Genetic and epigenetic changes to the oxytocin system, especially the oxytocin receptor (OXTR) gene on chromosome 3p25.3, are associated with the pathophysiology of BPD (Figure 2). Polymorphisms, genotypes, and haplotypes within this gene are variably linked with both aggressive and prosocial behaviors.12 For example, carriers of the OXTR rs53576 A allele are more likely to perceive others negatively, experience loneliness, and endorse subjective symptoms of psychological stress with correspondingly high cortisol and other stress-related biomarkers. Prosocial behaviors, such as empathy, confidence, and positivity, decrease.
Just as genetics may predispose an individual to the development of BPD, epigenetic changes are also likely to play a role. Epigenetic modifications influence gene expression without altering DNA sequences and are dynamically shaped through environmental factors (eg, trauma). Epigenetic modifications often occur via methylation of 5´-cytosine-phosphate-guanine-3´ (CpG) dinucleotide pairs. CpG methylation within the first 3 exons of the OXTR gene reduces transcription of the OXTR protein, thereby diminishing the effects of oxytocin.13 The unavailability of OXT receptors may account for the unexpectedly low treatment response to oxytocin administration in patients with BPD.14
Oxytocin as treatment
Oxytocin is believed to regulate social cognition through the frontolimbic system, in which structural and functional differences have been identified in persons with BPD.2 In facial recognition studies, individuals with BPD are more likely to perceive negative and untrustworthy emotions, which suggests that oxytocin’s role in the salience network influences interpersonal hypersensitivity in BPD.15 Oxytocin is also involved in regulating the hypothalamic-pituitary-adrenal axis, helping to habituate the fear circuitry and extinguish the startle response in the face of previously emotionally charged stimuli. Lastly, oxytocin’s modulation of attachment and affiliative systems may influence the anger, impulsivity, and emotional lability exhibited by persons with BPD in response to perceived insult.
Three studies support the use of oxytocin in the treatment of BPD. Simeon and colleagues16 concluded that oxytocin moderately decreased stress reactivity, measured from subjective reports of dysphoria and objective measurements of plasma cortisol, in response to the Trier Social Stress Test. Bertsch and associates17 demonstrated that oxytocin decreased threat hypersensitivity, measured via eye fixation and amygdala activity, in response to angry faces. Brüne and colleagues18 also found reduced attention and avoidant reactions to angry faces in subjects with BPD after oxytocin administration. Their data suggest that oxytocin administration may interfere with trust in patients with BPD, especially in those who have been exposed to trauma.
In addition to supplementary trials that directly examine the effects of oxytocin administration in patients with BPD and the influence of epigenetics on the oxytocin system, future research is warranted regarding oxytocin’s role as adjunctive treatment to current modalities. For example, oxytocin might be used to augment individual and group DBT by increasing social cognition while decreasing hypermentalization and interpersonal hypersensitivity.
Another potential area for research is oxytocin’s role in the prevention of BPD. It is possible that oxytocin can increase attachment and enhance psychosocial interventions among struggling parents, thereby mitigating maladaptive responses to childhood trauma.
During most of the 20th century, BPD was conceptualized in psychodynamic terms: a pattern of primitive defenses adaptive in aversive childhood experiences but increasingly maladaptive in adulthood. Despite the tremendous toll BPD takes on patients and society, its existence is frequently questioned and patients are stigmatized. Research clearly demonstrates that BPD evolves from a complex interaction between environmental, anatomical, functional, genetic, and epigenetic factors. There are many risk factors, and each one serves to strengthen the others.
To treat BPD more effectively, it helps to conceptualize the major symptoms as neuropsychiatric. fMRI findings have revealed tracking changes in connectivity between complex brain networks, and epigenetic research has shown that environment influences gene expression, perpetuating maladaptive cognitions and behaviors at the neurobiological level. While functional imaging and genetic studies are beginning to gain momentum, these preliminary findings await replication with larger sample sizes, longitudinal capacities, and more refined methodologies.
Drs Pier, Marin, and Goodman are psychiatrists at Icahn School of Medicine at Mount Sinai in New York. Dr Pier is a third-year resident, Dr Marin is a second-year resident, and Dr Goodman is Clinical Professor. Dr Goodman is also the Director of Dialectical Behavioral Therapy & Suicide Prevention Studies Clinical and Research Program at the James J. Peters Veterans Affairs Medical Center, and Mental Illness Research Education and Clinical Center (MIRECC), in Veterans Integrated Service Network (VISN) 3. Ms Wilsnack is a Research Coordinator for the VISN 3 MIRECC. The authors report no conflicts of interest concerning the subject matter of this article.
1. Ruocco AC, Amirthavasagam S, Choi-Kain LW, McMain SF. Neural correlates of negative emotionality in borderline personality disorder: an activation-likelihood-estimation meta-analysis. Biol Psychiatry. 2013;73:153-160.
2. Goodman M, Perez-Rodriguez M, Siever L. The neurobiology of adolescent-onset borderline personality disorder. In: Sharp C, Tackett JL, eds. Handbook of Borderline Personality Disorder in Children and Adolescents. New York: Springer Science and Business Media; 2014.
3. Schulze L, Schmahl C, Niedtfeld I. Neural correlates of disturbed emotion processing in borderline personality disorder: a multimodal meta-analysis. Biol Psychiatry. 2016;79:97-106.
4. New AS, Hazlett EAB, Buchsbaum AS, et al. Amygdala-prefrontal disconnection in borderline personality disorder. Neuropsychopharmacol. 2007;32:1629-1640.
5. Goodman M, Carpenter D, Tang CY, et al. Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder. J Psychiatr Res. 2014;57:108-116.
6. Krause-Utz A, Winter D, Niedtfeld I, Schmahl C. The latest neuroimaging findings in borderline personality disorder. Curr Psychiatry Rep. 2014;16:438.
7. Gunderson JG, Zanarini MC, Choi-Kain LW, et al. Family study of borderline personality disorder and its sectors of psychopathology. Arch Gen Psychiatry. 2011;68:753-762.
8. Kendler KS, Myers J, Reichborn-Kjennerud T. Borderline personality disorder traits and their relationship with dimensions of normative personality: a web-based cohort and twin study. Acta Psychiatr Scand. 2011;123:349-359.
9. Perez-Rodriguez M, Weinstein S, New AS, et al. Tryptophan-hydroxylase 2 haplotype association with borderline personality disorder and aggression in a sample of patients with personality disorders and healthy controls. J Psychiatr Res. 2010;44:1075-1081.
10. Amad A, Ramos N, Thomas P, et al. Genetics of borderline personality disorder: systematic review and proposal of an integrative model. Neurosci Biobehav Rev. 2014;40:6-19.
11. Ni X, Chan D, Chan K, et al. Serotonin genes and gene-gene interactions in borderline personality disorder in a matched case-control study. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:128-133.
12. 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;12:524-538.
13. Puglia MH, Lillard TS, Morris JP, Connelly JJ. Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain. Proc Natl Acad Sci. 2015;112:3308-3313.
14. Ebert A, Kolb M, Heller J, et al. Modulation of interpersonal trust in borderline personality disorder by intranasal oxytocin and childhood trauma. Soc Neurosci. 2013;8:305-313.
15. Herpertz SC, Bertsch K. A new perspective on the pathophysiology of borderline personality disorder: a model of the role of oxytocin. Am J Psychiatry. 2015;172:840-851.
16. Simeon D, Bartz J, Hamilton H, et al. Oxytocin administration attenuates stress reactivity in borderline personality disorder: a pilot study. Psychoneuroendocrinology. 2011;36:1418-1421.
17. 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;170:1169-1177.
18. Brüne M, Ebert A, Kolb M, et al. Oxytocin influences avoidant reactions to social threat in adults with borderline personality disorder. Hum Psychopharmacol. 2013;28:552-561.
19. Torgersen S, Kringlen E, Cramer V. The prevalence of personality disorders in a community sample. Arch Gen Psychiatry. 2001;58:590-596.