Clozapine in Treatment-Resistant Schizophrenia (TRS): improving access and utilisation

Schizophrenia is the most severe mental illness affecting humans. When the illness does not respond to treatment, it is even more devastating. When a patient fails to respond to two adequate, consecutive antipsychotic treatments, the illness is termed treatment-refractory schizophrenia (TRS). Clozapine is the only licensed and recognised effective treatment in TRS. Interestingly, rather than its current position as a third-line treatment, there are rather robust and convincing arguments for clozapine to be used as a second line. Sadly, in clinical practice there is widespread underuse of clozapine, with significant delays before it is prescribed in individuals with TRS, being relegated to the fifth or sixth line. Instead, non-evidence-based use of high-dose antipsychotics and the use of antipsychotics in combination is common practice, contributing to even longer delays. This is a compilation of 33 of my publications and public works (PWs) spanning over two decades, from 1999 to 2021. In these, I explore why clozapine is underused, when it should be used and how it should be used, employing different methodologies. This is a combination of my reviews of the literature and my practical recommendations on how to overcome difficulties in specific situations using case reports and case series. I have collaborated with colleagues from a wide variety of disciplines including psychiatrists, pharmacologists, cardiologists, haematologists and data experts to advance knowledge in the management of TRS through these works. I have investigated various databases and been involved in the design and conduct of randomised controlled trials in schizophrenia. My work has demonstrated that in the United Kingdom and probably in most other countries, significant variation exists in the rate of clozapine prescribing in patients with TRS. There is thus inequity in patient access to the most effective treatment in refractory schizophrenia. This has an enormous impact on patients and families and may be the difference between long-term institutional care and fulfilling, independent living in the community with freedom and liberty. The delay and underutilisation of clozapine are centred around four principal factors. These are related to the drug itself, factors that relate to the patient, clinician-related factors and finally, those that pertain to licensing and regulatory control of the drug. Clozapine is a life-prolonging drug, and concerted efforts to overcome these well-recognised barriers would go a long way in improving outcomes in patients with TRS. I believe that long-term solutions to the underuse of clozapine lie in education. Clinicians treating patients with schizophrenia need to identify patients with TRS as quickly as possible. Health systems to educate, support and encourage clinicians would provide much-needed confidence in evaluating risks and benefit to increase clozapine uptake. The stringent regulatory controls of clozapine should be thoroughly examined. The United States Food and Drugs Administration (FDA) has gone some way by lowering the haematological threshold for clozapine continuation, but more needs to be done. How can we be confident of overcoming all these seemingly impossible barriers? The answer, I believe, is in developing a national clozapine strategy. The United Kingdom is the centre of research in psychopharmacology. It houses the world-renowned Institute of Psychiatry, Psychology and Neurosciences (IoPPN) with expertise in the management of schizophrenia. A comprehensive national strategy that identifies all the barriers and a systematic approach to addressing the multifaceted problem would address these issues. This approach is not new. It has been successfully applied in countries such as the Netherlands. My PWs have shown that we can not only overcome these barriers, but substantially increase clozapine uptake. The negative prognostic implications of delay and underuse of clozapine are now becoming glaringly apparent. The outcome for patients where clozapine use is substantially delayed is not as good as in patients where it is initiated as soon as treatment refractoriness is ascertained. When we can fully utilise clozapine in patients with TRS, then we can turn our attention to the 40-50% of patients who have less than satisfactory response to clozapine, or those patients deemed as ultra treatment refractory

Evaluation of the Level of Variability of Niger Delta Community People’s Awareness and Knowledge of Chevron Regional Development Councils (RDCs) and Shell’s Cluster Development Boards (CDBs) Activities

The study's objectives were to evaluate the level of variability in community people's awareness and knowledge of Chevron Nigeria Limited (CNL) Regional Development Councils (RDCs) and Shell Petroleum Development Company of Nigeria (SPDC) Shell Cluster Development Boards (CDBs) and to determine whether the ascertained community people's awareness and knowledge have a significant impact on how well Multi-National Oil Corporations (MNOCs) development programmes are carried out in the host communities. Adopting the cross-sectional research design, the study surveyed 400 respondents from selected four states in the Niger Delta Oil Producing communities where RDCs and CDBs are operated. Descriptive statistics such as frequencies, means, and percentages were used to describe the socio-demographic information and the research questions. Inferential statistical tools like the One-Way Analysis of Variance and regression analysis had been used to take a look at the formulated hypotheses for the study. The findings indicate no relevant difference among community people in their state of awareness of the RDCs and CDBs but that the host community’s people poor involvement in the RDCs and CDBs resulted from inadequate requisite knowledge of the activities of MNOCs in their communities. The study recommended that every decision-making and taking process involve in project initiation, execution and implementation should involve the host communities in order to earn the people’s trust and respect

Integration of Environmental Public Health Into Primary Health Care Services for Low Income Pregnant Women

Objective: To assess the effectiveness of a pilot intervention using Integrated Pest Management (IPM) as a method to integrate environmental public health into primary health care services for low‐income pregnant women. Methods: Pregnant women > 18yrs old and clients of the Drexel University 11th Street Family Health Services Center were recruited. Pre‐intervention environmental knowledge assessments were conducted to measure knowledge of pest identification and toxicity of hazardous pesticides. Home visits were conducted along with delivery of IPM education and materials. Two weeks post intervention participants were contacted to complete a post‐intervention environmental knowledge assessment. Results: Frequencies of answer correct answer changes and two sample t‐test analysis results show that the delivered intervention result in a significant knowledge change among the cohort (p=0.04). Conclusion: The use of Integrated Pest Management as a method to integrateenvironmental public health into primary health care services for low income pregnant women is an effective method of creating knowledge change in the cohort.M.P.H., Public Health -- Drexel University, 200

An evaluation of the variation and underuse of clozapine in the United Kingdom

Background Clozapine is the only licensed treatment for treatment refractory schizophrenia. Despite this, it remains grossly underused relative to the prevalence of refractory schizophrenia. The extent of underuse and the degree of regional variation in prescribing in the United Kingdom is unknown. It is also unclear, how the UK compares with other European countries in rates of clozapine prescribing. Methods We obtained data relating to all clozapine prescribing in the UK from the relevant clozapine registries. We examined regional variation in clozapine use across England, corrected for the known prevalence of severe mental illness (SMI). We also compared the UK rate of clozapine use per 100,000 population to that described in other European countries. Findings There is substantial variation in clozapine prescribing across different regions of England and only about a third of potentially eligible patients were prescribed the drug in the UK. Clozapine prescribing rate in the UK was lower than in several European countries. Interpretation There is clear regional inequity in access to the most effective treatment in refractory schizophrenia in England. Strategies to increase clozapine use, by overcoming both real and perceived barriers, are urgently necessary to reduce treatment inequity for patients with refractory schizophrenia

Real-world effectiveness of admissions to a tertiary treatment-resistant psychosis service: 2-year mirror-image study

Background Treatment-resistant schizophrenia is a major disabling illness which often proves challenging to manage in a secondary care setting. The National Psychosis Unit (NPU) is a specialised tertiary in-patient facility that provides evidence-based, personalised, multidisciplinary interventions for complex treatment-resistant psychosis, in order to reduce the risk of readmission and long-term care costs. Aims This study aimed to assess the long-term effectiveness of treatment at the NPU by considering naturalistic outcome measures. Method Using a mirror image design, we compared the numbers of psychiatric and general hospital admissions, in-patient days, acuity of placement, number of psychotropic medications and dose of antipsychotic medication prescribed before and following NPU admission. Data were obtained from the Clinical Records Interactive Search system, an anonymised database sourced from the South London and Maudsley NHS Trust electronic records, and by means of anonymous linkage to the Hospital Episode Statistics system. Results Compared with the 2 years before NPU admission, patients had fewer mental health admissions (1.65 ± 1.44 v. 0.87 ± 0.99, z = 5.594, P < 0.0001) and less mental health bed usage (335.31 ± 272.67 v. 199.42 ± 261.96, z = 5.195 P < 0.0001) after NPU admission. Total in-patient days in physical health hospitals and total number of in-patient days were also significantly reduced (16.51 ± 85.77 v. 2.83 ± 17.38, z = 2.046, P = 0.0408; 351.82 ± 269.09 v. 202.25 ± 261.05, z = 5.621, P < 0.0001). The reduction in level of support required after treatment at the NPU was statistically significant (z = −8.099, P < 0.0001). Conclusions This study demonstrates the long-term effectiveness of a tertiary service specialising in treatment-resistant psychosis

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement

Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study

Background Clozapine is uniquely effective in treatment-resistant psychosis. In the UK, patients must discontinue clozapine indefinitely if they are placed on the Central Non-Rechallenge Database (CNRD) after their haematological parameters fall below particular thresholds. Under exceptional circumstances, patients can be rechallenged on clozapine under an off-licence agreement. In the USA in 2015, restrictive practice was discontinued to allow greater flexibility for clozapine maintenance. The absolute neutrophil count leading to treatment interruption was lowered from less than 1·5 × 109/L to less than 1·0 × 109/L and platelet and white cell count monitoring were ceased. We aimed to investigate the implications of a similar policy change on clozapine use in the UK. Methods This was a modelling study of all patients registered on the UK CNRD. First, we determined the proportion of patients placed on the database in the UK who would have had to discontinue clozapine treatment under the US Food and Drug Administration (FDA) criteria. Second, we compared the haematological characteristics of patients who did or did not meet FDA criteria for discontinuing clozapine, including the time to registration from clozapine initiation and the proportion of cases of severe neutropenia at registration. Third, we investigated the success rates of clozapine re-challenge for patients that had been placed on the CNRD. Successful rechallenge was defined as no recurrence of CNRD registration. Findings Between May 2, 2002 and March 1, 2021, 3731 patients were placed on the CNRD, with a mean age of 47 years (SD 15), including 1420 (38%) women and 2311 (62%) men, of whom 3089 (83%) were White, 360 (10%) were Black, 190 (5%) were Asian, and 92 (2%) were classified as other. 566 (15%) of 3731 patients met the equivalent criteria for clozapine discontinuation under the FDA guidelines. The median time to CNRD registration from clozapine initiation was 1·6 years (IQR 0·2–4·9). Data for 519 rechallenged patients were examined; 419 (81%) were successful. Clozapine rechallenge success rates were broadly similar between individuals who did not meet the US CNRD registration criteria (36 [78%] of 46) and those who did meet the criteria (383 [81%] of 473). Interpretation Implementing the revised FDA monitoring criteria in the UK would substantially reduce clozapine discontinuation for haematological reasons, which would greatly improve the mental health outcomes of these patients without having a major effect on their physical health