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

Vitamin D supplementation compared to placebo in people with First Episode psychosis - Neuroprotection Design (DFEND): a protocol for a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. METHODS/DESIGN: The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. DISCUSSION: The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. TRIAL REGISTRATION: ISRCTN, ISRCTN12424842. Registered on 25 February 2015

Consultant psychiatrists’ experiences of and attitudes towards shared decision making in antipsychotic prescribing, a qualitative study

Background: Shared decision making represents a clinical consultation model where both clinician and service user are conceptualised as experts; information is shared bilaterally and joint treatment decisions are reached. Little previous research has been conducted to assess experience of this model in psychiatric practice. The current project therefore sought to explore the attitudes and experiences of consultant psychiatrists relating to shared decision making in the prescribing of antipsychotic medications. Methods: A qualitative research design allowed the experiences and beliefs of participants in relation to shared decision making to be elicited. Purposive sampling was used to recruit participants from a range of clinical backgrounds and with varying length of clinical experience. A semi-structured interview schedule was utilised and was adapted in subsequent interviews to reflect emergent themes. Data analysis was completed in parallel with interviews in order to guide interview topics and to inform recruitment. A directed analysis method was utilised for interview analysis with themes identified being fitted to a framework identified from the research literature as applicable to the practice of shared decision making. Examples of themes contradictory to, or not adequately explained by, the framework were sought. Results: A total of 26 consultant psychiatrists were interviewed. Participants expressed support for the shared decision making model, but also acknowledged that it was necessary to be flexible as the clinical situation dictated. A number of potential barriers to the process were perceived however: The commonest barrier was the clinician's beliefs regarding the service users' insight into their mental disorder, presented in some cases as an absolute barrier to shared decision making. In addition factors external to the clinician - service user relationship were identified as impacting on the decision making process, including; environmental factors, financial constraints as well as societal perceptions of mental disorder in general and antipsychotic medication in particular. Conclusions: This project has allowed identification of potential barriers to shared decision making in psychiatric practice. Further work is necessary to observe the decision making process in clinical practice and also to identify means in which the identified barriers, in particular 'lack of insight', may be more effectively managed. © 2014 Shepherd et al.; licensee BioMed Central Ltd

A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis

Background Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored. Aims This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period. Method Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication. Results Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14–1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11–1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling. Conclusions Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature

Vortioxetine as adjunctive therapy in the treatment of schizophrenia

Background: The evidence for safe and effective interventions to treat the negative and cognitive symptoms of schizophrenia is lacking. Objectives: Vortioxetine is a novel antidepressant that has been used as adjunctive therapy for the treatment of psychosis; however, its effectiveness in clinical practice is relatively unknown. In this study, we aimed to determine the potential clinical effectiveness and safety and tolerability of vortioxetine in psychosis. Design: This is a non-interventional, retrospective study on the add-on use of vortioxetine in a group of people with schizophrenia-spectrum disorders in a large UK NHS mental health trust. Methods: Clinical effectiveness of vortioxetine was retrospectively assessed through the Clinical Global Impression – Severity (CGI-S) scale at 3 months. Safety and tolerability were evaluated through treatment discontinuation rates at 3, 6, and 12 months, and clinical reasons were evaluated at the primary endpoint of 3 months. Results: Data were available for 40 subjects with a diagnosis of schizophrenia or schizoaffective disorder–prescribed vortioxetine treatment; 30 (75%) remained on treatment at 3 months. At CGI-S assessment, 15 of the 35 evaluated subjects reported at least a 1-point improvement, from 5 at baseline to 4 after 3 months of treatment. Twenty-six (65%) remained on treatment at 1-year follow-up. The main reasons for those discontinuing treatment were inadequate response (10%) and manic switch (7.5%), while one subject refused treatment. Tolerability to treatment was good, and 36 subjects (90%) reported no adverse events specific to vortioxetine treatment. Conclusion: Schizophrenia is a complex illness, and there is insufficient treatment response in many individuals. A significant proportion of whom may require adjunctive treatments depending on the nature of the residual symptoms. Vortioxetine could be a potentially safe and effective option in such people, but further controlled studies are required

A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis

Background Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored. Aims This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period. Method Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication. Results Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14–1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11–1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling. Conclusions Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature