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A. Hyperactivity of the amygdala and prefontal cortex is characteristic of patients with BPD.

B. Increased acetylcholine activity in the hippocampus and neocortex accounts for impulsive aggression in patients with BPD.

C. Treatment of BPD with oxytocin increases hypermentalization by decreasing activity in the prefrontal cortex. 

D. Use of emotion regulation strategies taught in DBT correlates with decreased activity in the amygdala.

E. fMRI studies show that affective, cognitive, behavioral, and interpersonal difficulties are inherited rather than BPD itself.

What do functional magnetic resonance neuroimaging findings reveal about the neurobiology of borderline personality disorder? Take the quiz and learn more.

Mini Quiz: Neurobiology of Borderline Personality Disorder

For the answer, please see the next page >

Clinicians often see patients with personality disorders as treatment resistant-and, in some cases, untreatable. While it is true that patients with personality disorders may be challenging to treat, they are treatable.

Borderline Personality Disorder: Treatment Resistance Reconsidered

Do personality disorders get a bad rap? Take the quiz and learn more.

Mini Quiz: Borderline Personality Disorder

The concept of treatment resistance deserves reconsideration. Originally formulated in psychoanalytic terms, resistance in treatment referred to the inevitable ways patients unconsciously express their psychology in terms of defense mechanisms and transference enactment. This form of resistance provides a window into the patient’s problems; therefore, it is a major focus of the inquiry and intervention. Modern psychiatry defines treatment resistance as a lack of response to adequate treatment. Both conceptualizations locate treatment resistance within the patient, rather than as a product of limited, underdeveloped, and ineffective treatments. As a result, the term “treatment resistant” can fuel views of patients as “oppositional” and recalcitrant, instead of expectably symptomatic.

Trait Stages of Diagnosis for Borderline Personality Disorder

Treatment resistance is highly prevalent across most psychiatric disorders-even in common diagnoses generally associated with positive outcomes, such as depression. There are many more obstacles to effective treatment (

) than the patient’s psychological resistance alone. Identification of specific factors that diminish treatment response may provide more useful points of intervention than the label of treatment resistance.

Comorbid disorders contribute to poor treatment response. Treatment guidelines are often based on a false assumption that patients present with single disorders that respond to specific evidence-based treatments. Regardless of increasing attention to problems of comorbidity, guidelines for combining and prioritizing the treatment of different diagnoses remain largely underdeveloped.

Comorbid personality disorders complicate treatment. Over 50% of patients in specialized psychiatric settings have personality disorders.

 These patients are more likely to face social adversity, suffer from complex comorbidities, and drop out of treatment or not adhere to medication regimens-all of which contribute to an increased risk of a lack of response to treatment. The presence of a personality disorder, particularly borderline, predicts persistence of anxiety and substance use disorders as well as poorer outcomes in depressive disorders. Moreover, 13% of those who complete suicide have personality disorders.

Clinicians often see patients with personality disorders as treatment resistant-and, in some cases, untreatable.

 While it is true that patients with personality disorders may be challenging to treat, they are treatable. The self-defeating coping skills and difficulty with relationships that are central to personality disorders make a productive treatment alliance difficult to sustain. Clinicians prototypically react with feelings of frustration, disengagement, incompetence, confusion, helplessness, and even rage.

 The identification of these countertransference reactions can facilitate the diagnosis of personality disorders but can overwhelm and disturb clinicians, leading them to avoid diagnosis and personalize problems as a product of either the patient’s immutable character or the clinician’s limitations.

Our progress in understanding and treating borderline personality disorder (BPD) illustrates the benefits of centralizing the personality disorder diagnosis in care management. For over half a century, patients with BPD were identified by their negative therapeutic reactions, that is, worsening with what was thought to be otherwise appropriate treatment. While pessimism and stigma about the disorder remain, our notion of BPD’s prognosis has radically improved with research.

A major longitudinal study of BPD and other personality disorders with 16 years of follow-up showed that virtually all subjects with BPD achieve sustained remission for at least 2 years, and 78% sustain remission for 8 years. Recovery, that is attending work or school and sustaining at least one meaningful relationship, occurred for 60% of patients for 2 years, and was maintained in 40% over 8 years.

 This evidence suggests that the majority of individuals with BPD (and other personality disorders) can achieve remission and most can recover some sustained functioning, which challenges the notion that patients themselves resist treatment.

Research findings also demonstrate that BPD responds to a variety of treatments. Several specialized psychotherapies formulated for BPD-dialectical behavior therapy (DBT), mentalization-based treatment (MBT), schema-focused psychotherapy, and transference-focused psychotherapy (TFP)-reduce self-injury, suicide attempts, and hospitalizations.

These gains remain 3 years after the beginning of treatment.

Although the results are positive for long-term treatment effectiveness for BPD, difficulty in learning and implementing these psychotherapies because of their specialization and intensity renders them largely unavailable to most patients and clinicians.

 The difficulty in providing or referring patients to effective care is therefore a major factor in treatment resistance and challenges to treating BPD.

A recent meta-analysis of evidence-based psychotherapies for BPD suggests that structure and focus on BPD-related problems such as self-harm and suicidality, rather than intensity, determine outcomes.

 The small-to-medium effect sizes related to the efficacy of evidence-based therapies disappear in studies where the control treatment is structured. Intensity (ie, duration and exposure) did not appear to influence outcomes. This meta-analysis did not show significant differences between DBT and psychodynamic approaches (which included MBT and TFP). It also reported that cognitive behavioral therapy performed no better than control conditions, which indicates that structured treatment alone is not sufficient; the treatment needs to focus on BPD. These findings suggest that evidenced-based treatments might be simplified and still retain effectiveness by maintaining structure and specificity for BPD patients.

The findings from 2 large outpatient trials of DBT and MBT support the idea that less intensive but structured, informed, and systematic care of BPD patients can be effective. General Psychiatric Management (GPM)10 and Structured Clinical Management

 were compared with outpatient DBT and MBT, respectively. Both specialized and generalist approaches yielded similar decreases in suicidality and non-suicidal self-injury and improvements in interpersonal functioning and quality of life.

 While further research is needed, these findings suggest that treatment resistance can be overcome with informed and structured care. We propose the following strategies.

Good care for BPD begins with a diagnosis. Many clinicians avoid telling patients, particularly adolescents, that they have a personality disorder. But the BPD diagnosis can be made reliably before the age of 18, and early intervention is needed for better outcomes.

 When the diagnosis is made objectively and optimistically, patients typically feel less alienated and alone, as well as more hopeful. Sitting down with a patient to review the diagnostic criteria for BPD is an opportunity for clinicians and patients to think together about how each criterion can be applied to challenges the patient faces.

It is important to inform patients that social and vocational recovery is more difficult to achieve than symptom remission alone. These challenges and their course of treatment can be delivered in a clinical management approach that is not primarily psychotherapeutic. An essential part of this is to explain that difficulties in the clinical relationship are to be expected. This allows both patient and clinician to manage these disruptions, rather than react in overly personalized or pejorative ways.

The clarification of treatment goals and expectations, as well as predictions about therapeutic challenges, functions primarily to educate the patient. Psychoeducation alone can reduce symptoms of interpersonal instability and impulsivity.

 With a shared understanding of how interpersonal and emotional sensitivities connect to self-destructive tendencies (ie, self-harm or suicide attempts), the patient and clinician can communicate and collaborate around symptom management in a consistent way.

Evidence-based treatments for BPD stabilize high-intensity interchanges between self-destructive patients and their clinicians by providing an established framework for managing self-destructive behaviors. Good clinical management of any psychiatric diagnosis guides mental health professionals to establish a plan that patients can use when they have urges to hurt themselves at the beginning of treatment. When self-destructive problems arise, patients then have resources mapped out so that independent management can increasingly replace reflexive reliance on hospitalization or paging. According to GPM, clinicians can actively evaluate suicide risk by weighing risk factors (eg, prior attempts, access to means, dangerousness of plans, assessment of intent, substance use, and depression) against protective factors (eg, social supports, capacity to use skills and entertain alternatives). After these episodes, clinicians and patients can analyze what is working in the safety plan and what needs modification.

Chain analyses, reviews of the various events and internal reactions leading to self-destructive urges, are used in many evidence-based treatments for BPD.

 The chain analysis helps clinicians and patients to better understand what has happened and revise safety plans accordingly. With a shared system of managing safety and a shared expectation that reducing suicidality and self-harm is a focus of treatment, more treatment collaboration rather than resistance occurs.

BPD rarely presents without major comorbidity. Most patients with BPD also suffer from depression and anxiety disorders, and many have problems with substance use, eating, and other personality disorders. However, useful and scientifically informed guidelines for prioritizing focus on BPD over other comorbidities are provided in GPM (

 These guidelines encourage clinicians to prioritize BPD over its most common comorbidities of depression, panic disorder, generalized anxiety, and other personality disorders, because these comorbidities are less likely to remit if BPD symptoms do not improve. Moreover, randomized controlled trials of existing evidence-based treatments for BPD report concomitant reductions in depression and anxiety during and after treatment.

Other comorbidities, such as substance dependence, anorexia, and mania, must be prioritized over BPD treatments, because these disorders interfere with the learning required in BPD treatment. New evidence indicates that BPD and PTSD can be treated effectively at the same time. PTSD symptoms may even improve with the treatment of BPD alone.

These empirically informed guidelines mitigate the chaos and reactivity that challenge clinicians in their management of multiple comorbidities by providing an organizational framework. Improving BPD by enhancing coping and inter­personal functioning is likely to increase self-regulation and the sustainability of supportive relationships, while decreasing stressors. Informed management of comorbidities with BPD can reduce treatment resistance, with a focus on a central and treatable source of vulnerability and dysfunction.

Conservative prescribing of pharmacological and somatic therapies

No medication is FDA-approved for the treatment of BPD. Few randomized controlled trials have tested pharmacological treatments for BPD, and their results are inconclusive. European guidelines from the National Institute for Clinical Excellence state that existing evidence is insufficient to support any prescribing of medications, except for the treatment of diagnosable comorbidities. American Psychiatric Association guidelines, informed by meta-analysis of the small number of existing pharmacology studies, advocate for judicious use of mood stabilizers and antipsychotics for BPD symptoms related to affective instability, impulsivity, and cognitive perceptual symptoms.

Antidepressants show minimal benefit in the treatment of core BPD features. Similarly, BPD patients respond to ECT inconsistently, with lower degrees of antidepressant response and higher rates of relapse compared with patients without personality pathology.

 These psychopharmacological and somatic therapies for BPD patients should be used judiciously to target the symptoms of true comorbidities, rather than features of BPD. Conservative prescribing can reduce the burden of polypharmacy and exposure to an increasing number of treatments that are unlikely to achieve the desired results.

The concept of treatment resistance deserves reconsideration, especially in the case of BPD. While the treatment of BPD is challenging and potentially complex, the notion that it is treatment resistant is contradicted by longitudinal and treatment research that indicates high rates of remission over time, moderate rates of recovery, and significant response to structured treatments tailored to symptoms. Furthermore, exposure to adequate care is not the norm, since intensive evidence-based treatments for BPD are not easily learned or implemented. Structured generalist approaches, such as GPM, offer tips such as psychoeducation, systematic and informed management of self-destructive tendencies and comorbidities, and conservative use of pharmacological and somatic treatments. BPD may render comorbid disorders less responsive to therapy, but this may be an argument that treating BPD helps stabilize the expectable challenges and thereby reduces treatment resistance overall.

Dr. Choi-Kain is Director, Adult Borderline Center and Training Institute and McLean Gunderson Residence at McLean Hospital in Belmont, MA, as well as Assistant Professor of Psychiatry at Harvard Medical School in Boston; Mr. Glasserman and Ms. Finch are research assistants, McLean Hospital, Harvard Medical School.

The authors report no conflicts of interest concerning the subject matter of this article.

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Handbook of Good Psychiatric Management for Borderline Personality Disorder

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Borderline Personality Disorder: An Evidence-Based Guide for Generalist Mental Health Professionals

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 Harned MS, Chapman AL, Dexter-Mazza ET, et al. Treating co-occurring Axis I disorders in recurrently suicidal women with borderline personality disorder: a 2-year randomized trial of dialectical behavior therapy versus community treatment by experts. 

 Rasmussen KG. Do patients with personality disorders respond differentially to electroconvulsive therapy? A review of the literature and consideration of conceptual issues. 

While treatment of bipolar disorder challenging , the notion that it is treatment resistant is contradicted by longitudinal and treatment research that indicates high rates of remission over time, moderate rates of recovery, and significant response to structured treatments tailored to symptoms.

The authors describe an alternative model for BPD diagnosis that is dimensional in nature and requires fulfillment of 4 of 7 personality traits.

When a patient presents with episodes of depression, irritability, and emotional lability (especially tears and anger, with rapid changes), might he or she have borderline personality disorder (BPD)? Or could it be rapid cycling bipolar disorder (BD)? Although there are other possibilities, such as substance use, differentiating these 2 common conditions can be extremely difficult. DSM criteria have a roughly 90% overlap. Only

features are clearly present in one and absent in the other-namely, abandonment fear and chronic emptiness.

 as well as others have argued that borderlinity is just another version of bipolarity or at least that the “broadening of the bipolar diagnosis to include a spectrum of poorly defined conditions has added to the plausibility of this idea.”

 In refutation of this notion, data that demonstrate a clear difference between the 2 conditions-involving interpersonal trust-have 

The social psychology research tool called 

 Briefly: imagine that 2 criminals are caught simultaneously. If both cooperate with one another and tell the same false story, each can get off with a light sentence. But if one finks on the other (dubbed “Defect”), he gets off scot-free while the other takes the rap. However, if both defect, both are punished. This has been modeled in a game of cooperation. If both player and partner cooperate, each earns 40 pence. If both defect, each earns only 20 pence. But if one defects while the other cooperates, the defector earns 70 pence and the cooperator, nothing: he is punished for cooperating with a defector, whose score is actually better than could be achieved through mutual cooperation.

If such a game is played between 2 partners, just once, the best strategy is to defect: it limits losses. But if the game is played repeatedly, the best strategy in most circumstances is called “tit-for-tat”: play cooperation first and then follow the move of your partner. If he cooperates, do likewise. When he defects, also do likewise and continue thus until he plays cooperate-then follow that move as well.

The result is a test of willingness to cooperate. When euthymic bipolar patients played (ostensibly with another person, though the actual partner was a computer), they made choices very like control patients, choosing to cooperate almost 75% of the time. But patients with BPD cooperated only about 50% of the time (analysis of variance difference,

This is not a clinical tool: first of all, separation between the 2 groups was far from 100%. Second, iterative games of Prisoner’s Dilemma are not easily administered, even by computer. The point of this research is that an objectively measurable difference between BD and BPD was evident. Conclusions: (1) these 2 conditions are not variations within a species-they are different (though perhaps related) animals; and (2) the difference observed mirrors what we see clinically, namely an impairment in relationship.

Some might regard this as another instance in which social psychology goes to great lengths to prove an accepted observation (as remarked 

*: “. . . for more than 20 years I have been searching for one fact . . . discovered in a psychological laboratory which did not repeat what we already knew”5). But given the degree of controversy about the bipolar/borderline distinction, this finding seems worth passing along.

When one sits down with a patient and within 5 minutes is aware of something odd going on-excessive praise or an unwarranted devaluation or simply a sort of “latching on”-these feelings are data. Something is amiss in the social exchange. For example, you play Cooperate, he plays Defect, even after several overtures. In this context, your clinical hunch has been supported: BD may or may not be present, but the probability of borderlinity has gone up.

Thanks to our esteemed Samaritan Health Services librarian Ken Willer for access to articles like this.*

This article was originally posted on 4/12/2016 and has since been updated.

Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, OR. He is the Bipolar Disorder Section Editor for 

 Phelps J. Bipolar Disorder and “Borderline Personality Disorder.” Updated 2013. 

http://psycheducation.org/diagnosis/bipolar-disorder-and-borderline-personality-disorder/

 Deltito J, Martin L, Riefkohl J, et al. 

Do patients with borderline personality disorder belong to the bipolar spectrum?

Borderline personality disorder, but not euthymic bipolar disorder, is associated with a failure to sustain reciprocal cooperative behaviour: implications for spectrum models of mood disorders

https://en.wikipedia.org/wiki/Prisoner%27s_dilemma

 Fite W. The human soul and the scientific prepossession. 

http://www.unz.org/Pub/AtlanticMonthly-1918dec-00796

The Prisoner’s Dilemma reveals a clear distinction between the 2 conditions.

Borderline or Bipolar: Objective Data Support a Difference

Here's what's new in personality disorders: DBT treatment, DSM-5 criteria, borderline personality disorder, narcissistic personalities, and mentalization-based treatments.

The World of Personality Disorders in 6 Clinical Reports

Clarification of the molecular and biological underpinnings of borderline personality disorder (BPD) is imperative for a more thorough understanding of the disorder, one that anchors our quest for effective treatment. This article provides a brief overview of the neurobiology of BPD. Anatomical structures are reviewed as well as genetic and epigenetic factors that contribute to the pathophysiology and, potentially, to the treatment of this disorder.

Over the past decade, much of the literature concerning the biological basis of BPD has shifted to direct visualization of brain structure and function using neuroimaging. Most of the findings pertain to brain regions involved in emotional processing, such as the amygdala, insula, posterior cingulate cortex, hippocampus, anterior cingulate cortex, and prefrontal regulatory regions (

). These include the orbital frontal cortex, dorsal lateral prefrontal cortex, and ventral lateral prefrontal cortex.

. A meta-analysis of brain volume-which comprised 281 persons with BPD and 293 healthy controls-and 19 imaging studies noted left amygdala and right hippocampus gray volume decreases in persons with BPD.

 Volume studies in adolescent-onset BPD populations also exist but are limited by small sample size, discrepant imaging techniques, and highly comorbid presentations. They do not reproduce the volume differences reported in studies of adult BPD.

. A meta-analysis of functional MRI (fMRI) findings in persons with BPD revealed heightened activation during processing of negative emotional stimuli in the left amygdala, left hippocampus, and posterior cingulate cortex as well as diminished activation in prefrontal regions (including the dorsal lateral prefrontal cortex).

 Another meta-analysis showed heightened activity in the insula and less activation in the subgenual anterior cingulate cortex in persons with BPD but did not find amygdala hyperactivity.

Conflicting amygdala results are believed to result from the medication status of research participants because psychoactive drugs attenuate limbic activity. Pharmacologic probes have also shown decreased metabolic activity in the anterior cingulate cortex and orbital frontal cortex in response to serotonergic challenge in impulsive-aggressive and affectively unstable BPD populations, and decreased coupling of resting metabolism between the orbital frontal cortex and the ventral anterior cingulate cortex has been reported.

 (DBT) was found to attenuate amygdala hyperactivity at baseline, which correlated with changes in a measure of emotion regulation and increased use of emotion regulation strategies.

 Taken together, these findings highlight that dysfunctional circuits involving hyperactive limbic regions and hypoactive prefrontal modulation-most pronounced in the dorsal lateral prefrontal cortex-represent the anatomical corollaries to BPD.

. Connectivity studies developed over the past 2 years introduced novel research strategies that heavily rely on fMRI. Connectivity can be described in terms of anatomical and functional connectivity. Diffusion tensor variables of mean diffusivity and fractional anisotropy are measures of white matter integrity and anatomical connections. While such work in BPD is in its infancy, initial data suggest that deficits in frontolimbic connections relate to the severity of symptoms such as affective instability, avoidance of abandonment, and anger.

Functional connectivity analyses provide information about which brain regions are co-activated and can be studied using seed-based correlations (most often with the amygdala and dorsal anterior cingulate cortex) and independent component analysis. The 3 networks most salient in BPD are:

• The default mode: a network activated when the brain is at rest in the absence of goal-directed activity; it is influenced by the medial prefrontal cortex and posterior cingulate cortex and is responsible for self-referential thinking

• The salience network, including the orbital frontal insula and the dorsal anterior cingulate cortex

• The medial temporal lobe network, which is responsible for processing negative emotions

In BPD, there are alterations in the connections between these 3 networks with particularly problematic connectivity between salience detection and self-referential encoding. This results in misidentification with neutral stimuli as well as a failure to integrate salience information with internal representations.

These networks can be mapped on fMRI, which shows dampening of the negative correlations between the dorsal anterior cingulate cortex and the posterior cingulate cortex as well as increased connectivity of the amygdala and rostral anterior cingulate cortex. Connectivity is also heightened between the amygdala and parahippocampus as well as the ventral anterior cingulate cortex and insula. In a study that examined neural correlates of emotional distraction, persons with BPD showed positive connectivity between the amygdala and prefrontal regions (right default mode prefrontal cortex and left dorsolateral prefrontal cortex).

Symptoms of BPD are typically categorized into 4 phenotypes-the “borderline sectors”-that coexist in varying degrees within individuals with BPD and, often, in their family members.

 The affective sector includes emotions that are characteristically challenging for patients with BPD. These include loneliness, emptiness, inappropriate and intense anger, and quick fluctuations in mood.

The interpersonal sector of BPD refers to these patients’ penchant for intense and volatile relationships and their tendency to be at once manipulative, entitled, and devaluing as well as dependent, idealizing, and fearful of abandonment.

 The cognitive sector encompasses distressing perceptual disturbances, including dissociation and paranoia during times of stress.

The behavioral sector of BPD describes risky, impulsive behaviors as well as self-injury and threats of self-harm common in this population.

It is thought that the phenotypic expression of each of these sectors represents a confluence of genetic and environmental influences.

 conducted a family study to investigate the degree to which BPD clustered within families as well as how much of this clustering was attributable to genetic predispositions for borderline sectors as opposed to the disorder itself. In their study, the prevalence of BPD among relatives of probands with BPD was 14.1% compared with 4.9% in the family members of controls. The relative risk that if one family member had BPD, so too would another was 3.9 (95% confidence interval, 1.7 - 9.0) when compared with controls. Aggregation of BPD in families occurred in this study more than aggregation of any of the sectors, which supports a common pathway model of inheritance. In this model, borderline traits concentrate in families because of a genetic predisposition for the disorder rather than for the sectors themselves.

While family studies provide convincing evidence that BPD is inherited, twin studies have been invaluable to the study of heritability, the phenotypic variance attributable to genetic rather than environmental influences. A 2011 web-based study looked at the heritability of the disorder using responses to well-validated personality questionnaires.

 Study participants included 542 same-sex twin pairs, 441 of whom were monozygotic. The 4 dimensions of BPD loaded as one factor and provided further support for the common pathway model used by Gunderson and colleagues.

 Findings from the study indicate a heritability of 60%. This is similar to other twin and extended twin studies that estimate heritability to fall somewhere between 40% and 70%.

Molecular genetic studies have focused on the rate-limiting enzyme in serotonin (5-hydroxytryptamine [5-HT]) synthesis, as well as 5-HT receptor and transporter genes. 5-HT derives from tryptophan through a process mediated by tryptophan hydroxylase. Tryptophan hydroxylase 2 (TPH2) is a neuron-specific enzyme responsible for producing 5-HT in the CNS. Single nucleotide polymorphism and haplotype analyses have revealed that a gene encoding a specific TPH2 isoform is associated with higher rates of anxiety, depression, and suicidal behavior.

 genotyped patients with BPD and compared them with patients who had other personality disorders and healthy controls. They found that the previously identified TPH2 risk haplotype was more prevalent in patients with BPD (P < .05) than in controls. Subjects with the TPH2 risk haplotype exhibited higher aggression and emotional lability scores and increased suicidal behavior.

Of the serotonin receptor genes, polymorphisms in 

 have been most closely correlated with BPD. Variants of the 5HT2A receptor are known to correlate with suicide, affective lability, and impulse control. 5HTR2A polymorphisms correlate with borderline traits.

 analyzed polymorphisms in serotonin receptor genes in patients with BPD and matched controls. Their results showed an association between BPD and the 

 gene. Moreover, subjects who were homozygous for the 

 genotype had a higher frequency of the TPH2 “risk” haplotype. Taken together, the data suggest that a TPH2 “risk” haplotype may change serotonin in a way that predisposes to BPD. Patients may be more susceptible to a specific variant of 5HTR2C, which may further contribute to the pathogenesis of BPD.

Genetic and epigenetic changes to the oxytocin system, especially the oxytocin receptor (

) gene on chromosome 3p25.3, are associated with the pathophysiology of BPD (

). Polymorphisms, genotypes, and haplotypes within this gene are variably linked with both aggressive and prosocial behaviors.

 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 

 gene reduces transcription of the OXTR protein, thereby diminishing the effects of oxytocin.

 The unavailability of OXT receptors may account for the unexpectedly low treatment response to oxytocin administration in patients with BPD.

Oxytocin is believed to regulate social cognition through the frontolimbic system, in which structural and functional differences have been identified in persons with BPD.

 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.

 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 colleagues

 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 associates

 demonstrated that oxytocin decreased threat hypersensitivity, measured via eye fixation and amygdala activity, in response to angry faces. BrÃ¼ne and colleagues

 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.

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There is more to BPD than meets the eye. A complex interaction exists between environmental, anatomical, functional, genetic, and epigenetic factors. 

The Neurobiology of Borderline Personality Disorder

Mentalization-based treatment (MBT) is an evidence-based psychotherapeutic approach for borderline personality disorder. MBT is derived from both traditional psychoanalytic concepts and new discoveries from attachment and social cognition research. Mentalization simply describes the common psychological process that people use to understand mental states (ie, emotions, beliefs, desires-intentions that underlie interpersonal interactions). It covers a wide territory of psychological activity that determines the way people manage their emotions and thoughts coherently; effectively respond to their own experience and that of others; maintain satisfying relationships; and understand themselves, thereby stabilizing their sense of self (ie, identity). The stability, flexibility, benevolence, and honesty with which people mentalize underpins how their psychology works, or how their personality functions. Mentalization therefore lies at the root of psychological health and resilience as a common process relevant to all psychotherapies.

MBT’s simple, common-sense approach has practical advantages over dialectical behavioral therapy (DBT). Those who use MBT need little formal training to be effective.

 DBT requires skills coaching, a skills training curriculum with numerous handouts and worksheets, weekly individual therapy, and a consultation team to support therapists.

DBT formulates borderline personality disorder as a problem of emotional dysregulation and lack of skills to manage distress and relationships. MBT centralizes instability of attachment and its developmental byproduct, mentalization, as the core dysfunction. Fonagy and Allison

 extended the formulation of borderline personality disorder and personality disorders in general as a problem of epistemic trust, the capacity to “trust in the authenticity and personal relevance” of information presented in an interpersonal context. This revised notion explains the rigidity of thinking that individuals with borderline personality disorder (as well as those with other personality disorders) have with interpersonal relationships. Because of a tendency toward epistemic mistrust, individuals with borderline personality disorder have difficulty learning and changing despite repeated patterns of painful interpersonal problems and efforts by others to teach them how to manage less destructively.

According to attachment research and theory, infants activate attachment by communicating emotional distress to their caretakers. When all goes well, the caretaker responds in a way that re-regulates the infant. The first step of the optimal caretaking response is to recognize the infant’s distress and then reinstate confidence with soothing and optimistic encouragement to explore the environment (ie, via a secure base). Secure attachment facilitates self-regulation in terms of emotions, attentional control, and behavior. Early attachment also provides a template for expec­tations of oneself and others in relationships.

Secure attachment embodies a developmental process whereby the caretaker manages to reasonably imagine and interpret the mental states of the child, responding in a way that helps the child understand and manage his or her own distress. This is the process by which secure attachment facilitates the development of mentalization (

). For example, when a child falls and bursts into tears, a caretaker may respond in a marked contingent way with a sympathetic frown, underpinned by the idea “Poor baby, you fell and are hurt and scared.” An unmarked response might involve the caretaker actually mirroring the child and crying in distress. A noncontingent response would be completely nonresonant with the child’s experience: for example, an angry response with underlying cognitions such as “Why do you have to be so clumsy?”

If the caretaker is able to provide marked and contingent mirroring when the child is emotionally distressed, the child begins to develop a coherent sense of his own experience. This kindles the child’s ability to mentalize, allowing him to begin to understand the relationship between actions and mental states in an interpersonal interaction. This process ultimately becomes the basis of epistemic trust, which provides an openness to learn from others in a relational process. (See Bateman and Fonagy

 for a review of empirical data that support this model.)

The attachment styles most common in borderline personality disorder include preoccupied, fearful, and disorganized types that combine oscillatory, dependent, mistrustful, hostile, and incoherent features. The individual with borderline personality disorder has a tendency to engage (or make attachment bids to) others with disorganized, confusing, and controlling strategies, which in turn elicits disorganized, confusing, controlling tendencies in return.

This attachment transaction not only fails to regulate and re-establish a sense of safety, but also creates additional distress, increasing vulnerability and need in the child as well as the risk of dysregulation and burnout in the caretaker. As depicted in 

, this vicious cycle of distress and ineffective attachment functioning leads to a “hyperactivated” attachment, in which mentalizing in both child and caretaker is likely to be overwhelmed in favor of behavioral means of communication and problem solving.

While the clinical theories and neuroscientific evidence integrated in MBT’s formulation of borderline personality disorder are sophisticated, the techniques involved in MBT are simple and direct. At the base of the mentalizing stance is a position of curiosity, of being interested in exploring different perspectives of the patient’s experience both in relationships outside treatment and with the therapist. The job of the therpista is to encourage patients to mentalize, rather than do it for them by providing interpretations or by instructing them on how to manage behavior or distress. The only agenda is to sustain the mentalizing process to optimize the patient’s capacity to arrive at autonomous insight or behavioral change.

Mentalization is prone to go off­line in situations of stressful arousal (eg, intense emotion) and hyperactivated attachment. The MBT therapist intervenes when mentalizing becomes compromised. Detecting prementalistic states (

) prompts the clinician to recognize that the patient is unlikely to be able to understand her or others’ mental states realistically, benevolently, or flexibly. The clinician uses MBT techniques to broaden and thereby stabilize the patient’s capacity for empathy. According to this model, a common mistake in psychotherapeutic practice is to assume that the patient can mentalize when emotionally activated. Offering complex interpretations or behavioral plans when the patient is too vulnerable is useless because the patient is incapable of trusting the therapist or of making use of any interventions.

MBT begins with assessment and formulation of the patient’s problems and treatment goals within a mentalizing framework. The therapist and patient collaboratively explore presenting problems to establish joint attention to a shared understanding of the therapeutic work. This first step provides a secure base from which issues can be addressed as treatment unfolds.

Assessment of the patient’s overall mentalizing capacities starts with inviting a general account of problems that were the catalyst to seek treatment. Particular attention is paid to how breakdowns in mentalizing are linked to suicidal or self-destructive behaviors, and these vulnerability points are targeted as a central focus in the treatment. The therapist explores the patient’s capacity to maintain and recover mentalizing when challenged by emotionally laden interpersonal events, such as misunderstandings, disagreements, rejections (real or perceived), or intensification of intimacy. Important developmental events and attachment figures, past and present, are discussed to elucidate how robustly a person can mentalize within close relationships and where this capacity breaks down.

MBT presents a compromise to bridge the valuable history of psychoanalytic ideas to both modern psychiatric research as well as present public health needs and practice.

Borderline Personality