm in borderline personality disorder sug-

gest that a simplistic hypothesis o reduced oxytocin may

not capture the complexity o the infuence o oxytocin on

aliative systems and trust in this disorder (114). While

vasopressin has been implicated in aggression in person-ality disorders, there have been no naturalistic studies

o vasopressin administration in borderline personality

disorder. Thus, at this point, the need or more studies ex-

ploring these mechanisms is evident. Innovative studies

incorporating imaging and, i possible, a variety o behav-

ioral paradigms involving cooperation, trust, and aective

regulation are indicated.

Neuroimaging studies can evaluate components o

neuropeptide systems by measuring neuropeptide release

or receptors through displacement paradigms and recep-

tor binding studies. Functional neuroimaging studies can

also evaluate patterns o regional activation with a ocuson relevant limbic regions, such as the anterior cingulate

gyrus and the amygdala, in relation to aect regulation,

cooperation, and aliative behaviors using behavioral

laboratory paradigms with and without administration o

specic neuropeptides. In this way, the relevant circuitry

o the neuropeptides could be mapped and their unc-

tional implications evaluated.

As discussed, little inormation is available about indi-

vidual dierences in neuropeptide activity and the eects o

neuropeptides on the relevant brain circuitry. Longer-term

neuropeptide administration might be used in psycho-

pharmacologic treatment studies (see below). The study othese neuropeptides in the psychiatric disorders is only in

its inancy, and little is known about the association o any

o them with psychiatric disorders. Thus, the epidemiology

and the predictive value o neuropeptide activity is virtually

unknown in psychiatric populations. As newer and better

paradigms evolve to evaluate neuropeptide activity in psy-

chiatric disorders, it may be possible to evaluate the extent

and specicity o associations with any psychiatric disorder.

It is important to note that many biological correlates o

psychiatric disorders are actually consequences o the dis-

orders, not causes. This may be the case with the neuropep-

tides. Rutter (143) elegantly described the need to test the

causality o risk actors or psychiatric disorders and iden-

tied several paradigms or determining causality. Among

these paradigms are natural experiments, such as twin and

migration studies, to disentangle genetic and environmen-

tal eects; avoidance o selection bias designs in which all

individuals receive the same treatment; and mediational

studies that examine dierential eects o mediation on

subgroups. Ultimately, causality tests should be applied to

the study o neuropeptides in borderline personality dis-

order. It will also be crucial to distinguish between what

neuropeptide abnormalities are a consequence o early

childhood trauma, which has a high reported incidence in


12/16

STANLEY AND SIEVER


This articles contents are solely the responsibility o the authors

and do not necessarily represent the ofcial views o NCRR, NIH,

NIMH or NIAAA.

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baum JF: Fenfuramine challenge in unipolar depression with

and without anger attacks. Psychiatry Res 2000; 94:918

15. Krueger RF, Markon KE, Patrick CJ, Benning SD, Kramer MD:

Linking antisocial behavior, substance use, and personality: an

integrative quantitative model o the adult externalizing spec-

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Ultimately, a better understanding o these mechanisms

will enhance our appreciation o the dynamics o the in-

terpersonal vulnerabilities o individuals with borderline

personality disorder by more accurately pinpointing the

precise nature o these vulnerabilities and providing a

heuristic ramework rom which to explore the exquisite

sensitivity to interpersonal vicissitudes and the related

diculties in maintaining a homeostatic sense o well-being in this disorder.

Conclusions

The evidence reviewed here supports the testing o our

proposed model o altered neuropeptide unction underly-

ing the interpersonal susceptibilities o borderline person-

ality disorder. Areas o investigation can include 1) exami-

nation o basal decits and receptor supersensitivity o the

opioid system contributing to the chronic dysphoria, eel-

ings o emptiness, and sensitivity to rejection and abandon-

ment o borderline personality disorder and the relie rom

these eelings ollowing sel-injurious behaviors or admin-

istration o opioids; 2) dysregulation o oxytocin contribut-

ing to the mistrustul and antagonistic interpersonal modes

associated with borderline personality disorder; and 3) in-

creases in vasopressin associated with irritability and ag-

gression, particularly in the context o close interpersonal

relationships. The opioids, vasopressin, and oxytocin merit

urther investigation or their role in borderline personal-

ity disorder and are candidates or possible treatments. Ex-

ploring new avenues or treatment is particularly important

or this disorder because current approaches are ar rom

satisactory. While treatment with these agents is prema-

ture and raught with clinical complexities, preliminary

research interventions in the opioid systems with agents

such as buprenorphine or those targeting the oxytocin or

vasopressin systems could be explored to identiy better

treatments, genetic and epigenetic actors, biomarkers, and

early stressors that may presage the interpersonal suscepti-

bilities o borderline personality disorder, with implications

or early interventions.

Received May 28, 2009; revisions received Aug. 12 and Aug. 31,

2009; accepted Sept. 4, 2009 (doi: 10.1176/appi.ajp.2009.09050744).

From the Department o Psychiatry, Columbia University College oPhysicians and Surgeons; and the Department o Psychiatry, Mount

Sinai School o Medicine. Address correspondence and reprint re-

quests to Dr. Siever, Department o Psychiatry, Mount Sinai School o

Medicine, 1 Gustave L. Levy Place, Box 1230, New York, NY 10029;

[email protected] (e-mail).

The authors report no fnancial relationships with commercial in-

terests.

Supported by National Center or Research Resources (NCRR)

grant MO1-RR-00071, NIMH grants MH62665 and MH61017, and

National Institute o Alcoholism and Alcohol Abuse (NIAAA) grant

P20AA015630 to Dr. Stanley; NIMH grants MH63875 and MH56140

to Dr. Siever; and the Veterans Aairs VISN 3 Mental Illness Research,

Education, and Clinical Center.

The authors thank Drs. John Gunderson, Allen Frances, Peter Freed,

Eric Fertuck, and Scott Wilson or their helpul comments on earlier

versions o the manuscript.


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