REVIEWS AND OVERVIEWS This article addresses the Core Competency of Medical Knowledge

Mechanisms of Psychiatric Illness

A New Perspective on the Pathophysiology of Borderline

Personality Disorder: A Model of the Role of Oxytocin
Sabine C. Herpertz, M.D., Katja Bertsch, Ph.D.

Borderline personality disorder is characterized by three framework for future research in borderline personality disorder
domains of dysfunction: affect dysregulation, behavioral dys- that is based on oxytocinergic modulation of the following
control, and interpersonal hypersensitivity. Interpersonal hy- biobehavioral mechanisms: 1) the brain salience network fa-
persensitivity is associated with a (pre)attentive bias toward voring adaptive social approach behavior, 2) the affect regulation
negative social information and, on the level of the brain, en- circuit normalizing top-down processes, 3) the mesolimbic
hanced bottom-up emotion generation, while affect dysregu- circuit improving social reward experiences, and 4) modulating
lation results from abnormal top-down processes. Additionally, brain regions involved in cognitive and emotional empathy. In
the problems of patients with borderline personality disorder in addition, preliminary data point to interactions between the
interpersonal functioning appear to be related to alterations in oxytocin and cannabinoid system, with implications for pain
the (social) reward and empathy networks. There is increasing processing. These mechanisms, which the authors believe to be
evidence that the oxytocinergic system may be involved in these modulated by oxytocin, may not be specific for borderline
domains of dysfunction and may thus contribute to borderline personality disorder but rather may be common to a host of
psychopathology and even open new avenues for targeted psychiatric disorders in which disturbed parent-infant attach-
pharmacotherapeutic approaches. From studies in healthy and ment is a major etiological factor.
clinical subjects (including first studies with borderline per-
sonality disorder patients), the authors provide a conceptual Am J Psychiatry 2015; 172:840–851; doi: 10.1176/appi.ajp.2015.15020216

Borderline personality disorder affects about 1%22% of leading to interpersonal dysfunction in borderline person-
individuals in the general population, approximately 6% in ality disorder. These phenomena may be well depicted in the
primary care settings, and up to 10% of psychiatric out- notion of “threat hypersensitivity,” which has been strongly
patients (1, 2). Factor analyses have revealed three domains of associated with a life history of early maltreatment beyond
psychopathology in this disorder: affect dysregulation, be- various nosological categories (8).
havioral dyscontrol, and interpersonal hypersensitivity (for There are circular mechanisms among these three do-
reviews, see references 3–5). mains of psychopathology. Interpersonal hypersensitivity
Affect dysregulation comprises experiences of more in- may be regarded as a facet of enhanced emotional sensitivity
tense aversive emotions, higher tension, and more rapidly or “bottom-up emotion generation” (9), which reflects the
rising mood swings between dysphoria and euthymia in strength of the emotional response system and can be dis-
patients with borderline personality disorder compared with tinguished from poor affect regulation strategies (10).
healthy individuals (for a review, see reference 6). Behavioral Interpersonal hypersensitivity may contribute to the deve-
dyscontrol manifests as impulsive self-destructive and ag- lopment of a disorganized-ambivalent form of attachment
gressive behaviors and a failure to exhibit well-balanced typical of borderline personality disorder, which impedes
problem-solving behavior as well as future-oriented perspec- early co-regulation between child and caregivers and thus
tives on life. Self-injurious behavior, the clinically most trou- may favor the development of affective instability (4). Affect
bling manifestation of behavioral dyscontrol, is associated dysregulation has been shown to predict maladaptive in-
with diminished affective pain processing and dissociation terpersonal behaviors, impulsive coping behaviors (11), and
(7). Interpersonal hypersensitivity has only recently become reactive aggressive behavior (12). In addition, there is a
a major research target in the field of borderline person- strong association between affect regulation and social
ality disorder. According to the alternative DSM-5 model of cognition, with disturbances in emotion processing trans-
borderline personality disorder, “interpersonal hypersensi- lating into attentional biases and distorted expectations and
tivity” and “perceptions of others selectively biased toward interpretations in the social context, and vice versa (for
negative attributes” are the most prominent characteristics a review, see reference 13).

See related feature: AJP Audio (online)

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Why should one focus on the role of oxytocin in the The salience network is linked with the hypothalamus to reg-
pathophysiology of borderline personality disorder? In 2010, ulate stress hormones and with the brainstem to initiate au-
Stanley and Siever (14) provided a theory on the role of tomatic behaviors such as fight-or-flight mobilization or, in the
neuropeptides in borderline personality disorder. Since then, case of the experience of life threat, immobilization (29).
a vast amount of research on oxytocin has been conducted, Consistent with the notion of social stress hypersensitivity,
mostly in healthy subjects but also increasingly in patients steeper cortisol awakening responses (30) and increased hy-
with different psychiatric disorders, including some in patients pothalamic volumes (31) have been reported in patients with
with borderline personality disorder. There is now available borderline personality disorder. Recently, an event-related
evidence to advance the thesis that oxytocin exerts effects on potential (ERP) study by our group (32) strengthened the as-
several fundamental biobehavioral mechanisms that are sumption of an attentional bias toward threat cues in borderline
closely related to the above-described domains of dysfunction personality disorder: Patients with borderline personality dis-
in borderline personality disorder. However, we believe that order, compared with healthy controls, not only showed
the oxytocin system is one of many factors related to borderline a greater likelihood of classifying predominantly happy faces as
psychopathology and that the domains of dysfunction pre- angry, but these abnormalities in face perception were also
sented here are not specific to borderline personality disorder accompanied by enhanced P100 amplitudes, an ERP reflecting
but rather are related to disturbed parent-child attachment or early visual processing, while ERPs also indicated subsequent
early-life maltreatment (e.g., 8, 15). deficits in later structural face (N170) and categorical facial
emotion (P300) processing. This study suggests that the pro-
cessing of social threat cues is dominated by preattentive, reflex-
THE BIOLOGICAL BASIS OF BORDERLINE
like mechanisms of very early coarse perceptual processes in the
PERSONALITY DISORDER
occipital cortex at the cost of more detailed temporally and
In order to develop new treatments, it is necessary to disen- parietally located structural and categorical processes.
tangle the biobehavioral mechanisms related to borderline
personality disorder (16). Accordingly, in this review we begin Affect Dysregulation and Prefrontal-Limbic Circuitry
by describing abnormalities in biobehavioral dimensions as- Patients with borderline personality disorder are known to
sociated with borderline pathology that, according to findings in show deficits in affect regulation strategies. They 1) tend to
healthy and/or clinical subjects, seem to be interconnected with ruminate on negative emotions, 2) are inclined to suppress
the oxytocin system and thus could be promising targets for their emotions, 3) are characterized by experiential avoid-
oxytocin in future research on borderline personality disorder. ance, and 4) have difficulties in labeling their emotions and
distinguishing different emotional qualities (for a review, see
Interpersonal Hypersensitivity and the Salience reference 10). In addition to abnormal “bottom-up emotion
Network generation,” patients with borderline personality disorder
There is evidence of a profound negativity bias in facial emotion have been shown to exhibit abnormal neuronal activity in
recognition in patients with borderline personality disorder (for areas of the medial and lateral prefrontal cortex that control
a review, see reference 17), that is, they appear to be biased and modulate emotional activation, thereby covering “top-
toward identifying negative emotions in others (18–20). More down processes.” Functional neuroimaging studies have re-
specifically, they concentrate their initial attention more strongly vealed prefrontal hypometabolism during regulatory control
on negative facial expressions (21) and are more likely to ascribe processes (for a review, see reference 33), and a recent meta-
anger to ambiguous facial expressions (18). Recently, patients analysis of functional MRI (fMRI) studies across different
with borderline personality disorder were shown to also ex- stimulation procedures (26) revealed enhanced neuronal ac-
hibit a response bias toward perceiving other people’s faces as tivity in the insula but reduced activity in the subgenual anterior
more untrustworthy compared with healthy volunteers (22). cingulate cortex and dorsolateral prefrontal cortex in patients
Interestingly, an attentional bias toward negative infor- with borderline personality disorder as compared with healthy
mation in patients with borderline personality disorder is subjects. While patients had reduced activations in the rostral
reflected in brain imaging data showing increased and pro- anterior cingulate cortex during implicit affect regulation
longed amygdala responses (23, 24) as well as enhanced compared with healthy subjects (34), they showed decreased
neuronal activity in the anterior insula (25, 26). The amygdala orbitofrontal cortex activations in a task requiring instructed
and the anterior insula, in functional coupling with the an- reappraisal of negative emotions (25). Interestingly, a func-
terior cingulate cortex, mediate early bottom-up processes tional disconnection between the amygdala and ventral as well
of stimulus evaluation for valence and salience, that is, a as dorsal medial prefrontal cortical regions was observed in
stimulus’s capacity to be selected or prioritized by attention patients with borderline personality disorder in a recent fMRI
rather than other possible targets (27). Threat cues seem to study in which participants were exposed to either threat or
be of particularly high salience since, in healthy individuals, safe stimuli (35), similar to an earlier study by New et al. (36).
threat images evoke greater and earlier blood-oxygen-level- Interestingly, prefrontal and limbic areas involved in af-
dependent (BOLD) responses in the amygdala (and in the fect regulation strategies have also been reported to show
periaqueductal gray) than negative images in general (28). structural alterations in borderline personality disorder. A

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ROLE OF OXYTOCIN IN THE PATHOPHYSIOLOGY OF BORDERLINE PERSONALITY DISORDER

whole-brain voxel-based morphometry study showed volume differentiating between positive and negative feedback and
reduction in the cingulate gyri in addition to reduced volumes fail to adjust their behavior accordingly (52, 53).
in the hippocampus and amygdala (37). One MR spectroscopy In summary, the problems patients with borderline per-
study found reduced concentration of N-acetylaspartate in the sonality disorder have in interpersonal relationships may be
dorsolateral prefrontal cortex (38), while another showed related to increased sensitivity to threat and rejection (see
significantly higher levels of glutamate in the anterior cingulate above) and a more negative and mistrusting perception of
cortex (39). others, possibly in association with alterations in the brain’s
(social) reward system.
Distrust, Poor Social Reward Experiences, and
Mesolimbic Circuitry Poor Cognitive Empathy, Enhanced Emotional
Patients with borderline personality disorder are highly Contagion, and Abnormalities in Related Brain Circuits
sensitive to social rejection and have a generalized mistrust of Theory of mind is the ability to represent one’s own and other
others, that is, they expect to be rejected, negatively judged, people’s mental states and to infer their intentions, beliefs,
treated dishonestly, or otherwise emotionally hurt by others and feelings; in the case of others’ mental states, it may be
(22, 40–45). Recent studies demonstrate that patients with referred to as affective theory of mind or cognitive empathy
borderline personality disorder perceive neutral faces as less (54), which is very close to the National Institute of Mental
trustworthy and approachable than do healthy volunteers Health’s Research Domain Criteria subdomain “understand-
(22, 46). Moreover, the relationship between appraisal of ing mental states.” Reduced theory of mind or cognitive em-
untrustworthiness and borderline traits was mediated by pathic capacities in patients with borderline personality
rejection sensitivity (22, 44). In addition to deficits in the disorder were found in studies using self-report measures
perception of trustworthiness in other people, patients with (55, 56) or ecologically valid behavioral experiments (57, 58)
borderline personality disorder have been found to show (for a review, see reference 59). For instance, patients showed
alterations in their own facial expressions. Renneberg et al. (47) particular deficits in the inference of other people’s intentions, but
found that individuals with borderline personality disorder also their thoughts and emotions (60). In addition, some data
show more ambiguous facial expressions in social interactions, suggest that patients with borderline personality disorder try
and Matzke et al. (48) reported increased mimic reactions in excessively to interpret the mental states of others and/or over-
response to negative facial expressions but reduced mimic attribute others’ intentions (61). In tasks requiring cognitive or
reactions in response to positive facial expressions. affective empathic involvement, patients outperformed healthy
In economic exchange games, patients with borderline subjects (62, 63), possibly by (compensatory) overmobilizing af-
personality disorder have shown reduced trust in inter- fective empathic strategies such as emotional imitation.
personal interactions compared with healthy volunteers and With regard to neuroimaging data (57, 63, 64), in a cognitive
patients with major depression (45), as well as problems in empathy task, patients with borderline personality disorder
maintaining cooperation, repairing broken cooperation (43), showed reduced activations in the superior temporal gyrus and
and forgiving (49). In neural terms, the latter was associated sulcus compared with healthy volunteers, and they had en-
with an altered response pattern in the anterior insular cortex hanced amygdala and somatosensory cortex activations during
in patients with borderline personality disorder compared affective empathy. This may suggest an overactive and poorly
with healthy volunteers in response to offers from an in- controlled amygdala in patients with borderline personality
teraction partner (43). These results suggest that mistrust and disorder, which may call their unfiltered attention to pre-
deficient cooperation are core deficits of borderline per- dominantly negative and threatening social stimuli. Together
sonality disorder, which may stem from consistent experi- with emotional imitation processes reflected in increased
ences of invalidation, insecurity, and maltreatment during activation of the somatosensory cortex, this form of “empathy”
childhood and hence may be related to an insecure at- is likely to result in an affect-dominated and unmediated
tachment style (50). Consequently, patients with borderline perception of others, known as emotional contagion (5, 65).
personality disorder who perceive other people as more Enhanced emotional contagion is also suggested by elec-
threatening and less trustworthy may also experience social tromyographic data indicating higher imitation of mimic
interactions as less rewarding. Although little is yet known activities when negative facial emotions are presented in
about social learning in borderline personality disorder, patients with borderline personality disorder compared
neuroimaging studies have revealed alterations in patients’ with healthy volunteers, a finding that was associated with
activation of the brain reward system in response to so- self-report of more intense negative emotions (48).
cial stimuli. For instance, patients have been reported to show
a disturbed differentiation between reward and non-reward Abnormal Affective Pain Processing
anticipation in the pregenual anterior cingulate cortex bi- Reduced affective pain processing in the context of stress has
laterally as well as alterations in the ventral tegmental area and been consistently reported for individuals with borderline
ventral striatum compared with healthy volunteers (51). personality disorder (66–70). Hypoalgesia was found to be
In addition, electrophysiological data suggest that patients associated with a deactivation of the amygdala and lower
with borderline personality disorder have problems in posterior cingulate cortex connectivity with the dorsolateral

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prefrontal cortex during pain induction in patients with when attending to salient facial regions, such as the eye region
borderline personality disorder (68, 71). Consistent with the of angry faces and the mouth region of happy faces (84). A
hypothesis that self-injury is a maladaptive affect regulation threat-attenuating effect of oxytocin was indicated by the
strategy in the sense of strong sensory distraction, experi- authors’ observation that oxytocin decreased neural activi-
mentally induced pain resulted in normalization of amygdala ties within the fusiform gyrus and brainstem areas of healthy
activity; the latter was found to be enhanced following the males, as well as functional connectivity between the amyg-
presentation of highly arousing negative affective pictures (72). dala and the fusiform gyrus specifically for threat cues from
the eyes. Oxytocin effects were also found during emotion
processing tasks in the anterior insula. Domes et al. (85) found
BIOBEHAVIORAL MECHANISMS SERVING AS
enhanced activation in the insula in response to fearful and
TARGETS FOR OXYTOCIN
happy facial cues in females. Intensified activation of the
Oxytocinergic Modulation of Salience of Social Stimuli insula was also found when women listened to highly salient
Data consistently provide evidence that oxytocin facilitates acoustic stimuli of a crying infant (86).
the recognition of social stimuli, and particularly facial emo- Importantly, oxytocin effects appear to vary with gender
tions (73, 74). A number of studies suggest that oxytocin and interindividual factors (for reviews, see references 87,
specifically attenuates the processing of threatening social 88). In healthy women, amygdala activity was found to be
cues in healthy male volunteers. In a decision-making task in enhanced rather than diminished (as in healthy men) in re-
which participants learned whether a positive (“smiling”) or sponse to fearful faces and threatening scenes, independent
a negative (“angry” or “sad”) face was most often rewarded, of basal plasma levels of oxytocin, estradiol, and progesterone
oxytocin decreased the aversive aspects of angry faces, but following intranasal oxytocin administration (85, 89). With
exerted no effects on sad faces (75). In a study using video regard to interindividual factors that significantly modulate
sequences showing neutral faces gradually displaying a spe- oxytocin effects, psychopathology might be of particular
cific emotion, oxytocin decreased eye gaze in response to importance. While, for instance, oxytocin dampens amygdala
angry facial expressions in a large sample of healthy male response in individuals with social anxiety (90), it enhances
volunteers but augmented eye gaze toward neutral and happy amygdala activity in individuals with autism spectrum dis-
facial expressions (76). The modulating effects of oxytocin order (91) who experience low interest in their conspecifics.
were also shown to extend to very early automatic attentional In conclusion, oxytocin effects on attentional processing
processes. In a covert attentional task using the dot-probe of facial stimuli point to specific effects favoring social ap-
paradigm in healthy males, a pronounced shift of attention proach behavior, by modulating the salience of social stimuli.
was observed toward briefly presented happy but not angry The valence of social stimuli, however, does not appear to be
facial expressions (77). Interestingly, using a similar task in affected in the same way (for a review, see reference 92). The
healthy women, oxytocin did not enhance the attentional bias role of oxytocin apparently extends beyond a simple decrease
toward happy facial expressions, but diminished it toward the in emotional arousal, but studies from clinical samples—e.g.,
location of the faces presenting negative emotions. Notably, borderline personality disorder (see below)—suggest that
both mechanisms favor social approach rather than avoid- oxytocin rather modulates the salience of social cues to opti-
ance behavior (78). A further study in a gender-mixed sample mize social adaptation, probably also in accordance with dif-
showed increased attentional disengagement from angry and ferent gender-related generative tasks.
sad faces (79). Earlier studies also widely support the social
salience hypothesis, although data inconsistent with this have Oxytocinergic Modulation of Affect Regulation
also been published (80). As affect regulation is mediated in a prefrontal-limbic net-
On the neuronal level, oxytocin seems to reliably modulate work, it is of interest whether oxytocin also affects prefrontal
the brain salience network. Early studies applying an oxy- regulating areas. Indeed, oxytocin has been found to signif-
tocin challenge procedure reported amygdala deactivation icantly reduce the typically increased neuronal activity in the
compared with the placebo condition in healthy men viewing medial prefrontal cortex and the anterior cingulate cortex in
threatening faces or scenes (81). Domes et al. (82) replicated individuals with social anxiety disorder (93). In addition,
this finding but also extended it to facial stimuli independent oxytocin has been reported to attenuate activity in ventro-
of valence. Gamer et al. (83) suggest that oxytocin exerts lateral and dorsolateral prefrontal areas, which also play
different effects on subregions of the amygdala. In their study, a major role in emotion regulation (for a review, see reference
oxytocin attenuated activation in response to fearful faces but 94). Of particular interest are neuroimaging studies of ce-
increased activation in response to happy faces in the lateral rebral networks of functionally linked areas. These studies
and dorsal region of the amygdala. In addition, the posterior have elucidated preliminary information on how oxytocin
amygdala mediated oxytocin effects on reflexive gaze shifts may modulate brain circuits mediating affect regulation,
toward the eye region irrespective of the depicted emotional selecting the amygdala as the seed region in their analysis of
expression. A recent study by Kanat et al. (84) projects an neuronal networks (for a review, see reference 95).
even more complex picture of oxytocin effects, reporting that A study investigating oxytocin’s effects on functional
oxytocin decreased amygdala reactivity to masked emotions connectivity in a resting-state paradigm in healthy individuals

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ROLE OF OXYTOCIN IN THE PATHOPHYSIOLOGY OF BORDERLINE PERSONALITY DISORDER

showed increased connectivity between both amygdalae and volunteers, possibly because of an increased salience of happy
the rostral medial prefrontal cortex (96). A study in healthy faces after oxytocin administration.
men reported reduced coupling of the amygdala to brainstem Oxytocin administration was also found to increase the
regions involved in autonomic and behavioral manifestations proportion of positive communication behaviors and to re-
of fear while processing threatening faces (81). Most of the duce cortisol levels during couple conflict discussions (107)
studies that have focused on oxytocin’s effects on functional and to increase the attractiveness of the intimate partners
connectivity have been performed in individuals with social (108). The latter was associated with increased activations in
anxiety, targeting the regulation of social fear. In this pop- the brain reward system, including the ventral tegmental area
ulation, enhanced functional connectivity was found between and nucleus accumbens, and it appeared to be specific to
the amygdala and the left and right insula as well as the dorsal intimate partners, which is in line with the suggested in-
anterior cingulate gyrus during the processing of fearful faces teraction of oxytocin and dopamine in the rewarding com-
in the oxytocin compared with the placebo condition (97). ponent of intimate pair bonding and social attachment.
Using a resting-state paradigm, the same research group re- Recently, Kis et al. (109) reported that social treatment,
ported enhanced functional coupling between the amygdala including eye contact and social touch, and oxytocin ad-
and the rostral anterior cingulate cortex in individuals with ministration had similar effects on a subsequent facial re-
social phobia, with oxytocin normalizing the reduced amygdala- cognition task. Healthy male volunteers in both conditions
prefrontal connectivity compared with healthy controls rated negative facial expressions as more positive and
(98). trustworthy than did volunteers in the nonsocial or placebo
On the whole, preliminary data suggest that oxytocin does conditions.
not exert its effects solely on single areas, such as the Taken together, although evidence on oxytocin modula-
amygdala, the insula, and the prefrontal cortex, but it affects tion of unfamiliar faces and the reward learning from un-
the functioning of a broader affect regulation circuit. Since familiar (emotional) faces remains controversial, oxytocin
this network is highly significant for our understanding of the does seem to increase the perceived attractiveness of and
pathophysiology of borderline personality disorder, studies positive communication with intimate partners, which may
are warranted that focus on this network (see below) with the be associated with increased activations in brain reward
aim of clarifying whether modulating brain activity is in fact regions. Oxytocin might thus have the potential to improve
accompanied by improvement of affect regulation and thus social interactions with and attachment to familiar people
borderline psychopathology. such as friends or psychotherapists in patients with bor-
derline personality disorder.
Oxytocinergic Modulation of Social Reward Experiences
A high oxytocin receptor density has been found in brain Oxytocinergic Modulation of Cognitive and Emotional
regions involved in motivation and reward, such as the amyg- Empathic Capacity
dala (99), the ventral striatum, and the nucleus accumbens So far, little is known about the oxytocinergic modulation of
(100). In addition, results of rodent studies suggest that an empathic capacities beyond the above-discussed enhance-
interaction of oxytocin and dopamine, particularly within ment of emotion recognition in healthy volunteers. There is
the mesolimbic reward system, is involved in the formation some evidence of increased performance in tasks that involve
of pair bonds, affiliation, and social interaction (101, 102; for cognitive empathy capacities (110, 111) and of enhanced verbal
reviews, see references 103, 104). In humans, there is only emotional sharing (112) after oxytocin administration. For
limited direct evidence of an involvement of oxytocin in instance, oxytocin improved performance in the Reading the
social reward learning beyond the above-discussed findings Mind in the Eyes test in a large sample of healthy male
indicating an increased salience of positive, socially re- volunteers (111) and enhanced empathetic accuracy in less
warding stimuli. socially proficient healthy individuals, while it had no effect
Hurlemann et al. (105) showed that intranasal adminis- in highly socially proficient individuals when judging other
tration of oxytocin potentiates socially reinforced learning in people’s feelings (110). Oxytocin effects have also been
healthy men. Importantly, oxytocin did not have an effect on reported in regions involved in the processing of emotional
learning in general, as shown in a nonsocial control condition. states of others, such as the superior temporal gyrus, with
In addition, there is some evidence that oxytocin affects fi- increased activations during emotional face processing after
nancial reward learning in social situations. For instance, oxytocin administration in healthy women (85). In a study by
Evans et al. (75) found that oxytocin may reduce aversion Hurlemann et al. (105), however, oxytocin only facilitated
to angry faces, given that healthy male participants in the emotional empathy (measured by self-report) and did not
oxytocin condition chose an angry face more often when this have an effect on cognitive empathy in the Multifaceted
face was associated with a high financial reward, whereas Empathy Test.
participants in the placebo condition tended to avoid angry In summary, studies have mainly focused on oxytocinergic
but highly rewarding faces. However, in a second study, modulation of emotion recognition, and little is yet known
Clark-Elford et al. (106) revealed that oxytocin may selec- about the effects of oxytocin on the inference of other peo-
tively reduce reward learning from happy faces in healthy ple’s intentions and beliefs and thus their theory-of-mind

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capacities. Much more research is needed to disentangle the borderline personality disorder show insecure attachment
effects of oxytocin on the interwoven components of emotion classifications, with a high frequency of unresolved at-
recognition, emotional and cognitive empathy, theory of mind, tachment representations. Interestingly, an additional data
self-other differentiation, and emotion regulation, as they play analysis in one of the above-reported studies (118) revealed
a major role in the psychopathology of borderline personality that across patients with borderline personality disorder
disorder. and healthy volunteers, oxytocin increased cooperative
behavior for high-anxious, low-avoidant participants but
Oxytocinergic Modulation of Affective Pain Processing decreased cooperation for high-anxious, high-avoidant par-
Oxytocin synthesis and release from the hypothalamic mag- ticipants. Differences in acute stressors (121); comorbid dis-
nocellular neurons and neurohypophysis are modulated by orders, such as posttraumatic stress disorder (122); treatment
endocannabinoids (113). Interestingly, patients with bor- experiences; levels of endogenous oxytocin (see below),
derline personality disorder have recently been shown to vasopressin, cortisol, and/or testosterone (30); and variations
exhibit lower serum levels of the endocannabinoids anan- in the activity or function of the oxytocin and vasopressin
damide and 2-arachidonoylglycerol than do healthy subjects receptor genes may be particularly relevant modulators of
(114). An interesting question for future research will be oxytocin effects.
whether oxytocin, in linkage with the endocannabinoid To date, two studies have investigated the effects of in-
system, mediates abnormalities in affective pain perception tranasal administration of oxytocin on the emotional stimulus
in borderline personality disorder—all the more so because processing. Brüne et al. (123) compared 13 patients with
2-arachidonoylglycerol induces analgesia (115) and the en- borderline personality disorder and 13 healthy volunteers,
docannabinoid receptor CB1 plays a key role in the anti- using a dot-probe task to examine attentional biases to happy
hyperalgesic effect of oxytocin in a mouse model (116). The and angry faces. Oxytocin was found to attenuate avoidant
endocannabinoid system is also involved in brain circuits that reactions to angry faces in patients with borderline per-
modulate emotion regulation and reward processes and thus sonality disorder. Recently, our group provided first evidence
might have additional effects on abnormal biobehavioral that oxytocin has the potential to diminish threat hypersen-
mechanisms in borderline personality disorder. sitivity in borderline personality disorder (124). In a placebo-
controlled double-blind group design, 40 female patients
Oxytocin and Borderline Personality Disorder with borderline personality disorder and 41 healthy women
The first two pilot studies reporting an oxytocin effect in took part in a combined eye-tracking and fMRI emotion
borderline personality disorder were published in 2011. classification experiment. In this task, patients showed more
Simeon et al. (117) found that oxytocin may attenuate dys- and faster initial fixation changes to the eyes of very briefly
phoric emotional and salivary cortisol responses to social presented (150 ms) angry faces, which was associated with
stress in a small, mixed-gender sample of 14 patients with increased activation of the posterior amygdala. Oxytocin
borderline personality disorder and 13 healthy volunteers reduced posterior amygdala hyperactivity as well as the at-
who received either oxytocin or placebo. Contrary to pre- tentional bias toward socially threatening cues (i.e., the eyes
vious studies, no effects were observed in the healthy sample. of angry, but not fearful or happy faces) in patients.
The results of a second study by the same group (118), again Hence, there is limited evidence for beneficial effects from
consisting of 14 patients with borderline personality disorder exogenous oxytocin administration in borderline personality
and 13 healthy volunteers, indicate that in patients, oxytocin disorder, with reports of reduced amygdala-driven threat
may decrease trust and the likelihood of cooperative re- hypersensitivity and decreased avoidant behavior. Neverthe-
sponses in a financial trust game. The finding of reduced less, much more research is needed to address moderating
financial trust in patients after oxytocin administration was influences of gender and interindividual differences in trait
supported by a study by Ebert et al. (119) in a cross-over design variables, attachment style, and social functioning. It also
with 13 patients with borderline personality disorder and 13 remains unclear whether borderline personality disorder is
healthy volunteers. Despite the small sample sizes, which related to dysfunction in the oxytocin receptors that may
limit the interpretation of these studies, the results suggest yield greater binding of oxytocin to vasopressin receptors and
that oxytocin may have different effects on patients with hence could also lead to adverse effects if administered in
borderline personality disorder, depending on chronic inter- larger doses or on a regular basis. These questions need to be
personal insecurities, and possible differences in the oxytocin addressed in animal models and large genetic studies.
system regulation. This is in line with an “interactionist model”
proposed by Bartz et al. (87), who emphasized the moderating
EARLY MALTREATMENT, PARENTING, OXYTOCIN,
role of contextual factors and interindividual differences in
AND IMPACTS ON SOCIAL DEVELOPMENT
oxytocinergic modulations of social cognition and behavior.
For the study of borderline personality disorder, interin- From the few studies that have shown beneficial effects of
dividual differences in rearing conditions, including early- oxytocin on functional domains in borderline personality
life maltreatment and attachment style (120), appear to be of disorder, we do not conclude that these are disorder-specific
particular significance, as more than 90% of patients with effects, but rather regard these effects to be common to a host

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ROLE OF OXYTOCIN IN THE PATHOPHYSIOLOGY OF BORDERLINE PERSONALITY DISORDER

FIGURE 1. Model of the Implications of a Dysfunctional Oxytocin System on Parent-Child Bonding

Genetic factors Insecurely Genetic factors

(e.g., SS allele 5-HTTLPR CRHR1; attached adult (e.g., CC allele of CD38 rs3796863;
0 copies of TAT haplotype; GG allele of OXTR rs 2254298;
AA or AG allele of OXTR rs53576; TT allele of OXTR rs 1042778;
see reference 148) rs see reference 131)
cto
etic fa
Epigen

Insecurely Low parental

attached child oxytocin level

Poor parent-child Decreased reward Low salience for

bonding response to own child baby’s sensory cues

Low child
oxytocin levels
Low sensitivity to child:
poor cuddling and caring

of psychiatric disorders in which early-life stress and disturbed caregivers but plays a major role in establishing the early
parent-infant attachment trigger abnormal biobehavioral attachment relationship on both sides of the dyad. In line with
mechanisms as described above. Borderline personality disor- this, oxytocin administration to fathers has been found to
der appears to be an exemplary disorder for studying the effects augment peripheral concentrations not only in the fathers
of unsuccessful parent-child bonding on the oxytocinergic themselves but also in their 5-month-old infants with whom
system, with an impact on the development of brain circuits they had entered into social play (129). More specifically,
underlying adaptive affect regulation and social cognition. a cross-generation gene-by-environment effect was recently
During pregnancy, estrogen and progesterone levels rise, detected by the same research group (130), with low child
with estrogens priming the brain for synthesis of oxytocin and oxytocin levels being predicted by poor maternal care in
oxytocin receptors. At the end of pregnancy, a sudden drop infancy in interaction with a maternal high-risk CD38 allele
in progesterone level signals the upcoming parturition and that is associated with reduced release of oxytocin from
further enhances brain sensitivity to oxytocin and increases hypothalamic neurons (130). In addition, infants’ social re-
induction of oxytocin receptors (for a review, see reference ciprocity with a friend at age 3 was predicted by the child’s
103), contributing to preparing mothers for the establishment peripheral oxytocin concentration, by the mother’s oxytocin
of the early mother-infant bond (for a review, see reference levels and oxytocin-related genes, and by mother-child bond-
125). In correspondence with the major role played by ing. These findings suggest that maternal care in interaction
oxytocin in parenthood (also see reference 126), peripheral with oxytocin shapes the infant’s affiliative biology and actual
concentrations of oxytocin in the serum or saliva have been social interaction capacity.
shown to be positively correlated with sensitive and affec- Long-lasting effects on children’s development occur
tionate dyadic interactions of mothers and fathers with their because during this early co-regulation, neural links are
child (127); this means that the higher the parents’ oxytocin rapidly developing in brain circuits underlying emotional
level, the more they will touch and cuddle their baby. processing, cognitive empathy, and social reward, thus in-
Notably, neuronal activities in gender-specific brain circuits volving limbic structures, that is, the amygdala, the striatum,
that mediate parental behavior have been shown to corre- the ventral tegmental area, and the hippocampus, and their
late with oxytocin concentrations in mothers and fathers connections with the prefrontal cortex (e.g., the medial
(128). Interestingly, oxytocin not only exerts effects on early orbitofrontal cortex), all of which have a high density of

846 ajp.psychiatryonline.org Am J Psychiatry 172:9, September 2015

 HERPERTZ AND BERTSCH

FIGURE 2. Model of the Significance of the Oxytocin System on Biobehavioral Mechanisms Underlying Borderline Psychopathologya

Improvement of social functioning

Borderline
psychopathology

Attention bias Poor affect Poor social Abnormal

to social regulation reward Maladaptive pain
threat cues capacities experiences empathy processing

Modulation of
aINS vlPFC aINS brain circuits
mPFC
rACC VS
sTG Cannabinoid
AMY AMY AMY system
OFC

Oxytocin
administration

a
aINS5anterior insula; AMY5amygdala; vlPFC5ventrolateral prefrontal cortex; rACC5rostral anterior cingulate cortex; OFC5orbitofrontal cortex;
mPFC5medial prefrontal cortex; sTG5 superior temporal gyrus; VS5ventral striatum.

oxytocin receptors (131). It has been hypothesized that epi- a model of the implications of a dysfunctional oxytocin system
genetic processes play a major role in the long-lasting effects on parent-child bonding, although its significance for bor-
of early attachment relationships on brain functioning and derline personality disorder remains speculative.
that differential methylation of the oxytocin receptor gene
might provide a particularly significant mechanism for ex-
IMPLICATIONS FOR TREATMENT WITH OXYTOCIN
plaining individual differences in social behavior (for a re-
OR OXYTOCIN AGONISTS
view, see reference 132).
On the basis of these data on the biology of parenting, one Although standard psychiatric medications (antidepressants,
might speculate that decreased serum concentrations of antipsychotics, mood stabilizers) are known to exert effects
oxytocin in patients with borderline personality disorder on brain circuits significant for the understanding of bor-
compared with healthy subjects (133)—probably in interaction derline personality disorder—e.g., selective serotonin reuptake
with adverse genetic disposition—result from early maltreat- inhibitors (SSRIs) may increase the functional connectivity
ment, which has been frequently reported in borderline in the prefrontal-limbic circuit and decrease limbic activity
personality disorder (134), and correlated with oxytocin levels in response to negative stimuli (138), and antipsychotics may
in this study (133). This assumption is supported by data modulate the prefrontal output to basal ganglia circuits (for
showing lower cerebrospinal concentrations of oxytocin in a review, see reference 139)—they are of limited benefit in
individuals with a history of early traumatization (135). Low treating borderline personality disorder (140, 141). Psycho-
oxytocin concentrations may increase the risk of poor social therapy is recommended as the primary treatment for the
reciprocity in the adult life of individuals with borderline disorder (142), with evidence-based psychotherapy programs
personality disorder, may contribute to threat hypersensitivity, having common and differential treatment targets. Dialec-
and may impede affect regulation capacities and experiences tical behavior therapy has a major focus on improving af-
of social reward and support. Thus, oxytocin may be an im- fect dysregulation via modulation of amygdala activity and
portant mediator of the intergenerational transmission of early prefrontal-limbic connectivity (143; R. Schmitt et al., unpub-
adversities in borderline personality disorder (for a review, see lished 2015 data), mentalization-based therapy primarily
reference 136). This conclusion is supported by data show- targets attachment and empathy processes (144), and schema-
ing that mothers with secure attachment exhibited a higher focused therapy deals with rejection hypersensitivity and af-
oxytocin response while interacting with their 7-month-old fect dysregulation (145).
child compared with mothers with insecure/dismissing at- The development of more effective pharmacotherapy that
tachment, and oxytocin response was associated with greater may boost or enhance the effects of psychotherapy is urgently
neuronal activity in the reward circuit while the mothers were needed for this highly disabling psychiatric disorder. Al-
viewing their own child smiling and crying (137). Figure 1 provides though research on the therapeutic potential of oxytocin is in

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ROLE OF OXYTOCIN IN THE PATHOPHYSIOLOGY OF BORDERLINE PERSONALITY DISORDER

its infancy, this review suggests that oxytocin may exert Received February 17, 2015; revision received May 14, 2015; accepted May
effects on at least five biobehavioral mechanisms that are 15, 2015.
central to borderline psychopathology (Figure 2). Indeed,
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