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

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

Association of pharmacological treatments and real‐world outcomes in borderline personality disorder

“…Nevertheless, our findings align with the previous Danish nationwide observational study that also found an association between treatment with clozapine and a reduction in psychiatric admissions in patients with BPD 18 . Altogether, to date, as the only RCT on clozapine failed to enroll a significant number of patients with BPD, 19 the evidence supporting the treatment of clozapine in BPD is primarily based on a few observational studies and single‐patient cases 35…”

“…In fact, just a handful of RCTs have been published in recent years. 19,27,28 However, there is ongoing industry-funded research on novel pharmacotherapeutic treatments for BPD. 29 In accordance with prior epidemiological research, 3,25 more than half of the patients were administered benzodiazepines and related drugs.…”

“…34 Nevertheless, our findings align with the previous Danish nationwide observational study that also found an association between treatment with clozapine and a reduction in psychiatric admissions in patients with BPD. 18 Altogether, to date, as the only RCT on clozapine failed to enroll a significant number of patients with BPD, 19 the evidence supporting the treatment of clozapine in BPD is primarily based on a few observational studies and single-patient cases. 35 We discovered that treatment with pharmacological agents that raise extraneuronal dopamine and norepinephrine concentrations (i.e., bupropion, lisdexamphetamine, and methylphenidate) 36,37 was associated with improved real-world outcomes in BPD.…”

“…There has been a decline in the number of pharmacological publications conducted on individuals with BPD, which may suggest pessimism over the efficacy of pharmacotherapy in BPD. In fact, just a handful of RCTs have been published in recent years 19,27,28 . However, there is ongoing industry‐funded research on novel pharmacotherapeutic treatments for BPD 29…”

“…Medications having fewer than 100 patients or fewer than 50 outcomes were not reported. However, we presented results for clozapine (30 patients) and long-acting injectables (LAIs) (47 patients) owing to prior research interest 16,18,19 and demonstrated high effectiveness in schizophrenia. 20…”