Title: The Clinical Effectiveness and Cost Effectiveness of Clozapine for inpatients with Borderline Personality Disorder: Randomised controlled trial
Funder: Department of Health and Social Care

Abstract: DESIGN: Two-arm, parallel group, double-blind, placebo-controlled randomised trial with an integrated pilot study. Study participants will be followed up for six months in the first instance. SETTING: General adult mental health wards, psychiatric intensive care units, secure and forensic mental health inpatient units run by six provider organisations. TARGET POPULATION: Inpatients aged 18 years or over who meet DSM-IV diagnostic criteria for borderline personality disorder and have failed to make an adequate clinical response to existing pharmacotherapy, defined as taking antipsychotic medication other than clozapine for at least three months. EXCLUSION CRITERIA: People will be excluded if: they have a diagnosis of schizophrenia or bipolar I disorder, they are already prescribed clozapine, they are due to be discharged from the hospital within the following two weeks, they have any contraindication to clozapine. or they are unwilling or unable to provide written informed consent to take part in the study. HEALTH TECHNOLOGIES: Clozapine titrated up to a maximum dose of 400mg over a two to three week period on the basis of safety, tolerability and clinical response versus an inert placebo. All those taking part in the study will continue to receive all other treatment as usual including off-license pharmacotherapy. MEASUREMENT OF COSTS AND OUTCOMES: Our primary outcome is mental health measured at six months using the total score on the Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD). Secondary outcomes will be measured at three and six months after randomisation and comprise mental health (BPRS), incidence of violence to self or others (OAS-M), health-related quality of life (EQ-5D-5L), side effects of treatment, adherence and adverse reactions. Resource use and costs (from a societal perspective) will be assessed using a modified version of the Adult Service Use Schedule. Economic evaluation will be conducted from an NHS/PSS perspective. SAMPLE SIZE: 166 participants (83 prescribed clozapine and 83 prescribed placebo) will need to be randomised to have 90% power to detect a four point difference in ZAN-BPD score at six months, using a 0.05 level of statistical significance. To take account of 25% loss to follow-up we will recruit 222 subjects.

Lay abstract: Over a million people in Britain have borderline personality disorder. People with this condition have distressing changes in mood, together with feelings of hopelessness and despair. Many patients self-harm and a minority behave in ways that endanger their life or the lives of others. Such problems can lead to inpatient treatment, including long periods of time in costly secure units. Large amounts of medication are prescribed to inpatients with borderline personality disorder, but there are no licensed drugs for the treatment of this condition. Psychological treatment can help, but usually takes many months to deliver and inpatients may be too unwell to use them. In recent years doctors have tried prescribing ‘clozapine’ to inpatients with borderline personality disorder. Clozapine is an antipsychotic drug which may improve mental health and reduce the type of aggressive and self-harming behaviour which can lead to people having long inpatient admissions. However clozapine also has important side effects. These include reductions in white blood cells, which are potentially life-threatening if people are not properly monitored. Studies examining what happens to inpatients with borderline personality disorder that are treated with clozapine show that mental health improves and people require less costly treatment. However no clinical trials have been conducted to date. While clozapine has the potential to generate considerable savings for the NHS, the true risks and benefits of treating people with borderline personality disorder with this drug are not known. We plan to conduct a multi-centre randomised trial to compare the clinical effectiveness and cost effectiveness of clozapine versus placebo for inpatients with borderline personality disorder. We plan to recruit people aged 18 years or over who are inpatients, have a confirmed diagnosis of borderline personality disorder, and have failed to make an adequate clinical response to existing treatment despite taking other antipsychotic drugs for at least three months. We will exclude people who have a clinical diagnosis of psychosis and those already taking clozapine. We will recruit 222 people from inpatient services in the NHS and private sector inpatient services that are provided for NHS patients. At the start of the study we will assess patients’ mental health, level of self-harm, aggressive behaviour, health-related quality of life, side effects of treatment and costs of care. Each person in the study would have an equal chance of receiving clozapine or placebo in addition to the care they would normally receive. Researchers will conduct follow-up assessments at three and six months, and will not know whether people are being prescribed clozapine or the placebo. We will also seek written informed consent to follow up participants after six months using routine hospital records. People with lived experience of inpatient treatment for borderline personality disorder have commented on plans for this study. People with first-hand experience of being treated for this condition are part of our study team and will continue to be involved in overseeing the progress of the study and reporting the study findings. We believe that this study can help ensure that inpatients with borderline personality disorder get the best and safest treatment for their condition and that funding available for people with borderline personality disorder is used in the most effective way.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH