Therapeutic Advances in Psychopharmacology (Apr 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,
  • Verity C. Leeson,
  • Rachel Evans,
  • Barbara Barrett,
  • Aisling McQuaid,
  • Jack Cheshire,
  • Rahil Sanatinia,
  • Gary Lamph,
  • Piyal Sen,
  • Katina Anagnostakis,
  • Louise Millard,
  • Inti Qurashi,
  • Fintan Larkin,
  • Nusrat Husain,
  • Paul Moran,
  • Thomas R.E. Barnes,
  • Carol Paton,
  • Zoe Hoare,
  • Marco Picchioni,
  • Simon Gibbon

DOI
https://doi.org/10.1177/20451253221090832
Journal volume & issue
Vol. 12

Abstract

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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