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. 2022 Apr 29:12:20451253221090832.
doi: 10.1177/20451253221090832. eCollection 2022.

The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): a randomised placebo-controlled trial

Mike J Crawford  1 , Verity C Leeson  2 , Rachel Evans  3 , Barbara Barrett  4 , Aisling McQuaid  2 , Jack Cheshire  5 , Rahil Sanatinia  2 , Gary Lamph  6 , Piyal Sen  7 , Katina Anagnostakis  8 , Louise Millard  8 , Inti Qurashi  9 , Fintan Larkin  10 , Nusrat Husain  11 , Paul Moran  12 , Thomas R E Barnes  2 , Carol Paton  2 , Zoe Hoare  3 , Marco Picchioni  13 , Simon Gibbon  5
Affiliations

The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): a randomised placebo-controlled trial

Mike J Crawford et al. Ther Adv Psychopharmacol. .

Abstract

Background: Data from case series suggest that clozapine may benefit inpatients with borderline personality disorder (BPD), but randomised trials have not been conducted.

Methods: Multicentre, double-blind, placebo-controlled trial. We aimed to recruit 222 inpatients with severe BPD aged 18 or over, who had failed to respond to other antipsychotic medications. We randomly allocated participants on a 1:1 ratio to receive up to 400 mg of clozapine per day or an inert placebo using a remote web-based randomisation service. The primary outcome was total score on the Zanarini Rating scale for Borderline Personality Disorder (ZAN-BPD) at 6 months. Secondary outcomes included self-harm, aggression, resource use and costs, side effects and adverse events. We used a modified intention to treat analysis (mITT) restricted to those who took one or more dose of trial medication, using a general linear model fitted at 6 months adjusted for baseline score, allocation group and site.

Results: The study closed early due to poor recruitment and the impact of the COVID-19 pandemic. Of 29 study participants, 24 (83%) were followed up at 6 months, of whom 21 (72%) were included in the mITT analysis. At 6 months, 11 (73%) participants assigned to clozapine and 6 (43%) of those assigned to placebo were still taking trial medication. Adjusted difference in mean total ZAN-BPD score at 6 months was -3.86 (95% Confidence Intervals = -10.04 to 2.32). There were 14 serious adverse events; 6 in the clozapine arm and 8 in the placebo arm of the trial. There was little difference in the cost of care between groups.

Interpretation: We recruited insufficient participants to test the primary hypothesis. The study findings highlight problems in conducting placebo-controlled trials of clozapine and in using clozapine for people with BPD, outside specialist inpatient mental health units.

Trial registration: ISRCTN18352058. https://doi.org/10.1186/ISRCTN18352058.

Keywords: Borderline personality disorder; Clinical Trial; clozapine.

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Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article except TREB, who has been a member of an advisory board for Gedeon Richter and NH who has attended educational events organised by various pharmaceutical industries over the last five years.

Figures

Figure 1.
Figure 1.
CONSORT 2010 flow diagram.
Figure 2.
Figure 2.
Change in adjusted mean total ZAN-BPD score at 3 and 6 months (error bards represent 95% Confidence Intervals of mean scores).
See this image and copyright information in PMC

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