TY - JOUR

T1 - The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): A randomised placebo-controlled trial

AU - Crawford, Mike J.

AU - Leeson, Verity

AU - Evans, Rachel

AU - Barrett, Barbra

AU - McQuaid, Aisling

AU - Cheshire, Jack

AU - Sanatina, Rahil

AU - Lamph, Gary

AU - Sen, Piyal

AU - Anagnostakis, Katina

AU - Millard, Louise

AU - Qurashi, Inti

AU - Larkin, Fintan

AU - Husain, Nusrat

AU - Moran, Paul

AU - Barnes, Thomas R.E.

AU - Paton, Carol

AU - Hoare, Zoe

AU - Picchioni, Marco

AU - Gibbon, Simon

PY - 2022

Y1 - 2022

N2 - 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 registrationISRCTN18352058. https://doi.org/10.1186/ISRCTN18352058

AB - 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 registrationISRCTN18352058. https://doi.org/10.1186/ISRCTN18352058

KW - Borderline personality discordere

KW - Clinical Trial

KW - clozapine

U2 - https://doi.org/10.1177%2F20451253221090832

DO - https://doi.org/10.1177%2F20451253221090832

M3 - Article

VL - 12

JO - Theraputic Advances in Psychopharmacology

JF - Theraputic Advances in Psychopharmacology

SN - 2045-1253

ER -