Clozapine is an atypical antipsychotic used in treatment-resistant schizophrenia. Whilst clozapine is highly effective, there are some clinical scenarios, such as the emergence of severe side ...effects, that necessitate its discontinuation. There is an emerging literature suggesting that discontinuing antipsychotics, in particular clozapine, can cause an array of withdrawal symptoms. We review the evidence for the existence of clozapine-induced withdrawal symptoms, and in particular focus on withdrawal-associated psychosis, cholinergic rebound, catatonia and serotonergic discontinuation symptoms. To date, there has been surprisingly little clinical guidance on how to minimise the likeliness of withdrawal symptoms in patients who are stopped on clozapine abruptly or gradually. We discuss the key outstanding questions in this area and why there is a need for guidance on the management of withdrawal symptoms associated with clozapine discontinuation.
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.
Background:
To examine the risk of infection in patients prescribed clozapine compared with patients prescribed paliperidone palmitate long-acting injection (PPLAI).
Method:
A retrospective, 1-year, ...cohort study conducted on events occurring in eligible patients beginning treatment for the first time with clozapine or PPLAI between June 2017 and June 2019 in a UK mental health trust providing in-patient and out-patient services.
Results:
The study included 64 patients starting clozapine and 120 patients starting PPLAI. Incidence of infection was greater in clozapine starters than in PPLAI starters (28% vs 6%; p = 0.001; adjusted odds ratio 5.82 (95% confidence interval (CI) = 2.15–15.76, p = 0.001). Infectious episodes in clozapine patients were not related to changes in neutrophil counts. Incident infection in the clozapine group was highest in the first 3 months of treatment. The most commonly reported infection in the clozapine group was chest infection; however, the majority of infections were non-chest-related.
Conclusion:
Patients starting clozapine showed a substantially increased likelihood of infection compared with patients starting PPLAI.
Only about 50% of patients with treatment-resistant schizophrenia respond to clozapine, and many more patients continue to experience ongoing and prominent negative symptoms. These negative symptoms, ...for which there are limited pharmacological options, may represent the greatest barrier to functional recovery. Cariprazine is a novel antipsychotic drug that is a partial agonist at dopamine D2 and D3 receptors with preferential binding to the D3 receptor, antagonism of 5HT2B receptors, and partial agonism at 5HT1A receptors. Cariprazine is currently licenced for the treatment of schizophrenia in Europe and the United States and has also been approved for bipolar disorder in the United States. There is a limited body of evidence to suggest clinical effectiveness as an augmentation strategy for negative symptoms in those treated with clozapine. In this case series, we present five cases of successful treatment of negative symptoms by clozapine combined with cariprazine in treatment-resistant psychosis.
Aim:
In this study, we sought to determine clinical outcomes at 1 year for patients prescribed penfluridol in an inner London National Health Service Trust. Using noninterventional data, we describe ...the use, effectiveness and safety of this treatment modality.
Results:
We retrospectively followed up 17 patients prescribed penfluridol as part of routine clinical practice. All patients took penfluridol once weekly. Of these patients, 12 (70.6%) were considered treatment resistant. The average duration of illness for this cohort was 10 years (SD = 6.7). At 1 year, nine (53%) patients remained on treatment. Median survival time was not reached at 1-year follow-up; mean time on penfluridol was 251 days (95% confidence interval (CI), 184–318). The mean number of admissions to hospital in the year following penfluridol initiation was 0.6 compared with 0.8, 1 year before initiation (p = 0.465). The median number of bed days 1 year before penfluridol initiation was 24, whereas in the year following penfluridol initiation, it was 0 (p = 0.514).
Clinical Implications:
Although penfluridol is unlicensed in the United Kingdom, limited data suggest that this long-acting oral therapy has the potential to be used safely and effectively for the treatment of psychotic disorders. However, more data are required to establish the place of penfluridol and other potential long-acting oral antipsychotic formulations in the treatment of psychotic disorders.
Abstract
Background
Benign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly ...defined by an absolute neutrophil counts (ANC) below 1.8 × 10
9
cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment.
Methods
This was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again.
Results
The study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation.
Conclusions
Current evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.
Clozapine is the treatment of choice in refractory psychosis. In most countries, clozapine must be stopped indefinitely if white blood cells fall below a defined threshold during routine monitoring. ...Despite evidence of severe adverse consequences of clozapine discontinuation, published accounts on the lived experiences and perspectives of patients and carers are scarce.
We completed semi-structured interviews with patients (n = 4) and family carers (n = 4) on experiences of clozapine cessation following suspected drug-induced neutropenia. Interviews were audio-recorded, transcribed and analysed thematically.
The two overarching themes comprised:(i) stress of clozapine below threshold neutrophil results and (ii) patient and carer priorities.
There is a suggested need for evidence-based pharmacological and psychological approaches to support patients and carers after clozapine cessation. Such approaches will minimise the potentially negative physical and emotional sequela in the aftermath of a below threshold neutrophil result and reduce the likelihood of experiencing additional health and social inequalities after clozapine discontinuation.
The objective of the study is to explore the long-term effectiveness and tolerability of metoclopramide in the treatment of CIH.
This study is a retrospective, observational cohort study of patients ...prescribed metoclopramide for CIH at the South London & Maudsley (SLaM) NHS Foundation Trust.
Of the 96 patients identified, 14 patients were eligible for inclusion in our study. Five patients continued treatment with a mean duration of 27 months (SD = 17.8), and one patient continued until transfer with a duration of 3 months. Eight patients discontinued treatment after a mean duration of 8 months.
Metoclopramide may be an effective and tolerated drug in CIH, but more data is required to establish its place in the pharmacotherapy of this condition.
Clozapine remains the gold standard intervention for treatment-resistant schizophrenia; however, it remains underused, especially for some minority groups. A significant impediment is concern about ...propensity to neutropenia. The aim of this article is to provide an update on current knowledge relating to: the pattern and incidence of severe blood dyscrasias; the effectiveness of current monitoring regimes in reducing harm; the mechanisms of and the distinctions between clozapine-induced neutropenia and agranulocytosis; benign ethnic neutropenia; and changes to the monitoring thresholds in the USA and other international variations. These all have implications for the practical use of clozapine; specifically, how barriers to initiating, maintaining and restarting clozapine can be understood and in many cases overcome, especially for patients from minority groups, potentially with simpler approaches than the use of lithium or G-CSF.
Tobacco use is the single largest preventable cause of death in the United States (US). The national goal of reducing the prevalence of adult cigarette smoking to 12% was retained for 20 years due to ...non-attainment. Meanwhile, varenicline and electronic cigarettes (ECs) became available in the US in 2006 and 2007, respectively, and have been used by many smokers wanting to quit. The purpose of this review is to compare varenicline and ECs in terms of efficacy for smoking cessation after over a decade of widespread use in the US. Data collection for systematic review and qualitative synthesis by a PubMed search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelinesand the Oxford Quality Scale, respectively, was performed in June 2018 and updated in June 2020. Articles were eligible if published in English as original research in the form of a randomized clinical trial (RCT), a systematic review and meta-analysis, a systematic review, or a cross-sectional study. Eighteen studies were included: nine RCTs, four cross-sectional studies, two meta-analyses, one systematic review, one systematic review and meta-analysis, and one cohort study. No head-to-head RCT compared varenicline to ECs. In four RCTs, varenicline was more effective than placebo for smoking cessation. In two RCTs, ECs were more effective than placebo but a meta-analysis of 20 studies reported a statistically significant decrease in the odds of quitting smoking using ECs as compared to placebo. To conclude, varenicline and ECs have data suggesting efficacy for smoking cessation; however, unlike varenicline, ECs were not effective in all studies.Tobacco use is the single largest preventable cause of death in the United States (US). The national goal of reducing the prevalence of adult cigarette smoking to 12% was retained for 20 years due to non-attainment. Meanwhile, varenicline and electronic cigarettes (ECs) became available in the US in 2006 and 2007, respectively, and have been used by many smokers wanting to quit. The purpose of this review is to compare varenicline and ECs in terms of efficacy for smoking cessation after over a decade of widespread use in the US. Data collection for systematic review and qualitative synthesis by a PubMed search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelinesand the Oxford Quality Scale, respectively, was performed in June 2018 and updated in June 2020. Articles were eligible if published in English as original research in the form of a randomized clinical trial (RCT), a systematic review and meta-analysis, a systematic review, or a cross-sectional study. Eighteen studies were included: nine RCTs, four cross-sectional studies, two meta-analyses, one systematic review, one systematic review and meta-analysis, and one cohort study. No head-to-head RCT compared varenicline to ECs. In four RCTs, varenicline was more effective than placebo for smoking cessation. In two RCTs, ECs were more effective than placebo but a meta-analysis of 20 studies reported a statistically significant decrease in the odds of quitting smoking using ECs as compared to placebo. To conclude, varenicline and ECs have data suggesting efficacy for smoking cessation; however, unlike varenicline, ECs were not effective in all studies.
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