Efficacy and safety of cariprazine augmentation in patients treated with clozapine: a pilot study.

Background: Cariprazine, a novel antipsychotic drug, is a partial agonist of dopamine D2/D3 receptors with preferential binding to the D3 receptor. There has been an increasing interest in cariprazine augmentation to clozapine; however, the evidence thus far has been only limited to case reports and case series. Objectives: To evaluate the efficacy and safety of the augmentation of clozapine with cariprazine in patients with sub-optimal treatment response. Methods: Demographic and clinical information of the study population were collected from the electronic records and PANSS scale administered at baseline and 3 months. Tolerability and discontinuation reasons where applicable were also recorded. Results: Ten patients (four men and six women) with a mean age of 36.5 years (range = 26-45) were included. Reasons for cariprazine initiation included inadequate treatment response, persistent negative symptoms and/or tolerability issues with clozapine or previous augmentation options. Two patients discontinued cariprazine within the first 6 weeks due to restlessness and poor response, respectively. There was a significant reduction in the median total PANSS score from baseline to 3 months (from 59 to 22.5, p < 0.05), median positive PANSS score (from 11.5 to 5.5, p < 0.05) and in the median negative PANSS score (from 15.5 to 3, p < 0.05) which correspond to a 48%, 33.8% and 65.8% mean score reduction, respectively. Conclusion: This is the first pilot study evaluating the effectiveness of clozapine augmentation. The preliminary evidence suggests that this may be a safe and effective practice in patients failing to adequately respond to or tolerate clozapine and/or previous augmentation strategies.

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

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.

Effectiveness of paliperidone depot injection in seriously violent men with comorbid schizophrenia and dissocial personality disorder in a UK high-security hospital.

BACKGROUND: High-security hospital patients are often complex in presentation and are characterized by treatment resistance, medication nonadherence and history of violence. Paliperidone is licensed both as an oral and depot antipsychotic medication in the treatment of schizophrenia. Clinical trials have shown that paliperidone depot is well tolerated with similar efficacy to risperidone depot but with additional practical advantages. Whilst data exist for the effectiveness of paliperidone palmitate (PP), there are no studies involving patients in forensic settings or those with comorbid personality disorder. Our aim was to evaluate the effectiveness of PP on violence, aggression and personality disorder symptoms. METHODS: This project was a retrospective service evaluation involving 11 patients, carried out in a high-security hospital. A combination of patient records and interviews with the treating consultant psychiatrist were used to ascertain a Clinical Global Impression (CGI) score, the effect of PP on specific personality disorder symptom domains (cognitive-perceptual, impulsive-behavioural dyscontrol and affective dysregulation) and incidents of violence and aggression. Engagement with occupational and psychological therapies was also evaluated. Metabolic parameters were reviewed. RESULTS: A total of 6 out of 11 patients continued on PP, most of whom had schizophrenia and dissocial personality disorder with histories of violence. All showed improvement in the CGI score with associated benefits in the three personality symptom domains. Overall, two patients demonstrated a reduction in the risk of violence. There was improvement in engagement with occupational therapy and psychological work. No significant effects on metabolic parameters were noted although hyperprolactinaemia, albeit asymptomatic, was consistently recorded. CONCLUSIONS: This pragmatic service evaluation of a small but complex patient group demonstrated, for the first time, that PP was effective in reducing violence as well as improving personality pathology across all dimensions: a finding which could have significant implications for management of such high-security patients.

Psychotropic prescribing in seriously violent men with schizophrenia or personality disorder in a UK high security hospital.

OBJECTIVES: To analyze antipsychotic prescribing patterns in a UK high security hospital (HSH) that treats seriously violent men with either schizophrenia or personality disorder and examine how different groups consented to treatment and prescribing for metabolic conditions. We hypothesized that there would be high prevalence of antipsychotic polypharmacy, and high-dose antipsychotic and clozapine prescribing. BACKGROUND: HSHs treat seriously violent, mentally disordered offenders, and the extant literature on prescribing patterns in forensic settings is sparse. METHODS: Prescribing and clinical data on all 189 patients in a UK HSH were collected from the hospital's databases. Data were analyzed using SPSS. RESULTS: The population was split into the following groups: schizophrenia spectrum disorder (SSD-only), personality disorder (PD-only), and comorbid schizophrenia spectrum disorder and PD. The majority (93.7%) of all patients were prescribed at least one antipsychotic, and (27.5%) were on clozapine. Polypharmacy was prevalent in 22.2% and high-dose antipsychotic in 27.5%. Patients on clozapine were more likely to be prescribed antidiabetic, statins, or antihypertensive medication. Patients in the PD-only group were more likely to be deemed to have the capacity to consent to treatment and be prescribed clozapine in contrast to the SSD-only group. CONCLUSIONS: Rates of clozapine and high-dose antipsychotic prescribing were higher than in other psychiatric settings, while polypharmacy prescribing rates were lower. Higher clozapine prescribing rates may be a function of a treatment-resistant and aggressive population. A higher proportion of PD-only patients consented to treatment and received clozapine compared with in-house SSD-only as well as other psychiatric settings. Implications of the findings are discussed.

New technologies in the management of risk and violence in forensic settings.

Novel technological interventions are increasingly used in mental health settings. In this article, we describe 3 novel technological strategies in use for management of risk and violence in 2 forensic psychiatry settings in the United Kingdom: electronic monitoring by GPS-based tracking devices of patients on leave from a medium secure service in London, and closed circuit television (CCTV) monitoring and motion sensor technology at Broadmoor high secure hospital. A common theme is the use of these technologies to improve the completeness and accuracy of data used by clinicians to make clinical decisions. Another common thread is that each of these strategies supports and improves current clinical approaches rather than drastically changing them. The technologies offer a broad range of benefits. These include less restrictive options for patients, improved accountability of both staff and patients, less invasive testing, improved automated record-keeping, and better assurance reporting. Services utilizing technologies need also be aware of limitations. Technologies may be seen as unduly restrictive by patients and advocates, and technical issues may reduce effectiveness. It is vital that the types of technological innovations described in this article should be subject to thorough evaluation that addresses cost effectiveness, qualitative analysis of patients' attitudes, safety, and ethical considerations.

An evaluation of the use of olanzapine pamoate depot injection in seriously violent men with schizophrenia in a UK high-security hospital.

BACKGROUND: Oral olanzapine is a well-established treatment for patients suffering from schizophrenia. Advantages of depot olanzapine may include improved compliance. However, it is expensive, causes metabolic side effects, and carries a risk of postinjection syndrome. Clinical trials have shown olanzapine pamoate to be effective, but further work is needed in this area. This study was a retrospective service evaluation, carried out in a high-security hospital, where the majority of patients have complex, treatment resistant schizophrenia spectrum disorder and a very high propensity for violence. Compliance is a significant problem, both in the high-security setting and on discharge. There has been no previous published work that the authors are aware of evaluating the effects of olanzapine pamoate in this subgroup of patients. METHODS: The aim of the study was to evaluate the clinical efficacy of olanzapine pamoate, its effect on violence as well as its side effects, in a high-security setting for the first time. Anonymized patient records were used to identify the main outcome measure and clinical global improvement, and to ascertain secondary outcome measures which included seclusion hours, risk of violence and side effects. Metabolic parameters and number of incidents were also recorded. Eight patients were treated with olanzapine pamoate. RESULTS: Six showed an improvement in symptoms, with an associated decrease in violence and number of incidents. Four showed an associated decrease in seclusion hours. Two showed an increase in body mass index and two showed an increase in glucose. CONCLUSIONS: The findings of this study are important in showing that all patients who responded to olanzapine pamoate also showed a decrease in violent behaviour. The potential anti-aggression effects of olanzapine pamoate may represent a very promising area for further work. A depot antipsychotic medication that reduces violence could have significant implications for management of high-security patients.

Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial personality disorder in a UK high-security hospital.

OBJECTIVE: A number of studies have demonstrated the anti-aggressive properties of clozapine in schizophrenia and its positive effect in borderline personality disorder. There is no published literature on the treatment of antisocial personality disorder (ASPD) with clozapine. We present a case series of 7 patients with primary ASPD and high psychopathic traits treated with clozapine, having a significant history of serious violence and currently detained in a UK based high-security hospital. METHODS: A retrospective review of case notes was carried out to formulate Clinical Global Impression (CGI) scores and record incidents of violence and aggression. Effect on specific symptom domains (cognitive-perceptual, impulsive-behavioural dyscontrol, affective dysregulation) was also noted. Metabolic parameters and serum clozapine levels were also sampled. RESULTS: All 7 patients showed significant improvement on clozapine. It was shown to benefit all symptom domains, especially impulsive behavioral dyscontrol and anger. The number of violent incidents committed by 6 of the 7 patients reduced significantly, and all patients' risk of violence reduced. Clozapine serum levels for 6 of the 7 patients were in the range 150-350 ng/mL. CONCLUSION: Clozapine is of benefit in reducing the clinical severity of ASPD. It improved all symptom domains, especially impulsive-behavioral dyscontrol and anger, and reduced levels of aggression and violence, especially at lower doses (serum levels <350 ng/m). To our knowledge, this is the first account of clozapine treatment in patients with ASPD and high psychopathy.

Augmentation of clozapine with amisulpride: an effective therapeutic strategy for violent treatment-resistant schizophrenia patients in a UK high-security hospital.

OBJECTIVE: Clozapine is used in the management of treatment-resistant schizophrenia and is effective in reducing aggression; however a subgroup of patients is poorly responsive. For violent patients in this group, there is limited literature on the use of strategies to augment clozapine with other agents. Here we present a case series of 6 schizophrenia patients, within a high-security hospital, who have a history of serious violence and who were treated with clozapine augmented with amisulpride. METHODS: We reviewed case notes and health records for evidence of violence/aggression and positive factors such as engagement in activities, and Clinical Global Impression (CGI) scores were formulated. We also examined metabolic parameters before and after augmentation. RESULTS: All 6 of the patients showed clinical improvement in symptoms and a reduction in their risk of violence to others. Five patients had a reduction in number of violent/aggressive incidents, and all patients showed improvement in engagement in occupational, vocational, and/or psychological work. Metabolic parameters were largely unchanged except for 1 patient whose Body Mass Index (BMI) increased. Five patients reported side effects as unchanged or improved. CONCLUSION: These schizophrenia patients with a history of violence showed clinical improvement and reduced aggression and violence with amisulpride augmentation of clozapine. To our knowledge, this is the first report of an antiaggressive benefit of this combination in forensic psychiatric patients. Further studies are warranted to establish the efficacy and anti-aggressive effects of amisulpride augmentation of clozapine.