Meta-analysis and systematic review of vesicular monoamine transporter (VMAT-2) inhibitors in schizophrenia and psychosis.

RATIONALE: Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce dopaminergic transmission but have limited activity at postsynaptic receptors and so may have antipsychotic activity with lower risk of tardive dyskinesia. METHODS: We conducted a systematic database search from inception to September 2022 for articles describing the use of VMAT-2 inhibitors in psychosis. Inclusion criteria were as follows: Population: adults diagnosed with psychosis or schizophrenia; Intervention: treatment with tetrabenazine, deutetrabenazine or valbenazine; Comparison: comparison with placebo or/and antipsychotic drug; Outcomes: with efficacy outcomes (e.g. Brief Psychiatric Rating Scale (BPRS) change or clinician assessment) and adverse effects ratings (e.g. rating scale or clinician assessment or dropouts); and Studies: in randomised controlled trials and non-randomised studies. RESULTS: We identified 4892 records relating to VMAT-2 inhibitor use of which 5 (173 participants) met our a priori meta-analysis inclusion criteria. VMAT-2 inhibitors were more effective than placebo for the outcome 'slight improvement' (risk ratio (RR) = 1.77 (95% CI 1.03, 3.04)) but not for 'moderate improvement' (RR 2.81 (95% CI 0.27, 29.17). VMAT-2 inhibitors were as effective as active comparators on both measures for-'slight improvement' (RR 1.05 (95% CI 0.6, 1.81)) and 'moderate improvement' (RR 1.11 (95% CI 0.51, 2.42). Antipsychotic efficacy was also suggested by a narrative review of 37 studies excluded from the meta-analysis. CONCLUSIONS: VMAT-2 inhibitors may have antipsychotic activity and may offer promise for treatment of psychosis with the potential for a reduced risk of TD.

Clozapine augmentation with long-acting antipsychotic injections: A case series and systematic review.

BACKGROUND: Up to 30% of patients with a diagnosis of treatment-resistant psychosis remain symptomatic despite an optimal trial with the gold standard treatment, clozapine. Emerging evidence suggests the clinical utility of long-acting injections (LAI) in such clinical scenarios. In this study, we aimed to describe clozapine augmentation with LAIs in an inner London hospital and explore the literature on the clinical effectiveness of this treatment modality. METHODS: Patients prescribed clozapine, who were commenced on a LAI between 2007 and 2023 by the United Kingdom's largest mental health trust, were identified from electronic patient records. First, routine clinical data were used to describe the use, effectiveness, and safety of this augmentation strategy. Second, we conducted a literature search up to 1st June 2023 to identify published studies describing clinical outcomes after clozapine augmentation with a LAI. Clinical outcomes were collated and presented in a table, including hospitalisation rates and quantitative clinical assessments using validated scales. RESULTS: Of the 1248 patients prescribed clozapine in SLaM, three patients (0.2%) received augmentation with the following LAIs: olanzapine embonate, paliperidone palmitate and pipotiazine palmitate. This treatment strategy was clinically effective and generally well tolerated in all three cases. Twelve published studies between 2010 and 2022 were included in the review. Eight distinct LAIs were reported (4 first and 4 second generation antipsychotics), with risperidone and paliperidone most widely studied. All the identified studies were observational including mirror-image studies, case series and case reports. Duration of follow up varied from 3 months to 3 years. There was evidence that the use of LAIs with clozapine can significantly reduce clinical symptoms, hospitalisation rates and bed days. No serious adverse effects were reported. CONCLUSION: This preliminary evidence suggests clinical utility of LAIs in alleviating residual symptoms and subsequently reducing hospitalisation rates in patients optimised on clozapine treatment. The current study warrants further investigations including a randomised controlled study to establish the clinical efficacy, tolerability, and place in therapy of this treatment modality.

Clinical impact of reducing the frequency of clozapine monitoring: controlled mirror-image cohort study.

BACKGROUND: To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust. AIMS: To investigate the impact of this temporary policy change on clinical and safety outcomes. METHOD: All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined. RESULTS: Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02-28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection. CONCLUSIONS: There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Clozapine haematological monitoring for neutropenia: a global perspective.

AIMS: Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates. METHOD: We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons. RESULTS: One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita. CONCLUSIONS: Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

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.

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. FUNDING: None.

A retrospective case notes review of the effectiveness and tolerability of metoclopramide in the treatment of clozapine-induced hypersalivation (CIH).

OBJECTIVE: The objective of the study is to explore the long-term effectiveness and tolerability of metoclopramide in the treatment of CIH. METHOD: This study is a retrospective, observational cohort study of patients prescribed metoclopramide for CIH at the South London & Maudsley (SLaM) NHS Foundation Trust. RESULTS: 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. CONCLUSION: 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.

Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis.

The wider use of clozapine is limited by the risk of agranulocytosis and the associated requirement for monitoring of neutrophil counts. We searched local electronic patient records for cases of agranulocytosis occurring during clozapine treatment during the period 2007-2020. We found 23 episodes recorded as agranulocytosis in clozapine patients. Of these, nine met pre-defined criteria and were considered episodes of life-threatening agranulocytosis (LTA). These episodes of clozapine-induced LTA exhibited a distinct pattern of continuous and rapid neutrophil count decline to zero or near zero. Mean time for neutrophils to fall from ANC > 2 to ANC <0.5 × 109/L was 8.4 days (range 2-15 days). Each event was also characterised by a prolonged nadir and delayed recovery (range 4-16 days). Non-LTA episodes were, in contrast, brief and benign. We conclude that an important proportion of cases of agranulocytosis identified in people prescribed clozapine are not life-threatening and may not even be clozapine-related. Monitoring schemes should aim to identify true clozapine-induced LTA as opposed to threshold-defined nominal agranulocytosis. Genetics studies might benefit from examining associations with clozapine-induced LTA rather than with recorded cases of agranulocytosis or neutropenia.

Incident infection during the first year of treatment - A comparison of clozapine and paliperidone palmitate long-acting injection.

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.

Evaluation of the effectiveness and acceptability of the long-acting oral antipsychotic penfluridol: Illustrative case series.

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.

Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals.

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 × 109 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.

A multidimensional measure of polypharmacy for older adults using the Health and Retirement Study.

Polypharmacy is commonly defined based on the number of medications taken concurrently using standard cut-offs, but several studies have highlighted the need for a multidimensional assessment. We developed a multidimensional measure of polypharmacy and compared with standard cut-offs. Data were extracted for 2141 respondents of the 2007 Prescription Drug Survey, a sub-study of the Health Retirement Study. Latent classes were identified based on multiple indicators of polypharmacy, including quantity, temporality and risk profile. A four-class model was selected based on fit statistics and clinical interpretability: 'High risk, long-term' (Class 1), 'Low risk, long-term' (Class 2), 'High risk, short-term' (Class 3), and 'High risk for drug interactions, medium-term, regular' (Class 4). Classes differed regarding sex, cohabitation, disability and multimorbidity. Participants in the 'low risk' class tended to be male, cohabitating, and reported fewer health conditions, compared to 'high risk' classes. Polypharmacy classes were compared to standard cut-offs (5+ or 9+ medications) in terms of overlap and mortality risk. The three 'high risk' classes overlapped with the groups concurrently taking 5+ and 9+ medications per month. However, the multidimensional measure further differentiated individuals in terms of risk profile and temporality of medication taking, thus offering a richer assessment of polypharmacy.

There Is Life After the UK Clozapine Central Non-Rechallenge Database.

BACKGROUND AND AIMS: In the United Kingdom, patients on clozapine whose hematological parameters fall below certain thresholds are placed on the Central Non-Rechallenge Database (CNRD), meaning that they cannot be prescribed clozapine again except under exceptional circumstances. This practice was discontinued in the United States in 2015 by expanding the hematological monitoring guidelines, allowing more patients to receive clozapine. Our objective was to investigate the implications this policy change would have on clozapine utilization in the United Kingdom. METHODS: This was an observational, retrospective analysis of patients registered on the CNRD in a large mental health trust. The first objective was to compare the number of patients placed on the CNRD under the United Kingdom and the US Food and Drug Administration (FDA) criteria. The second objective was to explore the hematological and clinical outcomes of CNRD patients. The third objective was to investigate the hematological outcomes of patients rechallenged on clozapine after nonrechallengeable status. RESULTS: One hundred and fifteen patients were placed on CNRD from 2002 to 2019, of whom 7 (6%) met the equivalent criteria for clozapine discontinuation under the FDA guidelines. Clinical outcomes, as measured by the Clinical Global Impression-Severity scale, were worse 3 months after clozapine cessation than on clozapine (t = -7.4862; P < .001). Sixty-two (54%) patients placed on CNRD were rechallenged. Fifty-nine of those (95%) were successfully rechallenged; 3 patients were placed back on CNRD, only one of which would have had to stop clozapine again under FDA criteria. CONCLUSION: Implementation of the updated FDA's monitoring criteria in the United Kingdom would significantly reduce clozapine discontinuation due to hematological reasons. The evidence suggests an urgent need for revising the UK clozapine monitoring guidelines to improve outcomes in treatment-resistant schizophrenia.

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.

The side effect profile of Clozapine in real world data of three large mental health hospitals.

OBJECTIVE: Mining the data contained within Electronic Health Records (EHRs) can potentially generate a greater understanding of medication effects in the real world, complementing what we know from Randomised control trials (RCTs). We Propose a text mining approach to detect adverse events and medication episodes from the clinical text to enhance our understanding of adverse effects related to Clozapine, the most effective antipsychotic drug for the management of treatment-resistant schizophrenia, but underutilised due to concerns over its side effects. MATERIAL AND METHODS: We used data from de-identified EHRs of three mental health trusts in the UK (>50 million documents, over 500,000 patients, 2835 of which were prescribed Clozapine). We explored the prevalence of 33 adverse effects by age, gender, ethnicity, smoking status and admission type three months before and after the patients started Clozapine treatment. Where possible, we compared the prevalence of adverse effects with those reported in the Side Effects Resource (SIDER). RESULTS: Sedation, fatigue, agitation, dizziness, hypersalivation, weight gain, tachycardia, headache, constipation and confusion were amongst the highest recorded Clozapine adverse effect in the three months following the start of treatment. Higher percentages of all adverse effects were found in the first month of Clozapine therapy. Using a significance level of (p< 0.05) our chi-square tests show a significant association between most of the ADRs and smoking status and hospital admission, and some in gender, ethnicity and age groups in all trusts hospitals. Later we combined the data from the three trusts hospitals to estimate the average effect of ADRs in each monthly interval. In gender and ethnicity, the results show significant association in 7 out of 33 ADRs, smoking status shows significant association in 21 out of 33 ADRs and hospital admission shows the significant association in 30 out of 33 ADRs. CONCLUSION: A better understanding of how drugs work in the real world can complement clinical trials.

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.

Clozapine and Norclozapine Plasma Levels in Patients Switched Between Different Liquid Formulations.

BACKGROUND AND OBJECTIVE: Clozapine is the drug of choice for treatment-resistant schizophrenia. The primary objective of this study was to compare plasma clozapine and N-desmethylclozapine levels in patients switched between 2 liquid formulations [Denzapine suspension and clozapine oral solution (St George's ZTAS)]. Secondary objectives included comparison of safety, tolerability, and patient acceptability. METHODS: This was a noninterventional, observational, prospective follow-up of patients consecutively switched between formulations of clozapine liquid in a large inner-city NHS mental health trust. The authors also performed retrospective analysis of outcomes from patient case notes. RESULTS: The authors identified 43 patients receiving Denzapine suspension in the trust. Data were available for 43 patients switched from Denzapine to clozapine oral solution (St George's ZTAS), among whom, 15 (32%) were excluded from the analysis. Of the 28 patients for whom data were available, the 90% confidence interval for the ratio of mean values for corrected Cmin 91.5 (85.2%-98.4%) and uncorrected Cmin 91.2 (84.4%-98.6%) were within the guideline range of bioequivalence (80%-125%). Safety and tolerability profiles were comparable between the 2 formulations (P = 0.10). Patient acceptability was also similar between the brands in most domains. However, there was a taste preference for Denzapine suspension. CONCLUSIONS: No significant difference in clozapine plasma levels was observed after switching from Denzapine suspension to a recently introduced clozapine solution. This study also highlights the significance of medicinal characteristics such as taste for patient acceptability and compliance.

Need to bleed? Clozapine haematological monitoring approaches a time for change.

Regular haematological monitoring during clozapine treatment reduces the risk of complications and death from clozapine-related blood dyscrasias. However, many patients in the course of clozapine treatment develop neutropenia unrelated to drug treatment which leads to treatment discontinuation. The minimum haematological threshold allowed for the continuation of clozapine treatment was recently lowered in the US, but not in the UK. In this case series, we present four cases where lowering the haematological cut-off to that used in the US, allowed treatment continuation. Lowering the current UK threshold for clozapine cessation could avoid unnecessary interruptions in treatment with minimal impact on safety.

Haloperidol decanoate long-acting injection (HDLAI): Results of a 1-year mirror-image study.

BACKGROUND: We sought to determine clinical outcomes of the prescribing of haloperidol decanoate long-acting injection (HDLAI) at 1 year. METHOD: A 1-year mirror-image study of 84 inpatients initiated on HDLAI. Admissions and bed days in the year preceding HDLAI were compared with the year after initiation. Predictors for discontinuation were evaluated. RESULTS: At 1 year, 33% of patients remained on treatment. Patients starting HDLAI because of nonadherence were more likely to stop treatment [relative risk (RR) 1.72; 95% confidence interval (CI) 1.01, 2.91; p = 0.044] whilst patients with a longer duration of illness were more likely to remain on treatment (RR 0.88; 95% CI 0.78, 1.00; p = 0.050). In the bed days cohort overall, (n = 65), there was a significant reduction in mean hospital admissions (1.4/patient/year to 0.6/patient/year; p = 0.0001) but not bed days (55.6/patient to 45.0/patient; p = 0.07) in the year following HDLAI initiation compared with the year before. Continuers had a significant reduction in mean bed days (53.1 to 4.0; p = 0.0002) and hospital admissions (1.5 to 0.2; p = 0.0001). Discontinuers demonstrated a significant reduction in hospital admissions (1.5 to 0.8; p = 0.0001) but not bed days (56.7 to 64.5; p = 0.83). CONCLUSION: HDLAI was associated with a high treatment discontinuation rate. Hospital admissions fell in the year after HDLAI but there was no change in bed days. Our study suggests that patients with a longer duration of illness and patients initiated on HDLAI for reasons other than poor adherence may benefit from HDLAI initiation.

Associations between illness beliefs, medication beliefs, anticoagulation-related quality of life, and INR control: Insights from the Switching Study.

BACKGROUND: Anticoagulation control with vitamin-K antagonists (VKAs) in patients with atrial fibrillation (AF) or venous thromboembolism (VTE) can be measured using time in therapeutic range (TTR), where TTR >65% is considered good and low TTR may be associated with low adherence. METHODS: This cross-sectional observational study compared illness beliefs, treatment beliefs, and treatment satisfaction of patients with TTR >75% and TTR <50% using validated tools to determine their association with TTR. Adults requiring chronic VKA therapy were recruited from 2 hospital anticoagulation clinics in London, UK. RESULTS: 311 patients with TTR >75% and 214 with TTR <50% were recruited. TTR >75% patients had been taking warfarin on average over 2 years longer than TTR <50% patients (P < .001). Statistically significant differences in beliefs were found in all subscales other than in treatment control, general harm, and general overuse. Cluster analysis determined there were 4 distinct clusters of beliefs among patients. Multivariate binary logistic regression found VTE patients were least likely to have poor TTR (OR = 0.49; 95% CI 0.29, 0.77). Patients in the "cautious of therapy and fearful of illness" cluster were most likely to have low TTR (OR = 4.75; 95% CI 2.75, 8.77). CONCLUSION: Illness perceptions, medication beliefs and treatment satisfaction were associated with INR control. VTE patients and those who were accepting of both illness and treatment were most likely to have optimal INR control.