Marianne Goodman, MD

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.

 Use of emotion regulation strategies taught in 

 (DBT) correlates with decreased activity in the amygdala.

 of functional MRI (fMRI) findings in persons with borderline personality disorder (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).

 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 

 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.

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.

The Neurobiology of Borderline Personality Disorder

Neural correlates of disturbed emotion processing in borderline personality disorder: a multimodal meta-analysis

2. Ruocco AC, Amirthavasagam S, Choi-Kain LW, McMain SF. 

Neural correlates of negative emotionality in borderline personality disorder: an activation-likelihood-estimation meta-analysis

3. New AS, Hazlett EAB, Buchsbaum AS, et al. 

Amygdala-prefrontal disconnection in borderline personality disorder

4. Goodman M, Carpenter D, Tang CY, et al. 

Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder

This quiz was originally published on February 13, 2017, and has since been updated. -Ed

Poll

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

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.

. 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.

 Ruocco AC, Amirthavasagam S, Choi-Kain LW, McMain SF. Neural correlates of negative emotionality in borderline personality disorder: an activation-likelihood-estimation meta-analysis. 

 Goodman M, Perez-Rodriguez M, Siever L. The neurobiology of adolescent-onset borderline personality disorder. In: Sharp C, Tackett JL, eds. 

Handbook of Borderline Personality Disorder in Children and Adolescents

. New York: Springer Science and Business Media; 2014.

 Schulze L, Schmahl C, Niedtfeld I. Neural correlates of disturbed emotion processing in borderline personality disorder: a multimodal meta-analysis. 

 New AS, Hazlett EAB, Buchsbaum AS, et al. Amygdala-prefrontal disconnection in borderline personality disorder. 

 Goodman M, Carpenter D, Tang CY, et al. Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder. 

 Krause-Utz A, Winter D, Niedtfeld I, Schmahl C. The latest neuroimaging findings in borderline personality disorder. 

 Gunderson JG, Zanarini MC, Choi-Kain LW, et al. Family study of borderline personality disorder and its sectors of psychopathology. 

 Kendler KS, Myers J, Reichborn-Kjennerud T. Borderline personality disorder traits and their relationship with dimensions of normative personality: a web-based cohort and twin study. 

 Perez-Rodriguez M, Weinstein S, New AS, et al. Tryptophan-hydroxylase 2 haplotype association with borderline personality disorder and aggression in a sample of patients with personality disorders and healthy controls. 

 Amad A, Ramos N, Thomas P, et al. Genetics of borderline personality disorder: systematic review and proposal of an integrative model. 

 Ni X, Chan D, Chan K, et al. Serotonin genes and gene-gene interactions in borderline personality disorder in a matched case-control study. 

Prog Neuropsychopharmacol Biol Psychiatry

 Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. 

 Puglia MH, Lillard TS, Morris JP, Connelly JJ. Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain. 

 Ebert A, Kolb M, Heller J, et al. Modulation of interpersonal trust in borderline personality disorder by intranasal oxytocin and childhood trauma. 

 Herpertz SC, Bertsch K. A new perspective on the pathophysiology of borderline personality disorder: a model of the role of oxytocin. 

 Simeon D, Bartz J, Hamilton H, et al. Oxytocin administration attenuates stress reactivity in borderline personality disorder: a pilot study. 

 Bertsch K, Gamer M, Schmidt B, et al. Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. 

 BrÃ¼ne M, Ebert A, Kolb M, et al. Oxytocin influences avoidant reactions to social threat in adults with borderline personality disorder. 

 Torgersen S, Kringlen E, Cramer V. The prevalence of personality disorders in a community sample. 

Articles

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

Editor's note: CME testing has expired for this article. It is for informational purposes only.

After reading this article, you will be familiar with:



• Ways to distinguish between borderline personality disorder and bipolar disorder
• Diagnoses based on mood episodes, impulsivity, and longitudinal course of borderline personality disorder and bipolar disorder
• Treatment implications - pharmacological and psychosocial interventions



Who will benefit from reading this article?


Psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing and certification boards.

 diagnosis in DSM, there have been multiple efforts to recast the disorder as part of an Axis I illness category. While the initial focus was on the 

 more recent authors have attempted to link BPD to 

. There is considerable literature on the relationship between 

 and BPD, and although the current understanding posits distinct disorders, overlapping biological underpinnings do exist.

 Attention has now turned to bipolar disorder, with several vocal advocates who propose reclassifying BPD as bipolar spectrum disorder.

 This article discusses the overlapping phenomenology of 

 and BPD and highlights distinguishing features of clinical diagnosis and treatment.

, the prevalence of BPD is estimated at 2% of the general population, compared with 1% to 2% for bipolar disorder. Other estimates are closer to 5% for bipolar spectrum disorder.

 Depending on the population studied, there are varying estimates of the 

co-occurrence of BPD and bipolar disorder

. In a recent comprehensive review by Paris and colleagues,

 the rate of bipolar I disorder in BPD patients ranged from 5.6% to 16.1%, with a median of 9.2%. The rate of bipolar II disorder was only slightly higher, 8% to 19%, with a median of 10.7%. The 2 studies with the strongest methodologies that used structured diagnostic interviews with adequate sample sizes and a 6- to 7-year follow-up showed a low rate of new onset of bipolar disorder in patients with BPD, with no difference from the comparison groups.

 A recent study that used the large Collaborative Longitudinal Study of Personality Disorders (CLPS) database, however, showed an increased rate of bipolar I and II disorders in patients with BPD compared with patients who had personality disorders other than BPD, including schizotypal, avoidant, and obsessive-compulsive personality disorders (19.4% and 7.9%, respectively). In addition, BPD patients had a higher rate of bipolar I and II disorder onset (8.2% for BPD vs 3.1% for the other personality disorders) over 4 years.

 While these studies suggest a moderately increased risk for bipolar disorder in patients with BPD, it was not nearly as high as the risk for MDD or substance abuse.

The rate of BPD in patients with bipolar I disorder varies from 0.5% to 30%, with a median of 10.7%, while in patients with bipolar II disorder, the rates are 12% to 23%, with a median of 16%

 The relationship of BPD and cyclothymia has been examined in 1 study, and the results revealed exceptionally high comorbidity rates with BPD of 62%.

 However, while elevated rates of comorbid personality disorders have been found in patients with bipolar disorder, no differences between rates of BPD and the other personality disorders studied have emerged.6 These findings suggest that while BPD and bipolar disorder can co-occur, in general, comorbidity is not common.


Diagnosis of bipolar disorder or BPD can be difficult, because both can present with affective instability, irritability, and impulsivity. A comparison of DSM-IV-TR criteria is displayed in Table 1 and demonstrates considerable overlap.

 differs significantly from that of BPD. Factor analyses of manic symptoms have identified psychic and motor acceleration, psychosis, and irritability.

 A factor analysis and subsequent replication study revealed 3 factors for BPD: disturbed relatedness, behavioral dysregulation, and affective dysregulation.

 However, a number of recent studies have shown that the BPD factors correlate so highly with one another (with correlation coefficients of 0.92 to 0.98) that the factor analyses actually support a single overarching BPD construct.

Recent studies that explored the overlap of BPD and bipolar disorder have outlined sever­al parameters to distinguish the 2 diagnoses

• Quality of mood episodes
• Types of impulsivity
• Longitudinal course

Symptoms such as irritability and quality of de­pres­sion have not proved helpful.


While both disorders cause mood instability and affective reactivity, the phenomenologies of the mood episodes differ. In BPD, mood swings, usually of negative affect, are triggered by interpersonal stressors or perceived stressors, are transient, last from minutes to hours, and are highly dependent on the environment. In bipolar disorder, mood swings are more spontaneous and of longer duration, especially for bipolar I disorder, and there are more extended periods of elation. In addition, in bipolar disorder, acute episodes and symptom-free intervals occur, while in BPD, the affective instability is part of a characteristic pattern of emotional responding. Data suggest that these affective problems persist throughout the life course of the disorder and may be identified by par­ents of children with BPD as early as infancy.

The mood swings of BPD and bipolar II disorder differ in emotion type as well. Individuals with BPD swing from euthymia to anger, and euthymia is infrequent, while bipolar II disorder affective shifts are from euthymia to elation.

Shifts triggered by interpersonal stressors in BPD, which often involve rejection or perceived abandonment, are less prevalent in bipolar disorder.

 The differentiation of BPD and rapid cycling bipolar disorder remains problematic, as both disorders involve a high degree of affective instability, and the 2 entities are likely to have significant biological and possibly genetic overlap.

 Findings from these 3 studies suggest that careful detailing of the duration of mood episodes, qualitative emotional shifts, recurrent triggering events, and longitudinal patterns (episodic vs lasting) can help distinguish between BPD and bipolar disorder, although not rapid cycling forms of bipolar disorder.


Impulsivity is behavior that occurs without reflection, is inconsistent with context, and is seen in both BPD and bipolar disorder.

 Differential patterns of impulsivity have been characterized for the depressive and manic phases of bipolar disorder with motor impulsivity (tendency to act on the spur of the moment) specific to mania and non-planning impulsivity (lack of sense of the future) specific to depression. Impulsivity in BPD is also characterized as non-planning.

 These data support the premise that BPD may have more symptomatic overlap with the depressive pole of bipolar disorder than with the manic pole.

Similarly, BPD was distinguished from bipolar II disorder by the presence of hostility and differing patterns of impulsivity. Bipolar II disorder showed attentional impulsivity characterized by distractibility and inability to focus on a task, and BPD displayed non-planning impulsiveness. The highest rate of impulsivity was found in populations with comorbid BPD and bipolar II disorder, which suggests that this group may be at the highest risk for self-damaging behaviors.

 This finding argues for the need to make both diagnoses when appropriate.

Clinically, impulsivity is believed to be more episodic in bipolar disorder than in BPD, although inter-episode impulsivity is seen in bipolar disorder when comorbid substance abuse complicates the clinical picture.

 Impulsive acts such as suicidal behavior occur in both disorders, but in bipolar disorder these are predominantly found in the depressive phase, particularly in mixed depressive presentations, and they are related to hopelessness while in BPD, they are often a function of the inability to tolerate distress.


Long-term outcome studies in bipolar disorder and BPD seem to challenge the traditional Axis I/Axis II dichotomy, in which mood disorders are widely thought of as episodic and treatable, whereas personality disorders are considered life-long and treatment refractory. Many cases of bipolar disorder assume a chronic course, with long-term morbidity and substantial inter-episode symptomatology, whereas multiyear follow-up studies of patients with BPD have found that most people eventually stop meeting threshold criteria for the disorder.

 However, there appears to be a core subset of BPD symptoms, especially in the affective and interpersonal realms, that persist even after the more dramatic impulsive or demanding behaviors have subsided. There also appears to be a subset of remission-resistant BPD patients who continue to show poor judgment and high treatment utilization.

Findings from prospective studies on the interactive effects of both disorders indicate that comorbid bipolar disorder had no effect on the clinical course of BPD with respect to functional outcome, remission rates, or number of hospitalizations or other treatment utilization except for mood-stabilizer medication.


Differentiating BPD from bipolar disorder has ramifications for treatment planning, both pharmacological and psychosocial.


While randomized clinical trials of patients with BPD have been performed using mood stabili­zers, antidepressants, and typical and atypical antipsychotics, their effect sizes have not been particularly robust. This, coupled with small sample sizes, prompted the recent Cochrane review to state that there are “insufficient data” to sup­port any recommendations for pharmacological treatment in BPD. The report concluded that medication effects in BPD are “unimpressive.”

 Despite this, although not empirically validated, study findings suggest that polypharmacy for BPD is rampant, and it is not uncommon for patients with BPD to be treated with multiple agents.

 This can result in significant iatrogenic morbidity that may outweigh the marginal clinical benefits. In contrast, pharmacological treatment in bipolar dis­order is far more effective. Eleven drugs are FDA-approved for the treatment of bipolar disorder: 9 for mania/mixed phases, 2 for depressive phases, and 5 for maintenance therapy (several are approved for more than one phase of the illness).

Although similar medications are used for both BPD and bipolar disorder, the clinical effectiveness of the medications and target symptoms of the disorders differ. In bipolar I disorder patients, mood stabilizers are the first line of treatment. In BPD, randomized controlled trials of valproate and carbamazepine have targeted impulsivity and anger rather than affective instability, while a randomized controlled trial of lithium showed no benefit at all.

Similarly, randomized controlled trials of newer mood stabilizers such as topiramate and lamotrigine have been shown to target anger rather than affective instability.

A positive clinical response has been found for antidepressants of several classes including monoamine oxidase inhibitors and SSRIs, for both the depressed phase of bipolar disorder and for BPD. The propensity of antidepressants to produce manic symptoms in patients with bipolar disorder is always a consideration despite controversy about the magnitude or clinical importance of the risk, but this does not seem to be the case for BPD. SSRIs in BPD appear to target anger and impulsivity, rather than mood symptoms; a similar finding was noted by Paris

 in a study of atypical antipsychotics for both BPD and bipolar disorder.

The findings on medication treatment in patients with BPD suggest that an over-reliance on psychopharmacological strategies yields disappointing results. Medication efficacy is far more pronounced in patients with bipolar disorder.

 The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a longitudinal study of 4107 persons with bipolar disorder that evaluated treatment effectiveness, has generated valuable data on head-to-head medication trials and will continue to provide insights into optimal treatment strategies for the various phases of bipolar disorder.


Table 2 presents psychosocial treatments available to patients with bipolar disorder or BPD. Despite symptomatic overlap, the types of interventions differ by disorder.

In contrast to the meager efficacy of pharmacological treatment for BPD, psychosocial treatments have shown substantial promise and many psychotherapeutic interventions that focus on teaching emotion-regulation skills exist. These include:


• Systems training for emotional predictability and problem solving (STEPPS)

Psychoeducation has been identified as an inte­-gral component in the treatment of BPD, and it has been usefully extended to family members as well.

In bipolar disorder, the value of psychosocial interventions is gaining recognition as an im­portant adjuvant treatment. The therapeutic aims of psychosocial approaches for bipolar disorder include psychoeducation, stress management, and regularity in daily activitiesand biosocial rhythms.

John is a 50-year-old, white, never-married man who initially presented with irritability and depression. He denied any current or past suicidal or homicidal ideation but endorsed a past history of “mood swings.” He had been given a diagnosis of bipolar II disorder 10 years earlier. John described his moods as never vacillating to periods of elation but rather as centered on feelings of hostility and anger. He had a 20-year history of heavy alcohol use and reported that he had completed a court-mandated alcohol rehabilitation program several years earlier.

Over the next few sessions, his preoccupation with his partner’s fidelity and whereabouts, his dependency on others, identity confusion, and impulsivity manifested themselves. He had rapid mood shifts in session, particularly when the discussion centered on his current romantic relationship of 5 months. Given the quality of his mood swings and associated symptoms, BPD was diagnosed and John was referred for medication management and dialectical behavior therapy.

 and as exemplified by this case, persons with BPD often receive a diagnosis of bipolar spectrum disorder. The failure to appreciate the BPD diagnosis, whether from misdiagnosis or a hesitancy to offer a stigmatizing label, can affect treatment outcome. As previously discussed, the effects can range from overuse of medication and potential poly­pharmacy to an underappreciation of empirically validated psychological treatments of BPD.


BPD and bipolar disorder are both associated with significant levels of mortality and morbidity, and they present diagnostic challenges because of their phenotypic overlap. However, paying attention to the patient’s quality of mood shifts, types of impulsivity, and longitudinal course may aid in distinguishing between the 2 disorders. Accurate diagnosis is important because each disorder has a distinct medication response and set of psychosocial interventions. The possibility of comorbid presentation also requires consideration because this may have an impact on the risk of self-damaging behaviors.

Drugs Mentioned in This Article
arbamazepine (Carbatrol, Tegretol, others)
Lamotrigine (Lamictal)
Lithium (Eskalith, Lithane, Lithobid)
Topiramate (Topamax)
Valproate/Valproic acid (Depakote, others)

1. Lerner HD, Sugarman A, Gaughran J. Borderline and schizophrenic patients. A comparative study of defensive structure. J Nerv Ment Dis. 1981;169:705-711.
2. Goodman MN, Triebwaser J, Collins K, Siever LJ. Phenotype, endophenotype and genotype comparisons between borderline personality disorder and major depressive disorder. J Pers Disord. In press.
3. Akiskal HS, Chen SE, Davis GC, et al. Borderline: an adjective in search of a noun. J Clin Psychiatry. 1985;46:41-48.
4. Deltito J, Martin L, Riefkohl J, et al. Do patients with borderline personality disorder belong to the bipolar spectrum? J Affect Disord. 2001;67:221-228.
5. Fountoulakis KN. The contemporary face of bipolar illness: complex diagnostic and therapeutic challenges. CNS Spectr. 2008;13:763-774, 777-779.
6. Paris J, Gunderson J, Weinberg I. The interface between borderline personality disorder and bipolar spectrum disorders. Compr Psychiatry. 2007;48:145-154.
7. Links PS, Heslegrave RJ, Mitton JE, et al. Borderline psychopathology and recurrences of clinical disorders. J Nerv Ment Dis. 1995;183:
582-586.
8. Zanarini MC, Frankenburg FR, Hennen J, et al. Axis I comorbidity in patients with borderline personality disorder: 6-year follow-up and prediction of time to remission. Am J Psychiatry. 2004;161:2108-2114.
9. Gunderson JG, Weinberg I, Daversa MT, et al. Descriptive and longitudinal observations on the relationship of borderline personality disorder and bipolar disorder [published correction appears in Am J Psychiatry. 2006;163:1843]. Am J Psychiatry. 2006;163:1173-1178.
10. Perugi G, Toni C, Travierso MC, Akiskal HS. The role of cyclothymia in atypical depression: toward a data-based reconceptualization of the borderline-bipolar II connection. J Affect Disord. 2003;73:87-98.
11. Erkiran MS, SÃ¶nmez G, Evren C, et al. Factor analytic symptom structure of manic episode and its relationship with affective temperaments. Turk Psikiyatri Dergisi [Turkish Journal of Psychiatry]. 2008;
19:157-166.
12. Seretti A, Cusin C, Lattuada E, et al. Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol Psychiatry. 1999;4:280-283.
13. Sanislow CA, Grilo CM, McGlashan TH. Factor analysis of the DSM-III-R borderline personality disorder criteria in psychiatric inpatients. Am J Psychiatry. 2000;157:1629-1633.
14. Sanislow CA, Grilo CM, Morey LC, et al. Confirmatory factor analysis of DSM-IV criteria for borderline personality disorder: findings from the collaborative longitudinal personality disorders study. Am J Psychiatry. 2002;159:284-290.
15. Fossati A, Madeddu F, Maffei C. Borderline Personality Disorder and childhood sexual abuse: a meta-analytic study. J Pers Disord. 1999;
13:268-280.
16. Johansen M, Karterud S, Pedersen G, et al. An investigation of the prototype validity of the borderline DSM-IV construct. Acta Psychiatr Scand. 2004;109:289-298.
17. Clifton A, Pilkonis PA. Evidence for a single latent class of Diagnostic and Statistical Manual of Mental Disorders borderline personality pathology. Compr Psychiatry. 2007;48:70-78.
18. Magill CA. The boundary between borderline personality disorder and bipolar disorder: current concepts and challenges. Can J Psychiatry. 2004;49:551-556.
19. Paris J. The treatment of borderline personality disorder: implications of research on diagnosis, etiology, and outcome. Annu Rev Clin Psychol. 2009;5:277-290.
20. Stepp SD, Pilkonis PA. Age-related differences in individual DSM criteria for borderline personality disorder. J Pers Disord. 2008;22:427-432.
21. Goodman MP, Triebwasser J, Diamond E, et al. Parental viewpoint of trajectories to borderline personality disorder in female offspring.
J Pers Disord. In press.
22. Henry C, Mitropoulou V, New AS, et al. Affective instability and impulsivity in borderline personality and bipolar II disorders: similarities and differences. J Psychiatr Res. 2001;35:307-312.
23. Koenigsberg HW, Harvey PD, Mitropoulou V, et al. Characterizing affective instability in borderline personality disorder. Am J Psychiatry. 2002;159:784-788.
24. Mackinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8:1-14.
25. Moeller FG, Barratt ES, Dougherty DM, et al. Psychiatric aspects of impulsivity. Am J Psychiatry. 2001;158:1783-1793.
26. Swann AC, Steinberg JL, Lijffijt M, Moeller FG. Impulsivity: differential relationship to depression and mania in bipolar disorder. J Affect Disord. 2008;106:241-248.
27. Flory JD, Harvey PD, Mitropoulou V, et al. Dispositional impulsivity in normal and abnormal samples. J Psychiatr Res. 2006;40:438-447.
28. Wilson ST, Stanley B, Oquendo MA, et al. Comparing impulsiveness, hostility, and depression in borderline personality disorder and bipolar II disorder. J Clin Psychiatry. 2007;68:1533-1539.
29. Swann AC, Dougherty DM, Pazzaglia PJ, et al. Impulsivity: a link
between bipolar disorder and substance abuse. Bipolar Disord. 2004;
6:204-212.
30. Goldberg JF, Perlis RH, Bowden CL, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166:173-181.
31. Dumais A, Lesage AD, Alda M, et al. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am J Psychiatry. 2005;162:2116-2124.
32. Paris J. Chronic suicidality among patients with borderline personality disorder. Psychiatr Serv. 2002;53:738-742.
33. Thase ME, Denko T. Pharmacotherapy of mood disorders. Annu Rev Clin Psychol. 2008;4:53-91.
34. Zanarini MC, Frankenburg FR, Reich DB, et al. Adult experiences of abuse reported by borderline patients and Axis II comparison subjects over six years of prospective follow-up. J Nerv Ment Dis. 2005;193:412-416.
35. Zanarini MC, Frankenburg FR, Reich DB, et al. The subsyndromal phenomenology of borderline personality disorder: a 10-year follow-up study. Am J Psychiatry. 2007;164:929-935.
36. Zanarini MC, Frankenburg FR, Hennen J, Silk KR. Mental health service utilization by borderline personality disorder patients and Axis II comparison subjects followed prospectively for 6 years. J Clin Psychiatry. 2004;65:28-36.
37. Binks CA, Fenton M, McCarthy L, et al. Pharmacological interventions for people with borderline personality disorder. Cochrane Database Syst Rev. 2006;(1):CD005653.
38. Zanarini MC, Frankenburg FR, Khera GS, Bleichmar J. Treatment histories of borderline inpatients. Compr Psychiatry. 2001;42:144-150.
39. Hollander E, Swann AC, Coccaro EF, et al. Impact of trait impulsivity and state aggression on divalproex versus placebo response in borderline personality disorder. Am J Psychiatry. 2005;162:621-624.
40. Kavoussi RJ, Coccaro EF. Divalproex sodium for impulsive aggressive behavior in patients with personality disorder. J Clin Psychiatry. 1998;59:676-680.
41. Cowdry RW, Gardner DL. Pharmacotherapy of borderline personality disorder. Alprazolam, carbamazepine, trifluoperazine, and tranylcypromine. Arch Gen Psychiatry. 1988;45:111-119.
42. Links PS, Steiner M, Boiago I, Irwin D. Lithium therapy for borderline patients: preliminary findings. J Pers Disord. 1990;4:173-181.
43. Loew TH, Nickel MK, Muehlbacher M, et al. Topiramate treatment for women with borderline personality disorder: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2006;26:61-66.
44. Tritt K, Nickel C, Lahmann C, et al. Lamotrigine treatment of aggression in female borderline-patients: a randomized, double-blind, placebo-controlled study. J Psychopharmacol. 2005;19:287-291.
45. Fountoulakis KN, Vieta E. Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol. 2008;11:999-1029.
46. Nierenberg AA. Lessons from STEP-BD for the treatment of bipolar depression. Depress Anxiety. 2009;26:106-109.
47. Linehan M. Cognitive-Behavioral Treatment of Borderline Personality Disorder. New York: Guilford Press; 1993.
48. Blum N, St John D, Pfohl B, et al. Systems Training for Emotional Predictability and Problem Solving (STEPPS) for outpatients with borderline personality disorder: a randomized controlled trial and 1-year follow-up [published correction appears in Am J Psychiatry. 2008;
165:777]. Am J Psychiatry. 2008;165:468-478.
49. Giesen-Bloo J, van Dyck R, Spinhoven P, et al. Outpatient psychotherapy for borderline personality disorder: randomized trial of schema-focused therapy vs transference-focused psychotherapy [published correction appears in Arch Gen Psychiatry. 2006;63:1008]. Arch Gen Psychiatry. 2006;63:649-658.
50. Bateman A, Fonagy P. 8-Year follow-up of patients treated for borderline personality disorder: mentalization-based treatment versus treatment as usual. Am J Psychiatry. 2008;165:631-638.
51. Clarkin JF, Levy KN, Lenzenweger MF, Kernberg OF. Evaluating three treatments for borderline personality disorder: a multiwave study. Am J Psychiatry. 2007;164:922-928.
52. Zanarini MC, Frankenburg FR. A preliminary, randomized trial of psychoeducation for women with borderline personality disorder. J Pers Disord. 2008;22:284-290.
53. Hoffman PD, Fruzzetti AE. Advances in interventions for families with a relative with a personality disorder diagnosis. Curr Psychiatry Rep. 2007;9:68-73.
54. Frank E, Swartz HA, Kupfer DJ. Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biol Psychiatry. 2000; 48:593-604.
55. Lam DH, Watkins ER, Hayward P, et al. A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the first year. Arch Gen Psychiatry. 2003;60:145- 152.
56. Colom F, Vieta E, Martinez-Aran A, et al. A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry. 2003;60:402-407.
57. Rea MM, Tompson MC, Miklowitz DJ, et al. Family-focused treatment versus individual treatment for bipolar disorder: results of a randomized clinical trial. J Consult Clin Psychol. 2003;71:482-492.
58. Miklowitz DJ, George EL, Richards JA, et al. A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Arch Gen Psychiatry. 2003; 60:904-912.
59. Simoneau TL, Miklowitz DJ, Richards JA, et al. Bipolar disorder and family communication: effects of a psychoeducational treatment program. J Abnorm Psychol. 1999;108:588-597.
60. Frank E, Hlastala S, Ritenour A, et al. Inducing lifestyle regularity in recovering bipolar disorder patients: results from the maintenance therapies in bipolar disorder protocol. Biol Psychiatry. 1997;41:1165-1173.
61. Rucci P, Frank E, Kostelnik B, et al. Suicide attempts in patients with bipolar I disorder during acute and maintenance phases of intensive treatment with pharmacotherapy and adjunctive psychotherapy. Am J Psychiatry. 2002;159:1160-1164.
62. Perry A,Tarrier N, Morriss R, et al. Randomised controlled trial of efficacy of teaching patients with bipolar disorder to identify early symptoms of relapse and obtain treatment. BMJ. 1999;318:149-153.
63. Davidson K, Norrie J,Tyrer P, et al.The effectiveness of cognitive behavior therapy for borderline personality disorder: results from the borderline personality disorder study of cognitive therapy (BOSCOT) trial. J Pers Disord. 2006;20:450-465.
64.Weinberg I, Gunderson JG, Hennen J, Cutter CJ Jr. Manual assisted cognitive treatment for deliberate self-harm in borderline personality disorder patients. J Pers Disord. 2006;20:482-492.
65. Linehan MM, McDavid JD, Brown MZ, et al. Olanzapine plus dialectical behavior therapy for women with high irritability who meet criteria for borderline personality disorder: a double-blind, placebo-controlled pilot study. J Clin Psychiatry. 2008;69:999-1005.

Since the inclusion of the borderline personality disorder (BPD) diagnosis in DSM, there have been multiple efforts to recast the disorder as part of an Axis I illness category. While the initial focus was on the schizophrenia spectrum, more recent authors have attempted to link BPD to mood disorders.

Marianne Goodman, MD

Articles

Mini Quiz: Neurobiology of Borderline Personality Disorder

The Neurobiology of Borderline Personality Disorder

Borderline Personality Disorder and Bipolar Disorder-Distinguishing Features of Clinical Diagnosis and Treatment