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

Crawford, Mike J.; Leeson, Verity C.; Evans, Rachel; Barrett, Barbara; McQuaid, Aisling; Cheshire, Jack; Sanatinia, Rahil; Lamph, Gary; Sen, Piyal; Anagnostakis, Katina; Millard, Louise; Qurashi, Inti; Larkin, Fintan; Husain, Nusrat; Moran, Paul; Barnes, Thomas R.E.; Paton, Carol; Hoare, Zoe; Picchioni, Marco; Gibbon, Simon

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.

Citation

Crawford, M. J., Leeson, V. C., Evans, R., Barrett, B., McQuaid, A., Cheshire, J., …Gibbon, S. (2022). The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): a randomised placebo-controlled trial. Therapeutic Advances in Psychopharmacology, 12, 1-14. https://doi.org/10.1177/20451253221090832

• Journal Article Type: Article
• Acceptance Date: Mar 11, 2022
• Online Publication Date: Apr 29, 2022
• Publication Date: 2022-04
• Deposit Date: Feb 26, 2024
• Journal: Therapeutic advances in psychopharmacology
• Print ISSN: 2045-1253
• Publisher: SAGE Publications
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Pages: 1-14
• DOI: https://doi.org/10.1177/20451253221090832
• Keywords: borderline personality disorder, clinical trial, clozapine
• Publisher URL: https://journals.sagepub.com/doi/10.1177/20451253221090832
• PMID: 35510087