Borderline Personality Disorder

US Pharm. 2007;32(11):52-58.

Borderline personality disorder (BPD) is a psychiatric condition in which patients display a "pervasive pattern of instability of interpersonal relationships, self-image, affects, and marked impulsivity that begins by early adulthood and is present in a variety of contexts."¹ It is a severe and often chronic psychiatric condition causing limitations in patients' social and occupational functioning. BPD is the most common personality disorder, with an estimated prevalence of 1% to 2% in the general population, of 10% in outpatients receiving mental health care, and of 20% in inpatients in psychiatric facilities.^1-3 Among patients clinically treated for personality disorders, 30% to 60% have been identified as having BPD. This disorder is largely diagnosed in women, with an estimated female to male ratio of 3:1; however, some studies have contradicted this and demonstrated similar prevalence between males and females.³

The prognosis for patients with BPD is variable but generally better than for those with other psychiatric conditions.⁴ Two-hundred and ninety patients with BPD participated in a study to determine what baseline predictors were most relevant regarding time to remission. Patients were evaluated every two years for a total of 10 years to ascertain if they still met the diagnostic criteria for BPD. Eighty-eight percent of 275 patients who were reassessed at least once during the 10-year follow-up achieved remission. Sixty-two percent of patients achieved remission by four years.⁵ Factors that favor a better long-term outcome include a high IQ, being unusually talented or physically attractive, the absence of parental divorce and narcissistic entitlement, and the presence of physically self-destructive acts during the index admission. Factors associated with a poorer long-term outcome include affective instability, chronic dysphoria, younger age at first treatment, increased length of prior hospitalization, antisocial behavior, substance abuse, parental brutality, family history of psychiatric illness, a problematic relationship with one's mother, and the presence of maternal psychopathology.^4,5

Etiology and Pathophysiology

The etiology of BPD is multifactorial in nature and can be broken down into genetic, neurobiological, and psychosocial components. Genetics is thought to be a large part of BPD, although specific genetic factors have not been fully elicited. Individuals with first-degree relatives who suffer from BPD are five times more likely to inherit the disorder than individuals in the general population.¹ A Norwegian twin study of 92 monozygotic and 129 dizygotic pairs demonstrated concordance rates for BPD of 35% and 7%, respectively.⁶ Multivariate genetic analyses identified four genetic factors found in patients with BPD. The factors and their prevalence are emotional dysregulation (47%), dissocial behavior (50%), inhibitedness (48%), and compulsivity (38%).⁶

There is also evidence to support the neurobiological aspects of the disorder. It has been reported that impulsive aggression is a result of reduced serotonergic activity in the orbital and medial prefrontal cortex, while the noradrenergic system may contribute to the affective instability of patients with BPD.⁶ Increased dopaminergic activity has also been reported to be associated with some of the "mini psychotic episodes" displayed in borderline patients. ⁶ These possible mechanisms explain why certain classes of medication are utilized to treat BPD

Environmental factors are thought to be the major contributor in the psychosocial component of BPD. Many borderline patients have a history of childhood trauma such as sexual or physical abuse.⁶ Childhood sexual abuse is reported in 40% to 70% of inpatients with BPD.⁵ Researchers have suggested that this early trauma may reset the hypothalamo-pituitary-adreno (HPA) axis, normally utilized by the body to manage stress.⁶ Further research is needed to fully understand the etiology of BPD and the role of various components.

Diagnosis and Clinical Presentation
The diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) are listed in TABLE 1. A patient must display at least five of the nine criteria for a diagnosis. These behaviors should represent a pattern appearing by early adulthood. TABLE 2 lists examples of symptoms that fit into three behavioral dimensions of BPD. The dimensions are affective dysregulation, impulsive-behavioral dyscontrol, and cognitive-perceptual symptoms.²

Patients with BPD have a severe fear of abandonment, which frequently leads to unrealistic accusations, displaying inappropriate anger, self-mutilation, and making impulsive decisions. Relationships with others tend to be unstable, and "splitting" commonly occurs where people or situations in their lives are viewed as all good or  all bad, right or wrong. Patients may have identity disturbances and see themselves as evil or maybe not existing at all. They may quickly trade their own values and beliefs for another individual's. Chronic self-destructive behavior is common in these patients. This includes attempted and completed suicide, self-mutilation, unsafe sexual promiscuity, substance abuse, reckless driving, gambling, spending sprees, or binge eating. Approximately 8% to 10% of borderline patients commit suicide, with many more attempting suicide sometime in their life.^1,2 Occasionally, at times of high stress, borderline patients may have transient psychotic-like symptoms lasting for minutes to hours.² 

The most common clinical comorbidities associated with BPD are mood disorders, substance-related disorders, eating disorders (especially bulimia), posttraumatic stress disorder, panic disorder, and attention-deficit hyperactivity disorder (ADHD), as well as other personality disorders.^1,2

Treatment
Treatment options for BPD include psychotherapy and pharmacotherapy. One evidence-based form of psychotherapy is dialectical behavior therapy (DBT). This consists of weekly one-hour individual sessions with a therapist for a year and weekly 2.5-hour sessions of group skills training for six to 12 months. DBT has been shown to decrease parasuicidal behavior and psychiatric hospital admissions as well as improve symptoms of depression and anger.² Other psychotherapies, such as comprehensive validation therapy (CVT), interpersonal therapy, cognitive therapy, cognitive analytic therapy (CAT), a combination of cognitive and psychodynamic therapy, and systems training for emotional predictability and problem solving (STEPPS), are being evaluated in clinical trials.^2,3

Pharmacologic therapies do not cure this disorder; instead, they are used to treat the symptoms associated with the behavioral dimensions of BPD.² No agents are currently approved by the FDA for the treatment of BPD; however, medications that have been used include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), antipsychotics (typical and atypical), mood stabilizers, benzodiazepines (BZDs), naltrexone, and ethyl-eicosapentaenoic acid (E-EPA), an omega-3 fatty acid. There is little research comparing psychotherapy and pharmacotherapy. For this reason, a combination of psychotherapy and pharmacotherapy is recommended.

Pharmacotherapy
Antidepressants: Much of the data supporting the use of antidepressants in the treatment of borderline personality disorder is from the American Psychiatric Association guidelines developed in 2001. The treatment guidelines identify several small, open-label studies using fluoxetine, sertraline, and venlafaxine for symptoms such as aggression, irritability, depressed mood, and self-mutilation.² Three randomized, double-blind, placebo-controlled trials of fluoxetine mentioned in the guidelines also showed significant improvement in depressed mood, anger, anxiety, aggression, and global functioning.² There is limited evidence of SSRI efficacy, however, in more recent randomized controlled trials. Rinne et al. conducted a double-blind, 24-week, randomized trial of fluvoxamine in female patients.⁷ Subjects were randomized to either fluvoxamine or placebo for six weeks followed by a blind half crossover to fluvoxamine for those who were on placebo. Fluvoxamine was found to have a statistically significant effect on the occurrence of rapid mood shifts independent of coexisting PTSD or depression; however, no effects on anger and impulsivity were seen.⁷ In another randomized, double-blind trial, DBT plus placebo and DBT plus fluoxetine were compared. ⁸ The fluoxetine group was not found to improve symptoms of anger, depression, anxiety, or global symptoms over the placebo group. Zanarini et al. randomized women with BPD but without comorbid major depressive disorder to fluoxetine, olanzapine, or a combination of both.⁹ Fluoxetine was the least effective treatment for aggression and depressive symptoms compared to olanzapine and the combination.

TCAs have also been used in borderline patients for depressed mood, irritability, and mood lability. Amitriptyline, imipramine, and desipramine have been studied in double-blind, placebo-controlled trials in patients with BPD.² In a double-blind, placebo-controlled trial of amitriptyline and haloperidol, amitriptyline responders improved in global functioning, depression, psychoticism, and impulsive behavior, but not in self-rated hostility.¹⁰ Nonresponders, however, had paradoxical effects demonstrated by progressive worsening in global functioning, paranoid ideation, and impulsive behavior. ¹⁰ TCAs have a more unfavorable side-effect profile compared to SSRIs. Patients taking this class of drugs often complain of sedation, constipation, dry mouth, and weight gain. Also, borderline patients are at a greater risk for suicide, and overdosing on a TCA is dangerous and potentially fatal. TCAs are not viable options for patients with cardiac abnormalities since they can induce tachycardia and arrhythmias. The usefullness of TCAs to treat comorbid depression or other symptoms of affective dysregulation is ambiguous at best. ²

MAOIs are known to improve mood-related symptoms such as depression, hostility, and impulsivity in borderline patients.² Phenelzine showed global improvement in 92% of outpatients with atypical depression and BPD as a comorbid disorder compared to imipramine.¹¹ In another double-blind, placebo-controlled, crossover trial of alprazolam, carbamazepine, trifluoperazine, and tranylcypromine, both physician and patient ratings decreased for depression, anger, and rejection sensitivity in the patients using tranylcypromine. Impulsivity and suicidality also decreased in these patients while capacity for pleasure increased. Finally, an effect on behavior dyscontrol trended toward significance.¹² Although studies have shown the benefit of using MOAIs for BPD, this drug class may not be the safest choice of medication. MAOIs have dangerous drug interactions, such as serotonin syndrome and hypertensive crises, with multiple medications, many of which are found OTC. Patients taking MAOIs must implement strict dietary restrictions to foods containing tyramine, also linked with hypertensive crises.²

Despite a lack of recent evidence, SSRIs have better side-effect profiles than other antidepressant classes and fewer drug interactions, and they are relatively safe in overdose situations. For this reason, SSRIs are recommended before the use of TCAs and MAOIs.²

Mood Stabilizers: The guidelines report the results of a trial of lithium in patients with emotionally unstable character disorder, a DSM-I diagnosis prior to BPD. Lithium decreased variations in mood and increased global improvement. Further case reports in borderline patients demonstrate that lithium has mood-stabilizing and antiaggressive effects. In a double-blind, placebo-controlled crossover trial of lithium and desipramine, therapist ratings of impulsivity decreased with use of lithium compared to placebo.² There are no other known published trials of lithium since publication of the guidelines in 2001; however, lithium appears to be useful for mood stabilization and aggression in BPD.

Divalproex sodium or valproic acid (VPA) has been shown to decrease symptoms of behavior dyscontrol and affective dysregulation in small, open-label studies.² The first double-blind, placebo-controlled trial of VPA in BPD without bipolar disorder examined effects on global improvement and functioning, depression, aggression, irritability, and suicidality, all of which were not statistically significant. The authors suggest that this may be due to a small sample size and high drop-out rate.¹³ Frankenburg et al. conducted a double-blind, placebo-controlled trial of VPA in borderline patients with bipolar II disorder.¹⁴ Significant decreases in interpersonal sensitivity, irritability, anger, hostility, and impulsive aggressiveness were noted compared to placebo, but no effects were found on depression.¹⁴ In patients with higher baseline trait impulsivity and state aggression symptoms, VPA-treated patients responded significantly better than placebo-treated patients.¹⁵ Evidence suggests that VPA may be a good option for treatment of patients with impulsive aggression and mood variations.

Carbamazepine has been studied in two double-blind, placebo-controlled trials with different results. The first trial included patients with BPD, comorbid hysteroid dysphoria, and a significant history of behavioral dyscontrol. Compared to placebo, carbamazepine decreased the frequency and severity of behavioral dyscontrol and improved anxiety, anger, and euphoria. The second trial included patients with BPD but no other major psychiatric disorders. No significant differences in behavior, impulsivity, or global improvement were found from placebo.² An open-label study of oxcarbazepine in BPD showed improvement in global functioning, anxiety, interpersonal relationships, impulsivity, affective instability, and outbursts of anger. Scores for depression, abandonment, identity, parasuicidal behavior, emptiness, dissociation, and paranoid ideation were not significantly changed.¹⁶

Lamotrigine may be a new and promising therapy to treat patients with BPD. Impulsive sexual, drug-taking, and suicidal behaviors decreased in lamotrigine responders in an open-case series of patients who had failed other therapies.¹⁷ An eight-week, double-blind, placebo-controlled trial of female patients with BPD and aggression showed significant decreases in anger outbursts and increased ability to control anger overall.¹⁸ Lamotrigine is not currently recommended in the guidelines, and, until more clinical studies prove benefit, it should be saved for patients who have failed other medications.

Topiramate may also be a viable treatment option for BPD. Two double-blind, placebo-controlled trials--one in males and the other in females--demonstrated decreased intensity and readiness to react to anger in patients taking topiramate. A decrease in anger outbursts and increased ability to control anger were also noted. ^19,20 Loew et al. compared topiramate to placebo in a double-blind, placebo-controlled trial.²¹ Compared to placebo, a significant change in somatization, interpersonal sensitivity, anxiety, hostility, phobic anxiety, and severity of mental stress was noted. There was no change in obsessive–compulsiveness, depression, paranoid ideation, or psychoticism. Topiramate also improved health-related quality of life.²¹ Until more clinical data are revealed, topiramate should also be used after other therapies have failed.

Lithium and anticonvulsant medications have shown effectiveness in treating symptoms of BPD such as mood swings and improvement in aggression and impulsivity; however, they are not effective for borderline patients with depressive symptoms.

Antipsychotics: Typical and atypical antipsychotic medications are frequently used to treat schizotypal and psychotic symptoms as well as anger and hostility in patients with BPD.²

Typical antipsychotics studied in clinical trials include thioridazine, haloperidol, perphenazine, thiothixene, loxapine, and trifluoperazine.² Studies using these medications demonstrate improvement in affective and impulsive behavioral symptoms; however, double-blind, placebo-controlled trials of haloperidol have some conflicting evidence in effectiveness. In one study, haloperidol increased global improvement, self- and observer-rated depression, anger, hostility, schizotypal symptoms, psychoticism, and impulsivity in acutely ill inpatients compared to placebo. However, another study done by the same authors in less severe patients showed a difference only in hostility, impulsivity, and aggression. Another study of haloperidol found worsened depressive symptoms and improved irritability but no significant effect on hostility.²

Clozapine, the first atypical antipsychotic, has shown improvement in positive and negative psychotic symptoms and global functioning in borderline patients with comorbid major psychotic disorders. Researchers of these studies, however, are unsure if the psychotic symptoms stem from BPD. In a study of clozapine in which all patients with comorbid major psychotic disorders were excluded, clozapine improved cognitive-perceptual, affective, and impulsive-behavior symptoms, proving its effectiveness.² A limitation to clozapine use is the monitoring required by the Clozaril National Registry (CNR) due to the risk of agranulocytosis.

More recently, other atypical antipsychotics have been used because of the decreased risk of extrapyramidal side effects (EPS). Open-label studies of ziprasidone, risperidone, and quetiapine demonstrate improved global functioning and decreased symptoms of depression, anxiety, and aggression. Mixed results were found with improvement of psychotic symptoms.^22-25 As described above, a double-blind study of olanzapine, fluoxetine, and their combination was performed. The combination was better for symptoms of aggression compared to either drug alone; however, olanzapine improved depressive symptoms better than the combination or fluoxetine.⁹ Olanzapine significantly improved interpersonal sensitivity, anxiety, anger and hostility, and paranoia in a double-blind, placebo-controlled trial of female patients with BPD, although depression was unchanged.²⁶ In another double-blind, placebo-controlled study of olanzapine or placebo combined with DBT, the olanzapine-treated group had greater improvement in depressive symptoms, anxiety, and impulsive-aggressive behavior compared to placebo.²⁷ Contradictory to these studies, Bogenschutz and Nurnberg found significant improvement in global functioning but did not find any difference in anger, aggression, anxiety, or depressive symptoms.²⁸ They theorize that this may be secondary to a lack of power to show a difference. Aripiprazole has also been studied in a double-blind, placebo-controlled trial of borderline patients. While obsessive-compulsiveness, insecurity in social contacts, depression, anxiety, paranoid thinking, psychotic symptoms, and anger all improved, aripiprazole did not improve somatization.²⁹ The aripiprazole- and placebo-treated patients from this study were followed in an 18-month open-label trial, and the results from the previous trial persisted.³⁰

Although evidence exists for the use of typical antipsychotics, EPS and sedation limit their use. Atypical antipsychotics offer similar efficacy with fewer side effects and should be used before typical antipsychotics, although long-term metabolic complications should be considered before instituting their use.

Other Therapies: BZDs are widely used as anxiolytics in patients with BPD. In a double-blind, placebo-controlled, crossover study of outpatients with BPD, hysteroid dysphoria, and behavioral dyscontrol, alprazolam was associated with increased suicidality and behavior dyscontrol.² Case reports of clonazepam as adjunctive therapy have shown beneficial effects.² BZDs have limited therapeutic evidence and therefore should not be used as monotherapy for symptom management of BPD.

Opiate antagonists, such as naloxone, have shown some benefit in case reports of borderline patients who self-mutilate. The suggested mechanism behind their use is the blockade of mutilation-induced analgesia or euphoria, thereby reducing self-injurious behavior. Lack of evidence suggests this strategy should not be used routinely. ²

A double-blind, placebo-controlled study using 1 g of E-EPA in female borderline patients was published in 2003. Results showed that E-EPA–treated patients had significant reductions in aggression and depressive symptoms.³¹ There are no other clinical trials to validate the results, but future studies may prove E-EPA beneficial for treatment of patients with BPD.

Summary
Treatment of BPD is complex and at times extremely challenging. A combination of psychotherapy and symptom-based pharmacotherapy is the most effective and comprehensive treatment for patients. Pharmacotherapy has been used to treat symptoms of affective dysregulation, impulsive-behavioral dyscontrol, and cognitive-perceptual disturbances. Treatment options include SSRIs, TCAs, MAOIs, lithium, anticonvulsant mood stabilizers, typical and atypical antipsychotics, BZDs, opiate antagonists, and omega-3 fatty acids. SSRIs are first-line treatment for symptoms of affective dysregulation and impulsive-behavioral dyscontrol. Second- or third-line therapies are TCAs and MAOIs. Antipsychotics are first-line treatment for cognitive-perceptual disturbances. Most patients will require multiple medications, including antidepressants, mood stabilizers, and antipsychotics to treat their variety of symptoms.

References
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