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Tales From the Clinic: The Art of Psychiatry,

 we cover an intriguing case of dual substance use super-imposed on mood, anxiety, and trauma clinical picture. A significant challenge for this group of patients is the need for patient, methodical, consistent care to unravel the complex multifaceted triggers and perpetuating factors for continued maladaptive behaviors. The case description spans years of treatment and, while the details may seem sensational, they reflect the reality of what the addiction treatment clinic team encounters. In addition, there is much difficulty in hearing and processing patient accounts of trauma, which could lead to physician burnout.

“Ms Martin” is a 45-year-old female with bipolar disorder, generalized anxiety disorder, and suspected borderline personality disorder. She was transferred to the substance use disorders clinic by another psychiatrist after a diagnosis of opioid use disorder was obvious. At the time of her transfer, she was involved in prostitution to finance her roughly 25 tablets of acetaminophen and hydrocodone daily. Her opioid use disorder history had a protracted course, with her first exposure to prescription opioids at the age of 16 following a significant injury requiring surgical intervention. Her longest lifetime period of sobriety was 2 years.

Her immediate environment was not conducive to recovery, as she lived in a trailer with a male roommate who had mutual acquaintances that provided pain pills. In addition, Ms Martin engaged in sexual activity with the roommate in exchange for opioids. As time progressed, the relationship became physically abusive; she left after her roommate tried to hit her with a vacuum cleaner when she “didn’t do a good job cleaning the trailer.” At the time, she had been in treatment for 1 year, was started in medication-assisted therapy (MAT), and had been prescribed buprenorphine. She moved into an apartment with her mother, which greatly reduced access to opioids. She responded very well to MAT, with an absence of significant relapses as evidenced by the drug screenings during her monthly visits.

Three years into treatment, Ms Martin met a new boyfriend. Her urine drug screen (UDS) resulted positive for amphetamine. He provided her with substances that boosted her energy and aided in weight loss. She was not fully aware of what she was taking, but she thought it might have been amphetamine since it came in a “large jar with many capsules.” Testing verified the presence of methamphetamine.

These results were shared with Ms Martin, to her genuine surprise, and she expressed earnest motivation to stop methamphetamine use. Unfortunately, over the next year, she eventually met criteria for stimulant (methamphetamine) use disorder. This paralleled toxic developments in her relationship. She described a continued strong sexual attachment to her partner, and she remained intimate with him despite knowledge that he was simultaneously sexually active with her mother. She later bashfully admitted engaging in group intercourse with her partner and mother. During intercourse she described her partner’s derogatory and sadistic tendencies, which she felt she “deserved.”

Eventually, she developed disgust toward him. This resulted in an internal conflict because while she described feeling revolted by him, she simultaneously experienced severe loneliness and feelings of abandonment when he did not give her attention. This fueled further methamphetamine use as she wanted to be “skinny and pretty.”

The ongoing sexual relationship between her partner and mother resulted in significant tension within the apartment they all shared. On multiple occasions, Ms Martin described anxiety that her partner and mother were colluding against her. Methamphetamine use may have intensified these feelings. Although at times she expressed a desire to leave, she felt she had nowhere to go. Her partner contributed to paying bills, which further complicated her situation.

For the next year, Ms Martin continued to express significant ambivalence about her relationship. She recognized how the situation placed a strain on her relationship with her mother, yet she simultaneously feared the rejection, abandonment, and loneliness that would result from a breakup. She described symptoms of anxiety and sadness when away from her partner, and he was using methamphetamine pills as a tool to control her. She compared her “love-hate” relationship with her significant other with that of her relationship with the methamphetamine pills.

In addition to work in building Ms Martin’s feelings of self-worth and autonomy, a motivational interviewing style was utilized to help her resolve some of her ambivalence toward the relationship. Although she voiced much more change talk to end the relationship, compared to sustain talk, she had difficulty committing to ending the relationship.

Due to the alarming rate of opioid overdoses secondary to fentanyl, clinicians and those struggling with substance use are becoming aware that the product purchased is not always as marketed. Anecdotal reports of increasing concomitant opioid and amphetamine use abound, but the condition is not well understood, nor systematically studied. In the case of this patient, confirmatory test showed methamphetamine, whereas she believed she was getting amphetamine or methylphenidate; she may have inadvertently gained access to a supply of methamphetamine.

Currently, there are no US Food and Drug Administration-approved treatments for methamphetamine use disorder. Some studies suggest the use of bupropion, naltrexone, and mirtazapine may have some limited efficacy in 

 In addition to treating Ms Martin’s SUD, the team addressed co-occurring mood and anxiety symptoms (she had witnessed her brother injured in a car accident). Her initial regimen included duloxetine and aripiprazole for depression, anxiety, and mood stabilization. Bupropion was not tried due to her concern of its risk of exacerbating her anxiety, and she declined mirtazapine due to its risk of weight gain because she already struggled with her body image. After Ms Martin expressed concerns that aripiprazole may be contributing to her weight gain, she was switched to cariprazine with the perceived potential benefit of weight-neutrality, since a desire for weight loss was a contributing factor to continued methamphetamine use. Another potential benefit of cariprazine includes preliminary interest in the D3 receptor affecting addictive behaviors.

Methylphenidate and lisdexamfetamine were other pharmacological therapies considered for treatment, given that Ms Martin has shown good response to replacement therapy such as buprenorphine. However, agonist substitution, while an excellent harm reduction approach, still faces stigma and resistance in clinical practice, especially for stimulant use.

According to the Centers for Disease Control, 40.4% of adults using methamphetamine within the last year also misused prescription opioids, and 16.9% used heroin between 2015 and 2018. In the United States there has been an increase in overdose deaths and hospital admissions involving 

 After limited availability of ephedrine and pseudoephedrine due to regulations, synthesis returned partially back to using phenyl-2-propanone (P2P).

 Due to increased purity and potency, there is concern that the P2P formulation may be contributing to addiction.

 This is something to keep in mind when treating a patient diagnosed with both opioid and stimulant use disorders. Unfortunately, there is no guideline as to whether MAT should be discontinued if a co-occurring substance use is still ongoing.

Ms Martin maintained abstinence from opioids while on MAT, but continued to use methamphetamine pills. The treatment team wondered if she was truly benefiting from the current level of care, and considered tapering off buprenorphine and referring her to a residential treatment program or a methadone clinic. However, Ms Martin did not have the financial resources for the latter and, in regards to the former, expressed anxiety and fear about being separated from her dog as well as the feeling of “being locked up.” Thus, her treatment team sought to maximize psychosocial support and psychotherapy interventions, but she had stopped going to group therapy and declined virtual therapy sessions.

With continued work, despite ongoing significant trauma, interpersonal conflict, financial instability, and continued methamphetamine use, Ms Martin increased engagement in treatment and is adherent with all medication management visits. The treatment team ultimately decided not to taper off the buprenorphine, given her gradual progress toward treatment goals was a product of a harm-reduction approach. She could have benefited from inpatient rehabilitation. However, reluctance to go into rehabilitation is common in patients with SUD. Additionally, most states do not allow involuntary inpatient SUD treatment as they do for involuntary psychiatric care, so patients have to suffer legal repercussion to be forced to attend court-ordered rehabilitation. Finally, many residential treatment programs may not be able to accommodate patients on MAT, as some are not yet comfortable with a harm-reduction approach or medical model of addictions treatment.

This case highlights several clinical and psychotherapeutic challenges that may arise in the treatment of substance use disorders. First, it is important to look for the presence of significant trauma in a patient with several barriers to care preventing access to psychotherapy, as there is a known link between a history of trauma and the development of 

 In this case, Ms Martin was a victim of physical, emotional, and sexual abuse. Unfortunately, there are limited standardized or manualized approaches to addressing trauma in patients with substance use disorders. When trauma informed therapy is available, access is often limited.

Similarly, another significant factor contributing to Ms Martin’s ambivalence about leaving the relationship was the codependency that existed with her partner.

Medication management visits typical to community psychiatry practice are likely not of sufficient length to address complex issues involving psychopharmacology and psychotherapy. Although the COVID-19 pandemic has accelerated the development of telepsychiatry, many patients do not have the technological means to make these visits and may not have private and safe living spaces where they can share sensitive information.

Additionally, drug use is perpetuated by perceived benefits, and cessation of use does not happen unless the patient appreciates the negative impact of substance use on their lives. When Ms Martin finally understood she was taking methamphetamine, it created an opportunity to see its use as a problem instead of an agent for cognitive enhancement/weight loss.

Methamphetamine is commonly used to improve sexual function. In fact, 

 has described methamphetamine as increasing sexual desire, pleasure, reducing the refractory period between intercourse, exacerbating impulsiveness, and impacting behavioral inhibition.

 In this case, it would be worth further exploring that idea, as the patient’s partner was supplying methamphetamine and requesting particular sexual demands.

A major challenge in the field continues to be the lack of available effective pharmacologic treatments for stimulant use disorders. Contingency management in combination with community reinforcement is a proven effective behavioral treatment for stimulant use disorders, as confirmed by 

 However, there are considerable barriers to implementing contingency management at this time, including public stigma and limited Medicaid support.

Lastly, in the context of treatment, it is often easy to feel patients are to blame for maladaptive, promiscuous, or risky behaviors. Countertransference feelings or bias may hinder patients getting expanded treatment options, especially if they display anger and hostility upon exploration of sensitive topics in session.

However, despite significant barriers to care, the presence of trauma, and ongoing struggles with stimulant use, patients demonstrate resilience and often continue to express desire for full recovery. Cognitive-behavioral therapy, relapse prevention, mindfulness, and psychodynamic therapies are all useful in treatment, but the level of complexity of patients with SUD often means a prolonged course of treatment with multiple modalities needed.

is a PGY-4 general psychiatry resident in the Menninger Department of Psychiatry & Behavioral Sciences at Baylor College of Medicine. He plans to pursue a fellowship in Addiction Psychiatry after graduation.

is an associate professor and addiction-boarded faculty at Harris Health System in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. 

 is associate professor, Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine, and Ben Taub Adult Outpatient Services director, medical director, Stabilization, Treatment & Rehabilitation (STAR) Program for Psychosis. She also serves on

1. Colfax GN, Santos GM, Das M, et al Mirtazapine to reduce methamphetamine use: a randomized controlled trial. 

2. Elkashef AM, Rawson RA, Anderson AL, et al. Bupropion for the treatment of methamphetamine dependence. 

3. Trivedi MH, Walker R, Ling W, et al. Bupropion and naltrexone in methamphetamine use disorder. 

4. Jones CM, Underwood N, Compton W. Increases in methamphetamine use among heroin treatment admissions in the United States, 2008-2017. 

5. Maxwell JC, Brecht M-L. Methamphetamine: Here we go again? 

6. Dolatshahi B, Farhoudian A, Falahatdoost M, et al. A qualitative study of the relationship between methamphetamine abuse and sexual dysfunction in male substance abusers. 

7. Wiechelt SA, Straussner SLA. Introduction to the special issue: Examining the relationship between trauma and addiction. 

8. Colfax G, Shoptaw S. The methamphetamine epidemic: Implications for HIV prevention and treatment. 

9. De Crescenzo F, Ciabattini M, D’Alò GL, et al. Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis. 

10. McMahan VM, Kingston S, Newman A, et al. Interest in reducing methamphetamine and opioid use among syringe services program participants in Washington State. 

A patient presents with multiple substance use disorders super-imposed on mood and anxiety disorders. Where does a clinician even begin?

I Had to Use

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

. Washington, DC: American Psychiatric Publishing; 2014.

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

. Oxford University Press: New York; 2013.

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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.

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

Borderline Personality