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 RESEARCH ARTICLE

A case series of clozapine for borderline personality disorder

Catherine Frogley, BSc

St. Andrew’s Academic Centre, Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, King’s College London, Northampton, United Kingdom

Katina Anagnostakis, MRCPsych

St. Andrew’s Women’s Service, Northampton, United Kingdom

Shawn Mitchell, MRCPsych

St. Andrew’s Women’s Service, Northampton, United Kingdom

Fiona Mason, FRCPsych

St. Andrew’s Healthcare, Northampton, United Kingdom

David Taylor, PhD

King’s College London, South London and Maudsley National Health Service Foundation Trust, London, United Kingdom

Geoff Dickens, PhD

St. Andrew’s Academic Centre, Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, King’s College London, Northampton, United Kingdom

Marco M. Picchioni, MRCP, MRCPsych, PhD

St. Andrew’s Academic Centre, Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, King’s College London, Northampton, United Kingdom

BACKGROUND: Borderline personality disorder (BPD) is a common, debilitating disorder for which the evidence base for treatment is modest. This case series aimed to explore preliminary evidence of clozapine’s effectiveness for patients with severe BPD.

METHODS: We examined the case notes of 22 female inpatients with a primary diagnosis of BPD who had started treatment with clozapine. Baseline routine clinical data were extracted from the records and at 6 monthly intervals thereafter, up to a maximum of 18 months after starting treatment. Patients also were interviewed about their experiences.

RESULTS: We found evidence for a beneficial effect of clozapine across several clinical domains. Symptom severity, need for enhanced observations, use of additional medication, and the number of aggressive incidents all significantly improved after clozapine. The greatest improvements appeared within the first 6 months of initiating treatment. There also was a significant increase in weight.

CONCLUSIONS: The results suggest that clozapine, with suitable health monitoring, may be beneficial for this clinical population. Larger, randomized, blinded, and controlled prospective studies are needed to confirm these findings.

KEYWORDS: antipsychotic, clozapine, borderline personality disorder, emotionally unstable personality disorder, treatment, pharmacotherapy

ANNALS OF CLINICAL PSYCHIATRY 2013;25(2):125-134

  INTRODUCTION

Borderline personality disorder (BPD) is a serious mental disorder characterized by pervasive instability of affect, self-image, behavior, and relationships.1 It affects up to 6% of adults, commonly young women.2 Patients experience high levels of psychiatric and physical morbidity, in particularly high rates of self-harm behavior.3-5 BPD patients make extensive use of mental health services, accounting for a significant proportion of all psychiatric admissions.6 Women are less likely than men to be admitted to secure mental health services; however, those who are admitted are more likely to be diagnosed with a primary personality disorder, especially BPD.7 Typically these women experience profound symptoms, with high levels of aggression directed at themselves and others. This group of women present significant therapeutic and risk management needs at considerable personal and societal cost.

Treatment guidelines for BPD vary internationally,8-11 and although the psychosocial model has dominated, many patients are prescribed multiple medications, often simultaneously, off-label, and at high doses with uncertain benefit. Aside from a small number of high-quality studies,12,13 the lack of pharmacological evidence to inform clinical practice recently was highlighted.8,14 More recently, clinicians have been challenged to develop and evidence effective treatments for personality disorders.15

Aside from a small number of case reports,16-18 5 studies have investigated clozapine for BPD. All reported improvements, whether in affective and psychotic symptoms, global functioning, self-harm behavior, use of emergency tranquilization, or psychological treatment.19-23 However, the studies are criticized for being retrospective, small, mixing community and inpatient samples, failing to characterize the baseline, lacking structured ratings, lacking serum level or side effect data, or failing to follow-up patients for sufficiently long.

The aims of this case series review were:

  • to identify whether clozapine can alleviate symptoms in women with a primary diagnosis of severe BPD

  • to explore clozapine’s tolerability in this group of patients

  • to identify themes in the patients’ experiences of treatment with clozapine for this disorder.

  METHODS

Participants

The case series sample was drawn from all female inpatients age 18 to 65, with a primary diagnosis of BPD who were inpatients at St. Andrew’s Healthcare between January 2002 and July 2010 and were treated with clozapine. St. Andrew’s is a specialist secure psychiatric hospital in Northampton, United Kingdom. Its Women’s Service has >100 inpatient beds. Psychiatrists consider clozapine for women with severe BPD, who are assessed to be at high risk for engaging in self-harm or aggression to others, and who have responded poorly to other medications and interventions in the past. We included all women who had started clozapine, whether they were still taking it or not and whether they were still inpatients or not. Exclusion criteria included a learning disability (IQ <70) and diagnosis of schizophrenia or other psychotic disorder. The study review was approved by the local Research Ethics Committee (ref: 11/EM0042) and every patient who took part gave their written informed consent, after receiving a full verbal and written description of the study protocol.

Data collection

Demographic and clinical data were extracted from the patients’ medical records (TABLE 1). Clinical diagnoses were established by each patient’s consultant psychiatrist in collaboration with their full multi-disciplinary team, using all available data. These sources included clinical interview, inpatient observation, interviews with third-party family and clinical informants, serial mental state examinations, and structured personality evaluation using the Millon Clinical Multiaxial Inventory–III.24 Extensive outcome data were collected routinely via standard clinical care at baseline, before the women started clozapine, and at 6-month intervals thereafter, coinciding with the multidisciplinary clinical case reviews for up to 18 months after starting clozapine. For the purpose of this review patients were “on” clozapine once they had been taking it for 12 weeks and had discontinued if they stopped it for ≥14 days.


TABLE 1

Demographic characteristics (N=22)

Age at clozapine initiation Mean (SD)
  28.2 (7.7)
Months on clozapine Mean (SD)
  26.2 (22.0)
Highest educational achievement n (%)
No qualifications 12 (54.5%)
GCSE/ordinary level 3 (13.6%)
College vocational level 6 (27.3%)
Advanced level 1 (4.5%)
Prior paid work 14 (63.6%)
Comorbid Axis I disorder n (%)
None 12 (54.4%)
Posttraumatic stress disorder 2 (9.1%)
Recurrent depressive disorder 3 (13.6%)
Mental and behavioral disorders due to use of alcohol: dependence 2 (9.1%)
Mental and behavioral disorder due to multiple drugs: dependence 1 (4.5%)
Disturbance of activity and attention 1 (4.5%)
Mild mental retardation 2 (9.1%)
Trichotillomania 1 (4.5%)
Past substance misuse history 15 (78.9%)
Level of security at clozapine initiation n (%)
Medium 14 (63.6)
Low 7 (31.8%)
Open 1 (4.5%)
Years as inpatient at clozapine initiation Mean (range)
  2.4 (0.1 to 8.5)
Legal statusa n (%)
37/41b 11 (50%)
37b 1 (4.5%)
47/49c 2 (9.1%)
47c 1 (4.5%)
3d 6 (27.3%)
Informal 1 (4.5%)
History of previous admissions to secure services n (%)
  18 (81.8%)
Number of antipsychotics prior to clozapine initiation Mode (range)
  3 (1 to 6)
aRefer to sections of the Mental Health Act of 1983, the legislation that governs detention of mentally ill person in hospitals.
bCourt orders warranting transfer to a convicted person to hospital for treatment at the time of sentencing.
cCourt orders warranting transfer of a serving prisoner from a prison to a hospital for treatment.
dCivil order allowing detention of a patient in a hospital for treatment.
GCSE: General Certificate of Secondary Education.

Primary outcomes included the Brief Psychiatric Rating Scale (BPRS),25 Global Assessment of Functioning (GAF),26 the number of days on enhanced (1-to-1) observations in the 4 weeks preceding routine assessment, the number of therapeutic sessions (eg, clinical psychology) attended, the count of risk incidents in the 4 weeks preceding assessment (verbal aggression, physical aggression to objects, against self, and towards others), and their weighted scores using the modified version of the Overt Aggression Scale.27 Secondary measures included clozapine dose and serum level, other medicines prescribed, body weight, and serum glucose. We also extracted the number and type of side effects reported and reasons for clozapine discontinuation if applicable.

Each participant was interviewed by a research assistant (C.F.) to establish qualitative data regarding their experience of clozapine. A semi-structured interview schedule was developed to explore the experience of clozapine, together with potential problems and side effects. Questions were posed in an open, neutral manner in interviews that lasted between 20 and 45 minutes. Interviews were audio-taped and transcribed for later analysis.

Hypothesis

On the basis of previous data and clinical experience we hypothesized that treatment with clozapine would be associated with:

  • reduced frequency and severity of risk behaviors

  • reduced severity of symptoms

  • improved functioning

  • improved nonpharmacological therapeutic engagement

  • reduced concomitant pharmacological treatment.

Data analysis

The data was analyzed with SPSS (version 18). Any missing data were accounted for using last observation carried forward. Patient demographics that could act as potential confounders were assessed for significant correlations with outcomes using Spearman test. If an overall effect of time was significant for an outcome variable, subsequent post hoc contrasts between the time points, baseline vs 6 months, 6 vs 12 months, and 12 vs 18 months were completed using repeated measures analysis of variance. Results are given at a significance level of <.05, and <.005 corrected for multiple comparisons.

The qualitative data were subject to a thematic analysis to develop an understanding of the womens’ experiences taking clozapine from their narrative accounts. We used the Braun and Clarke28 analytical process. Two raters (C.F. and G.D.) completed open coding of the narrative identifying basic semantic segments that were combined into themes, with further recoding following review and discussion.

  RESULTS

Clinical data

Twenty-two eligible women agreed to participate (FIGURE). Ten women had a history of other major mental illnesses. All of the women had been admitted previously to other psychiatric hospitals, with 18 previously detained involuntarily in secure psychiatric hospitals; more than two-thirds were detained under criminal legislation provisions. The women had already spent an average of >2 years in secure hospitals before starting clozapine, most in medium security. Every woman previously had been prescribed ≥1 antipsychotic, the mode was 3, some had received up to 6 antipsychotics.

FIGURE: Study flow chart
RC: responsible clinician.

Outcome data

Clinical symptoms decreased significantly after clozapine (P < .001) (TABLE 2). This improvement was most marked in the first 6 months (P = .002). Mean BPRS scores halved from 29 (95% CI, 22 to 37) at baseline to 14 (95% CI, 8 to 19) by 18 months.


TABLE 2

  Statistical tests
Outcome Baseline (0) 6 months (6) 12 months (12) 18 months (18) Overall test 0 vs 6 6 vs 12 12 vs 18
  N Mean (CI) N Mean (CI) N Mean (CI) N Mean (CI) P F      
BPRS score 21 29.4
(21.5 to 37.3)
21 20.0
(14.0 to 26.0)
21 15.3
(9.5 to 21.2)
18 13.5
(7.8 to 19.2)
>.001a 9.202 0.002a 0.015b 0.382
GAF score 18 21
(14 to 28)
17 19
(14 to 24)
18 20
(16 to 24)
15 22
(18 to 27)
.402 0.809 0.973 0.644 0.031b
Observations (days enhanced) 22 10.9
(6.3 to 15.4)
22 2.7
(0 to 5.9)
22 1.3
(0 to 3.2)
18 1.2
(0 to 2.7)
.001a 12.297 <0.001a 0.432 0.688
Sessions (number attended) 21 34
(25 to 42)
21 47
(37 to 57)
21 44
(35 to 55)
19 41
(31 to 51)
.184 1.672 0.310 0.692 0.63
Sessions (% attended) 21 57.3
(44.4 to 70.2)
21 66.8
(56.5 to 77.1)
21 69.2
(58.8 to 79.6)
18 66.1
(53.2 to 79.1)
.308 1.214 0.123 0.664 0.800
MOAS score 22 12.2
(6.0 to 18.4)
22 3.6
(0.2 to 7.0)
22 3.5
(0.1 to 6.8)
18 4.6
(0 to 9.8)
.013b 6.594 0.002a 0.734 0.592
MOAS weighted score 22 65.3
(31.4 to 99.5)
22 19.4
(1.2 to 38.2)
22 16.4
(1.3 to 31.5)
18 19.4
(0 to 39.8)
.017b 6.322 0.006b 0.388 0.95
MOAS self-harm score 22 4
(1.4 to 6.6)
22 0.6
(0 to 1.3)
21 0.7
(0.1 to 1.3)
17 0.4
(0 to 0.8)
.026b 5.766 0.012b 0.658 0.138
MOAS self-harm weighted score 22 33.8
(8.9 to 58.7)
22 5.7
(-2 to 13.5)
21 5.7
(-2 to 13.5)
17 3.4
(0.4 to 7.1)
.035b 5.058 0.022b 0.894 0.159
aSignificant at 0.005.
bSignificant at 0.05.
BPRS: Brief Psychiatric Rating Scale; GAF: Global Assessment of Functioning; MOAS: Modified Overt Aggression Scale; Sessions: treatment sessions.

The total number and the weighted scores of aggressive incidents significantly decreased over time (P = .013 and P = .017 respectively), but did not survive correction for multiple testing. The mean count of aggressive incidents fell from 12 (CI, 6 to 18) to 5 (CI, 0 to 10), and the weighted score from 65 (CI, 31 to 100) to 19 (CI, 0 to 40). This occurred between baseline and 6 months (P = .002 and P = .006), and remained significant at the trend level after adjusting for time (P = .059 and P = .06 respectively). The count of self-directed aggression also reduced significantly (P = .026), from 34 (CI, 9 to 59) to 3 (CI, 0 to 7) by 18 months, again principally in the first 6 months (P = .022).

The number of days on enhanced observations decreased significantly after clozapine, most markedly in the first 6 months (P < .001). Although therapy session attendance appeared to increase, this was not significant; GAF score did not change.

Effects on use of other medications

The mean dose of clozapine did not change significantly after the first 6 months of treatment (P = .72) and was <300 mg/d. The number of patients prescribed other antipsychotics reduced from 19 to 0 in the first 6 months (TABLE 3), while the number and cumulative dose of additional “as required” or emergency antipsychotic medication decreased from baseline to 6 months (both P < .001). Similarly “as required,” emergency anxiolytic medication administrations and cumulative doses declined (P = .001 and P = .018 respectively).


TABLE 3

As required medication

  Baseline
(n = 21)
6 months
(n = 21)
12 months
(n = 19)
18 months
(n = 17)
Statistical tests
Overall 0 vs 6 6 vs 12 12 vs 18
P F      
Antipsychotic administered, total count (CI) 27
(17 to 36)
8
(3 to 14)
7
(1 to 13)
4
(1 to 6)
>.001a 16.75 .001a 0.425 0.176
Antipsychotic administered, cumulative dose (mg) (CI) 2,725
(1,920 to 3,531)
738
(293 to 1,184)
714
(194 to 1,234)
357
(92 to 622)
>.001a 24.799 >.001a 0.926 0.129
Anxiolytic administered, total count (CI) 17
(9 to 26)
5
(1 to 8)
6
(2 to 10)
3
(1 to 5)
.001a 6.771 .002a 0.604 0.055
Anxiolytic administered, cumulative dose (mg) (CI) 233
(112 to 354)
48
(5 to 93)
72
(6 to 138)
33
(3 to 64)
.018b 5.261 .001a 0.194 0.474
As required, antipsychotic and anxiolytic medication was recorded over the preceding 4-week period at each time point.
Mean total count refers to the mean total number of administrations and the mean cumulative dose refers to mean total dose administered over the preceding 4 weeks and their confidence intervals.
Antipsychotic medication was converted in chlorpromazine equivalents.
Anxiolytic medication was converted to diazepam equivalents.
aSignificant at P < .0125.
bSignificant at P < .05.
Monitoring and physical health outcomes

Mean serum levels were between 360 and 430 ng/mL (TABLE 4). At baseline, 2 patients (of 19; 10.5%) were glucose intolerant, which increased to 4 at 6 (of 16; 25%) and 12 months (of 17; 24%). Weight increased significantly (P = .008) in the first and second 6-month period (P = .05 and 0.03 respectively). These results remained significant after adjusting for time. Drowsiness was the most commonly reported side effect, but reduced over time. Other adverse effects included hypersalivation and tachycardia, which lead to 1 discontinuation.


TABLE 4

Physical measures

  Test
  Baseline 6 months 12 months 18 months Overall 0 vs 6 6 vs 12 12 vs 18
  N Mean (CI) N Mean (CI) N Mean (CI) N Mean (CI)
Plasma clozapine (ng/mL) 22 0
(0)
13 430
(200 to 570)
13 410
(290 to 540)
8 360
(280 to 440)
n/a      
Weight (kg) 22 89.5
(82.2 to 96.8)
22 97.3
(89.0 to 105.5)
22 101.4
(93.1 to 109.7)
17 106.7
(97.3 to 116.2)
0.008 0.05 0.03 0.18
Glucose (mg/dL) 19 76.7
(63.0 to 90.9)
16 88.9
(64.6 to 113.0)
17 88.6
(64.3 to 112.9)
14 85.1
(62.6 to 107.6)
n/a      
Qualitative data

In total, 20 women were interviewed. Analysis suggested 2 main themes around clozapine’s properties.

Clozapine was perceived as facilitative by the women in 3 ways. First, they reported, improved internal symptoms, typically improved mood and inner calm, self-esteem, and reduced thought intensity.

    “My thoughts are calmer…. Before they were pretty much all over the place and they were a bit strange. Yeah, I was a bit mad and all over the place before, Clozaril [clozapine] calmed them down.” (Patient 30)

Secondly, they reported reduced external symptoms, reduced impulsivity and aggression or self-harm, and improved relationships:

    “My relationships are better now than they have ever been, with staff and the patients…because I’m stable and they aren’t worried about what I’m going to say next.” (Patient 24)

Seventy percent of the women noted both improved internal and external symptoms. Some drew an explicit link between these 2 themes and a third, identifying clozapine as facilitative through access to other therapeutic interventions:

    “…before because my mood was unstable, I ended up being out of therapy because I wasn’t achieving or working towards goals.… I’m really stable and I’ve started applying the skills that we learn in DBT [dialectical behavioral therapy].” (Patient 24)

Some participants noted that clozapine was comparatively better than other medications they had been prescribed.

The second theme to emerge was around clozapine’s restrictive effects, largely related to accounts of its side effects:

    “The only reason I came off it was because it makes my heart beat really fast on it and my blood pressure goes up.… It scares me.” (Patient 18)

    “…if being overweight it is what it takes then so be it.… The negative effects are just glitches in a big oil painting.” (Patient 2)

One patient viewed clozapine as restrictive because of its negative effect on the internal and external symptoms of BPD.

  CONCLUSIONS

This study represents the largest case series of women treated with clozapine for BPD and the longest follow-up period to date, to our knowledge. It is the first to offer structured clinical outcome data, albeit retrospectively and unblinded, but the first to report on serum levels and tolerability. We believe that the results suggest the presence of a potentially important beneficial clinical effect.

Outcomes

The data revealed clozapine’s clinically relevant effect across multiple domains. Symptom severity, number of days on enhanced observations, the use of additional emergency antipsychotic and anxiolytic medication, and the number and severity of aggressive and self-harm incidents all improved.

The greatest improvements were seen early in treatment, a finding consistent with the treatment trajectory of antipsychotics for psychosis.29-31 The temporal relationship with clozapine initiation—improvement was greatest early on and was sustained—and improvement across multiple subjectively and objectively rated clinical domains suggest a genuine clinical therapeutic effect attributable to clozapine.

An alternate theory is that these effects are the more gradual or coincidental improvements sometimes seen in patients with a personality disorder through the course of inpatient admission.32 However these women had been in the hospital for 2 years and had failed to stabilize on other antipsychotics before clozapine. Many had been treated with high-dose polypharmacy before clozapine. Indeed, these patients were considered for clozapine because of those treatment failures and in effect were “treatment resistant.” Alternatively these effects could be the placebo effect, increasingly seen in psychiatric research.33,34 However, the women had been treated with other antipsychotics and other medications in the past and did not respond. It could be that clozapine is associated with a more powerful placebo effect, mediated through more intense observation and blood tests. This cannot be excluded in this single compound, retrospective trial.

An alternative prospect is that some of these women—inevitably severe cases—were experiencing “true” psychotic illnesses. In recent years the view that classically defined psychosis is a “fuzzy” construct, commonly found in the general population,35,36 and with a significant inter-relationship with affective and cognitive symptoms37 has grown. It is impossible, and perhaps irrelevant, to say that these women did not experience brief, time-limited, and in many circumstances, intense psychotic-like experiences.38 However, these women did not suffer from ICD-10 psychotic disorders such as schizophrenia or bipolar disorder, and clozapine was exerting its beneficial effect outside of those diagnostic constructs.39

The results in the context of past studies

Given the clinically complex nature of our cohort, these improvements are important and do not limit the generalizability of the findings. One small study explored the effects of clozapine in inpatients with severe BPD,22 with a small number of case reports that supported clozapine’s beneficial effects, most prominently on self-harming behavior and psychotic-like symptoms.16-18 Other studies in less severe BPD cohorts have shown improvements in BPRS,20,40 GAF scores,20,21,40 “as required” medication,21 and aggression towards the self20-23 and others.20,21 Our study replicates those findings in a larger cohort and over a longer follow-up; the improvements were sustained.

The mechanism by which clozapine could be mediating any beneficial effect in BPD is unknown. Clozapine’s advantage in treatment-resistant schizophrenia is well established,41 but not the pharmacological mechanism. Contenders range across its D1, D2, D4, 5-HT2, and 5-HT6 and γ-aminobutyric acid receptor binding properties.42 From a more clinical perspective it may be that clozapine is a better anxiolytic than other antipsychotics,43,44 which is of critical importance in BPD.

Adverse effects

Earlier studies of clozapine failed to investigate its side effect profile. The women in our study gained weight significantly and was cited as a limiting factor and contributed to their decisions about continuation. The rates of weight gain are consistent with findings in schizophrenia45 where >70% gain weight over 2 years,46 although the risk may be even greater for women than men.47 Weight gain for some women in this case series was significant. This is an important consideration given the long-term health burden of excessive weight gain48 and the significant mortality gap between individuals prescribed antipsychotics and the general public.49 It may be particularly important in BPD given its association with eating disorders.50,51

A number of our patients developed new impaired glucose tolerance over 18 months of treatment. This was lower than is seen in similar studies in schizophrenia.52,53 Nevertheless, the generally high continuation rates of clozapine in this study (95.5%)—albeit in detained women in whom treatment could be enforced—is consistent with the qualitative data that suggests that many patients consider clozapine’s advantages to outweigh its disadvantages.

Limitations

There are methodological weaknesses that limit interpretation of our results. The retrospective nature of the case series, combined with the lack of a control group means that we cannot be sure the effects are attributable to clozapine. Placebo response remains a key limitation for any pharmacological study and may be as high as 70% in BPD.54 This effect might be even greater for clozapine; however, research in schizophrenia confirm its effectiveness after controlling for monitoring frequency and intensity.55 Also, patients were not actively participating in research when assessed, except for the later interviews. Furthermore, all of these patients had failed to respond adequately to other forms of pharmacological treatment before clozapine.

Only 22 women of a possible total of 42 agreed to allow examination of their notes for this series. We were unable to determine if patients refused to consent because of problems they experienced on clozapine, either through lack of efficacy or side effects. It is possible that our cohort comprised a subgroup of women who had a positive experience of clozapine, while those who found it ineffective or intolerable refused. Data extracted for this study were collected as part of routine clinical practice by multiple clinicians. Recording practices could have differed in a way we were unable to assess.

This study used the BPRS to rate BPD symptomatology. Data collection for this study began in 2002, before the publication of the Zanarini Rating Scale for Borderline Personality Disorder in 2003,56 the first dedicated rating scale for BPD symptoms. In its defense, the BPRS is a robust and well validated instrument that has good reliability in the clinical setting.57 The BPRS was selected because it offers good coverage of the key domains of BPD psychopathology such as mood and emotional arousal, anxiety, and suicidality. Furthermore, by virtue of its ability to index other aspects of psychopathology it allowed us to be confident that these phenomenologically complex patients were not suffering from significant Axis I pathology. Finally, our study does not rely on the BPRS alone and we have presented other clinical indices, including patient report, that corroborate meaningful improvement.

Pharmacological interventions often are used to help patients with BPD. Our preliminary data suggest that clozapine may be useful in helping patients with BPD, at least in those with more severe symptoms. The qualitative data suggested that many women experienced clozapine as more facilitative than restrictive. Our findings do not negate the importance of comprehensive psychosocial interventions, but suggest that clozapine may help when other treatments have failed.58,59 This therapeutic effect may be direct, through symptom reduction or indirect by means of enabling engagement in other nonpharmacological treatment. The effect appears within 6 months of treatment. Dosing and serum levels mirror those in schizophrenia, as do side effects. Larger, randomized, blinded, and controlled prospective studies are needed to confirm these findings.

DISCLOSURES: Ms. Frogley and Drs. Mitchell, Picchioni, Dickens, and Mason report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Taylor has received grant or research support from Bristol-Myers Squibb and Janssen; is a consultant to Servier; and is a speaker for Janssen and Lundbeck.

    REFERENCES

  1. Gunderson JG. Borderline personality disorder: ontogeny of a diagnosis. Am J Psychiatry. 2009;166:530–539.
  2. Grant BF, Chou SP, Goldstein RB, et al. Prevalence, correlates, disability, and comorbidity of DSM-IV borderline personality disorder: results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2008;69:533–545.
  3. Soloff PH, Lis JA, Kelly T, et al. Self-mutilation and suicidal behavior in borderline personality disorder. J Pers Disord. 1994;8:257–267.
  4. Gardner DL, Cowdry RW. Suicidal and parasuicidal behavior in borderline personality disorder. Psychiatr Clin North Am. 1985;8:389–403.
  5. Soloff PH, Lynch KG, Kelly TM. Childhood abuse as a risk factor for suicidal behavior in borderline personality disorder. J Pers Disord. 2002;16:201–214.
  6. Zanarini MC, Frankenburg FR, Khera GS, et al. Treatment histories of borderline inpatients. Compr Psychiatry. 2001;42:144–150.
  7. Coid J, Kahtan N, Gault S, et al. Women admitted to secure forensic psychiatry services: I. Comparison of women and men. Journal of Forensic Psychiatry. 2000;11:275–295.
  8.  National Collaborating Centre for Mental Health (UK). Borderline personality disorder: treatment and management. Leicester United Kingdom: British Psychological Society; 2009. (NICE Clinical Guidelines, No. 78).
  9.  American Psychiatric Association. Treatment of patients with borderline personality disorder. Arlington VA: American Psychiatric Association; 2001.
  10. Oldham JM. Guideline watch: practice guideline for the treatment of patients with borderline personality disorder. Arlington VA: American Psychiatric Association; 2005.
  11. Tyrer P, Silk KR. A comparison of UK and US guidelines for drug treatment in borderline personality disorder. Int Rev Psychiatry. 2011;23:388–394.
  12. Schulz SC, Zanarini MC, Bateman A, et al. Olanzapine for the treatment of borderline personality disorder: variable dose 12-week randomised double-blind placebo-controlled study. Br J Psychiatry. 2008;193:485–492.
  13. Zanarini MC, Schulz SC, Detke HC, et al. A dose comparison of olanzapine for the treatment of borderline personality disorder: a 12-week randomised, double blind, controlled study. J Clin Psychiatry. 2011;72:1353–1362.
  14. Lieb K, Völlm B, Rücker G, et al. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry. 2010;196:4–12.
  15.  Personality disorder: no longer a diagnosis of exclusion. Policy implementation guidance for the development of services for people with personality disorder. London United Kingdom: National Institute for Mental Health for England; 2003.
  16. Vohra AK. Treatment of severe borderline personality disorder with clozapine. Indian J Psychiatry. 2010;52:267–269.
  17. Rutledge E, O’Regan M, Mohan D. Borderline personality disorder and clozapine. Irish Journal of Psychological Medicine. 2007;24:40–41.
  18. Biswas AB, Gibbon S, Gangadharan SK. Clozapine in borderline personality disorder and intellectual disability: A case report of four-year outcome. Mental Health Aspects of Developmental Disabilities. 2006;9:13–17.
  19. Frankenburg FR, Zanarini MC. Clozapine treatment of borderline patients- a preliminary study. Compr Psychiatry. 1993;34:402–405.
  20. Benedetti F, Sforzini L, Colombo C, et al. Low-dose clozapine in acute and continuation treatment of severe borderline personality disorder. J Clin Psychiatry. 1998;59:103–107.
  21. Chengappa KNR, Ebeling T, Kang JS, et al. Clozapine reduces severe self-mutilation and aggression in psychotic patients with borderline personality disorder. J Clin Psychiatry. 1999;60:477–484.
  22. Swinton M. Clozapine in severe borderline personality disorder. Journal of Forensic Psychiatry. 2001;12:580–591.
  23. Parker GF. Clozapine and borderline personality disorder. Psychiatr Serv. 2002;53:348–349.
  24. Millon T, Millon C, Davis R, et al. Millon Clinical Multiaxial Inventory–III manual. 4th ed. Minneapolis, MN: Pearson Assessments; 2009.
  25. Overall JE. The brief psychiatric rating scale in psychopharmacology research. In: Pichot P ed. Psychological measurements in psychopharmacology. Modern Problems in Pharmacopsychiatry. Vol 7. Basel, Switzerland: Karger; 1974:67–78.
  26.  Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.
  27. Alderman N, Knight C, Morgan C. Use of a modified version of the Overt Aggression Scale in the measurement and assessment of aggressive behaviors following brain injury. Brain Inj. 1997;11:503–523.
  28. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3:77–101.
  29. Stauffer V, Case M, Kollack-Walker S, et al. Trajectories of response to treatment with atypical antipsychotic medication in patients with schizophrenia pooled from 6 double-blind, randomized clinical trials. Schizophr Res. 2011;130:11–19.
  30. Marques TR, Arenovich T, Agid O, et al. The different trajectories of antipsychotic response: antipsychotics versus placebo. Psychol Med. 2011;41:1481–1488.
  31. Kinon BJ, Chen L, Ascher-Svanum H, et al. Early response as a response predictor: use of individual variability in clinical trials. Eur Neuropsychopharmacol. 2009;19(suppl 3):S183.
  32. Gunderson JG, Stout RL, McGlashan TH, et al. Ten-year course of borderline personality disorder. Arch Gen Psychiatry. 2011;68:827–837.
  33. Potkin S, Agid O, Siu C, et al. Placebo response trajectories in short-term and long-term antipsychotic trials in schizophrenia. Schizophr Res. 2011;132:108–113.
  34. Kinon BJ, Potts AJ, Watson SB. Placebo response in clinical trials with schizophrenia patients. Curr Opin Psychiatry. 2011;24:107–113.
  35. Hanssen M, Peeters F, Krabbendam L, et al. How psychotic are individuals with nonpsychotic disorders? Soc Psychiatry Psychiatr Epidemiol. 2003;38:149–154.
  36. Linscott RJ, van Os J. Systematic reviews of categorical versus continuum models in psychosis: evidence for discontinuous subpopulations underlying a psychometric continuum. Implications for DSM-V DSM-VI, and DSM-VII. Ann Rev Clin Psychol. 2010;6:391–419.
  37. Wigman JT, Lin A, Vollebergh WA, et al. Subclinical psychosis and depression: co-occurring phenomena that do not predict each other over time. Schizophr Res. 2011;130:277–281.
  38. Barnow S, Arens EA, Sieswerda S, et al. Borderline personality disorder and psychosis: a review. Curr Psychiatry Rep. 2010;12:186–195.
  39. Glaser JP, Van Os J, Thewissen V, et al. Psychotic reactivity in borderline personality disorder. Acta Psychiatr Scand. 2010;121:125–134.
  40. Frankenburg FR, Zanarini MC. Clozapine treatment of borderline patients: a preliminary study. Compr Psychiatry. 1993;34:402–405.
  41. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine Arch Gen Psychiatry. 1988;45:789–796.
  42. López-Muñoz F, Álamo C. Neurobiological background for the development of new drugs in schizophrenia. Clin Neuropharmacol. 2011;34:111–126.
  43. Mead A, Li M, Kapur S. Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide. Pharmacol Biochem Behav. 2008;90:551–562.
  44. Marx CE, VanDoren MJ, Duncan GE, et al. Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology. 2003;28:1–13.
  45. Bai YM, Lin CC, Chen JY, et al. Association of weight gain and metabolic syndrome in patients taking clozapine: an 8-year cohort study. J Clin Psychiatry. 2011;72:751–756.
  46. Covell NH, Weissman EM, Essock SM. Weight gain with clozapine compared to first generation antipsychotic medications. Schizophr Bull. 2004;30:229–240.
  47. Seeman MV. Secondary effects of antipsychotics: women at greater risk than men. Schizophr Bull. 2009;35:937–948.
  48. Lett TA, Wallace TJ, Chowdhury NI, et al. Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry. 2012;17:242–266.
  49. Brauer R, Douglas I, Smeeth L. The association between antipsychotic agents and the risk of myocardial infarction: a systematic review. Br J Clin Pharmacol. 2011;72:871–878.
  50. Marino MF, Zanarini MC. Relationship between EDNOS and its subtypes and borderline personality disorder. Int J Eat Disord. 2001;29:349–353.
  51. Grilo CM, Sanislow C, Skodol AE, et al. Do eating disorders co-occur with personality disorders? Comparison groups matter. Int J Eat Disord. 2003;33:155–164.
  52. Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry. 2000;157:975–981.
  53. Krakowski M, Czobor P, Citrome L. Weight gain metabolic parameters, and the impact of race in aggressive inpatients randomized to double-blind clozapine, olanzapine or haloperidol. Schizophr Res. 2009;110:95–102.
  54. Schulz SC, Zanarini MC, Bateman A, et al. Olanzapine for the treatment of borderline personality disorder: variable dose 12-week randomised double-blind placebo-controlled study. Br J Psychiatry. 2008;193:485–492.
  55. Potkin SG, Alphs L, Hsu C, et al; InterSePT Study Group. Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial. Biol Psychiatry. 2003;54:444–452.
  56. Zanarini MC, Vujanovic AA, Parachini EA, et al. Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD): a continuous measure of DSM-IV borderline psychopathology. J Pers Disord. 2003;17:233–242.
  57. Overall JE, Gorman DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812.
  58. Rosenheck R, Tekell J, Peters J, et al. Does participation in psychosocial treatment augment the benefit of clozapine? Arch Gen Psychiatry. 1998;55:618–625.
  59. Grace J, Bellus SB, Raulin ML, et al. Long-term impact of clozapine and psychosocial treatment on psychiatric symptoms and cognitive functioning. Psychiatr Serv. 1996;47:41–45.

CORRESPONDENCE: Marco M. Picchioni, MRCP, MRCPsych, PhD PO23 Department of Forensic and Neurodevelopmental Science Institute of Psychiatry De Crespigny Park London, SE5 8AF, United Kingdom E-MAIL: marco.picchioni@kcl.ac.uk