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C. Review of Pharmacotherapy and Other Somatic Treatments

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1. SSRI antidepressants

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a) Goals

In borderline personality disorder, SSRIs are used to treat symptoms of affective dysregulation and impulsive-behavioral dyscontrol, particularly depressed mood, anger, and impulsive aggression, including self-mutilation.

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b) Efficacy

Early case reports and small open-label trials with fluoxetine, sertraline, and venlafaxine (a mixed norepinephrine/serotonin reuptake blocker) indicated significant efficacy for symptoms of affective dysregulation, impulsive-behavioral dyscontrol, and cognitive-perceptual difficulties in patients with borderline personality disorder (44–49, 67). Aggression, irritability, depressed mood, and self-mutilation responded to fluoxetine (up to 80 mg/day), venlafaxine (up to 400 mg/day), or sertraline (up to 200 mg/day) in trials of 8–12 weeks (45). An unexpected finding in some of these early reports was that improvement in impulsive behavior appeared rapidly, often within the first week of treatment, and disappeared as quickly with discontinuation or nonadherence. Improvement in impulsive aggression appeared to be independent of effects on depression and anxiety and occurred whether or not the patient had comorbid major depressive disorder (67). Nonresponse to one SSRI did not predict poor response to all SSRIs. For example, some patients who did not respond to fluoxetine, 80 mg/day, responded to a subsequent trial of sertraline. Similarly, patients who did not respond to sertraline, paroxetine, or fluoxetine subsequently responded to venlafaxine. In one study, higher doses and a longer trial (24 weeks) with sertraline converted half of sertraline nonresponders to responders (45).

Three double-blind, placebo-controlled studies have been conducted. Salzman and colleagues (44) conducted a 12-week trial of fluoxetine (20–60 mg/day) in 27 relatively high-functioning subjects (mean Global Assessment Scale score of 74) with borderline personality disorder or borderline traits. Other axis I or axis II comorbid diagnoses were absent, as were recent suicidal behavior, self-mutilation, substance abuse, and current severe aggressive behavior (i.e., behaviors typical of patients with borderline personality disorder seeking treatment). This strategy diminishes generalizability to more seriously ill patients but has the advantage of allowing for a test of efficacy in the absence of comorbidity. For the 22 subjects who completed the study (13 given fluoxetine and 9 who received placebo), significant reduction in symptoms of anger and depression and improvement in global functioning were reported for subjects given fluoxetine compared with those given placebo. Improvement in anger was independent of improvement in depressed mood. Improvement was modest, with no subject improving more than 20% on any measure. In addition, a large placebo response was noted.

Markovitz (45) studied 17 patients (9 given fluoxetine, 80 mg/day, and 8 given placebo) for 14 weeks. This patient group was noteworthy for the high rate of comorbid axis I mood disorders (10 with major depression and 6 with bipolar disorder), anxiety disorders, and somatic complaints (e.g., headaches, premenstrual syndrome, irritable bowel syndrome). While this group is more typical of an impaired borderline personality disorder patient population, comorbidity with affective and anxiety disorders confounds interpretation of results. Patients receiving fluoxetine improved significantly more than those given placebo in depression, anxiety, and global symptoms. Measures of impulsive aggression were not included in this study. Some patients with premenstrual syndrome and headaches noted improvement in these somatic presentations with fluoxetine, whereas none improved with placebo.

A double-blind, placebo-controlled study by Coccaro and Kavoussi (67) focused attention on impulsive aggression as a dimensional construct (i.e., a symptom domain found across personality disorders but especially characteristic of borderline personality disorder). Forty subjects with prominent impulsive aggression in the context of a personality disorder, one-third of whom had borderline personality disorder, participated. There was a high rate of comorbidity with dysthymic disorder or depressive disorder not otherwise specified; subjects with major depression and bipolar disorder were excluded. Anxiety disorders, as well as alcohol and drug abuse, were common. In this 12-week, double-blind, placebo-controlled trial, fluoxetine (20–60 mg/day) was more effective than placebo for treatment of verbal aggression and aggression against objects. Improvement was significant by week 10, with improvement in irritability appearing by week 6. Global improvement, favoring fluoxetine, was significant by week 4. As in the open-label trials and the aforementioned Salzman et al. study (44), these investigators found that the effects on aggression and irritability did not appear as a result of improvement in mood or anxiety symptoms.

In summary, these three randomized, double-blind, placebo-controlled studies show efficacy for fluoxetine for affective symptoms—specifically, depressed mood (44, 45), anger (44), and anxiety (45, 67)—although effects on anger and depressed mood appear quantitatively modest. Efficacy has also been demonstrated for impulsive-behavioral symptoms—specifically, verbal and indirect aggression (67)—and global symptom severity (44, 45, 67). Effects on impulsive aggression (67) and anger (44) were independent of effects on affective symptoms, including depressed mood (44, 67) and anxiety (67). Although the three published double-blind, placebo-controlled trials used fluoxetine, open-label studies and clinical experience suggest potential usefulness for other SSRIs.

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c) Side effects

The side effect profile of the SSRIs is favorable compared with that of older tricyclic, heterocyclic, or MAOI antidepressants, including low risk in overdose. Side effects reported in these studies are consistent with routine clinical usage.

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d) Implementation issues

The SSRI antidepressants may be used in their customary antidepressant dose ranges and durations (e.g., fluoxetine, 20–80 mg/day; sertraline, 100–200 mg/day). One investigator used very high doses of sertraline (200–600 mg/day) for nonresponders, with some improved efficacy (45). At these high doses, peripheral tremor was noted. There are no published studies of continuation and maintenance strategies with SSRIs, although anecdotal reports suggest continuation of improvement in impulsive aggression and self-mutilation for up to several years while the medication is taken and rapid return of symptoms upon discontinuation (49, 172, 173). The duration of treatment is therefore a clinical judgment that depends on the patient's clinical status and medication tolerance at any point in time.

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2. Tricyclic and heterocyclic antidepressants

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a) Goals

In borderline personality disorder, antidepressants are used for affective dysregulation, manifested most commonly by depressed mood, irritability, and mood lability. Evaluation of antidepressant trials in the treatment of borderline personality disorder must take into account the presence of comorbid axis I mood disorders, which are common in patients with borderline personality disorder. Studies in which there is a preponderance of comorbid axis I depression would be expected to demonstrate a favorable response to antidepressant treatments but may not reflect the pharmacological responsiveness of borderline personality disorder.

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b) Efficacy

Double-blind, placebo-controlled trials of tricyclic antidepressants in borderline personality disorder have used amitriptyline, imipramine, and desipramine in both inpatient and outpatient settings. Mianserin, a tetracyclic antidepressant not available in the United States, has been used in an outpatient setting. Most of these studies were parallel comparisons with another medication and placebo. A 5-week inpatient study of patients with borderline personality disorder that compared amitriptyline (mean dose=149 mg/day) with haloperidol and placebo found that amitriptyline decreased depressive symptoms and indirect hostility and enhanced attitudes about self-control compared with placebo (51). It is interesting to note that amitriptyline was not effective for the "core" depressive features of the Hamilton Depression Rating Scale but rather was effective for the seven "associated" symptoms of diurnal variation, depersonalization, paranoid symptoms, obsessive-compulsive symptoms, helplessness, hopelessness, and worthlessness. Patients who had major depression were not more likely to respond. Schizotypal symptoms and paranoia predicted a poor response to amitriptyline.

A small crossover study comparing desipramine (mean dose=162.5 mg/day) with lithium carbonate (mean dose=985.7 mg/day) and placebo in outpatients with borderline personality disorder and minimal axis I mood comorbidity found no significant differences between desipramine and placebo in improvement of affective symptoms, anger, or suicidal symptoms or in therapist or patient perceptions of improvement after 3 and 6 weeks (61).

A small open-label study that assessed the use of amoxapine (an antidepressant with neuroleptic properties) in patients with borderline personality disorder with or without schizotypal personality disorder found that it was not effective for patients with only borderline personality disorder (174). However, it was effective for patients with borderline personality disorder and comorbid schizotypal personality disorder, who had more severe symptoms. This latter group had improvement in cognitive-perceptual, depressive, and global symptoms (174).

In outpatients with a primary diagnosis of atypical depression (which required a current diagnosis of major, minor, or intermittent depression plus associated atypical features) and borderline personality disorder as a secondary diagnosis, imipramine (200 mg/day) produced global improvement in 35% of patients with comorbid borderline personality disorder. In contrast, phenelzine had a 92% response rate in the same sample (57). The presence of borderline personality disorder symptoms predicted a negative global response to imipramine but a positive global response to phenelzine.

One longer-term study was conducted in patients hospitalized for a suicide attempt who were diagnosed with borderline personality disorder or histrionic personality disorder but not axis I depression (175). In this 6-month, double-blind, placebo-controlled study of a low dose of mianserin (30 mg/day), no antidepressant or prophylactic efficacy was found for mianserin compared with placebo for mood symptoms or recurrence of suicidal acts. (The same investigators did demonstrate efficacy against recurrent suicidal acts in this high-risk population with a depot neuroleptic, flupentixol [80].)

These data suggest that the utility of tricyclic antidepressants in patients with borderline personality disorder is highly questionable. When a clear diagnosis of comorbid major depression can be made, SSRIs are the treatment of choice. When atypical depression is present, the MAOIs have demonstrated superior efficacy to tricyclic antidepressants; however, they must be used with great caution given the high risk of toxicity. (Although the SSRIs have not been extensively studied in atypical depression, at least one double-blind study has indicated comparable efficacy for fluoxetine and phenelzine for the treatment of atypical depression [176].) The efficacy of SSRIs in borderline personality disorder and their favorable safety profile argue for their empirical use in patients with borderline personality disorder with atypical depression.

At best, the response to tricyclic antidepressants (e.g., imipramine) in patients with borderline personality disorder appears modest. The possibility of behavioral toxicity and the known lethality of tricyclic antidepressants in overdose support the preferential use of an SSRI or related antidepressant for patients with borderline personality disorder.

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c) Side effects

Common side effects of tricyclic antidepressants include sedation, constipation, dry mouth, and weight gain. The toxicity of tricyclic antidepressants in overdose, including death, indicates that they should be used with caution in patients at risk for suicide. Patients with cardiac conduction abnormalities may experience a fatal arrhythmia with tricyclic antidepressant treatment. For some inpatients with borderline personality disorder, treatment with amitriptyline has paradoxically been associated with behavioral toxicity, consisting of increased suicide threats, paranoid ideation, demanding and assaultive behaviors, and an apparent disinhibition of impulsive behavior (50, 177).

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d) Implementation issues

Other antidepressants are generally preferred over the tricyclic antidepressants for patients with borderline personality disorder. If tricyclic antidepressants are used, the patient should be carefully monitored for signs of toxicity and paradoxical worsening. Doses used in published studies were in the range of 150–250 mg/day of amitriptyline, imipramine, or desipramine. Blood levels may be a useful guide to whether the dose is adequate or toxicity is present.

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3. MAOI antidepressants

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a) Goals

MAOIs are used to treat affective symptoms, hostility, and impulsivity related to mood symptoms in patients with borderline personality disorder.

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b) Efficacy

MAOIs have been studied in patients with borderline personality disorder in three placebo-controlled acute treatment trials (55–57). In an outpatient study of phenelzine versus imipramine that selected patients with atypical depression (with borderline personality disorder as a secondary comorbid condition), global improvement occurred in 92% of patients given 60 mg/day of phenelzine compared with 35% of patients given 200 mg/day of imipramine (57). In a study of tranylcypromine, trifluoperazine, alprazolam, and carbamazepine in which borderline personality disorder was a primary diagnosis but comorbid with hysteroid dysphoria (55), tranylcypromine (40 mg/day) improved a broad spectrum of mood symptoms, including depression, anger, rejection sensitivity, and capacity for pleasure. Cowdry and Gardner (55) noted that "the MAOI proved to be the most effective psychopharmacological agent overall, with clear effects on mood and less prominent effects on behavioral control." Tranylcypromine also significantly decreased impulsivity and suicidality, with a near significant effect on behavioral dyscontrol. When borderline personality disorder is the primary diagnosis, with no selection for atypical depression or hysteroid dysphoria, results are clearly less favorable. Soloff and colleagues (56) studied borderline personality disorder inpatients with comorbid major depression (53%), hysteroid dysphoria (44%), and atypical depression (46%); the patient group was not selected for presence of a depressive disorder. Phenelzine was effective for self-rated anger and hostility but had no specific efficacy, compared with placebo or haloperidol, for atypical depression or hysteroid dysphoria. These three acute trials were 5–6 weeks in duration. A 16-week continuation study of the responding patients in a follow-up study (68) showed some continuing modest improvement over placebo beyond the acute 5-week trial for depression and irritability. Phenelzine appeared to be activating, which was considered favorable in the clinical setting.

On balance, these studies suggest that MAOIs are often helpful for atypical depressive symptoms, anger, hostility, and impulsivity in patients with borderline personality disorder. These effects appear to be independent of a current mood disorder diagnosis (56), although one study found a nonsignificantly higher rate of MAOI response for patients with a past history of major depression or bipolar II disorder (55).

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c) Side effects

Phenelzine can cause weight gain (56) and can be difficult to tolerate. Other side effects include orthostatic hypotension (55). Fatal hypertensive crises are the most serious potential side effect of MAOIs, although no study reported any hypertensive crises due to violation of the tyramine dietary restriction. The initial clinical picture of MAOI poisoning is one of agitation, delirium, hallucinations, hyperreflexia, tachycardia, tachypnea, dilated pupils, diaphoresis, and, often, convulsions. Hyperpyrexia is one of the most serious problems (178).

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d) Implementation issues

Doses of phenelzine and tranylcypromine used in published studies ranged from 60 to 90 mg/day and 10 to 60 mg/day, respectively. Experienced clinicians may vary doses according to their usual practice in treating depressive or anxiety disorders. Adherence to a tyramine-free diet is critically important and requires careful patient instruction, ideally supplemented by a printed guide to tyramine-rich foods and medication interactions, especially over-the-counter decongestants found in common cold and allergy remedies. Given the impulsivity of patients with borderline personality disorder, it is helpful to review in detail the potential for serious medical consequences of nonadherence to dietary restrictions, the symptoms of hypertensive crisis, and an emergency treatment plan in case of a hypertensive crisis. Patients must be instructed to discontinue an SSRI long enough in advance of instituting MAOI therapy to avoid precipitating a serotonin syndrome.

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4. Lithium carbonate and anticonvulsant mood stabilizers

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a) Goals

Lithium carbonate and the anticonvulsant mood stabilizers carbamazepine and divalproex sodium are used to treat symptoms of behavioral dyscontrol in borderline personality disorder, with possible efficacy for symptoms of affective dysregulation.

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b) Efficacy

The efficacy of lithium carbonate for bipolar disorder led to treatment trials in patients with personality disorders characterized by mood dysregulation and impulsive aggression. Rifkin and colleagues (179, 180) demonstrated improvement in mood swings in 21 patients with emotionally unstable character disorder, a DSM-I diagnosis characterized by brief but nonreactive mood swings, both depressive and hypomanic, in the context of a chronically maladaptive personality resembling "hysterical character." In this placebo-controlled crossover study (each medication was taken for 6 weeks), there was decreased variation in mood (i.e., fewer "mood swings") and global improvement in 14 of 21 patients during lithium treatment. Subsequent case reports demonstrated that lithium had mood-stabilizing and antiaggressive effects in patients with borderline personality disorder (181, 182).

One double-blind, placebo-controlled crossover study compared lithium with desipramine in 17 patients with borderline personality disorder (61). All patients took lithium for 6 weeks (mean dose=985.7 mg/day) and received concurrent psychotherapy. Among 10 patients completing both lithium and placebo treatments, therapists' blind ratings indicated greater improvement during the lithium trial, although patients' self-ratings did not reflect significant differences between lithium and placebo. The authors noted that therapists were favorably impressed by decreases in impulsivity during the lithium trial, an improvement not fully appreciated by the patients themselves. There has never been a double-blind, placebo-controlled trial of the antiaggressive effects of lithium carbonate in patients with borderline personality disorder selected for histories of impulsive aggression.

The anticonvulsant mood stabilizer carbamazepine has been studied in two double-blind, placebo-controlled studies that used very different patient groups, resulting in inconsistent findings. Gardner and Cowdry (55, 62), in a crossover trial, studied female outpatients with borderline personality disorder and comorbid hysteroid dysphoria along with extensive histories of behavioral dyscontrol. Patients underwent a 6-week trial of carbamazepine (mean dose=820 mg/day) and continued receiving psychotherapy. Patients had decreased frequency and severity of behavioral dyscontrol during the carbamazepine trial. Among all patients, there were significantly fewer suicide attempts or other major dyscontrol episodes along with improvement in anxiety, anger, and euphoria (by a physician's assessment only) with carbamazepine treatment compared with placebo.

De la Fuente and Lotstra (63) failed to replicate these findings, although this may be due to their small study group size (N=20). These investigators conducted a double-blind, placebo-controlled trial of carbamazepine in inpatients with a primary diagnosis of borderline personality disorder. Patients with any comorbid axis I disorder, a history of epilepsy, or EEG abnormalities were excluded. Unlike in the Cowdry and Gardner study (55), patients were not selected for histories of behavioral dyscontrol. There were no significant differences between carbamazepine and placebo on measures of affective or cognitive-perceptual symptoms, impulsive-behavioral "acting out," or global symptoms.

Divalproex sodium has been used in open-label trials targeting the agitation and aggression of patients with borderline personality disorder in a state hospital setting (70) and mood instability and impulsivity in an outpatient clinic (66). Wilcox (70) reported a 68% decrease in time spent in seclusion as well as improvement in anxiety, tension, and global symptoms among 30 patients with borderline personality disorder receiving divalproex sodium (with dose titrated to a level of 100 mg/ml) for 6 weeks in a state hospital. Patients did not have "psychiatric comorbid conditions" (by clinical assessment), although 5 had an EEG abnormality (but no seizure disorders); concurrent psychotropic medications were allowed. An abnormal EEG predicted improvement with divalproex sodium. The author noted that both the antiaggressive and antianxiety effects of divalproex sodium appeared instrumental in decreasing agitation and time spent in seclusion.

An open-label study by Stein and colleagues (66) enrolled 11 cooperative outpatients with borderline personality disorder, all of whom had been in psychotherapy for a minimum of 8 weeks and were free of other medications before starting divalproex sodium treatment, which was titrated to levels of 50–100 mg/ml. Among the 8 patients who completed the study, 4 responded in terms of global improvement and observed irritability; physician ratings of mood, anxiety, anger, impulsivity, and rejection sensitivity; and patient ratings of global improvement. There were no significant changes in measures specific for depression and anxiety, but baseline depression and anxiety scores were low in this population.

Kavoussi and Coccaro (69) also reported significant improvement in impulsive aggression and irritability after 4 weeks of treatment with divalproex sodium in 10 patients with impulsive aggression in the context of a cluster B personality disorder, 5 of whom (4 completers) had borderline personality disorder. Among the 8 patients who completed the 8-week trial, 6 had a 50% or greater reduction in aggression and irritability. All patients had not responded to a previous trial with fluoxetine (up to 60 mg/day for 8 weeks).

Only one small, randomized controlled trial of divalproex has been reported that involved patients with borderline personality disorder (65). Among 12 patients randomly assigned to divalproex, only 6 completed a 10-week trial, 5 of whom responded in terms of global measures. There was improvement in depression, albeit not statistically significant, and aggression was unchanged. None of the 4 patients randomly assigned to placebo completed the study.

In summary, preliminary evidence suggests that lithium carbonate and the mood stabilizers carbamazepine and divalproex may be useful in treating behavioral dyscontrol and affective dysregulation in some patients with borderline personality disorder, although further studies are needed. The only report on the newer anticonvulsants (i.e., gabapentin, lamotrigine, topiramate) in borderline personality disorder is a case series in which three of eight patients had a good response to lamotrigine (183). Because of the paucity of evidence concerning these agents, careful consideration of the risks and benefits is recommended when using such medications pending the publication of findings from systematic studies.

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c) Side effects

Although lithium commonly causes side effects, most are minor or can be reduced or eliminated by lowering the dose or changing the dosage schedule. More common side effects include polyuria, polydipsia, weight gain, cognitive problems (e.g., dulling, poor concentration), tremor, sedation or lethargy, and gastrointestinal distress (e.g., nausea). Lithium may also have renal effects and may cause hypothyroidism. Lithium is potentially fatal in overdose and should be used with caution in patients at risk of suicide.

Carbamazepine's most common side effects include neurological symptoms (e.g., diplopia), blurred vision, fatigue, nausea, and ataxia. Other side effects include skin rash, mild leukopenia or thrombocytopenia, and hyponatremia. Rare, idiosyncratic, but potentially fatal side effects include agranulocytosis, aplastic anemia, hepatic failure, exfoliative dermatitis, and pancreatitis. Carbamazepine may be fatal in overdose. In studies of patients with borderline personality disorder, carbamazepine has been reported to cause melancholic depression (64).

Common dose-related side effects of valproate include gastrointestinal distress (e.g., nausea), benign hepatic transaminase elevations, tremor, sedation, and weight gain. With long-term use, women may be at risk of developing polycystic ovaries or hyperandrogenism. Mild, asymptomatic leukopenia and thrombocytopenia occur less frequently. Rare, idiosyncratic, but potentially fatal adverse events include hepatic failure, pancreatitis, and agranulocytosis.

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d) Implementation issues

Full guidelines for the use of these medications can be found in the APA Practice Guideline for the Treatment of Patients With Bipolar Disorder (85; included in this volume). Lithium carbonate and the anticonvulsant mood stabilizers are used in their full therapeutic doses, with plasma levels guiding dosing. Routine precautions observed for the use of these medications in other disorders also apply to their use in borderline personality disorder, e.g., plasma level monitoring of thyroid and kidney function with prolonged lithium use, periodic measure of WBC count with carbamazepine therapy, and hematological and liver function tests for divalproex sodium.

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5. Anxiolytic agents

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a) Goals

Anxiolytic medications are used to treat the many manifestations of anxiety in patients with borderline personality disorder, both as an acute and as a chronic symptom.

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b) Efficacy

Despite widespread use, there is a paucity of studies investigating the use of anxiolytic medications in borderline personality disorder. Cowdry and Gardner (55) included alprazolam in their double-blind, placebo-controlled, crossover study of outpatients with borderline personality disorder, comorbid hysteroid dysphoria, and extensive histories of behavioral dyscontrol. Use of alprazolam (mean dose=4.7 mg/day) was associated with greater suicidality and episodes of serious behavioral dyscontrol (drug overdoses, self-mutilation, and throwing a chair at a child). This occurred in 7 (58%) of 12 patients taking alprazolam compared with 1 (8%) of 13 patients receiving placebo. However, in a small number of patients (N=3), alprazolam was noted to be helpful for anxiety in carefully selected patients with borderline personality disorder (52). Case reports suggest that clonazepam is helpful as an adjunctive agent in the treatment of impulsivity, violent outbursts, and anxiety in a variety of disorders, including borderline personality disorder (54).

Although clinicians have presented preliminary experiences with nonbenzodiazepine anxiolytics in patients with borderline personality disorder (e.g., buspirone) (184), there are currently no published studies of these anxiolytics in borderline personality disorder.

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c) Side effects

Behavioral disinhibition, resulting in impulsive and assaultive behaviors, has been reported with alprazolam in patients with borderline personality disorder. Benzodiazepines, in general, should be used with care because of the potential for abuse and the development of pharmacological tolerance with prolonged use. These are particular risks in patients with a history of substance use.

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d) Implementation issues

In the absence of clear evidence-based recommendations, dose and duration of treatment must be guided by clinical need and judgment, keeping in mind the potential for abuse and pharmacological tolerance.

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6. Opiate antagonists

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a) Goals

It has been suggested that the relative subjective numbing and physical analgesia that patients with borderline personality disorder often feel during episodes of self-mutilation, as well as the reported sense of relative well-being afterward, might be due to release of endogenous opiates (185–187). Opiate antagonists have been employed in an attempt to block mutilation-induced analgesia and euphoria and thereby reduce self-injurious behavior in patients with borderline personality disorder.

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b) Efficacy

Clinical case reports (188) and several small case series have assessed the efficacy of opiate antagonists for self-injurious behavior, and two suggested some improvement in this behavior (189, 190). One small, double-blind study involving female patients with borderline personality disorder with a history of self-injurious behavior who underwent a stress challenge showed no effect of opiate receptor blockade with naloxone on cold pressor pain perception or mood ratings (191). While the stress level may not have been high enough to mimic clinical situations, the study does not support the theory that opiate antagonism plays a role in reducing self-injurious behavior.

Despite the few promising clinical case reports, these reports are very preliminary, and there is no clear evidence from well-controlled trials indicating that opiate antagonists are effective in reducing self-injurious behavior among patients with borderline personality disorder.

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c) Side effects

Nausea and diarrhea are occasionally reported (190).

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d) Implementation issues

In published reports, the typical dose of naltrexone was 50 mg/day. No time limit for treatment emerges from the literature, but the effect is presumably reversed when the medication stops.

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7. Neuroleptics

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a) Goals

The primary goal of treatment with neuroleptics in borderline personality disorder is to reduce acute symptom severity in all symptom domains, particularly schizotypal symptoms, psychosis, anger, and hostility.

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b) Efficacy

Early clinical experience with neuroleptics targeted the "micropsychotic" or schizotypal symptoms of borderline personality disorder. However, affective symptoms (mood, anxiety, anger) and somatic complaints also improved with low doses of haloperidol, perphenazine, and thiothixene. An open-label trial of thioridazine (mean dose=92 mg/day) led to marked improvement in impulsive-behavioral symptoms, global symptom severity, and overall borderline psychopathology (78). Similar findings were reported for adolescents with borderline personality disorder treated with flupentixol (mean dose=3 mg/day) (77), with improvement in impulsivity, depression, and global functioning.

Systematic, parallel studies that compared neuroleptics without a placebo control condition also reported a broad spectrum of efficacy. Leone (73) found that loxapine succinate (mean dose=14.5 mg/day) or chlorpromazine (mean dose=110 mg/day) improved depressed mood, anxiety, anger/hostility, and suspiciousness. Serban and Siegel (74) reported that thiothixene (mean dose=9.4 mg/day, SD=7.6) or haloperidol (mean dose=3.0 mg/day, SD=0.8) produced improvement in anxiety, depression, derealization, paranoia (ideas of reference), general symptoms, and a global measure of borderline psychopathology.

Subsequent double-blind, placebo-controlled trials also suggested a broad spectrum of efficacy for low-dose neuroleptics in the treatment of borderline personality disorder. Acute symptom severity improved in cognitive-perceptual, affective, and impulsive-behavioral symptom domains, although efficacy for schizotypal symptoms, psychoticism, anger, and hostility was most consistently noted.

Many of the double-blind, placebo-controlled studies of neuroleptics in borderline personality disorder are noteworthy for biases in sample selection that strongly affected outcomes. In a study of patients with borderline or schizotypal personality disorder and at least one psychotic symptom (which biased the sample toward cognitive-perceptual symptoms), thiothixene (mean dose=8.7 mg/day for up to 12 weeks) was more effective than placebo for psychotic cluster symptoms—specifically illusions and ideas of reference—and self-rated obsessive-compulsive and phobic anxiety symptoms but not depression or global functioning (75). The more severely symptomatic patients were at baseline (e.g., in terms of illusions, ideas of reference, or obsessive-compulsive and phobic anxiety symptoms), the better they responded to thiothixene (75).

Cowdry and Gardner (55) conducted a complex, placebo-controlled, four-drug crossover study in borderline personality disorder outpatients with trifluoperazine (mean dose=7.8 mg/day). Patients were required to meet criteria for hysteroid dysphoria and have a history of extensive behavioral dyscontrol, introducing a bias toward affective and impulsive-behavioral symptoms. All patients were receiving psychotherapy. Those patients who were able to keep taking trifluoperazine for 3 weeks or longer (7 of 12 patients) had improved mood, with significant improvement over placebo on physician ratings of depression, anxiety, rejection sensitivity, and suicidality.

Soloff and colleagues (50, 51) studied acutely ill inpatients, comparing haloperidol with amitriptyline and placebo in a 5-week trial. Patients who received haloperidol (mean dose=4.8 mg/day) improved significantly more than those receiving placebo across all symptom domains (50), including global measures, self- and observer-rated depression, anger and hostility, schizotypal symptoms, psychoticism, and impulsive behaviors (51). Haloperidol was as effective as amitriptyline for depressive symptoms.

However, a second study by the same group (56) that used the same design but compared haloperidol with phenelzine and placebo failed to replicate the broad-spectrum efficacy of haloperidol (mean dose=3.9 mg/day). Efficacy for haloperidol was limited to hostile belligerence and impulsive-aggressive behaviors, and placebo effects were powerful. Patients in this study had milder symptoms, especially in the cognitive-perceptual and impulsive-behavioral symptom domains, than patients in the first study.

Cornelius and colleagues (68) followed a subset of the aforementioned group who had responded to haloperidol, phenelzine, or placebo for 16 weeks following acute treatment. Patients' intolerance of the medication, a high dropout rate, and nonadherence were decisive factors in this study. The attrition rates at 22 weeks were 87.5% for haloperidol, 65.7% for phenelzine, and 58.1% for placebo. Further significant improvement with haloperidol treatment (compared with placebo) occurred only for irritability (with improvement for hostility that was not statistically significant). Depressive symptoms significantly worsened with haloperidol treatment over time, which was attributed, in part, to the side effect of akinesia. Clinical improvement was modest and of limited clinical importance.

Montgomery and Montgomery (80) controlled for nonadherence by using depot flupentixol decanoate, 20 mg once a month, in a continuation study of recurrently parasuicidal patients with borderline personality disorder and histrionic personality disorder. Over a 6-month period, patients receiving flupentixol had a significant decrease in suicidal behaviors compared with the placebo group. Significant differences emerged by the fourth month and were sustained through 6 months of treatment. This important study awaits replication.

The introduction of the newer atypical neuroleptics increases clinicians' options for treating borderline personality disorder. To date, findings from only two small open-label trials have been published, both with clozapine. Frankenburg and Zanarini (81) reported that clozapine (mean dose=253.3 mg/day, SD=163.7) improved positive and negative psychotic symptoms and global functioning (but not depression or other symptoms) in 15 patients with borderline personality disorder and comorbid axis I psychotic disorder not otherwise specified who had not responded to (or were intolerant of) other neuroleptics. Improvement was modest but statistically significant. Patients were recruited from a larger study of patients with treatment-resistant psychotic disorders, raising the question of whether their psychotic symptoms were truly part of their borderline personality disorder.

These concerns were addressed by Benedetti and colleagues (71), who excluded all patients with axis I psychotic disorders from their cohort of patients with refractory borderline personality disorder. Target symptoms included "psychotic-like" symptoms that are more typical of borderline personality disorder. Patients had not responded to at least 4 months of prior treatment with medication and psychotherapy. In a 4-month, open-label trial of 12 patients treated with clozapine (mean dose=43.8 mg/day, SD=18.8) and concurrent psychotherapy, a low dose of clozapine improved symptoms in all domains—cognitive-perceptual, affective, and impulsive-behavioral.

Despite a lack of data, clinicians are increasingly using olanzapine, risperidone, and quetiapine for patients with borderline personality disorder. These medications have less risk than clozapine and may be better tolerated than the typical neuroleptics. Schulz and colleagues (83) presented preliminary data from a double-blind, placebo-controlled, 8-week trial of risperidone in 27 patients with borderline personality disorder who received an average dose of 2.5 mg/day (to a maximum of 4 mg/day). On global measures of functioning, there was no significant difference between risperidone and placebo, although the authors noted that risperidone-treated patients were "diverging from the placebo group" in paranoia, psychoticism, interpersonal sensitivity, and phobic anxiety (83). The same group conducted an 8-week, open-label study of olanzapine in patients with borderline personality disorder and comorbid dysthymia (82). Patients received an average dose of 7.5 mg/day (range=2.5–10 mg/day). Among the 11 completers, significant improvement was reported across all domains, with particular improvement noted in depression, interpersonal sensitivity, psychoticism, anxiety, and anger/hostility. These medications require further investigation in double-blind studies.

In summary, neuroleptics are the best-studied psychotropic medications for borderline personality disorder. The literature supports the use of low-dose neuroleptics for the acute management of global symptom severity, with specific efficacy for schizotypal symptoms and psychoticism, anger, and hostility. Relief of global symptom severity in the acute setting may be due, in part, to nonspecific "tranquilizer" effects of neuroleptics, whereas symptom-specific actions against psychoticism, anger, and hostility may relate more directly to dopaminergic blockade. Acute treatment effects of neuroleptic drugs in borderline personality disorder tend to be modest but clinically and statistically significant.

Two studies that addressed continuation and maintenance treatment of a patient with borderline personality disorder with neuroleptics had contradictory results. The Montgomery and Montgomery study (80) reported efficacy for recurrent parasuicidal behaviors, whereas the Cornelius et al. study (68) suggested very modest utility for only irritability and hostility. More controlled trials are needed to investigate low-dose neuroleptics in continuation and maintenance treatment.

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c) Side effects

Dropout rates in neuroleptic trials in borderline outpatients range from 13.7% for a 6-week trial (73) to 48.3% for a 12-week trial (75) to 87.5% for a 22-week continuation study (68). In acute studies, patient nonadherence is often due to typical medication side effects, e.g., extrapyramidal symptoms, akathisia, sedation, and hypotension. Patients with borderline personality disorder who have experienced relief of acute symptoms with low-dose neuroleptics may not tolerate the side effects of the drug with longer-term treatment. The risk of tardive dyskinesia must be considered in any decision to continue neuroleptic medication over the long term. Thioridazine has been associated with cardiac rhythm disturbances related to widening of the Q-T interval and should be avoided. In the case of clozapine, the risk of agranulocytosis is especially problematic. While the newer atypical neuroleptics promise a more favorable side effect profile, evidence of efficacy in borderline personality disorder is still awaited. Neuroleptics should be given in the context of a supportive doctor-patient relationship in which side effects and nonadherence are addressed frequently.

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d) Implementation issues

All studies have used a low dose and demonstrated beneficial effects within several weeks. With the exception of one study that used a depot neuroleptic (flupentixol, which is not available in the United States), all medications were given orally and daily. Acute treatment studies are a good model for acute clinical care and typically range from 5 to 12 weeks in duration. There is insufficient evidence to make a strong recommendation concerning continuation and maintenance therapies. At present, this is best left to the clinician's judgment after carefully weighing the risks and benefits for the individual patient. CBC monitoring must be done if clozapine is used.

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8. ECT

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a) Goals

The goal of ECT in patients with borderline personality disorder is to decrease depressive symptoms in individuals with a comorbid axis I mood disorder, which is present in as many as one-half of hospitalized patients with borderline personality disorder.

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b) Efficacy

Most of the clinical and empirical literature that describes experience with ECT in patients with major depression comorbid with personality disorders does not report results specifically for borderline personality disorder. Although studies that used a naturalistic design have had inconsistent findings, patients with major depression and a comorbid personality disorder were generally less responsive to somatic treatments than patients with major depression alone.

In one naturalistic follow-up study (based on chart review), there was no significant difference in recovery rates for 10 patients with major depressive disorder and a personality disorder (40% recovery) compared with 41 patients with major depressive disorder alone (65.9% recovery) (192). In another study, involving 1,471 depressed inpatients, depressed patients with a personality disorder were 50% less likely to be recovered at hospital discharge than depressed patients without a personality disorder (193).

Several uncontrolled studies found that outcome was dependent on the time of assessment. In one small study (194), there were no significant differences in immediate response to ECT between depressed subjects with or without a personality disorder; however, at a 6-month follow-up evaluation, the patients with a personality disorder had more rehospitalizations and more severe depression symptoms. Conversely, in another uncontrolled study of inpatients with major depression (195), compared with depressed patients without a personality disorder, those with a personality disorder had a poorer outcome in terms of depression and social functioning immediately following treatment. However, after 6 and 12 weeks of follow-up, there were no differences between the two groups in terms of depression and social functioning. The number of rehospitalizations did not differ between groups at the 6-month and 12-month follow-up evaluations.

In another small study (N=16) (196–198) that used the self-rated Millon Clinical Multiaxial Inventory—II and assessed borderline personality disorder, there was significant improvement in avoidant, histrionic, aggressive/sadistic, and schizotypal personality traits with ECT. Improvements were noted in passive-aggressive and borderline personality traits that did not reach statistical significance. The presence of pretreatment borderline traits predicted poorer outcome with ECT (198).

Although the results of these studies appear somewhat divergent, most found that patients with major depression and a personality disorder have a less favorable outcome with ECT than depressed patients without a personality disorder.

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c) Adverse effects

Because ECT is not recommended for borderline personality disorder per se, adverse effects are not described here and can be found in the APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder (84; included in this volume).

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d) Implementation issues

The affective dysregulation, low self-esteem, pessimism, chronic suicidality, and self-mutilation of patients with borderline personality disorder are often misconstrued as axis I depression. Clinical experience suggests that, not infrequently, these characterological manifestations of borderline personality disorder are treated with ECT, often resulting in a poor outcome. Although there is a paucity of ECT studies involving patients with borderline personality disorder, a recommendation for ECT in these patients with comorbid major depression should be guided by the presence and severity of verifiable neurovegetative symptoms, e.g., sleep disturbance, appetite disturbance, weight change, low energy, and anhedonia. These symptoms should ideally be confirmed by outside observers, as they provide an objective way to assess treatment response. Perhaps the greatest challenge for the clinician is not when to institute ECT in the depressed patient with borderline personality disorder but when to stop. As the neurovegetative symptoms of major depression resolve, many patients continue to have borderline features that clinical experience suggests are unresponsive to ECT. Knowledge of the patient's personality functioning before the onset of major depression is critical to knowing when the "baseline" has been achieved. Many patients with borderline personality disorder who are considered nonresponsive to ECT because of persistence of depressive features are, in fact, already in remission from their axis I depression but continue to experience chronic characterological depressive features.

Notable progress has been made in our understanding of borderline personality disorder and its treatment. However, there are many remaining questions regarding treatments with demonstrated efficacy, including how to optimally use them to achieve the best health outcomes for patients with borderline personality disorder. In addition, many therapeutic modalities have received little empirical investigation for borderline personality disorder and require further study. The efficacy of various treatments also needs to be studied in populations such as adolescents, the elderly, forensic populations, and patients in long-term institutional settings. The following is a sample of the types of research questions that require further study.

References

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