Current Pharmaceutical Design, 2015, 21, 000-000                            

Ali Amad^1,2, Pierre Thomas², M. Mercedes Perez-Rodriguez^3,4

1King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; ²Pôle de psychiatrie, Université de Lille, CHRU de Lille, France; ³Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; ⁴Centro de Investigacion Biomedica en Red en el Area de Salud Mental (CIBERSAM), Madrid, Spain

 

Abstract: Borderline personality disorder (BPD) is a common mental disorder characterized by a pervasive pattern of emotional lability, impulsivity, interpersonal difficulties, identity disturbances, and disturbed cognition. Traditional pharmacotherapies are effective in treating some of these core symptoms but have only modest effects on the domain of interpersonal dysfunction of BPD. Thus there is a need to develop new, neurobiologically informed pharmacological treatments for BPD. This review focuses on the potential use of intranasal oxytocin (OXT), which has key roles in the regulation of complex social cognition and behaviors, to target symptoms of interpersonal dysfunction in BPD. Surprisingly, despite promising data on the prosocial effects of OXT, only 5 trials in BPD have been published to date. These trials show mixed results with on one hand, a decrease of emotional responses to stress and on the other hand, some “paradoxical” reactions with worsened interpersonal anxiety and decreased cooperative behavior. These mixed results are interpreted according to different theoretical models and also in light of some methodological limitations. Further studies are needed to understand the effect of OXT in patients with BPD and ongoing clinical trials will provide some answers to remaining questions on the use of OXT in BPD. Recommendations for future studies are also proposed in this review.

 

INTRODUCTION

Borderline personality disorder (BPD) is a common mental disorder characterized by a pervasive pattern of emotional lability, impulsivity, interpersonal difficulties, identity disturbances, and disturbed cognition (e.g., dissociative and psychotic-like symptoms) [1]. According to factor analyses and neurobiological data, symptoms of BPD may also be conceptualized along three core domains of interpersonal dysfunction, impulsive aggression and affective dysregulation [2].

BPD is estimated to occur in 0.5–5.9% of the general population [3, 4] and is the most common personality disorder in clinical settings, affecting 10% of all psychiatric outpatients and 15%–20% of inpatients [5]. Although women are overrepresented in most clinical samples, the disorder is equally prevalent among men and women in the community [4, 6] and is likely to be diagnosed in early adulthood [3]. Follow-up studies show a decrease in impulsivity with age [7, 8]. However, associated mood disorders, functional impairment and interpersonal difficulties appear to be persistent and chronic [8]. BPD is commonly comorbid with other psychiatric disorders, notably mood disorders, anxiety disorders, substance abuse, and other personality disorders [5, 9]. Lastly, BPD is associated with high mortality due to suicide (up to 10% of patients die by suicide), frequent hospitalization, substance use, and poor quality of interpersonal relationships [5].

The etiology of borderline personality disorder is complex. Patients with BPD report many negative events during childhood, such as neglect (92%), sexual abuse (40%-70%), physical abuse (25%-73%) [10, 11], parental divorce or illness [12], and parental psychopathology [13]. However, none of these antecedents is considered specific to BPD [14]. Interestingly, the existence of a genetic component in the genesis of BPD is largely supported [15] and several recent reports, including one performed across three countries (The Netherlands, Belgium, and Australia), have consistently estimated heritability to be approximately 40%, and two studies proposed heritabilities above 60%. Moreover, studies using genetic models based on large twin cohorts provided evidence of both gene–environment interaction and gene–environment correlation.

This increasing recognition of the underlying neurobiology associated with BPD lead to reconsider treatment from the exclusive use of psychotherapy to the development of strategic approaches for evidence-based psychopharmacology [16]. In fact, several practical guidelines recommend psychotherapy with pharmacotherapy as an adjunctive component of treatment that targets state symptoms during periods of acute decompensation and trait vulnerabilities [17]. Moreover, given the key role of the serotonergic and dopaminergic systems in the core BPD symptom domains  of impulsive aggression and affective dysregulation, it is not surprising that traditional pharmacological interventions for BPD used drugs primarily targeting these two neurotransmitter systems (e.g., tricyclic antidepressants [TCAs], serotonin reuptake inhibitors [SSRIs], and antipsychotics). Subsequent multiple reviews and meta-analyses [17, 18] then converged on the effectiveness of specific anticonvulsants and atypical antipsychotic agents [16]. These traditional pharmacotherapies are effective in treating some of the core symptoms of BPD particularly in the domains of impulsive aggression and affective dysregulation and comorbid disorders such as major depressive episodes, but have only modest effects on the domain of interpersonal dysfunction and on the severity of BPD as a whole [19]. Thus, there is a need to develop new, neurobiologically informed pharmacological treatments for BPD, such as the use of intranasal oxytocin (OXT) to target symptoms of interpersonal dysfunction, which will be detailed in this review.

For many years, the dearth of knowledge regarding the neurobiological underpinnings of the interpersonal dysfunction in BPD hampered the development of specific medications targeting this symptom dimension. However, recent discoveries supporting a key role of the oxytocinergic system in modulating social cognition and interpersonal functioning have lead to subsequent clinical trials testing the effect of intranasal OXT on social cognition in BPD [2, 19]. What follows is an overview of the pharmacology of OXT, the data supporting oxytocinergic dysfunction in BPD and a review of the clinical trials of intranasal OXT in BPD.

 

PHARMACOLOGY OF INTRANASAL OXYTOCIN

OXT is a neuropeptide hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus by magnocellular and parvocellular neurons. OXT is released into the peripheral circulation from secretory vesicles stored in axonal terminals in the posterior lobe of the pituitary. OXT is also released into the extracellular space, resulting in diffusion to both local and distant targets in the brain. Finally, oxytocinergic axons from the hypothalamus project to brain regions including the amygdala, hippocampus, striatum, suprachiasmatic nucleus, bed nucleus of stria terminalis and brainstem, where OXT acts as a neuromodulator and neurotransmitter [20].

OXT has key roles in the regulation of complex social cognition and behaviors, such as attachment, social exploration, recognition and aggression, as well as anxiety, fear conditioning and fear extinction. Multiple aspects of social cognition are modulated by the balance between OXT and vasopressin, another neuropeptide [20].

OXT can be non-invasively delivered to the brain in humans, with clear behavioral and neural systems-level consequences [21]. As only a small fraction passes the blood–brain barrier after intravenous administration, most studies use intranasal OXT which is thought to provide a more direct pathway to the brain. Intranasal OXT is believed to be absorbed through three pathways: 1) Via blood capillaries underneath the nasal mucosa, into the systemic circulation, reaching peripheral targets containing OXT receptors, such as the gut, the kidneys and the heart; 2) Via the olfactory nerve and olfactory bulb, reaching brain areas including the amygdala and prefrontal cortex; 3) Via the trigeminal nerve, reaching the brainstem. There is some evidence that exogenous OXT administration also triggers endogenous OXT release [22].

Moreover, the intranasal pathway allows to avoid  peripheral side effects (e.g. uterus contraction in females) [20]. Intranasal  OXT generally promotes prosociality – e.g., increasing in-group trust and cooperation – and improves social cognitive abilities such as emotion recognition and perception of mental states [23].

The mechanism by which OXT improves social cognition and behavior is largely unknown, and may be mediated by an increase  in salience, attention towards social stimuli [24] and rewarding properties of social stimuli, through interaction with dopaminergic reward circuitry [25]. Additionally, the positive effects of OXT may be mediated by a broader reduction in the stress response in social situations. OXT exerts anxiolytic and antidepressant effects through modulating stress reactivity, mediated by interactions with monoaminergic, serotonergic and corticotrophin releasing factor systems [26]. Clinical studies indicate that OXT reduces limbic and hypothalamic-pituitary-adrenal (HPA) axis reactivity to social stressors [27–29], and that it mediates the anxiolytic and stress-protective effects of positive social interaction [20]. At the neural level, neuroimaging studies consistently found that stimulus-related  responses of the amygdala and associated areas within the prefrontal and temporal cortices are modulated by OXT administration [30]. A recently published model suggests that OXT has both bottom-up anxiolytic and approach-related behavioral effects (through binding to OXT receptors in the brainstem and peripheral targets including the gut, the kidneys and the heart), and top-down effects modulating social information processing (through binding to OXT receptors in brain regions including the amygdala and the prefrontal cortex). Thus, the brainstem and peripheral effects “would provide the “momentum” (via increases in appetitive approach behaviors), whereas the amygdala and prefrontal structures guide the “direction” (via the modulation of social information)” [22].

 

OXYTOCIN AND BORDERLINE PERSONALITY DISORDER

Considering the biological features and the effects of OXT on the human brain, a dysregulation in the oxytocinergic system has thus been suggested to contribute to the neurobiology of BPD [2]. Indeed, severe deficits in interpersonal and social functioning are a core feature of patients with BPD, who have social cognitive abnormalities causing significant disability [31–33].

Interpersonal difficulties of patients with BPD are clinically marked by unstable relationships, identity disturbance, chronic feelings of emptiness, and stress-related paranoid ideation (typically, rejection-related paranoid feelings). Critically, perceived rejection and loss often serve as triggers to impulsive, suicidal and self-injurious behavior, affective reactivity and angry outbursts [2]. On a more cognitive perspective, social abnormalities in BPD include excessive salience of social stimuli with excessive emotional reactions and attention towards social stimuli, poor mentalizing accuracy due to excessive, distorted mentalizing – termed hypermentalization [34, 35], and attentional biases towards negativelyvalenced social stimuli [36–39].

There is some limited direct evidence of any abnormalities in the oxytocinergic system in BPD. Only one study so far has assessed oxytocin levels in BPD, reporting reduced plasma oxytocin levels in female patients, even after controlling for menstrual cycle phase, estrogen, progesterone, and contraceptive intake. Plasma oxytocin was also inversely correlated with childhood emotional neglect and abuse [40]. Moreover, two recently published studies found a significant role of OXT receptor genotypes in moderating the link between early childhood adversity and later BPD symptoms [41, 42].

 

REVIEW OF CLINICAL TRIALS

For this review, electronic searches were carried out using Medline, Sciencedirect, and Google Scholar for the following terms: “borderline personality disorder” and “oxytocin”. Despite the potential promise of using OXT for BPD and the high frequency of this disorder in the general population, only 5 published trials have been found. These studies are summarized in table 1. This literature review has been completed by looking for ongoing trials (summarized in table 2) on the ClinicalTrials.gov website.

The first clinical trials using OXT in BPD treatment were published in 2011. In their pilot study, Simeon and colleagues hypothesized that OXT would attenuate emotional and hormonal responses to stress in BPD. Then, 14 patients with BPD and 13 healthy control (HC) adults received intranasal OXT or placebo in double-blind randomized order followed by the Trier Social Stress Test (TSST). The TSST is a standardized psychosocial laboratory stressor that includes public speaking and mental arithmetic and has been reliably shown to induce mild to moderate HPA axis, cardiovascular,  and psychological stress responses in clinical and non-clinical samples. Compared to HC participants, the BPD group presented a significant attenuation of the dysphoric emotional response to stress after single-dose OXT administration [43].

The same year, Bartz et al. investigated the effects of intranasal OXT on trust and cooperation in BPD. Thirteen HC and 14 patients with BPD received intranasal OXT or placebo and played a social dilemma game with a partner. Results showed that, in patients with BPD, OXT decreased trust and the likelihood of cooperative responses. These results suggest that OXT could have different effects on patients with BPD depending on chronic interpersonal insecurities, and possible differences in the OXT system regulation [36].

 

Table 1.      Clinical trials of oxytocin’s effect in borderline personality disorder.

Study	Healthy controls N (M/F)	BPD patients N (M/F)	Dosing	Other psychotropic drugs	Design	Main findings
Bartz et al. 2011 [35]	13 (7/6)	14 (4/10)	40 IU	None	RDBPC	Decreases trust and cooperation in anxiously attached BPD
Bertsch et al. 2013 [38]	41 (0/41)	40 (0/40)	26 IU	None	RDBPC	Decreases attentional bias (gaze) and amygdala reactivity to angry faces
Brune et al. 2013 [37]	13 (3/10)	13 (5/8)	24 IU	Most patients received selective serotonin reuptake inhibitors	RDBPC/CO	Decreases avoidant reactions and attentional bias to angry faces
Ebert et al. 2013 [40]	13 (3/10)	13 (5/8)	24 IU	11 patients received antidepressant (serotonin reuptake inhibitor or melatonergic)	RDBPC/CO	Decreases trust (inversely correlated with childhood emotional neglect)
Simeon et al. 2011 [39]	13 (4/9)	14 (8/6)	40 IU	None	RDBPC	Decreases emotional response, trend level decrease in cortisol response to stress

BPD = Borderline Personality Disorder; N = sample size; RDBPC = randomized, double blind, placebo-controlled, CO = cross-over

 

 

Table 2.      Ongoing Clinical trials of oxytocin’s effect in borderline personality disorder according to https://clinicaltrials.gov/

Sponsor of the study	Title of the project	Main goal of the trial	Estimated enrollment	Drugs and dosing	Design
Mount Sinai School of Medicine and MIRECC at the James J. Peters VAMC	The Effect of Oxytocin Administration on Interpersonal Cooperation in Borderline Personality Disorder Patients and Healthy Adults	Examination of behavioral patterns and underlying neural correlates which distinguish BPD from healthy controls participating in a two-person trust game	60	OXT : 24 and 40 IU Placebo	RDBPC/CO
University of Freiburg	Effects of Oxytocin on Borderline Personality Disorder.	Assess the effect of OXT as an adjunct to psychotherapy in patients with BPD	150	_	RDBPC
Mount Sinai School of Medicine and MIRECC at the James J. Peters VAMC	Examining Dose-Related Effects of Oxytocin on Social Cognition Across Populations	Assess the effect of intranasal oxytocin (OXT) as a regulator and novel treatment of social cognition impairment in BPD	45	OXT : 24 and 40 IU Placebo	RDBPC/CO

RDBPC= Randomized, double-blind, placebo-controlled; CO=Cross-Over design

 

Ebert et al. examined the effect of OXT on interpersonal behavior on 13 BPD patients and 13 HC who played a trust game after receiving OXT or placebo in a randomized, double-blind crossover design. Patients transferred less money in the OXT condition compared to placebo [44]. These results seem to support the findings from Bartz et al. [36], suggesting that patients with BPD may respond “paradoxically” to OXT, that is, they invest less in others upon the administration of OXT.

As it has been shown that OXT improves facial recognition and shifts attention away from negative social information, Bertsch  et al. investigated whether BPD patients would benefit from OXT administration. In a randomized placebo-controlled double-blind group design, 40 BPD patients and 41 matched HC took part in an emotion classification task 45 minutes after intranasal administration of OXT or placebo. BPD patients exhibited more and faster initial fixation changes to the eyes of angry faces combined with increased amygdala activation in response to angry faces compared with the HC. These abnormalities improved after OXT administration. The authors conclude that OXT may decrease social threat hypersensitivity and thus reduce anger and aggressive behavior in BPD [39].

Finally, in a double-blind randomized placebo-controlled study, Brüne et al. compared 13 BPD patients and 13 HC that performed a dot probe task to examine attentional biases to happy and angry faces after intranasal application of OXT or placebo. In the placebo condition, BPD patients showed an avoidant reaction to angry faces that was reduced by OXT [38].

 

DISCUSSION AND PERSPECTIVES FOR FUTURE RESEARCH

To summarize, the effects of intranasal OXT in patients with BPD have been mixed (see Table 1). On the one hand, OXT decreased emotional responses to stress [43], decreased avoidant reactions and attentional biases to angry facial stimuli [38], and improved the hypersensitivity to social threat found in BPD patients [39]. On the other hand, other clinical trials of OXT administration in BPD show negative or mixed results, with worsened interpersonal anxiety and decreased cooperative behavior in BPD, in comparison to HC [44], particularly among those with a history of emotional neglect in childhood [44] or those reporting anxious attachment [36].

These results may indicate differential effects of OXT depending on situational or personal characteristics (e.g. attachment style). Several explanations can be proposed to account for these differences. From a theoretical point of view, it seems that the effect of OXT is much more complex than just a pro-social effect. To explain that intranasal administration of OXT not only mediates positive social behaviors and emotions, but also negative social emotions and related behaviors, Shamay-Tsoory et al. proposed the social salience hypothesis of OXT [45]. This hypothesis posits that OXT is involved in modulating social emotions by increasing the perceived salience of social cues and that OXT mediated salience of both positivelyand negatively valenced social emotions and corresponding behaviors as a function of the context characterizing the social interaction (for review see [46]). The interactionist model proposed by Bartz et al., could also account for the mixed results observed in BPD [37]. This model proposes that OXT only enhances social cognitive function in patients with social cognitive deficits. Thus, as BPD is more characterized by social cognitive distortions and attentional biases, the effect of OXT could result in misinterpretation of social stimuli and/or excessive reaction to social cues [37].

These contrasting results could also be interpreted as due to some limitations of these trials. First, the number of patients included in these trials is very small. Only one trial recruited a wellpowered sample of 40 patients with BPD and 41 controls  [39]. Other trials were carried out on small samples of less than 15 PD patients and controls. Thus, the number of subjects recruited may not provide enough power to detect a significant effect of oxytocin. For example, Simeon et al. did not find an effect of oxytocin on the stress response in healthy volunteers (n = 13) [43], as has previously been reported in larger samples of healthy volunteers [47]. In addition, most studies, (with some exceptions [39]) did not control for menstrual cycle phase and gender, which have been shown to play an important role on the effects of OXT in healthy volunteers. Indeed, OXT levels fluctuate throughout the menstrual cycle [48] and interact with sex hormones, particularly estrogen [49]. Therefore, female subjects may respond differently to OXT administration compared to male subjects because of sex differences in circulating levels of OXT [23]. Moreover, 2 of the 5 trials included patients treated with antidepressants (selective serotonin reuptake inhibitors or melatonergic drugs). Although these treatments were chronic and stable, the role of antidepressants in the results is far from negligible since OXT interacts with many neurotransmitters including serotonin and dopamine [20]. In addition, 4 of the 5 trials study mixed groups of men and women while there is a growing body of evidence showing differential effects of OXT depending on sex [50].

Besides taking into account these limitations, future studies should compare refined phenotypes within BPD. In fact, BPD has a potentially high clinical heterogeneity. For example, with nine DSM-IV criteria and a threshold of five positive criteria for a diagnosis of BPD, there are 151 theoretically possible ways of diagnosing this disorder [5]. To refine the group of studied patients, it may be useful to perform studies on BPD patients matched for a clinical dimension such as social cognition impairment which represents a

dimension consistent with the Research Domain Criteria (RDoC) initiative [51]. The development of standardized measures of social cognition is necessary to allow for comparison of data across studies. The relationship between changes in social cognitive measures and social and interpersonal functioning also needs to be established. The problem of the optimal dosing and mode of administration of OXT will also have to be addressed because little is known about the relationship between dosing and efficacy, and mode of administration may have a key impact on drug delivery to its targets [52]. In fact, all published trials of OXT in BPD patients have used  a single-dose paradigm and an intranasal delivery mode. However, clinical trials on patients with other psychiatric disorders (e.g., schizophrenia and anxiety disorder)[23, 53] seem to indicate that some of OXT’s effects may take weeks to become clinically meaningful. Moreover, data suggest that there may be significant differences between the effects of acute and chronic administration of OXT [52]. Based on these data, it could be argued that chronic  OXT administration would be more likely to achieve a therapeutic effect in BPD patients. However, precautious must be taken because chronic administration of OXT could lead to paradoxical effects and potential dysregulation of the endogenous oxytocinergic system. This may be of particular concern when OXT is administered during development [54]. For example, a preclinical animal study recently showed that high-dose chronic intracerebroventricular OXT infusion induces an anxiogenic phenotype in mice [55].

Several key questions remain unclear, including the exact onset and duration of OXT’s effects, and whether the effects on behavior are due to central or peripheral actions of OXT [22]. Moreover, the development of new modes of administration (e.g., oral formulations of OXT agonists and antagonists that cross the blood-brain barrier) is critical for a more precise and user-friendly OXT delivery.

The study of the effect of OXT on BPD could also benefit from the application of several specific study designs. First, a pharmacogenetic design could help to understand the variability in individual responses to OXT. In fact, the gene coding for the OXT receptor (OXTR) presents several single nucleotide polymorphisms (SNPs) that have emerged as particularly promising candidates in the study of socio-behavioral phenotypes [56]. Finally, another potential application could be to use OXT as an adjunct for non pharmacological interventions for example in combination with psychotherapy, administered immediately before a session to enhance its effects [57]. OXT may indeed enhance effects of psychotherapy as it, at least in some patients, leads to improved social cognition, self perception and reduced social anxiety [58]. OXT may also enhance the effects of social cognitive remediation, as has been shown in patients with schizophrenia [59]. Recommendations for future research are summarized in box 1.

 

CONCLUSION

To conclude, despite the potential promise of using OXT for BPD only 5 published trials have been published to date. These studies show mixed results that can be interpreted according to different theoretical models but also in light of some methodological limitations. Interestingly these studies show that the effect of OXT cannot be reduced to a “pro-social” role in BPD but its effect seems much more complex. It is thus too early to imagine using OXT in BPD patients in clinical practice. Further studies are needed to understand the effect of OXT in patients with BPD and the underlying mechanisms. Recommendations for future studies are thus proposed in this article (see Box 1). Ongoing clinical trials, summarized in Table 2, will hopefully provide some answers to remaining questions on the use of OXT in BPD such as OXT dosing or its use as a monotherapy or an adjunctive therapy.

 

Box 1. Recommendations for future research regarding the use of OXT in BPD.

 

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENT

Declared none.

REFERENCES

• Lieb K, Zanarini MC, Schmahl C, Linehan MM, Bohus M. Borderline personality disorder. The Lancet 2004; 364(9432): 453-61.
• Stanley B, Siever LJ. The interpersonal dimension of borderline personality disorder: toward a neuropeptide model. Am J Psychiatry 2010; 167: 24-39.
• Lenzenweger MF, Lane MC, Loranger AW, Kessler RC. DSM-IV Personality Disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007; 62(6): 553-64.
• Grant BF, Chou SP, Goldstein RB, et al. Prevalence, correlates, disability, and comorbidity of DSM-IV borderline personality disorder: results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 2008; 69(4): 533-45.
• Skodol AE, Gunderson JG, Pfohl B, Widiger TA, Livesley WJ, Siever LJ. The borderline diagnosis I: psychopathology, comorbidity, and personality structure. Biol Psychiatry 2002; 51(12): 936-50.

• De Moor MHM, Distel MA, Trull TJ, Boomsma DI. Assessment of borderline personality features in population samples: is the Personality Assessment Inventory-Borderline Features scale measurement invariant across sex and age? Psychol Assess 2009; 21(1): 125-30.
• Stevenson J, Meares R, Comerford A. Diminished Impulsivity in Older Patients With Borderline Personality Disorder. Am J Psychiatry 2003; 160(1): 165-6.
• Zanarini MC, Frankenburg FR, Reich DB, Silk KR, Hudson JI, McSweeney LB. The Subsyndromal Phenomenology of Borderline Personality Disorder: A 10-Year Follow-Up Study. Am J Psychiatry 2007; 164(6): 929-35.
• Tomko RL, Trull TJ, Wood PK, Sher KJ. Characteristics of Borderline Personality Disorder in a Community Sample: Comorbidity, Treatment Utilization, and General Functioning. J Personal Disord 2013; 1-17.
• Zanarini MC, Williams AA, Lewis RE, et al. Reported pathological childhood experiences associated with the development of borderline personality disorder. Am J Psychiatry 1997; 154(8): 1101-6.
• Zanarini MC, Yong L, Frankenburg FR, et al. Severity of reported childhood sexual abuse and its relationship to severity of borderline psychopathology and psychosocial impairment among borderline inpatients. J Nerv Ment Dis 2002; 190(6): 381-7.
• Paris J, Zweig-Frank H, Guzder J. Psychological risk factors for borderline personality disorder in female patients. Compr Psychiatry 1994; 35(4): 301-5.
• Trull TJ. Relationships of borderline features to parental mental illness, childhood abuse, Axis I disorder, and current functioning. J Personal Disord 2001; 15(1): 19-32.
• Paris J. The nature of borderline personality disorder: multiple dimensions, multiple symptoms, but one category. J Personal Disord 2007; 21(5): 457-73.
• Amad A, Ramoz N, Thomas P, Jardri R, Gorwood P. Genetics of borderline personality disorder: systematic review and proposal of an integrative model. Neurosci Biobehav Rev 2014; 40: 6-19.
• Ripoll LH. Psychopharmacologic treatment of borderline personality disorder. Dialogues Clin Neurosci 2013; 15(2): 213-24.
• Lieb K, Vollm B, Rucker G, Timmer A, Stoffers JM. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry 2010; 196(1): 4-12.
• Stoffers J, Völlm BA, Rücker G, Timmer A, Huband N, Lieb K. Pharmacological interventions for borderline personality disorder. Cochrane Database Syst Rev 2010; (6):
• Perez-Rodriguez MM, Derish NE, New AS. The Use of Oxytocin in Personality Disorders: Rationale and Current Status. Curr Treat Options Psychiatry 2014; 1(4): 345-57.
• Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci 2011; 12: 524-38.
• Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002; 5(6): 514-6.
• Quintana DS, Alvares GA, Hickie IB, Guastella AJ. Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav Rev 2014;
• Bakermans-Kranenburg MJ, van I Jzendoorn MH. Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry Nature Publishing Group; 2013; 3(5):
• Groppe SE, Gossen A, Rademacher L, et al. Oxytocin influences processing of socially relevant cues in the ventral tegmental area of the human brain. Biol Psychiatry 2013; 74: 172-9.
• Love TM. Oxytocin, motivation and the role of dopamine. Pharmacol Biochem Behav 2014; 119: 49-60.
• Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci Elsevier Ltd; 2012; 35(11): 649-59.
• Ditzen B, Schaer M, Gabriel B, Bodenmann G, Ehlert U, Heinrichs Intranasal Oxytocin Increases Positive Communication and Reduces Cortisol Levels During Couple Conflict. Biol Psychiatry 2009; 65: 728-31.

• Quirin M, Kuhl J, Düsing R. Oxytocin buffers cortisol responses to stress in individuals with impaired emotion regulation abilities. Psychoneuroendocrinology 2011; 36(6): 898-904.
• Zink CF, Meyer-Lindenberg A. Human neuroimaging of oxytocin and vasopressin in social cognition. Horm Behav Elsevier B.V.; 2012; 61(3): 400-9.
• Kanat M, Heinrichs M, Domes G. Oxytocin and the social brain: Neural mechanisms and perspectives in human research. Brain Res 2014; 1580: 160-71.
• Jeung H, Herpertz SC. Impairments of interpersonal functioning: empathy and intimacy in borderline personality disorder. Psychopathology 2014; 47(4): 220-34.
• Lazarus SA, Cheavens JS, Festa F, Zachary Rosenthal M. Interpersonal functioning in borderline personality disorder: A systematic review of behavioral and laboratory-based assessments. Clin Psychol Rev 2014; p: 193-205.
• Mak ADP, Lam LCW. Neurocognitive profiles of people with borderline personality disorder. Curr Opin Psychiatry 2013; 26: 906.
• Dziobek I, Preißler S, Grozdanovic Z, Heuser I, Heekeren HR, Roepke S. Neuronal correlates of altered empathy and social cognition in borderline personality disorder. NeuroImage 2011; 57: 53948.
• Sharp C, Pane H, Ha C, et al. Theory of mind and emotion regulation difficulties in adolescents with borderline traits. J Am Acad Child Adolesc Psychiatry 2011; 50: 563-73.
• Bartz J, Simeon D, Hamilton H, et al. Oxytocin can hinder trust and cooperation in borderline personality disorder. Soc Cogn Affect Neurosci 2011; 6(5): 556-63.
• Bartz J a, Zaki J, Bolger N, Ochsner KN. Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci Elsevier Ltd; 2011; 15(7): 301-9.
• Brüne M, Ebert A, Kolb M, Tas C, Edel M-A, Roser P. Oxytocin influences avoidant reactions to social threat in adults with borderline personality disorder. Hum Psychopharmacol 2013;
• Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. Am J Psychiatry 2013; 170(10): 1169-77.
• Bertsch K, Schmidinger I, Neumann ID, Herpertz SC. Reduced plasma oxytocin levels in female patients with borderline personality disorder. Horm Behav 2013; 63(3): 424-9.
• Hammen C, Bower JE, Cole SW. Oxytocin Receptor Gene Variation and Differential Susceptibility to Family Environment in Predicting Youth Borderline Symptoms. J Personal Disord 2014; 1-16.
• Cicchetti D, Rogosch FA, Hecht KF, Crick NR, Hetzel S. Moderation of maltreatment effects on childhood borderline personality symptoms by gender and oxytocin receptor and FK506 binding protein 5 genes. Dev Psychopathol 2014; 26(3): 831-49.
• Simeon D, Bartz J, Hamilton H, et al. Oxytocin administration attenuates stress reactivity in borderline personality disorder: a pilot study. Psychoneuroendocrinology Elsevier Ltd; 2011; 36(9): 141821.
• Ebert A, Kolb M, Heller J, Edel M-A, Roser P, Brüne M. Modulation of interpersonal trust in borderline personality disorder by intranasal oxytocin and childhood trauma. Soc Neurosci 2013; 8: 30513.
• Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y. Intranasal administration of oxytocin increases envy and schadenfreude (gloating). Biol Psychiatry 2009; 66(9): 864-70.
• Harari-Dahan O, Bernstein A. A general approach – avoidance hypothesis of Oxytocin: Accounting for social and non-social effects of oxytocin. Neurosci Biobehav Rev 2014; 47: 506-19.
• Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003; 54(12): 138998.
• Salonia A, Nappi RE, Pontillo M, et al. Menstrual cycle-related changes in plasma oxytocin are relevant to normal sexual function in healthy women. Horm Behav 2005; 47(2): 164-9.
• Skuse DH, Gallagher L. Dopaminergic-neuropeptide interactions in the social brain. Trends Cogn Sci 2009; 13(1): 27-35.
• Hoge EA, Anderson E, Lawson EA, et al. Gender moderates the effect of oxytocin on social judgments. Hum Psychopharmacol 2014; 29(3): 299-304.
• Insel T, Cuthbert B, Garvey M, et al. Research Domain Criteria (RDoC): Toward a New Classification Framework for Research on Mental Disorders. Am J Psychiatry 2010; 167(7): 748-51.
• Macdonald K, Feifel DM. Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders. Neuroendocr Sci 2013; 7:
• Gumley A, Braehler C, Macbeth A. A meta-analysis and theoretical critique of oxytocin and psychosis: prospects for attachment and compassion in promoting recovery. Br J Clin Psychol Br Psychol Soc 2014; 53(1): 42-61.
• Bales KL, Solomon M, Jacob S, et al. Long-term exposure to intranasal oxytocin in a mouse autism model. Transl Psychiatry 2014; 4: e480.
• Peters S, Slattery DA, Uschold-Schmidt N, Reber SO, Neumann Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrinology 2014; 42: 225-36.
• Kumsta R, Heinrichs M. Oxytocin, stress and social behavior: neurogenetics of the human oxytocin system. Curr Opin Neurobiol 2013; 23(1): 11-6.
• MacDonald K, MacDonald TM, Brüne M, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology 2013; 38(12): 2831-43.
• Perez-Rodriguez M, Mahon K, Russo M, Ungar AK, Burdick KE. Oxytocin and social cognition in affective and psychotic

Eur Neuropsychopharmacol 2015; 25(2): 265-82

• Davis MC, Green MF, Lee J, et al. Oxytocin-augmented social cognitive skills training in schizophrenia. Neuropsychopharmacol 2014; 39(9): 2070-7.

 

 

 

 

Received: April 9, 2015                                                             Accepted: June 11, 2015