Clozapine Titration Research Articles

Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals.

Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation. We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date. We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days. Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset. A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.

Evaluation of major adverse events of clozapine based on accordance to an international titration guideline.

Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal outcomes. An International Adult Clozapine Titration Guideline categorizes patients into normal or slow metabolizers. Categorization provides clozapine titration schedules and recommends regular c-reactive protein (CRP) and clozapine concentration monitoring to reduce the risk of adverse drug reactions (ADRs). The impact of the guideline on clozapine ADRs has not been evaluated. A retrospective chart review assessed clozapine titrations, laboratory monitoring, ADRs, and discontinuations for clozapine-naive adult inpatients at a single center from January 1, 2013, to June 1, 2022. Each patient's cumulative weekly clozapine dosage was compared with their guideline recommended dosage to create a percent accordance. Linear logistic regression evaluated the relationship between titration speed and the presence of an ADR, while descriptive statistics analyzed laboratory monitoring. Forty-three patients were included, with the majority being White males with schizophrenia. An inverse relationship existed between the last inpatient week clozapine dose percent accordance and the probability of an ADR. Nonobese patients were less likely than obese patients to experience an ADR (odds ratio = 0.17; 95% CI, 0.03-0.99). CRP and clozapine concentration monitoring was suboptimal. Based on our small retrospective review of primarily White males, more aggressive clozapine titrations did not increase ADRs. Future studies with more diverse samples are needed and should focus on specific ADRs, which may have increased occurrence with rapid titrations. Obese patients were at higher risk of ADRs, correlating with the guideline-recommended slower titrations for these patients.

Can Slow Personalized Titration Using C-Reactive Protein Monitoring Decrease the High Rates and Mortality of Clozapine-Associated Myocarditis Seen in Some Countries? A Call for Research.

The hypothesis that slower personalized titration may prevent clozapine-associated myocarditis and decrease the disproportion incidence of 3% found in Australia was not described in a recent Australian article in this journal. Six countries in addition to Australia have published information suggesting a similar incidence of clozapine-associated myocarditis. On September 19, 2023, PubMed searches were updated for articles from the United States, Korea, Japan, Canada, New Zealand, and Turkey. An incidence of 3.5% (4/76) was found in a US hospital, but US experts were the first to propose that clozapine-associated myocarditis may be a hypersensitivity reaction associated with rapid titration and possibly preventable. Koreans and Japanese are of Asian ancestry and need lower minimum therapeutic doses for clozapine than patients of European ancestry. A 0.1% (2/1408) incidence of myocarditis during clozapine titration was found in a Korean hospital, but pneumonia incidence was 3.7% (52/1408). In 7 Japanese hospitals, 34% (37/110) of cases of clozapine-associated inflammation were found during faster titrations (based on the official Japanese titration) versus 13% (17/131) during slower titrations (based on the international titration guideline for average Asian patients). Recent limited studies from Canada, New Zealand, and Turkey suggest that slower personalized titration considering ancestry may help prevent clozapine-associated myocarditis. Other countries have very limited published data on clozapine-associated myocarditis. Based on a recent Australian case series and these non-Australian studies, the author proposes that Australia (and other countries) should use slow personalized titration for clozapine based on ancestry and c-reactive protein monitoring.

Patterns of C-reactive protein trends during clozapine titration and the onset of clozapine-induced inflammation: a case series of weekly and daily C-reactive protein monitoring.

International guidelines for clozapine titration recommend measuring C-reactive protein (CRP) weekly for 4 weeks after clozapine initiation to prevent fatal inflammatory adverse events, including myocarditis. However, limited evidence exists regarding whether weekly CRP monitoring can prevent clozapine-induced inflammation. We examined the relationship between CRP trends and the development of clozapine-induced inflammation. We also explored the usefulness and limitations of CRP monitoring during clozapine titration. This study presents 17 and 4 cases of weekly and daily CRP monitoring during clozapine initiation, respectively. Among 17 patients with weekly CRP measurements, 7 had fever. Elevated CRP levels were detected before the onset of fever in two of the seven patients. Of the five remaining patients, the CRP levels on a previous test had been low; however, the fever developed suddenly. Of the 10 patients with no fever under weekly CRP monitoring, three had elevated CRP levels >3.0 mg/dL. Refraining from increasing the clozapine dose may have prevented fever in these patients. Among four patients with daily CRP measurements, two became febrile. In both cases, CRP levels increased almost simultaneously with the onset of fever. Weekly and daily CRP monitoring during clozapine titration is valuable for preventing clozapine-induced inflammation, assessing its severity, and guiding clozapine dose adjustments. Weekly CRP monitoring may not adequately predict clozapine-induced inflammation in some cases. Consequently, clinicians should be aware of the sudden onset of clozapine-induced inflammation, even if CRP levels are low. Daily CRP monitoring is better for detecting clozapine-induced inflammation.

Slower clozapine titration is associated with delayed onset of clozapine-induced fever among Japanese patients with schizophrenia

Clozapine-induced fever marks the beginning of its inflammatory and potentially life-threatening adverse effects, such as myocarditis. We retrospectively analyzed the correlation between clozapine titration rate and fever onset date in 254 Japanese patients, including 55 with treatment-resistant schizophrenia who developed clozapine-induced fever. Pearson’s product-moment correlation indicated a significant delay in the fever onset date with slower titration. Most fever onset cases occurred within 4 weeks, even with slow titration. Therefore, clinicians should remain vigilant in monitoring clozapine-induced fever within 4 weeks of clozapine initiation, regardless of the titration rate.

Clozapine-associated pericarditis and pancreatitis in children and adolescents: A systematic literature review and pharmacovigilance study using the VigiBase database

BackgroundThe literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents. MethodsCases of clozapine-associated pericarditis and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC). ResultsThe PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC025 = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC025 = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases. ConclusionsDespite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration.

An International Adult Guideline for Making Clozapine Titration Safer by Using Ancestry-Based Personalized Dosing Titrations, C-Reactive Protein and Serum Clozapine Levels: Korean Translation and Its Clinical Application Cases

Objectives: During the initial clozapine titration, it is crucial to monitor for inflammatory reactions to ensure safe and effective administration. Clozapine metabolism varies by ancestry, particularly among Asians, warranting lower dosage. Recently, Dr. De Leon introduced guidelines based on ancestral differences. We aimed to provide a Korean translation, focusing on illustrating the necessity through clinical cases.Methods: The Korean translation of the guidelines, approved by Dr. De Leon, involved two psychiatrists who reviewed and revised each other’s work. An additional board-certified psychiatrist conducted an independent review. We examined two clinical cases from our institution’s database, where clozapine titration faced challenges due to fever and pneumonia, assessing guideline applicability.Results: The guidelines recommend a target clozapine dose of 175-300 mg/day for Asians with average metabolism and a slower titration rate compared to other ancestries. In both cases, CRP elevation was detected either before or simultaneously with the onset of fever, with a concentration-to-dose ratio ranging from 3.06 to 6.97.Conclusion: The initial clozapine titration process should consider metabolic differences by ancestry and monitor for inflammation. Further research is needed to optimize the titration process for Koreans, considering metabolic rates, usage patterns, and side effects.

Association between initial clozapine titration and pneumonia risk among patients with schizophrenia in a Korean tertiary hospital

Pneumonia is a significant adverse drug reaction (ADR) associated with clozapine, characterized by high mortality and potential linkage with other inflammatory responses. Despite the critical nature, research regarding the development of pneumonia during initial clozapine titration remains limited. This retrospective study included 1408 Korean inpatients with schizophrenia spectrum disorders. Data were collected from January 2000 to January 2023. Pneumonia developed in 3.5 % of patients within 8 weeks of clozapine initiation. Patients who developed pneumonia were taking a greater number and higher dose of antipsychotics at baseline (2.14 vs. 1.58, p < 0.001; 25.64 vs. 19.34, p = 0.012). The average onset occurred 17.24 days after initiation, on an average dose of 151.28 mg/day. Titration was either paused or slowed in most of these patients, with no reported fatalities. The types of pneumonia included aspiration pneumonia, mycoplasma pneumonia, bronchopneumonia, and COVID-19 pneumonia. Myocarditis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and urinary tract infections were also identified. Logistic regression analysis revealed that a greater number of concomitant antipsychotics (odds ratio [OR] = 1.59, p = 0.027) and concomitant benzodiazepine use (OR = 2.33, p = 0.005) at baseline were associated with an increased risk of pneumonia. Overall, pneumonia development during clozapine titration is linked with other inflammatory ADRs, suggesting a shared immunological mechanism. Close monitoring is recommended, especially for patients taking multiple antipsychotics and benzodiazepines. Further studies involving repeated measures of clozapine concentrations at trough and steady state, along with a more detailed description of pneumonia types, are warranted.

Predicting clozapine dose required to achieve a therapeutic plasma concentration - A comparison of a population algorithm and three algorithms based on gene variant models.

Clozapine is the most effective antipsychotic but requires careful titration to therapeutic blood levels. Methods to predict therapeutic doses are based on population data. We aimed to construct a model based on genetic variants which accurately predicted plasma levels for clozapine. We measured clozapine plasma levels in patients on a stable dose of clozapine who were known to be fully compliant. Measured plasma levels were adjusted for sampling time and dose. Hepatic enzyme variants were analysed and models were constructed to predict the required dose. These predictions were compared with a standard population-based algorithm. We measured plasma clozapine concentrations in 18 adherent patients on stable doses of clozapine and recorded the exact timing of sampling. For the algorithm-predicted dose, the mean difference was -49.9 mg/day ((SD 155.9), r = 0.36) from the actual dose required to give a plasma concentration of 0.35 ng/ml. The gene variant activity score predicted a dose for which the mean difference was -43.5 mg/day ((SD 140.1), r = 0.55). For the gene variant activity score with omeprazole correction predicted dose, the mean difference was -31.0 mg/day ((SD 140.8), r = 0.54), and with the gene variant CYP1A2 inducibility predicted dose the mean difference was 44.9 mg/day ((SD 160.8), r = 0.32). Our gene variant activity score with omeprazole correction gave the best estimate of the clozapine dose required to achieve a minimum therapeutic plasma concentration. The use of this model will allow safer titration of clozapine and may reduce the need for plasma-level monitoring during titration.

Association between initial pattern of clozapine titration, concentration-to-dose ratio, and incidence of fever in patients with schizophrenia spectrum disorders in a Korean tertiary hospital

Safe and effective administration of clozapine requires careful monitoring for inflammatory reactions during the initial titration. The concentration-to-dose (C/D) ratio must be taken into account, which may vary among ethnicities. In this retrospective study, 1408 Korean schizophrenia inpatients were examined for during the first 8 weeks of clozapine titration. The average doses of clozapine administered during weeks 1, 2, 4, and 8 were 77.37, 137.73, 193.20, and 212.83 mg/day, with significantly lower doses for females than males. The average C/D ratio was significantly higher in females (1.75 ± 1.04 and 1.11 ± 0.67 ng/mL per mg/day). Patients with higher C/D ratios were more likely to experience fever and were prescribed lower doses of clozapine starting from week 4. In total, 22.1 % of patients developed a fever at an average of 15.74 days after initiating clozapine. Patients who developed a fever were younger, used more antipsychotics at baseline, had a higher C/D ratio, and had a higher incidence of an elevated C-reactive protein level. A higher C/D ratio, use of a greater number of antipsychotics at baseline, and concomitant olanzapine use were risk factors for the development of inflammatory reactions. The incidence of pneumonia, agranulocytosis, and myocarditis within 8 weeks were 3.7 %, 0.3 %, and 0.1 %. In summary, the target dose of clozapine titration is lower for Korean schizophrenia patients, with a higher C/D ratio and more frequent fever compared to Western patients; however, myocarditis occurs rarely. Our findings may contribute to the titration methods for clozapine for the East Asian population.

Slower clozapine titration than the official Japanese protocol led to fewer inflammatory adverse effects: A retrospective chart review of seven hospitals

BackgroundHigher frequencies of inflammatory adverse effects of clozapine have been reported in Japan. As the international titration protocol for Asians has set slower dose titration than the Japanese package insert, we hypothesized that a dose titration speed slower than the recommendation of the guideline would be associated with fewer inflammatory-related adverse events. MethodsThe medical records of all 272 patients who were first started on clozapine at seven hospitals between 2009 and 2023 were studied retrospectively. Of those, 241 were included in the analysis. The patients were divided into two groups regarding whether the titration speed was faster or slower than the guideline for Asians. The incidence of inflammatory adverse events with clozapine was compared between the groups. ResultsThe frequency of inflammatory adverse events was 34 % (37/110) in the faster titration group and 13 % (17/131) in the slower titration group, and a significant difference was observed by Fisher exact test (odds ratio 3.38; 95 % confidence interval 1.71–6.91; p < 0.001). Serious adverse effects, fever for more than five days, and clozapine discontinuation were significantly more frequent in the faster titration group. Logistic regression analysis indicated significantly more inflammatory adverse events in the faster titration group (adjusted odds ratio 4.01; 95 % confidence interval 2.02–7.87; p < 0.001) considering age, sex, body mass index, concomitant valproic acid, and smoking as confounding factors. ConclusionClozapine-induced inflammatory adverse events were less frequent in Japanese individuals when a titration rate was more gradual than the protocol recommended in the Japanese package insert.

Hepatotoxicity of Clozapine : Case report and brief Review

IntroductionClozapine is an effective Atypical antipsychotic used in the treatment of resistant schizophrenia .However it can induce liver dysfunction from a simple transient asymptomatic cytolisis (30 to50 %) toa serious fulminant liver failure (0.001 %).ObjectivesTo show the heptotoxicity potential of Clozapine and adress the importance of monitoring the liver function tests in clozapine titration to prevent sever conditionsMethodsA case report of a fifty-year old Tunisian male patient diagnosed with resistant schizophrenia who developed a hepatototoxicity under a low dose of clozapine within five days of treatment .ResultsMr F is a 50 year old patient diagnosed with schizophrenia in 2018 . He had received various antypical and typical antipsychotic treatments including ( Haloperidol , Risperidone , Amisulpride , Olanzapine ) at effective doses and minimal periods of six weeks . He had no history of systemic diseases or substance use disorder . He smokes 10 cigarettes a day . He had a history of hepatotoxicity on olanzapine. These medications have failed to resolve the persecutory delusion and auditory hallucinations , and the trial of clozapine was institued . Baseline examination and laboratory tests were normal . The previous antipsychotic medication was not continued and a dose of 25 mg clozapine was administred . A marking drowsiness was present in the fisrt days , so we decided to keep the same dose . Five days later , he had high levels of Liver function test (LFT) : Elevated aspartate ( 5 times above normal) and alanine aminotransferase levels (4 times above normal ) , white blood cell count and bilirubine levels were normal . He had no fever or jaundice . The abdominal examination showed a mild sensiblity in the right upper quadrant . Clozapine was immediatly discontinuated . 24 hours later LFT continued to escalate to 5 times greater then normal . Then it decreased continueoslyConclusionsClozapine has a potential of hepatotoxicity even at lower dose . Screening liver function tests must be integrated in survey recommendations of clozapine treatment . Further researches must be conducted to understand the mechanism of this side effect in order to avoid sever conditions .Disclosure of InterestNone Declared

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing.

This review article argues against trusting standard clozapine references, including the US package insert, because they do not include advances in the sciences of pharmacokinetics and pharmacovigilance and ignore the effects of ethnic ancestry on therapeutic dosing. The minimum therapeutic dose leading to the minimum therapeutic concentration of 350 ng/mL in serum/plasma can be used to compare individuals/groups with treatment-resistant schizophrenia. The US clozapine package insert recommends targeting doses of 300-450 mg/day and, subsequently, increments of up to 100 mg with a maximum dose of 900 mg/day. Ethnic ancestry is defined by DNA ancestry group. Asians (people with ancestry ranging from Pakistan to Japan) and Indigenous Americans are similar in clozapine dosing; their average clozapine minimum therapeutic dose ranged from 166 mg/day (female non-smokers) to 270 mg/day (male smokers). For those with European ancestry, average clozapine minimum therapeutic doses ranged from 236 mg/day (female non-smokers) to 368 mg/day (male smokers). Based on limited studies, Black (African sub-Saharan ancestry) patients may be treated with typical US doses (300-600 mg/day), assuming no poor metabolism (PM) status. Ancestry's impact on clozapine lethality in four countries is discussed (two countries with highly homogenous populations, Denmark and Japan, and two countries with increasingly heterogenous populations due to immigration, Australia and the UK). An international guideline with 104 authors from 50 countries/regions was recently published, providing 6 personalized clozapine titration schedules for adult inpatients (3 ancestry groups and PM/non-PM schedules) and recommending c-reactive protein monitoring at baseline and weekly for 4 weeks.

Japanese patients need slower, personalized clozapine titrations: A comment on the case described by Kikuchi et al.

Japanese patients need slower, personalized clozapine titrations: A comment on the case described by Kikuchi et al.

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine

White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or...

Treatment strategies for clozapine-induced hypotension: a systematic review.

Background:Clozapine is the most effective medication for treatment–refractory schizophrenia but is associated with significant adverse drug effects, including hypotension and dizziness, which have a negative impact on quality of life and treatment compliance. Available evidence for the management of clozapine-induced hypotension is scant.Objectives:Due to limited guidance on the safety and efficacy of pharmacological treatments for clozapine-induced hypotension, we set out to systematically review and assess the evidence for the management of clozapine-induced hypotension and provide guidance to clinicians, patients, and carers.Design:We undertook a systematic review of the safety and efficacy of interventions for clozapine-induced hypotension given the limited available evidence.Data Sources and Methods:PubMed, Embase, PsycINFO, CINAHL, and the Cochrane trial Registry were searched from inception to November 2021 for literature on the treatment strategies for clozapine-induced hypotension and dizziness using a PROSPERO pre-registered search strategy. For orthostatic hypotension, we developed a management framework to assist in the choice of intervention.Results:We identified nine case studies and four case series describing interventions in 15 patients. Hypotension interventions included temporary clozapine dose reduction, non-pharmacological treatments, and pharmacological treatments. Midodrine, fludrocortisone, moclobemide and Bovril® combination, and etilefrine were associated with improvement in symptoms or reduction in orthostatic hypotension. Angiotensin II, arginine vasopressin, and noradrenaline successfully restored and maintained mean arterial pressure in critical care situations. A paradoxical reaction of severe hypotension was reported with adrenaline use.Conclusion:Orthostatic hypotension is a common side effect during clozapine titration. Following an assessment of the titration schedule, salt and fluid intake, and review of hypertensive and nonselective α1-adrenergic agents, first-line treatment should be a temporary reduction in clozapine dose or non-pharmacological interventions. If orthostatic hypotension persists, fludrocortisone should be trialled with monitoring of potassium levels and sodium and fluid intake. Midodrine may be considered second-line or where fludrocortisone is contraindicated or poorly tolerated. For patients on clozapine with hypotension in critical care settings, the use of adrenaline to maintain mean arterial pressure should be avoided.Registration:PROSPERO (Registration No. CRD42020191530)

Management of Clozapine Titration in the Setting of Cardiac Comorbidities

Treatment-resistant schizophrenia is commonly treated by the initiation of Clozapine therapy. Clozapine (Clozaril) has a wide side effect profile with significant mortality stemming from early myocarditis or late cardiomyopathy. This risk profile is complicated in those with preexisting comorbidities.A 67-year-old male with a decade-long history of paranoid schizophrenia. His previous treatment regimen consisted of a combination of Haloperidol-Decanoate, Aripiprazole, and Olanzapine. On his most recent admission, the patient presented with an acute exacerbation of his schizophrenia with incontinence, agitation, and difficulty following commands. Due to the refractory nature of his symptoms, Clozapine therapy was initiated. During this time serial C-reactive protein (CRP) measurements increased markedly. This increase was seen in the context of worsening lower leg edema and air hunger. Clozapine taper was held, and the medical team was consulted. The consultation resulted in an echocardiogram showing signs of diastolic failure with an unknown etiology. Subsequent CT chest, however, ruled out any pericardial pathology and eliminated suspicion for clozapine-induced myocarditis. Clozapine taper was then restarted.When beginning clozapine in a patient with underlying cardiac risk factors, it is paramount to take into consideration the patient’s baseline cardiopulmonary function. This report outlines the necessity of a baseline echocardiogram for patients with severe cardiac comorbidities. This in turn may have prevented a four-day delay of clozapine titration. Earlier and more frequent CRP measurements titration would have also guided clinical assessment as well. Furthermore, this case stresses the larger implications of investigating medical comorbidities among patients presenting on a psychiatric unit.

Clozapine initiation in the Belfast Health and Social Care Trust (BHSCT)

AimsThe aim of this project is to improve the quality of documentation and recording of the assessment and monitoring of patients commencing clozapine in BHSCT.BackgroundClozapine is an effective treatment for patients with schizophrenia who have not responded to at least two other antipsychotics. Due to clozapine's significant side effect profile patients must be carefully assessed prior to treatment initiation with close monitoring of their physical observations and reported side effects during initiation.The BHSCT Clozapine Pathway currently uses a Clozapine Assessment Integrated Care Pathway (ICP) common to inpatient and outpatient clozapine titrations and a Clozapine Titration ICP which varies slightly between inpatient and outpatient titrations.MethodThe Clozapine ICPs of patients commenced on clozapine in BHSCT in a 9 month period commencing January 2019 were reviewed. Handwritten clinical records were used to collect data on rates of completion of all aspects of the pathway.These results were used to identify areas of the pathway that were being poorly completed and the “Method for Improvement Model” used to trial changes to the pathway using Plan-Do-Study-Act (PDSA) cycles.Result20 patients in BHSCT were commenced on clozapine in the 9 month period. 1 Clozapine Initiation Pathway could not be located; therefore data were collected on 19 patients. 2 patients were initiated in the community and 17 patients initiated as inpatients.The results showed that sections of the Clozapine Assessment ICP were poorly completed; for example only 27% of the “Patient Baseline Preparation Checklist” were complete, with 60% partially complete and 13% completely blank.In the inpatient clozapine titration ICP the physical observations record was complete in only 20% of patients and the side effects monitoring record complete in only 13% of patients. Conversely the physical observations and side effects monitoring records were complete in 100% (n = 2) of patients.ConclusionBHSCT Clozapine Pathways were being poorly completed, with outpatient pathways being completed better than inpatient pathways. Analysis of the data shows that repetition of information in various parts of the pathway leads to gaps in documentation.Parts of the pathway that were poorly completed have been redesigned and the impact of these changes assessed using the PDSA cycle method. It is hoped that this along with education of staff will lead to an improvement in the assessment and monitoring of patients being commenced on clozapine.

A 25-Year-Old Man with Refractory Schizophrenia and Clozapine-Induced Myocarditis Diagnosed by Non-Invasive Cardiovascular Magnetic Resonance

Patient: Male, 25-year-oldFinal Diagnosis: Clozapine-induced myocarditisSymptoms: Elevated troponin • fever • leukocytosis • somnolence • tachycardiaMedication: —Clinical Procedure: Cardiovascular magnetic resonance • electrocardiogram • transthoracic echocardiogramSpecialty: Cardiology • General and Internal MedicineObjective:Rare diseaseBackground:Clozapine, a second-generation antipsychotic, is often prescribed for refractory schizophrenia; however, it can cause life-threatening adverse events including agranulocytosis and myocarditis. Making the diagnosis of clozapine-induced myocarditis can be challenging given the non-specific presentation as well as risk involved in obtaining an endomyocardial biopsy. As clozapine-induced myocarditis carries a mortality risk of up to 30%, timely recognition, diagnosis, and management are vital. This report presents a case of clozapine-induced myocarditis in a 25-year-old man with refractory schizophrenia who was diagnosed using non-invasive imaging with cardiovascular magnetic resonance (CMR).Case Report:A 25-year-old man with refractory schizophrenia was admitted with severe psychotic symptoms and started on a rapid titration of clozapine. During his hospitalization he developed somnolence, fever, and tachycardia with leukocytosis, elevated inflammatory markers, and cardiac biomarkers concerning for clozapine-induced myocarditis. Alternative etiologies were ruled out and CMR was used to confirm the diagnosis. The patient’s symptoms resolved following discontinuation of clozapine and initiation of supportive therapies.Conclusions:Clozapine-induced myocarditis is challenging to diagnose due to a lack of consensus on diagnostic criteria, reliance on voluntary reporting, and non-specific presentation. This report highlights that myocarditis can be associated with clozapine pharmacotherapy in patients with schizophrenia and demonstrates the value of diagnosis using non-invasive CMR. Additional studies are needed to understand the mechanism of clozapine-induced myocarditis and how clozapine titration may affect risk.

Clinical Utility and Safety of Slower-than-Recommended Titration of Clozapine for Treatment-Resistant Schizophrenia: a Retrospective Cohort Study.

Slow titration of clozapine is recommended given the risk of serious adverse effects. However, the utility and safety of slower-than-recommended titration of clozapine remain unclear. Consequently, we aimed to investigate the clinical utility and safety of slower-than-recommended titration of clozapine for treatment-resistant schizophrenia. We conducted a retrospective chart review of 152 inpatients with treatment-resistant schizophrenia who had been newly started on clozapine in a tertiary psychiatric public hospital between April 2012 and March 2018. The primary outcome was clozapine continuation for the first 18weeks. We performed multivariate logistic regression to identify the association between the rate of clozapine dose titration and clozapine continuation for the first 18weeks. Among the 152 inpatients, 122 (80%) could continue clozapine for the first 18weeks. There was no significant association between the rate of clozapine dose titration and clozapine continuation for the first 18weeks (adjusted odds ratio 1.23; 95% CI 0.29-5.26; p = 0.78). Our findings indicate that slower-than-recommended titration of clozapine may not improve toward clozapine continuation for the first 18weeks. Therefore, it may not be a beneficial option in terms of safe clozapine continuation when starting clozapine for treatment-resistant schizophrenia.