Clozapine in borderline personality disorder: A review of the evidence

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1 ANNALS OF CLINICAL PSYCHIATRY ANNALS OF CLINICAL PSYCHIATRY 2014;26(2): REVIEW ARTICLE Clozapine in borderline personality disorder: A review of the evidence Anand Beri, MRCPsych South London and Maudsley NHS Foundation Trust Maudsley Hospital London, United Kingdom Jane Boydell, MRCPsych, PhD Institute of Psychiatry King s College London London, United Kingdom BACKGROUND: Borderline personality disorder (BPD) is a serious mental disorder that is difficult to treat. Possible targets for pharmacotherapy include affective symptoms, cognitive disturbances, and impulsive, self-injurious behaviors. Although many of the medications tested for treatment of BPD have been demonstrated to be useful, no clear pharmacologic treatment has emerged. Clozapine is one of the medications that has been evaluated for the treatment of severe BPD. The aim of this review is to summarize the evidence examining the effectiveness of clozapine in the treatment of BPD. METHODS: A comprehensive search of the health science databases PubMed, EMBASE, CINAHL, PsycINFO, Web of Science, Cochrane Library, and Google Scholar was performed for studies describing the use of clozapine in the treatment of BPD. RESULTS: After the initial search, no randomized controlled trials evaluating the effectiveness of clozapine in BPD were identified. Therefore, case reports and case series were reviewed, with 12 articles selected for final review. CORRESPONDENCE Anand Beri, MRCPsych South London and Maudsley NHS Foundation Trust Maudsley Hospital Denmark Hill, London SE5 8AZ United Kingdom CONCLUSIONS: This review suggests that clozapine may be a beneficial treatment option for BPD especially in controlling symptom severity, psychotic symptoms, impulsivity, self-mutilation, number of days on enhanced observation, use of restraint, and overall functioning. KEYWORDS: clozapine, borderline personality disorder, pharmacotherapy, antipsychotics Anand.beri@slam.nhs.uk AACP.com Annals of Clinical Psychiatry Vol. 26 No. 2 May

2 CLOZAPINE IN BORDERLINE PERSONALITY DISORDER: A REVIEW OF THE EVIDENCE INTRODUCTION Borderline personality disorder (BPD) is a serious mental disorder that is resistant to treatment. 1 First recognized in the 19th century, BPD was believed to exist on the borderline between psychosis and neurosis. 2 The disorder is characterized by severe psychosocial impairment, 3 including instability in affect regulation, impulse control, interpersonal relationships, and self-image. BPD affects about 1% to 2% of the general population, up to 10% of psychiatric outpatients, and 20% of inpatients, 4 and occurs in a 3:1 female:male ratio. 5 Among patients with BPD, the mortality rate due to suicide is high; up to 10% of patients commit suicide. 6 BPD is a heterogeneous condition, and its symptoms overlap considerably with depressive, psychotic, impulsive, dissociative, and identity disorders. Substance misuse, posttraumatic stress disorder, other anxiety disorders, and eating disorders are common among individuals with BPD. 7 There is evidence that long-term psychotherapy can be useful in treating patients with BPD, 8 and it often is preferred to pharmacologic treatment because of the limited efficacy of drug therapy. 9 However, up to 66% of patients with BPD cannot engage in psychotherapy or do not benefit from it. 10 Pharmacotherapy is frequently used as an adjunctive, symptom-targeted component of treatment. 11,12 Various classes of medications, including antidepressants, antipsychotics, and mood stabilizers, have been used for treating BPD. Studies have suggested that pharmacotherapy could be used to target certain aspects of BPD, such as cognitive-perceptual symptoms, emotional dysregulation, and impulsive-behavioral dyscontrol. 13 Specifically, antipsychotics are believed to be effective in improving impulsivity, aggression, anxiety, and psychotic symptoms. 14 Olanzapine, 15 haloperidol, 16 risperidone, 17 aripiprazole, 18 and quetiapine 19 have been used with some effectiveness to treat BPD. In small studies of patients with BPD, clozapine has been found to be beneficial in controlling aggression, severe self-mutilation, and psychotic symptoms, and in reducing use of services, bed occupancy, need for seclusion, and need for close observation on inpatient wards METHODS The health science databases PubMed, EMBASE, CINAHL, PsycINFO, Web of Science, Cochrane Library, and Google Scholar were searched for studies describing the use of clozapine in the treatment of BPD. The search was limited to human studies, with no language restrictions. The reference lists of the identified publications were hand searched for additional relevant studies. WorldCat, an online library catalog, and PsycEXTRA, a gray literature database (ie, a database populated with materials not commonly available in standard health science databases), were also searched. The keywords used were clozapine, clozaril, zaponex, leponex, borderline personality disorder, borderline PD, borderline personality, and emotionally unstable personality disorder. The intervention considered was clozapine for the treatment of BPD, with or without ongoing psychotherapy. Treatment settings included psychiatric inpatient and community or secure hospital (high-, medium-, or low-security) facilities. The inclusion criteria for studies considered in this review were adult patients age 18 having a diagnosis of BPD using the operational criteria described by either the DSM-IV-TR or ICD-10. Patients with BPD who had comorbid mental health problems were also included. Twelve studies were included in the final review: Frankenburg and Zanarini, ; Chengappa et al, ; Benedetti et al, ; Chengappa et al, ; Swinton, ; Parker, ; Ferreri et al, ; Biswas et al, ; Rutledge et al, ; Vohra, ; Zarzar and McEvoy, ; and Frogley et al, A total of 78 participants from 12 studies were included in the review (TABLE). Characteristics of individual studies Frankenburg and Zanarini, Fifteen patients participated in and were recruited from a larger study (N = 110) of the efficacy of clozapine for treatment-resistant psychotic patients. All were inpatients. This subset met both the Diagnostic Interview for Borderlines Revised (DIB-R) and DSM-III-R criteria for BPD. All 15 also had a DSM-III-R psychotic disorder not otherwise specified (NOS) (atypical psychosis). Nine of these patients were women (60.0%) and 6 were men (40.0%). The age range was 18 to 51 years, with a mean age of 29.1 ± 8.6 years. The patients were rated blindly for a period of 2 to 9 months (mean duration of treatment, 4.2 months). The mean clozapine dose was mg/d ± mg/d. The outcome measures used were the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) scale, and Global Assessment Scale (GAS). The overall symptomatology as rated on BPRS decreased from a mean of 57.0 ± 10.4 to a mean of 37.8 ± 7.7 (t = 7.03; df = 14; P =.001). There also was a sig- 140 May 2014 Vol. 26 No. 2 Annals of Clinical Psychiatry

3 ANNALS OF CLINICAL PSYCHIATRY nificant reduction on the positive, negative, and overall general symptom score on BPRS. The symptom severity measured by the CGI scale also decreased significantly (t = 6.55; df = 14; P =.001). The GAS score increased significantly from a mean of 30.8 ± 4.7 to a mean of 43.1 ± 28.6 (t = 5.19; df = 14; P =.001). It is not clear if this is the true effect of clozapine on BPD symptoms or a result of bias, ie, a confounding effect of psychosis. Chengappa et al, described the improvement in a 32-year-old woman taking clozapine, 300 mg. Several previous trials of psychotropic medicines and behavioral interventions had failed. She had a 7-year history of inpatient treatment, with multiple suicide attempts and episodes of self-harm. Use of clozapine brought about a reduction in self-mutilating behavior, and she was discharged into the community after 3 months of treatment. Benedetti et al, reported a case series of 12 inpatients (10 females, 2 males) with BPD (DSM-IV) on the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). The mean age of the participants was 29.8 ± 5.5 years. Additional diagnoses included schizotypal (n = 2), antisocial (n = 1), and narcissistic (n = 1) personality disorders. Previous history showed repeated hospitalization and unsuccessful drug treatment, and marked functional impairment (stopped working or studying for the past 6 months). Patients were excluded from the study if they currently had major depression; a current or past psychotic disorder, including bipolar disorder; and major medical or neurologic disorders. The clozapine dose ranged from 25 to 100 mg/d (mean ± SD = 43.8 ± 18.8 mg/d). Mean ± SD length of hospitalization after beginning treatment was 20.3 ± 7.2 days. A decrease of psychotic-like symptoms occurred within the first 2 weeks. After 1 month, BPRS showed a statistically significant mean decrease of 54% of baseline level (t = 10.18; df = 11; P <.001). Significant reductions were seen in the number of suicide attempts (t = 4.69; df = 11; P <.001) and physical fights (t = 2.57; df = 11; P <.026). Hamilton Depression Rating Scale (HAM-D) scores showed a significant and sustained decrease, with a mean decrease of 43% of baseline level after 1 month. There was substantial improvement in the global functioning as rated by the GAF scale. Chengappa et al, reported a case series of 7 white female patients diagnosed with BPD and Axis I diagnosis of psychosis NOS (n = 2), schizoaffective disorder (n = 2), bipolar I disorder (n = 1), and chronic paranoid schizophrenia (n = 1). All of the patients had a history of self-mutilation and aggression, and all were treated with clozapine, at a mean dose of 421 mg/d (range, 300 to 500 mg/d). A mirror-image design of data collection from clinical notes was used from the start of clozapine treatment to a maximum of 1 year. Data were collected on incidents of self-mutilation, restraint, seclusion, use of medications taken as required, injuries to staff and fellow patients, hospital privileges, and GAF scores. Significant improvement was seen in all measured outcomes. All but one patient had persistent psychosis in addition to a diagnosis of BPD. The psychosis was unlike the transient psychosis seen in patients with BPD. It is unclear if the effect of clozapine was real, confounded by the effect of clozapine on psychosis, or merely part of the natural course of the disorder. Two of the 7 patients had maintained improvement for more than 3.5 years, and one had 2 brief community hospitalizations. Two patients were from a secure setting and could not be discharged into the community for legal reasons but were well enough for discharge. Swinton, reported an open-label, 12-month retrospective inpatient study of 5 women with severe personality difficulties in a high-security hospital who were taking clozapine. The diagnosis of BPD was by clinical consensus. The outcome variables were levels of nursing observation or rates of self-injury over the past 12 months. The average dose of clozapine was 400 to 500 mg/d. Lithium and antidepressants were continued during the study period. Days of specialized nursing observation decreased from a pretreatment group mean of 25.9 per month to a posttreatment group mean of 8.5, and days of self-injury per month declined from a pretreatment mean of 4.0 to a posttreatment group mean of 1.4. Weaknesses of this report were the lack of a placebo group, that ratings were not blind, and that the psychosis was not controlled for. Parker, described a case series of 6 women and 2 men with BPD who were treated with clozapine between 1996 and The clozapine dosage was based on clinical response; the mean daily dosage at the time of discharge was 334 mg (range, 175 to 550 mg). Seven of the 8 patients were discharged on clozapine, including 2 extended-stay patients. Parker describes both a reduced number of hospital admissions and reduced length of hospital admission. Readmissions to the hospital occurred 4 times and were caused by decompensation after discontinuation of clozapine. Ferreri et al, reported a case report of a 19-yearold female patient who was hospitalized for several years for severe self-mutilation, depressive symptoms, anorexia AACP.com Annals of Clinical Psychiatry Vol. 26 No. 2 May

4 CLOZAPINE IN BORDERLINE PERSONALITY DISORDER: A REVIEW OF THE EVIDENCE TABLE Key study characteristics Author Design; treatment duration Frankenburg and Open-label study; 9 Zanarini, months Chengappa et al, Case report, 3 months Patients (no.); diagnosis N = 15 (9 females); BPD and psychotic disorder NOS N = 1 (female); BPD with psychotic symptoms (DSM-III-R) Benedetti et al, Open-label; 16 weeks N = 12 (10 females); BPD, psychotic symptoms (DSM-IV, SCID-II) Chengappa et al, Case series; months Swinton, Open-label, retrospective selfreport N = 7 (all females); BPD and Axis I comorbidity (DSM-IV) N = 5 (all females); BPD (consensus diagnosis) Parker et al, Open trial; 3 years N = 8 (6 females); BPD with psychotic symptoms Ferreri et al, Case report; 4 weeks N = 1 (female); BPD (DSM-IV) Biswas et al, Case report; 6 weeks of treatment, 4 years of follow-up N = 1 (female); BPD and mild LD Rutledge et al, Case report N = 1 (female); BPD (DSM-IV) Vohra, Case report; 8 weeks N = 1 (female); BPD (DSM-IV-TR) Zarzar and McEvoy, Frogley et al, Case series; 18 months Clozapine, mean dose (range) 253 mg/d (75 to 550 mg/d) Outcome measures Improvement in BPRS, CGI, GAS; reduced emotional withdrawal 300 mg/d Clinical improvement 43.8 mg/d (25 to 100 mg/d) 421 mg/d (300 to 550 mg/d) Improvement in BPRS, HAM-D, GAF Clinical and GAF improvement 400 to 500 mg/d Less observed self-mutilation and hostility, level of nursing observation from a mean of 29.5 days per month to mg/d (175 to 550 mg/d) Case report N = 4 (all females); BPD 237 mg/d (150 to 400 mg/d) N = 22 (all females); BPD Clinical and functional improvement 300 mg/d Stopped self-mutilation, improved anxiety and social functioning 100 mg/d Reduction in deliberate selfharm, physical aggression, damage to property, hospital admission 300 mg/d Clinical improvement 175 mg/d Clinical and functional improvement Serum levels between 360 and 430 ng/ml Reduction in self-harm, discontinuation of 1:1 observation, elimination of physical restraint, no further hospitalization BPRS, GAF, reduction in aggression, days on enhanced observation reduced from a mean of 10.9 at baseline to 2.7 at 6 months BPD: bipolar disorder; BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; GAF: Global Assessment of Functioning; GAS: Global Assessment Scale; HAM-D: Hamilton Depression Rating Scale; LD: learning disability; NOS: not otherwise specified. nervosa, and severe anxiety. She was treated with clozapine after a failure of several psychotropic medications. The daily clozapine dose was titrated to 300 mg/d. In addition to clozapine, the patient continued to take fluoxetine, carbamazepine, and oxazepam, and continued weekly psychotherapy and psychodrama sessions. The outcome measures used were complete stoppage of self-mutilation, self-reported relief from anxiety, and improvement in social functioning, as indicated by resumption of education and improvement in interpersonal relationships. 142 May 2014 Vol. 26 No. 2 Annals of Clinical Psychiatry

5 ANNALS OF CLINICAL PSYCHIATRY Biswas et al, reported a case of a 29-year-old woman with mild intellectual disability and BPD, with repeated self-harm, aggressive behavior, assaults, damage to property, and frequent hospital admissions. She was treated with a number of psychotropic medications with no benefit. Clozapine at a dose of 50 mg twice daily achieved a marked reduction in the level of disturbed behavior within 2 weeks. By the end of the sixth week of treatment, she was well enough to be discharged. The outcome measures used were deliberate self-harm, physical aggression, damage to property, and hospital admission. The follow-up duration was 4 years. Rutledge et al, reported the case of a 36-yearold woman with severe BPD, with symptoms of psychosis, aggression, and violence. The patient had been taking clozapine for the past 6 years with overall benefit. Clozapine was discontinued because of various physical health problems, which led to a significant deterioration in the patient s mental state. Clozapine was restarted 15 months later, with stabilization in some of the behavioral symptoms. The outcome measures used were reduced intensive nursing input, days in seclusion, and the patient s subjective experience of distressing symptoms. Vohra, reported a case of a 24-year-old white woman with a long history of psychiatric admissions due to self-harm, challenging behavior, substance misuse, and aggressive and impulsive behavior. After the failure of several psychotropic medications, she began taking clozapine (dosage, 175 mg/d). The outcome measures were reduction of self-mutilating behavior and improvement in mood and interpersonal relationships. Zarzar and McEvoy, reported a case series of 4 patients with BPD and persistent self-injurious behavior, aggression, repeated hospitalization, requiring intensive levels of observation, and physical restraint. The mean dose of clozapine was 237 mg/d (range, 150 to 400 mg/d). The outcome measures were reduction in suicidality and self-harm, discontinuation of 1:1 observation, elimination of physical restraint, and no further hospitalization. Frogley et al, reported a case series of 22 female inpatients with a primary diagnosis of BPD who were treated with clozapine. Symptom severity, need for enhanced observation, use of additional medication, and number of aggressive incidents all significantly improved after clozapine. The primary outcomes included the BPRS, GAF, number of days on enhanced observation, and verbal and physical aggression. DISCUSSION Despite a comprehensive search, no randomized controlled trials for clozapine in the treatment of this relatively common condition were found. Only case reports and case series have been published so far. Pharmacologic treatment of BPD remains preliminary despite expanding data indicating that medications can provide symptomatic relief. From the available data, it is clear that patients with BPD can benefit from clozapine, resulting in improvement in multiple domains eg, symptom severity, psychotic symptoms, impulsivity, self-mutilation, number of days on enhanced observation, use of restraint, and overall functioning. The improvement occurs relatively quickly, ie, within weeks, and is sustained. The number of hospitalizations is reduced, and even where hospitalization is necessary, the days spent in the hospital are reduced. It is not known how clozapine exerts its beneficial effect in BPD; its affinity for a myriad of receptors, including D1, D2, D4, 5-HT2, and 5-HT6, and gamma-aminobutyric acid, may play a role. The antiaggressive effect of clozapine is independent of sedation and may in part be due to the anxiolytic effect. 32 Clozapine also has affinity for 5-HT2A receptors, which are important in impulsivity and aggression. 33 In addition to its benefit in improving psychosis, clozapine has been reported to be effective in reducing hostility. 34 Clozapine has a favorable effect on comorbid use of alcohol and drugs in individuals with schizophrenia, possibly by reducing craving. 35 Polysubstance abuse is prevalent in many BPD patients, and clozapine can effectively reduce reliance on drugs and alcohol. Given that approximately 10% of patients with BPD die from suicide, clozapine may have significant antisuicidal properties 36,37 in this population. Frogley et al 31 reported a reduction in the number and cumulative doses of additional as required or emergency antipsychotic medication as well as as required emergency anxiolytic medication with clozapine treatment. Finally, clozapine also may be useful in stabilizing the mental state of BPD patients to facilitate their participation in psychotherapeutic treatment modalities. Limitations These data are limited by the small size of the trials, inconsistent outcome measures, and enrollment bias that tends to include mildly to moderately ill patients and AACP.com Annals of Clinical Psychiatry Vol. 26 No. 2 May

6 CLOZAPINE IN BORDERLINE PERSONALITY DISORDER: A REVIEW OF THE EVIDENCE exclude those who are more severely affected. The serious methodological limitations of the identified studies include small sample sizes and lack of generalizability; lack of a control group; selection bias; diagnosis being confounded by psychosis, reporting bias, publication bias, and short follow-up periods; nonetheless, the data provide some basis to consider the possible effectiveness of clozapine for patients with BD. More complex considerations include the possibility that prescribing a potentially lethal drug altered staff attitudes toward and interactions with patients and this, in turn, had a positive impact on patient symptomatology. These findings can be used as a basis to conduct randomized, double-blind, placebo-controlled trials to gain more evidence regarding the efficacy and generalizability of the use of clozapine in the treatment of patients with BD. CONCLUSIONS Despite unclear evidence, pharmacological treatment is widely used in patients with BPD. There is emerging evidence of efficacy of clozapine which needs to be confirmed with rigorously controlled studies. Findings of open studies need to be interpreted cautiously because of the high placebo response rate in BPD. Clozapine can be beneficial in many domains including self-harm, suicidality, interpersonal relationships, number of days spent in the hospital, and intensity of interventions required when in hospital. It also has a positive effect on mood and anxiety. On the other hand, serious side effects of agranulocytosis, weight gain, and development of diabetes need to be taken into consideration. DISCLOSURES: The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. REFERENCES 1. Kernberg OF, Michels R. Borderline personality disorder. Am J Psychiatry. 2009;166: Stone MH. 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