Antipsychotic prescribing practices for outpatients with schizophrenia and reasons for non-clozapine treatment - Data from a Danish quality assessment audit.

BACKGROUND: Clozapine is the gold standard for treating treatment-resistant schizophrenia (TRS) although widely underutilised. Both organisational, patient- and clinician related reasons for the underutilisation have been reported, however, the clinical impact of either in real-world settings is not fully elucidated. AIM: This audit aimed to evaluate the local antipsychotic (AP) prescribing practices for outpatients with schizophrenia and to assess the spectrum and prevalence of journalised reasons for non-clozapine treatment amongst eligible outpatients. METHODS: Data on demographics, current and former AP treatments, as well as documented reasons for non-clozapine treatment, was extracted through chart audit. RESULTS: Of the 668 affiliated outpatients with schizophrenia, 43% were treated with AP polytherapy (APP) and 19.6% with clozapine. The most prevalent reason for clozapine discontinuation was related to side effects whereas the most prevalent reason for refusal or omission of clozapine treatment was related to the associated monitoring regimen. CONCLUSIONS: This audit showed that APP prescribing is a highly prevalent practice in our services when treating outpatients with schizophrenia and that clozapine is underutilised in a 'last resort' manner. The blood-monitoring regimen associated with clozapine treatment was found to be an important factor in the underutilisation. It seemed, however, that the monitoring constituted a barrier for different reasons, requiring different approaches to remedy. Future studies, directly involving both patients and clinicians in the identification and management of the most clinically relevant barriers and their corresponding facilitators, are warranted.

Correlation between assessment of cytochrome P450 1A2 activity and enzyme activity scores, and their relation to clozapine exposure.

AIMS: Cytochrome P450 1A2 (CYP1A2) is involved in the metabolism of antipsychotic drugs such as clozapine and olanzapine. Personalization of these treatments requires an accurate estimation of CYP1A2 activity. In this study, we aimed (1) to evaluate the correlation between activity score (AS), covariate-corrected activity score (CCS) and the phenotype of CYP1A2 using a caffeine test probe and (2) to investigate their relationship with dose-adjusted clozapine concentrations in a subgroup of the cohort. METHODS: A multicentric, retrospective and observational study was carried out in the French university hospitals of Marseille and Tours. CYP1A2 activity was calculated by the paraxanthine/caffeine (17X/137X) ratio determined 4 h after an oral intake of 100 mg caffeine. AS was calculated according to the CYP1A2*1F alleles. CCS was calculated according to the CYP1A2*1F alleles, smoking status and the presence of concomitant inhibitors. RESULTS: As expected, among the 89 patients included, the 17X/137X ratio was significantly higher in patients who smoked. We found a significant but modest correlation between the 17X/137X ratio and CCS (R2 = 0.3, P = 1.74 × 10-8 ) but none between the 17X/137X ratio and AS (R2 = -0.007, P = 0.52). AS was not correlated with dose-adjusted clozapine levels, contrary to CCS (R2 = 0.19, P = 0.016) and especially the 17X/137X ratio (R2 = 0.42, P = 1.7 × 10-5 ). CONCLUSIONS: Correlation with clozapine concentrations showed the advantage of the 17X/137X ratio over the CCS in clozapine dose optimization. CYP1A2 activity, especially when determined by the caffeine probe, may be used to personalize clozapine dosing for patients experiencing treatment failure.

Ethnic disparity in clozapine dosing and cardiotoxicity in New Zealand.

AIMS: To investigate ethnic disparities in the treatment and incidence of cardiotoxicity for patients prescribed clozapine in New Zealand. METHODS: A post hoc analysis was undertaken using data from four studies investigating clozapine cardiotoxicities in New Zealand: two population studies (one prospective, one retrospective) conducted in the Auckland District Health Board (2011-2017), and two studies of coronial autopsy records (2001-2016). The relationship between ethnicity and cases (N=26) of myocarditis and/or cardiomyopathy was examined in comparison to non-cases in the rest of the study population (N=161). Patient demographics, comorbidities, and risk factors were investigated for any associations with ethnicity, where data was available. RESULTS: Maori and Pacific patients were over-represented in the population studies. Moreover, across the cohorts investigated 46% of myocarditis and cardiomyopathy cases were Maori. In contrast, only one case (4%) of cardiomyopathy was identified in a patient of Pacific descent. Where clozapine titration data was available, the rate of dose escalation was higher in Maori and Pacific peoples, as was the cumulative dose received before the first case of cardiotoxicity (day 13 of dose titration). Maori patients were more likely to be co-medicated with sodium valproate than others during clozapine titration, and sodium valproate was also significantly associated with myocarditis in these patients. CONCLUSIONS: The factors underpinning the more rapid titration of Maori and Pacific patients onto clozapine and the increased use of concomitant sodium valproate in Maori are unclear. While the latter may explain the heightened risk of clozapine-induced myocarditis in Maori, further work is required to mitigate the effects of this inequity on the safe use of clozapine in New Zealand.

Clozapine's multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia.

Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine's multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HT2R, D1R, α2c, and muscarinic receptors, the relatively low occupancy at dopamine D2R, the interaction with receptor dimers, as well as the potential confounder effects resulting in biased ligand action, and lastly, the role of the moiety responsible for lipophilic and alkaline features of clozapine are highlighted. Finally, the role of transcription and protein changes at the synaptic level, and the possibility that clozapine can directly impact synaptic architecture are addressed. Although clozapine's exact MOAs that contribute to its unique efficacy and some of its severe adverse effects have not been fully understood, relevant information can be gleaned from recent mechanistic understandings that may help design much needed additional therapeutic strategies for TRS.

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK.

Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.

[Should C-Reactive Protein and Troponin Be Monitored for Early Diagnosis of Clozapine Induced Myocarditis? An Assessment Within the Framework of Two Cases]. / Klozapinle Iliskili Miyokardit Erken Tanisi için C-Reaktif Protein ve Troponin Takibi Yapilmali mi? Iki Olgu Çerçevesinde Bir Degerlendirme.

Clozapine is an important treatment option in patients with treatmentresistant schizophrenia and bipolar disorder. Clozapine has multiple systemic side effects with myocarditis and cardiomyopathy being considered as serious cardiovascular outcomes. Although the aetiology of myocarditis is still unknown, its frequent occurrence in the early stages of clozapine use suggests that type 1 drug hypersensivity may underlie. Although rare, the cardiovascular side effects can be lifethreatening and must be recognized and treated promptly. The nonspecific clinical presentation of these conditions makes risk evaluation and identification of the affected patients difficult. A consensus has not yet been formed on following up the patients without the suspected clinical cardiac symptoms. In this article we presented two cases of myocarditis associated with clozapine. We aimed to emphasize that C-Reactive Protein and troponin monitoring, in accordance with the current clozapine guidelines, was practical and useful for early detection of myocarditis in asymptomatic patients. We also wanted to draw attention to the factors that may increase the cardiovascular risk such as polypharmacy and concomitant use of lithium and valproate with clozapine.

What about regular hematological monitoring during clozapine treatment? A compliance analysis using the French health insurance database.

BACKGROUND: The inherent risk of agranulocytosis associated with clozapine requires the realization of weekly white blood cell monitoring (WBCM) during the 18 first weeks of treatment. The aim of this study was to assess the compliance with WBCM during clozapine initiation for schizophrenia and Parkinson's disease (PD) subjects. RESEARCH DESIGN AND METHOD: The analysis was conducted using SNDS data on a cohort of new users of clozapine in 2018. We analyzed all reimbursements for WBCM from 2 weeks before the index date to 18 weeks after (optimal monitoring during hospitalization was assumed). The primary outcome was the proportion of good realization of WBCM according to different thresholds of completion (70%; 80%; 90%). Descriptive and comparative analyses with chi-squared test or Student's t-test were performed. RESULTS: Two hundred and ninety-six subjects were included. Rates of patients with WBCM realization over 70%, 80%, and 90% of WBCM expected were, respectively, 78.1%, 70.0%, and 56.9% for subjects with schizophrenia and 71.3%, 63.2%, and 47.8% for PD subjects. Only hospitalization during the follow-up period for schizophrenia subjects was significantly associated with good WBCM realization. CONCLUSIONS: We observed rather good results for compliance with clozapine initial monitoring. Other studies are needed to confirm our results.

Evaluation of bioequivalence between generic and brand-name clozapine in Chinese schizophrenic patients: A randomized, two-period, crossover study.

OBJECTIVE: Clozapine is the most effective therapy for schizophrenia. This study compared the bioequivalence of a generic formulation of clozapine (ChangZhou Pharmaceutical Factory Co. Ltd. Jiangsu, China) to the brand name formulation (Clozaril, HLS Therapeutics, Inc., Philadelphia, PA, USA) after multiple doses in Chinese schizophrenic patients. MATERIALS AND METHODS: This was a randomized, open-label, multiple-dose, 2-way crossover study in which patients with schizophrenia received the generic clozapine or Clozaril 100 mg twice daily for 10 days before crossing over to the alternate formulation for the next 10 days. Blood samples were collected at regular intervals during each treatment period, and plasma concentration of clozapine was determined by high-performance liquid chromatography. RESULTS: 26 patients were enrolled, of whom 24 completed the study and were included in the steady-state analyses. The mean AUC0-12 was 6,003.29 h×ng/mL for generic clozapine and 6,347.53 h×ng/mL for Clozaril. The mean Cmax,ss was 698.52 ng/mL for generic clozapine and 739.75 ng/mL for Clozaril. The ratio of the adjusted geometric means and its 90% CI of the ratios for AUC0-12 was 96.24% (89.60 - 103.36%), and for Cmax,ss was 95.90% (88.91 - 103.44%). A total of 66 adverse events were reported by 22 (84.62%) subjects. Among them, 34 occurred in 17 (65.38%) patients during dosing of generic clozapine, and 32 occurred in 16 (61.54%) patients during dosing of brand-name clozapine. CONCLUSION: The result demonstrated that the generic clozapine was bioequivalent to brand-name clozapine (Clozaril). This would provide physicians with reassurance that patients who receive the studied generic clozapine will achieve similar plasma drug concentrations to those of brand-name clozapine (Clozaril).

Clozapine treatment: Ensuring ongoing monitoring during the COVID-19 pandemic.

The current coronavirus pandemic (COVID-19) has led mental health systems to uncertainty regarding safe continuation of clozapine monitoring protocols. Clozapine is without doubt the only antipsychotic available with repeatedly proven efficacy in treatment resistant schizophrenia.1 Replacing clozapine with an alternative antipsychotic in patients stabilized with clozapine can potentially lead to higher risk of relapse or exacerbation of severity of illness.1 Clozapine, as already known, has a number of side effects, some of which can be serious, thus patients receiving clozapine require ongoing scheduled monitoring. Side effects of clozapine include neutropenia or agranulocytosis, myocarditis, fever, hypersalivation, weight gain and constipation. These side effects can be detected and treated when recognized on time decreasing the possibility of serious consequences making the implementation of an ongoing treatment monitoring protocol for patients on clozapine mandatory.2 Since it was advised for all mental health providers in most countries worldwide to limit non-urgent hospital visits and procedures to reduce the risk of contamination a challenge arose for patients' ability to access health care facilities for their routine clozapine monitoring. Nevertheless, the majority of Mental Health Care Authorities decided to ensure access for all patients on clozapine to their routine monitoring protocol.3,4 To date, no data exist on any potential relationship between antipsychotic use and the risk of contamination with SARS-CoV-2 or the development of severe symptoms of the infection. The literature suggests that patients receiving antipsychotics, especially clozapine, have an increased risk of developing pneumonia, leading to the assumption that patients receiving clozapine are at higher risk to develop COVID-19. 1 Balancing the importance of monitoring continuation against the increased risk for COVID-19, an International Consensus Statement was recently published addressing a monitoring protocol with reduced visits. The Consensus suggested reduced hematologic monitoring frequency of every 3 months with a prescription of 90 days clozapine supply (if safe). The above applies to patients receiving clozapine for at least one year without neutropenia. Τhe risk of neutropenia after 12 months of clozapine treatment falls significantly.4 Based on the above it is suggested to all clozapine clinics to implement a guidance monitoring protocol for all patients on clozapine to ensure safety during the pandemic. Besides hematological monitoring that requires physical contact with healthcare workers it is significant to implement a telemedicine appointment in frequent intervals to monitor symptoms of infection, symptoms of cardiovascular diseases and constipation. Patient should also be advised to regularly monitor one's blood pressure and pulses and ideally be educated on how by a member of the staff. If a patient is detected with any symptoms related to the above an emergency appointment for evaluation should be planned. Overall, since both the consequences and the duration of the pandemic are unknown, mental health services must work jointly to implement a clozapine monitoring plan to ensure safe continuation in such a vulnerable population.

Use of cardiovascular and antidiabetic drugs before and after starting with clozapine versus other antipsychotic drugs: a Dutch database study.

Reports of decreased mortality among patients with schizophrenia who use clozapine may be biased if clozapine is prescribed to relatively healthy patients and if intensive monitoring during its use prevents (under-treatment of) somatic disorder. We aimed to assess whether there is a difference in: (1) somatic comorbidity between patients who start with clozapine and those who start with other antipsychotics and (2) prescribed somatic medication, between patients using clozapine and those using olanzapine. Cohort study based on insurance claims (2010-2015). After selecting new users of antipsychotics and those who subsequently switched to clozapine (N = 158), aripiprazole (N = 295), olanzapine (N = 204) or first-generation antipsychotics (N = 295), we compared the clozapine starters to others on cardiovascular or diabetic comorbidity. Those using clozapine and olanzapine were compared on new prescriptions for cardiovascular or antidiabetic drugs. The ORadj of cardiovascular or diabetic comorbidity among other starters compared with clozapine starters was 0.77 [95% confidence interval (CI): 0.43-1.39], that is, a nonsignificantly increased prevalence associated with clozapine was found. Users of clozapine received significantly more new prescriptions for cardiovascular or antidiabetic medication (ORadj: 2.70, 95% CI: 1.43-5.08). Starters with clozapine were not cardiovascular/metabolic healthier than starters with other antipsychotics. During its use, they received more somatic treatment.

A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia.

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (ß = -0.9, P = 4.21 × 10-21), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10-7). This genotype, also termed "Duffy-null", has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatment.

Incidence and Management of Clozapine-Induced Myocarditis in a Large Tertiary Hospital.

OBJECTIVE: Clozapine, an antipsychotic reserved for management of treatment-resistant schizophrenia, is associated with severe adverse effects, including myocarditis. This study aims to determine the incidence of clozapine-induced myocarditis at a large tertiary hospital compared to what is reported in the literature. METHODS: Medical records of adult patients admitted to psychiatry units receiving clozapine between January 1, 2010, and July 31, 2016, were retrospectively reviewed. Cases of clozapine-induced myocarditis were defined as having elevated C-reactive protein (CRP) or detectable troponin and at least 1 sign or symptom of myocarditis, in the absence of alternative plausible aetiologies. The primary outcome was incidence of clozapine-induced myocarditis during the study period. Secondary outcomes included rate and description of the management of clozapine-induced myocarditis. RESULTS: In total, 316 patients were screened; 10 patients met the case definition for clozapine-induced myocarditis. The incidence of this adverse drug reaction over the study period was 3.16%. Reduced left ventricular ejection fraction was observed in 60% of cases, and electrocardiography changes were noted in 60% of cases. Clozapine was discontinued in all cases. Rechallenge was performed in 2 patients; recurrent CRP elevation resulted in discontinuation in each case. Medications for management of myocarditis were used in 50% of cases. Although 2 patients required transfer to critical care, the in-hospital mortality rate was 0%. CONCLUSIONS: The incidence of clozapine-induced myocarditis at the study hospital was consistent with the higher range reported in the literature. Further research is necessary to elucidate risk factors, definitive diagnostic criteria, and effective management of clozapine-induced myocarditis.

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine.

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

A Review and Assessment of Drug-Induced Thrombocytosis.

OBJECTIVES: The purpose of this article is to review the current literature on drug-induced thrombocytosis with the goal of critically assessing causality and providing a comprehensive review of the topic. Thrombopoietic growth factors, such as thrombopoietin-receptor agonists (romiplostim and eltrombopag) and erythropoietin are not included in our review. DATA SOURCES: The literature search included published articles limited to the English language and humans in MEDLINE, EMBASE, and Web of Science databases. MEDLINE/PubMed (1966 to September 2018) was searched using the MeSH terms thrombocytosis/chemically-induced and thrombocytosis/etiology. EMBASE (1980 to September 2018) was searched using the EMTAGS thrombocytosis/side effect. Web of Science (1970 to September 2018) was searched using the search term thrombocytosis. References of all relevant articles were reviewed for additional citations and information. STUDY SELECTION AND DATA EXTRACTION: Review articles, clinical trials, background data, case series, and case reports of drug-induced thrombocytosis were collected, and case reports were assessed for causality using a modified Naranjo nomogram. DATA SYNTHESIS: Drug-induced thrombocytosis, a form of reactive thrombocytosis cannot be easily differentiated from more common etiologies of reactive thrombocytosis. In all, 43 case reports of drug-induced thrombocytosis from a wide variety of drugs and drug classes were reviewed using a modified Naranjo probability scale that included criteria specific for thrombocytosis. CONCLUSIONS: Drug-induced thrombocytosis is a relatively rare adverse drug reaction. The strongest evidence of causality supports low-molecular-weight heparins and neonatal drug withdrawal. Weaker evidence exists for all-trans retinoic acid, antibiotics, clozapine, epinephrine, gemcitabine, and vinca alkaloids.

Understanding medicines with a propensity to increase the risk of heart failure: Combining existing knowledge with targeted population assessment.

PURPOSE: Existing knowledge of medicines that increase the risk of an adverse event may be corroborated and augmented by population studies specifically assessing the risk associated with the concurrent use of these medicines and use by patients with existing comorbidity. An American Heart Association review recently identified a variety of medicines that may cause or exacerbate heart failure (HF), many with evidence from limited evaluation of population data. We assessed the risk of first-time HF associated with the use of 50 of these medicines by New Zealand's primary care population. METHODS: Case-control study utilising national pharmaceutical use and hospital admissions data 2007-2015; 22,989 patients with first-time HF 2008-2015 were matched with 114 498 control patients. The primary outcome was first-time HF and its association with medicine exposure in the prior 90 days, estimated using conditional logistic regression. We also assessed the risk associated with new use of medicines in the prior month, concurrent use, and in patients with existing comorbidity. RESULTS: Eleven medicines were significantly associated with HF with several other infrequently used medicines providing signals of increased risk. A high risk was associated with the use of salbutamol (adjusted odds ratio 2.63; 95% CI, 2.48-2.78), clozapine (2.70; 2.46-4.98), diltiazem (1.52; 1.44-1.60), indomethacin (2.51; 1.54-4.10), pioglitazone (1.50; 1.16-1.95), and antifungal medicines. New use of medicines and use of medicine combinations increased this risk in many cases. CONCLUSIONS: Our study provides further evidence to inform cautious use of these medicines in patients with HF or at risk of developing HF.

Learned lessons from patients who take clozapine: A case study.

PURPOSE: The purpose of this report is to provide clinical strategies to manage patients with schizophrenia taking clozapine. CONCLUSIONS: Serious side effects and required blood monitoring impede the use of clozapine, despite the benefits of clozapine for managing psychiatric symptoms. Well-managed patients receiving evidence-based interventions exhibit reduced symptoms, improved functioning, and better adherence to treatment. PRACTICE IMPLICATIONS: Preexisting medical conditions should be considered before prescribing clozapine. Ongoing education on medication and mental illness for patients and family members is essential to prepare them for adherence to management plans. Healthcare providers are responsible for monitoring the side effects of clozapine.

Evaluating the Effect of the Changes in FDA Guidelines for Clozapine Monitoring.

BACKGROUND: Concerns exist that clozapine is underutilized in the management of treatment-resistant schizophrenia. Although a 2015 change in the US Food and Drug Administration (FDA) monitoring recommendations lowered the threshold of the absolute neutrophil count for treatment interruption from 1,500/µL to 1,000/µL and removed white blood cell count thresholds from the monitoring algorithm, the implications of this policy change on clozapine interruptions remain unknown. METHODS: We analyzed outpatient prescribing records for antipsychotic medications in the Veterans Integrated Service Network 7 (VISN 7) database between 1999 and 2012 to assess the potential impact of the recent changes in FDA neutropenia monitoring recommendations on clozapine treatment discontinuation. We evaluated results of complete blood count monitoring to compare percentages of patients who developed or would have developed ≥ 1 hematologic event under the previous and current FDA guidelines in the first year following initiation of clozapine. RESULTS: From a cohort of 14,620 patients with schizophrenia (ICD-9-295.x), 246 patients received clozapine treatment (1.7%). No agranulocytosis was observed during the study period. Under the former recommendations, 5 patients in the clozapine initiation cohort (n = 160, 3.1%; 95% CI, 0.43-5.83) qualified for treatment interruption during the first year of clozapine treatment, while only 1 patient (0.6%) qualified under the current recommendations. Under the former recommendations, hematologic events occurred at a similar rate for individuals taking and not taking clozapine. CONCLUSIONS: While clozapine remains an underused medication, the new FDA monitoring guidelines are likely to substantially reduce the percentage of patients who meet criteria for clozapine-associated hematologic events requiring treatment interruption. This decrease may reduce the clinical burden of managing patients on clozapine and therefore increase the number of individuals treated with this uniquely effective medication. However, prospective studies of individuals treated under the new guidelines are needed to fully assess safety of the FDA's change.