Search

Objectives: Clozapine, an atypical antipsychotic used to treat people with schizophrenia, has been proposed as a possible treatment for salivary gland hypofunction. This scoping review investigated the available literature on clozapine's impact on salivary Row, in order to determine whether it could be used by dental practitioners in low doses as a treatment for dry mouth. Data sources: An electronic search was completed using Ovid MEDLINE (1996 to Nov 2021). Key MeSH search terms included "clozapine," "Clozaril," "salivation," "salivary Row rate," "sialorrhea," "hypersalivation," and "drooling." Two reviewers independently reviewed eligible articles and extracted the data based on the inclusion and exclusion criteria. Results: The initial search identiRed 129 studies, six of which were included in this review. Four of them (one cross-sectional and three interventional) described salivary flow rates in schizophrenic patients taking clozapine, while one of those and two others focused on the mechanism of clozapine-induced sialorrhea, with one study covering both. There were mixed findings, with one study observing a moderate association between clozapine dose and salivary flow, and the others reporting no differences. Findings on the putative mechanisms for clozapine-induced sialorrhea (CIS) were inconclusive. Conclusion: There is insufficient high-quality information to justify using low-dose clozapine to increase salivary flow in dental patients with salivary gland hypofunction. Well-designed interventional studies and randomized control trials are required. [ABSTRACT FROM AUTHOR]

The task of a psychiatrist is to select the most appropriate medication or combination of drugs to treat the symptoms of schizophrenia while minimizing the risk of side effects and ensuring the patient achieves the highest level of functioning possible. This is a challenging task as the action of each drug or group of drugs is different. The efficacy of cariprazine, which affects D3 receptors as a D3/D2 receptor partial agonist, has been extensively studied and is one of the first medication choices by practicing psychiatrists when treating patients with negative symptomatology. In this clinical case, we demonstrate the effective and safe treatment of a patient's positive and affective symptoms using a combination of cariprazine, clozapine, and venlafaxine. [ABSTRACT FROM AUTHOR]

Ongoing psychiatric follow-up and medication adherence improve outcomes for patients with psychotic disorders. Due to COVID-19, outpatient care may have been disrupted, impacting healthcare utilization. A retrospective population-wide study was conducted for adults in Manitoba, Canada. Medication adherence and healthcare utilization were examined from 2019 to 2021. The presence of a diagnosed psychotic disorder was identified in the five years before the index date in each year. The LAI and clozapine cohorts consisted of those who received at least two prescriptions in each year 180 days before the March 20th index date. The change in adherence was measured using the average Medication Possession Ratio. Healthcare utilization rates were compared using Generalized Estimating Equation models. There were no significant differences between LAI and clozapine discontinuation rates before and during the pandemic. In the LAI cohort, general practitioner visits decreased significantly (−3.5 %, p = 0.039) across four quarters of 2021 versus 2019. All-cause hospitalizations decreased by 16.8 % in 2020 versus 2019 (p = 0.0055), while psychiatric hospitalizations decreased by 18.7 % across four quarters in 2020 (p = 0.0052) and 13.7 % in 2021 (p = 0.0425), versus 2019 in the LAI cohort. There was a significant transition to virtual care during the first wave of COVID-19 (71 % in clozapine, 51 % in LAI cohorts). Trends in total outpatient visits and non-psychiatric hospitalizations remained stable. COVID-19 had no substantial impact on LAI and clozapine discontinuation rates for patients previously adherent. Outpatient care remained stable, with a significant proportion of visits being done virtually at the outset of the pandemic. [ABSTRACT FROM AUTHOR]

Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs. We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280. We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82–1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09–1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92–2.25]). In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs. • Differences in the incidence of new-onset diabetes caused by second-generation antipsychotics were compared. • Clozapine and olanzapine cause a similar incidence of new-onset diabetes. • Clozapine is more likely to cause new-onset diabetes than risperidone. • Explored relationship between therapy duration and incidence [ABSTRACT FROM AUTHOR]

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges. [ABSTRACT FROM AUTHOR]

Treatment-Resistant Schizophrenia (TRS) represents a main clinical issue, associated with worse psychopathological outcomes, a more disrupted neurobiological substrate, and poorer neurocognitive performance across several domains, especially in verbal abilities. If cognitive impairment is a major determinant of patients' functional outcomes and quality of life, targeting cognitive dysfunction becomes even more crucial in TRS patients in order to minimize cognitive and functional deterioration. However, although Cognitive Remediation Therapy (CRT) represents the best available tool to treat cognitive dysfunction in schizophrenia, specific evidence of its efficacy in TRS is lacking. Based on these premises, our study aimed at investigating possible differences in CRT outcomes in a sample of 150 patients with schizophrenia, stratified according to antipsychotic response (TRS vs. non-TRS). Subjects were assessed for neurocognition through Brief Assessment of Cognition in Schizophrenia (BACS) and the Wisconsin Card Sorting Test (WCST) at baseline and after CRT. As expected, we observed greater baseline impairment among TRS patients in BACS-Verbal Memory and WCST-Executive Functions. Repeated measures ANCOVAs showed significant within-group pre-/post-CRT differences in the above-mentioned domains, both among non-TRS and TRS subjects. However, after CRT, no differences were observed between groups. This is the first study to indicate that CRT represents a highly valuable resource for TRS patients, since it may be able to fill the cognitive gap between treatment response groups. Our finding further highlights the importance of early implementation of CRT in addition to pharmacotherapy to reduce the cognitive and functional burden associated with the disease, especially for TRS patients. [ABSTRACT FROM AUTHOR]

Clozapine is a second-generation antipsychotic drug that offers superior treatment results in patients with schizophrenia but is also associated with significant risks. This study analyzes data on pharmacotherapy with clozapine and the associated adverse drug reactions (ADRs) in an inpatient setting including 38,349 patients. Data about the use of clozapine and reports of severe ADRs within the period 1993–2016 were obtained from the multicentered observational pharmacovigilance program "Arzneimittelsicherheit in der Psychiatrie" (AMSP). In total, 586 severe clozapine-associated ADRs were documented (1.53% of all patients exposed). Patients aged ≥65 years had a higher risk of ADRs than patients aged <65 years (1.96 vs. 1.48%; p = 0.021). Significantly more ADRs were attributed to clozapine alone (396; 67.6% of all 586 ADRs) than to a combination with other drugs. The most frequent ADRs were grand mal seizures (0.183% of all 38,349 patients exposed), delirium (0.180%), increased liver enzymes (0.120%), and agranulocytosis (0.107%). We detected 24 cases (0.063%) of clozapine-induced extrapyramidal symptoms, of which 8 (0.021%) were attributed to clozapine alone. Five ADRs resulted in death (0.013%): 2 due to agranulocytosis (41 cases total) (mortality = 4.88%) and 3 due to paralytic (sub)ileus (16 cases) (mortality = 18.75%). The median dose of clozapine in all patients treated was 300 mg/day, in patients who developed ADRs 250 mg/day. The main risk factor for an ADR was pre-existing damage of the affected organ system. Overall, the results of this study highlight the importance of alertness—especially of frequently overlooked symptoms—and appropriate monitoring during treatment with clozapine, even at low doses. [ABSTRACT FROM AUTHOR]

Background: This case explores the challenges encountered in managing treatment-resistant paranoid schizophrenia, focusing on the limitations of using clozapine due to the risk of neutropenia. The United Kingdom Clozapine Patient Monitoring Service (UK CPMS) and its eligibility criteria are discussed, highlighting the potential benefits of expanding access to clozapine for patients who could potentially benefit from this medication. The integration of clozapine genetic testing as a personalized approach is explored, emphasizing the importance of identifying patients with a favorable genetic profile for clozapine response. Methods: Case report. Results: The case presentation of Mr. X exemplifies the difficulties faced in managing treatment-resistant schizophrenia when access to clozapine is restricted, leading to persistent negative symptoms. Conclusion: The article underscores the importance of innovative solutions and personalized care to enhance the treatment outcomes for patients with treatment-resistant paranoid schizophrenia. It acknowledges that certain restrictions of clozapine use may limit the effective management of patients with this condition. [ABSTRACT FROM AUTHOR]

Genetic investigations do not form part of the routine assessment of patients with psychosis in secure settings. The case of a man admitted to a low secure unit after initial civil detention is presented. He was arrested after violence at home and there followed persistent violence in adult general wards. Many risk factors for violence were present and would usually be considered sufficient explanations for the totality of his presentation and risk. The novel aspect was the results of genetic testing. This revealed associations with his physical appearance, development and neurodevelopment, early onset violence and aggression, psychosis, and possibly the excellent response to clozapine. Array Comparative Genomic Hybridisation (aCGH) revealed a 15q13.2-13.3 microduplication, with the genetic report suggesting that many of the clinical aspects were, at least in part, attributable to this finding. This provided a complimentary narrative explanation for a presentation which had been difficult to treat and understand by both the patient and treating team. This is the only case report to describe this specific diagnosis from the patient’s perspective and the helpful impact of the genetic diagnosis, particularly for the patient himself. A brief overview of genetic findings relevant to forensic practice is described. [ABSTRACT FROM AUTHOR]

Background: Clozapine is the only recommended antipsychotic medication for individuals diagnosed with treatment-resistant schizophrenia. Unfortunately, its wider use is hindered by several possible adverse effects, some of which are rare but potentially life threatening. As such, there is a growing interest in studying clozapine use and safety in routinely collected healthcare data. However, previous attempts to characterise clozapine treatment have had low accuracy. Aim: To develop a methodology for identifying clozapine treatment dates by combining several data sources and implement this on a large clinical database. Methods: Non-identifiable electronic health records from a large mental health provider in London and a linked database from a national clozapine blood monitoring service were used to obtain information regarding patients' clozapine treatment status, blood tests and pharmacy dispensing records. A rule-based algorithm was developed to determine the dates of starting and stopping treatment based on these data, and more than 10% of the outcomes were validated by manual review of de-identified case note text. Results: A total of 3,212 possible clozapine treatment periods were identified, of which 425 (13.2%) were excluded due to insufficient data to verify clozapine administration. Of the 2,787 treatments remaining, 1,902 (68.2%) had an identified start-date. On evaluation, the algorithm identified treatments with 96.4% accuracy; start dates were 96.2% accurate within 15 days, and end dates were 85.1% accurate within 30 days. Conclusions: The algorithm produced a reliable database of clozapine treatment periods. Beyond underpinning future observational clozapine studies, we envisage it will facilitate similar implementations on additional large clinical databases worldwide. [ABSTRACT FROM AUTHOR]

Purpose: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients. Methods: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies. Results: The SMDs with 95% CIs of AUC0–12, Cmax,ss, C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD = − 0.05, 95% CI [− 0.25, 0.15], p = 0.63). Conclusion: The combination with propranolol could significantly increase systemic exposure and extended T1/2 of clozapine, and thus need to be considered in prescribing decisions. [ABSTRACT FROM AUTHOR]

Objective: This pharmacovigilance study evaluated the profile of clozapine-related adverse events by region using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We categorized each case into five regions (America, Europe/West Asia, Oceania, Asia, and Africa) based on the reporting country information in the FAERS database. The number of clozapine-related adverse events reported in each region was aggregated according to the preferred term (PT) and the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ). Results: A total of 101,872 clozapine-related adverse events were registered in the FAERS database. In America and Europe, leukocyte or neutrophil count abnormalities accounted for half of the top 10 PTs by relative reporting rate. However, Asia had higher relative reporting rates of pyrexia and salivary hypersecretion (13.91% and 10.85%, respectively). Regarding the SMQ, the relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, gastrointestinal obstruction, and hyperglycaemia/new onset diabetes mellitus were higher in Asia than in other regions (5.26%, 9.72%, 12.65%, 5.13%, and 8.26%, respectively), with significant differences even after adjusting for confounding factors using multivariate logistic regression analysis. Conclusion: Spontaneous reports of adverse events associated with clozapine show regional disparities, particularly in Asia, where concentration-dependent adverse events are more frequently reported. However, the spontaneous reporting system has several limitations, requiring further research for validation. [ABSTRACT FROM AUTHOR]

Accurately measuring drug and its release kinetics in both in vitro and in vivo environments is crucial for enhancing therapeutic effectiveness while minimizing potential side effects. Nevertheless, the real-time visualization of drug release from microspheres to monitor potential overdoses remains a challenge. The primary objective of this investigation was to employ fluorescence imaging for the real-time monitoring of drug release from microspheres in vitro, thereby simplifying the laborious analysis associated with the detection of drug release. Two distinct varieties of microspheres were fabricated, each encapsulating different drugs within PLGA polymers. Cy5 was selected as the donor, and Cy7 was selected as the acceptor for visualization and quantification of the facilitated microsphere drug release through the application of the fluorescence resonance energy transfer (FRET) principle. The findings from the in vitro experiments indicate a correlation between the FRET fluorescence alterations and the drug release profiles of the microspheres. [ABSTRACT FROM AUTHOR]

Objectives: This paper critiques the haematological monitoring guidelines for clozapine. It describes the history of clozapine, as well as the pathophysiology and epidemiology of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA). The paper appraises the extant literature on mandatory clozapine haematological monitoring. Conclusion: Contemporary Australian protocols for clozapine haematological monitoring are not consistent with the current evidence base. CIN and CIA are rare occurrences, and the associated risk of death is low. Potential modifications to existing guidelines include changing neutrophil thresholds for patients with benign ethnic neutropenia and reducing the frequency or removing haematological monitoring after two years of clozapine treatment. [ABSTRACT FROM AUTHOR]

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30–60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40–70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR−). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR−. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR− = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11–12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR−, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response. [ABSTRACT FROM AUTHOR]

A nationwide cohort study conducted in Finland has found that risk of clozapine‐induced agranulocytosis, while greater than that associated with other antipsychotics, decreases considerably with longer‐term use of the medication. The study's findings lend support to the idea that hematological monitoring requirements for patients receiving clozapine could be relaxed over time, the investigators stated. Study results were published online April 29, 2024, in Lancet Psychiatry. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Clozapine is an effective antipsychotic for treatment‐resistant schizophrenia, but its discontinuation leads to discontinuation syndrome/catatonia complicated by benzodiazepine‐resistance and rhabdomyolysis.This study determined time‐dependent effects of exposure and subsequent discontinuation of clozapine on expression of connexin43, 5‐HT receptors, intracellular L‐β‐aminoisobutyrate (L‐BAIBA) and 2nd‐messengers and signalling of AMPK, PP2A and Akt in cultured astrocytes and rat frontal cortex.Intracellular L‐BAIBA levels increased during clozapine exposure but immediately recovered after discontinuation. Both exposure to clozapine and L‐BAIBA increased connexin43 and signalling of AMPK/Akt time‐dependently, but reduced PP2A signalling, 5‐HT receptor expression and IP3 level. These changes recovered within 2 weeks after discontinuation, while 5‐HT receptors and IP3 transiently increased during the recovery process. L‐BAIBA activated AMPK signalling, leading to attenuated PP2A signalling. Astroglial D‐serine release was increased by clozapine exposure but continued to increase within 1 week after discontinuation via activation of IP3 receptor function.Clozapine discontinuation restored PP2A signalling due to decreased L‐BAIBA, increased 5‐HT receptor expression via probably enhanced 5‐HT receptor recycling, but increased astroglial D‐serine release persisted by transiently activated IP3 receptors via transiently increased IP3 level. Decreased L‐BAIBA caused by clozapine discontinuation is, at least partially, involved in the transiently increased 5‐HT receptor and astroglial D‐serine release. [ABSTRACT FROM AUTHOR]

Objective: Previous research has suggested that demographic factors affect the likelihood of a patient with schizophrenia receiving a clozapine prescription. The authors aimed to determine the impact of race, social determinants of health, gender, rurality, and care patterns on clozapine prescription rates. Methods: This cross-sectional observational study used structured electronic health records data from 3,160 adult patients diagnosed as having schizophrenia between October 1, 2015, and November 30, 2021, in a multifacility health system. The social vulnerability index (SVI) was used to quantify social determinants of health. Descriptive data analysis, logistic regression, and sensitivity analysis were conducted to identify differences between patients with schizophrenia who received a clozapine prescription and those who received antipsychotic medications other than clozapine. Results: Overall, 401 patients with schizophrenia were given a clozapine prescription during the study period, and 2,456 received antipsychotics other than clozapine. Results of the logistic regression indicated that White race (OR=1.71, compared with Black race), community minority status and language SVI score (OR=2.97), and increased treatment duration (OR=1.36) were significantly associated with a higher likelihood of clozapine prescription; gender, rurality, age at first diagnosis, and ethnicity did not influence the likelihood of receiving clozapine. Conclusions: Black patients with schizophrenia had a lower likelihood of receiving a clozapine prescription compared with White patients, even after analyses accounted for demographic variables, social determinants of health, and care access patterns. Given the effectiveness of clozapine in managing treatment-resistant schizophrenia, it is crucial for future research to better understand the factors contributing to this treatment disparity. [ABSTRACT FROM AUTHOR]

Experimental evidence indicates that the noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists ketamine and MK‐801 induce schizophrenia‐like symptoms in rodents, including cognitive deficits. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders comprising schizophrenia. The present study was designed to evaluate the efficacy of the joint administration of sub‐effective doses of crocins with those of the atypical antipsychotics clozapine and risperidone in alleviating nonspatial recognition and emotional memory deficits induced either by ketamine (3 mg/kg) or MK‐801 (0.1 mg/kg) in the rat. To this end, the object recognition and the step‐through passive avoidance tests were used. Co‐administration of sub‐effective doses of crocins (5 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted nonspatial recognition and emotional memory deficits induced by NMDA receptor antagonists. The current findings suggest that this combinatorial treatment was efficacious in attenuating cognitive impairments related to the blockade of the NMDA receptor. In addition, the present results support the potential of crocins as an adjunctive drug for the therapy of schizophrenia. [ABSTRACT FROM AUTHOR]

Purpose: Examine the alterations in antipsychotic concentrations following coronavirus disease-2019 (COVID-19) infection among hospitalized patients with mental disorders and conduct an analysis of the factors influencing these changes. Methods: Data were collected from inpatients at Beijing Huilongguan Hospital between December 12, 2022, and January 11, 2023, pre- and post-COVID-19. Based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 329 inpatients with mental disorders were included (3 with incomplete data excluded). Primary outcomes assessed changes in antipsychotic concentrations pre- and post-COVID-19, while secondary outcomes examined factors linked to concentration increases and antipsychotic dose adjustments. Results: Clozapine (P < 0.001), aripiprazole (P < 0.001), quetiapine (P = 0.005), olanzapine (P < 0.001), risperidone (P < 0.001), and paliperidone (P < 0.001) concentrations increased post-COVID-19 in patients with mental disorders. Notably, clozapine concentration surpassing pre-infection levels was highest. Clozapine users were more likely to adjust their dose (50.4%) compared to olanzapine (17.5%) and other antipsychotics. Moreover, traditional Chinese patent medicines and antibiotics during COVID-19 infection were associated with antipsychotic reduction or withdrawal (OR = 2.06, P = 0.0247; OR = 7.53, P = 0.0024, respectively). Conclusion: Antipsychotic concentrations in hospitalized patients with mental disorders increased after COVID-19 infection, that may be related not only to COVID-19, but also to the use of Chinese patent medicines during infection. The pre-infection concentration and types of antipsychotics, patient's gender, and combination of traditional Chinese medicine or antibiotics, were factors found to correlate with increased drug concentrations and necessitate dose adjustments. [ABSTRACT FROM AUTHOR]

Smoking cessation in patients treated with clozapine might lead to elevated plasma concentrations and severe side effects. This case report investigated the trajectory of clozapine plasma concentrations over time after smoking cessation in a Chinese inpatient with schizophrenia. This case report delineates the temporal response of plasma clozapine concentrations and dose-corrected clozapine plasma concentrations in a 33-year-old inpatient with schizophrenia who had a substantial smoking history and ceased smoking abruptly during dose titration. This case report presents a sudden increase in plasma clozapine concentrations and dose-corrected plasma clozapine concentrations after smoking cessation, followed by a rapid decline in dose-corrected plasma clozapine concentrations during the initial 2 weeks and a return to precessation levels approximately 1 month later. The findings suggest that clinicians and pharmacists should adjust clozapine dosage in accordance with changes in smoking status, taking into consideration the temporal effects. Postsmoking cessation adjustments to clozapine dosage should be coupled with therapeutic drug monitoring, especially for patients with heavy smoking habits. Moreover, the advice of the clinical pharmacist should be considered in complex cases to ensure safe use of clozapine. [ABSTRACT FROM AUTHOR]

Background Case Presentation Conclusion In patients with schizophrenia, violent behavior is a clinically important factor that prevents their discharge. Clozapine is an effective antipsychotic medication for treatment‐resistant schizophrenia, and its usefulness for aggressive behavior has also been suggested.We present the case of a 38‐year‐old male patient diagnosed with schizophrenia who was successfully treated with clozapine after recurrent violent behavior. He was diagnosed with schizophrenia during his adolescence. He was hospitalized for treatment in his teens, but his hallucinations and delusions persisted even after discharge. In his 30s, he became noticeably emotionally unstable, and despite being treated for an adequate period with sufficient doses of several antipsychotics, his symptoms did not improve. This led to repeated hospitalizations triggered by violent behavior toward his parents and siblings within the home. During his fourth hospitalization, clozapine was initiated due to multiple incidents of violence toward nursing staff secondary to hallucinations and delusions. As the dose of clozapine was gradually increased with therapeutic drug monitoring, the patient's hostility, uncooperativeness, and suspiciousness markedly improved, and his aggressive behavior disappeared. He was discharged to a facility on day 194 after starting clozapine and has continued outpatient visits.Clozapine was suggested to be effective for aggressive behavior in patients with treatment‐resistant schizophrenia and should be actively considered. In such cases, regular measurement of blood concentration is useful for adjusting the dosage of clozapine. [ABSTRACT FROM AUTHOR]

The article presents questions and answers related to adjunctive agents for suboptimal response to clozapine, combination of clozapine and a first-generation antipsychotic for treatment of neuroleptic malignant syndrome, management of the adverse effects of clozapine, and changes in the frequency of complete blood count monitoring and absolute neutrophil count.

Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management. [ABSTRACT FROM AUTHOR]

Background and Objectives: Clozapine is the medication of choice for treatment-resistant schizophrenia. However, it has a complex metabolism and unexplained interindividual variability. The current work aims to develop a pharmacokinetic model of clozapine and norclozapine in non-smokers and assess the impact of demographic and genetic predictors. Methods: Healthy volunteers were recruited in a population pharmacokinetic study. Blood samples were collected at 30 min and 1, 2, 3, 5 and 8 h following a single flat dose of clozapine (12.5 mg). The clozapine and norclozapine concentrations were measured via high-performance liquid chromatography–ultraviolet method. A semi-physiological pharmacokinetic model of clozapine and norclozapine was developed using nonlinear mixed-effects modeling. Clinical and genetic predictors were evaluated, including CYP1A2 (rs762551) and ABCB1 (rs2032582), using restriction fragment length polymorphism. Results: A total of 270 samples were collected from 33 participants. The data were best described using a two-compartment model for clozapine and a two-compartment model for norclozapine with first-order absorption and elimination and pre-systemic metabolism. The estimated (relative standard error) clearance of clozapine and norclozapine were 27 L h-1 (31.5 %) and 19.6 L h-1 (30%), respectively. Clozapine clearance was lower in sub-Saharan Africans (n = 4) and higher in Caucasians (n = 9) than Asians (n = 20). Participants with CYP1A2 (rs762551) (n = 18) and ABCB1 (rs2032582) (n = 12) mutant alleles had lower clozapine clearance in the univariate analysis. Conclusions: This is the first study to develop a semi-physiological pharmacokinetic model of clozapine and norclozapine accounting for the pre-systemic metabolism. Asians required lower doses of clozapine as compared with Caucasians, while clozapine pharmacokinetics in sub-Saharan Africans should be further investigated in larger trials. [ABSTRACT FROM AUTHOR]

Background: Clozapine is known to cause agranulocytosis. Mandatory monitoring schemes are aimed at reducing the risk of agranulocytosis and of the consequences of agranulocytosis. All cases of agranulocytosis occurring in people prescribed clozapine are assumed to be caused by clozapine. Methods: In a previous study, we examined a cohort of patients listed on our hospital database as having had clozapine-induced agranulocytosis and applied specific criteria to identify those with confirmed clozapine-related, life-threatening agranulocytosis. In this study, we examine the cases not meeting these specific criteria. Results: In the original study, 9 of 23 cases met the criteria for clozapine-induced, life-threatening agranulocytosis. Of the 13 remaining cases for whom data were available, 5 were probably caused by clozapine but were not life-threatening. Three cases were the result of concomitant cancer chemotherapy. Three were anomalous results probably related to measurement error. For the remaining two cases, the cause was not identified. Conclusion: Not all cases of agranulocytosis occurring in people taking clozapine are caused by clozapine. The widely used threshold criterion-based diagnosis overestimates the risk of agranulocytosis. True clozapine-related agranulocytosis is best identified by pattern-based criteria: rapid fall in neutrophil counts over around 2 weeks to below 0.5 × 109/L for two consecutive days (unless clozapine is stopped very early or granulocyte colony stimulating factor is given) where other possible causes (benign ethnic neutropenia, cancer chemotherapy) can be ruled out. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson's disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care. [ABSTRACT FROM AUTHOR]

Background Clozapine is the recommended treatment for managing treatment-resistant schizophrenia (TRS), and immunological mechanisms may be involved in its unique antipsychotic efficacy. This study investigated whether baseline immune abnormalities measured with blood cell count ratios can predict the clinical response after initiating treatment with clozapine in patients with clozapine naïve TRS. Methods A longitudinal design was developed, involving 32 patients diagnosed with treatment-resistant, clozapine-naïve schizophrenia-spectrum disorder. Patients were evaluated at baseline before clozapine starting and 8 weeks of follow-up. Psychopathological status and immune abnormalities (blood cell count ratios: neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], platelet-lymphocyte ratio [PLR] and basophil-lymphocyte ratio [BLR]) were evaluated in each visit. Results Baseline NLR (b=− 0.364; p=0.041) and MLR (b =− 0.400; p=0.023) predicted the change in positive symptoms over the 8-week period. Patients who exhibited a clinical response showed higher baseline NLR (2.38±0.96 vs. 1.75±0.83; p=0.040) and MLR (0.21±0.06 vs. 0.17±0.02; p=0.044) compared to non-responders. In the ROC analysis, the threshold points to distinguish between responders and non-responders were approximately 1.62 for NLR and 0.144 for MLR, yielding AUC values of 0.714 and 0.712, respectively. No statistically significant differences were observed in the blood cell count ratios from baseline to the 8-week follow-up. Conclusion Our study emphasizes the potential clinical significance of baseline NLR and MLR levels as predictors of initial clozapine treatment response in patients with TRS. Future studies with larger sample sizes and longer follow-up periods should replicate our findings. [ABSTRACT FROM AUTHOR]

Schizophrenia is a mental illness characterized by disturbances in the perception of reality, thinking, emotions, and social functioning. This significantly impacts the quality of life of patients and leads to long-term disability. Despite advances in understanding its pathogenesis and treatment, schizophrenia remains a clinical challenge, especially due to the diversity of its symptoms and the complexity of its mechanisms. Schizophrenia is associated with abnormal functioning of the dopaminergic system, disturbances in glutamatergic neurotransmission, and oxidative stress in the brain. In recent years, there has been increasing interest in optimizing the treatment of mental disorders. The potential use of ascorbic acid, or vitamin C, in the therapy of schizophrenia could bring substantial benefits to patients. Ascorbic acid exhibits antioxidant and neuroprotective properties, suggesting its potential efficacy in reducing brain oxidative stress and improving neurotransmission. Additionally, there have been reports of its positive effects on psychotic symptoms and its potential in reducing the side effects of antipsychotic drugs. In this review article, we present the current state of knowledge on the potential use of ascorbic acid in the treatment of schizophrenia as an adjunct to standard pharmacological therapy. We analyze existing clinical studies and the mechanisms of action of vitamin C, suggesting its promising role as an adjunctive therapy in the treatment of schizophrenia. These insights, though not yet widely disseminated, may be significant for the further development of therapeutic strategies for this mental illness. [ABSTRACT FROM AUTHOR]

Clozapine is an antipsychotic drug whose accumulation in white cells can sometimes prove toxic; understanding the transporters and alleles responsible is thus highly desirable. We used a strategy in which a yeast (Saccharomyces cerevisiae) CRISPR-Cas9 knock-out library was exposed to cytotoxic concentrations of clozapine to determine those transporters whose absence made it more resistant; we also recognised the structural similarity of the fluorescent dye safranin O (also known as safranin T) to clozapine, allowing it to be used as a surrogate marker. Strains lacking the mitochondrial ABC transporter MDL1 (encoded by YLR188W) showed substantial resistance to clozapine. MDL1 overexpression also conferred extra sensitivity to clozapine and admitted a massive increase in the cellular and mitochondrial uptake of safranin O, as determined using flow cytometry and microscopically. Yeast lacking mitochondria showed no such unusual accumulation. Mitochondrial MDL1 is thus the main means of accumulation of clozapine in S. cerevisiae. The closest human homologue of S. cerevisiae MDL1 is ABCB10. [ABSTRACT FROM AUTHOR]

Background: Catatonia has been reported with withdrawal of medications. Among the various psychotropics, clozapine has been implicated to cause catatonia when abruptly withdrawn. The data regarding clozapine withdrawal catatonia are scarce and are mostly available in the form of case reports and series. Aim: In this case series, we present three cases of clozapine withdrawal catatonia and review the available literature on clozapine withdrawal clozapine. Results: All the three patients developed catatonia within 48 h to 14 days of stoppage of clozapine in the doses of 100-350 mg/day. Two of the patients experiencing clozapine withdrawal improved with reinstitution of clozapine in the previous doses along with benzodiazepines. However, one patient additionally required electroconvulsive therapy (ECT) for the management of withdrawal catatonia. A review of literature showed that clozapine withdrawal catatonia has male preponderance and has been reported with withdrawal of clozapine doses of 50-550 mg/day. The catatonia usually starts in 48 h to 2 weeks of stopping clozapine. Available literature suggests that most of the patients have been managed with restarting of clozapine, along with lorazepam and occasional patients require ECT. Conclusions: To conclude our case series and the available review of literature suggests that sudden discontinuation of clozapine can lead to withdrawal catatonia. Our cases also highlight the importance of reviewing treatment history, especially of abrupt discontinuation of clozapine when a patient on clozapine present with catatonia. This can be very helpful in deciding about further management. [ABSTRACT FROM AUTHOR]

Introduction: Currently, 21 million people live with the disease, mostly in low to middle-income countries. We aimed to assess the survival of patients with schizophrenia using clozapine compared with non-clozapine atypical antipsychotics provided by the Brazilian National Health System using realworld data. Materials and methods: This is an open retrospective cohort study of patients diagnosed with schizophrenia to whom atypical antipsychotics were dispensed by the Brazilian National Health System between 2000 and 2015, based on deterministic-probabilistic pairing of administrative data records. The Kaplan-Meier method was used to estimate the cumulative probability of survival and the Cox proportional hazards model was adjusted to assess the risk factors for survival via the hazard ratio (HR). Result: Participants were 375,352 adults with schizophrenia, with an overall survival rate of 76.0% (95%CI 75.0-76.0) at the end of the cohort. Multivariate analysis indicated a greater risk of death for men (HR=1.30; 95%CI 1.27-1.32), older adults (HR=17.05; 95%CI 16.52-17.60), and in the Southeast region of Brazil (HR=1.20; 95%CI 1.17-1.23). Patients who used non-clozapine atypical antipsychotics had a 21% greater risk of death when compared to those taking clozapine (HR=1.21; 95%CI 1.14-1.29). Additionally, a history of hospitalization for pneumonia (HR=2.17; 95%CI 2.11-2.23) was the main clinical variable associated with increased risk of death, followed by hospitalization for lung cancer (HR=1.82; 95%CI 1.58-2.08), cardiovascular diseases (HR=1.44; 95%CI 1.40-1.49) and any type of neoplasia (HR=1.29; 95%CI 1.19-1.40). Discussion: This is the first published Brazilian cohort study that evaluated survival in people with schizophrenia, highlighting the impact of atypical antipsychotics. In this real-world analysis, the use of clozapine had a protective effect on survival when compared to olanzapine, risperidone, quetiapine, and ziprasidone. [ABSTRACT FROM AUTHOR]

RationaleDesigner receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist.ObjectivesSecond-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit.MethodsMale and female TH:Cre + rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons of TH:Cre + rats. All rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in counterbalanced order.ResultsAll three CNO doses reduced operant rewards earned in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest J60 dose tested significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre + rats were correlated and were present in both sexes.ConclusionsFindings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

Abstract Background Clozapine is the only recommended antipsychotic medication for individuals diagnosed with treatment-resistant schizophrenia. Unfortunately, its wider use is hindered by several possible adverse effects, some of which are rare but potentially life threatening. As such, there is a growing interest in studying clozapine use and safety in routinely collected healthcare data. However, previous attempts to characterise clozapine treatment have had low accuracy. Aim To develop a methodology for identifying clozapine treatment dates by combining several data sources and implement this on a large clinical database. Methods Non-identifiable electronic health records from a large mental health provider in London and a linked database from a national clozapine blood monitoring service were used to obtain information regarding patients' clozapine treatment status, blood tests and pharmacy dispensing records. A rule-based algorithm was developed to determine the dates of starting and stopping treatment based on these data, and more than 10% of the outcomes were validated by manual review of de-identified case note text. Results A total of 3,212 possible clozapine treatment periods were identified, of which 425 (13.2%) were excluded due to insufficient data to verify clozapine administration. Of the 2,787 treatments remaining, 1,902 (68.2%) had an identified start-date. On evaluation, the algorithm identified treatments with 96.4% accuracy; start dates were 96.2% accurate within 15 days, and end dates were 85.1% accurate within 30 days. Conclusions The algorithm produced a reliable database of clozapine treatment periods. Beyond underpinning future observational clozapine studies, we envisage it will facilitate similar implementations on additional large clinical databases worldwide.

Yin Cao,1– 4 Qingrong Xia,1– 4 Jun Liang,1– 4 Jiequan Wang,1– 4 Feng Shan,1– 4 Biao Dai1– 4 1Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei, People’s Republic of China; 3Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, People’s Republic of China; 4Department of Clinical Pharmacy, Anhui Clinical Research Center for Mental Disorders, Hefei, People’s Republic of ChinaCorrespondence: Jun Liang, Department of Pharmacy, Hefei Fourth People’s Hospital, 316 Huangshan Road, Hefei, 230000, People’s Republic of China, Email amhcliangj@163.comObjective: The present study aims to investigate the effect of common cold on the serum clozapine concentrations in hospitalized patients with schizophrenia.Methods: A total of 65 schizophrenic patients with common cold receiving clozapine treatment were retrospectively enrolled. The demographic data, medication situation, clozapine concentration, and parameters of routine haematological and biochemical laboratory tests were obtained from the medical record system. The serum clozapine concentration and clozapine concentration/dose (C/D) ratios between the baseline period and cold period were compared by paired-sample t tests. Association between the changes in serum concentration and C/D ratios of clozapine and changes in white blood cell (WBC) and neutrophil (NE) counts was evaluated using Pearson correlation analysis.Results: The serum clozapine concentration (t = − 9.856, P < 0.001) and clozapine C/D ratios (t = − 10.071, P < 0.001) were found to be significantly elevated in the cold period compared to the baseline period. Moreover, the changes in the serum clozapine concentration were found to be significantly elevated in female patients compared to male patients (t = − 2.483, P = 0.017). Furthermore, changes in the serum clozapine concentration were positively correlated to the changes in WBC (r = 0.303, P = 0.014) and NE (r = 0.315, P = 0.011) counts. Similarly, changes in clozapine C/D ratios were positively correlated to the changes in WBC (r = 0.275, P = 0.027) and NE (r = 0.328, P = 0.008) counts.Conclusion: The serum clozapine concentrations in patients with schizophrenia during the common cold period were increased, which might by related to the elevated WBC and NE counts.Keywords: clozapine, blood drug concentration, schizophrenia, white blood cell count, neutrophil count, common cold

Cognitive dysfunction is a core feature of schizophrenia. Although treatment-resistant schizophrenia (TRS) exhibits wide-ranging neuropsychological deficits, factors defining cognitive prognosis in TRS are unclear. We aimed to clarify the association between cognitive dysfunction and factors, such as plasma concentrations of clozapine (CLZ), N-desmethylclozapine (NDMC), and homovanillic acid (HVA), due to differences in antipsychotic responses in patients with schizophrenia. This pilot cross-sectional study included 60 Japanese patients (35 with TRS and 25 with non-CLZ antipsychotic responders (AR)). Cognitive function was evaluated using the Brief Assessment of Cognition Short Form (BAC-SF). Plasma concentrations of HVA, CLZ, and NDMC were analyzed by high-performance liquid chromatography. The cognitive performance of patients with AR was better than that of patients with TRS in all tasks. No significant cognitive differences were detected between the CLZ responders and non-responders. The severity of negative and extrapyramidal symptoms was found to be potentially negatively associated with BAC-SF composite and several subtest scores. In patients with TRS, chlorpromazine equivalents and the CLZ/NDMC ratio were identified as factors negatively associated with Digit Sequencing and the Symbol Coding subtest scores of the BAC-SF, respectively. Our study suggests that patients with TRS experience worse cognitive dysfunction than those with AR, and CLZ responsiveness in TRS may be not associated with cognitive dysfunction. Additionally, higher chlorpromazine equivalents and the CLZ/NDMC ratio may be associated with severity of cognitive dysfunction in patients with TRS. Further studies are required to clarify the relationship between treatment response and cognitive dysfunction in schizophrenia. [ABSTRACT FROM AUTHOR]

Clozapine remains the only effective medication for treatment-resistant schizophrenia (TRS), with response rates [greater than or equal to] 40% in controlled trials, compared with < 5% for other antipsychotics, and [...]

Background: Catatonia has been reported with withdrawal of medications. Among the various psychotropics, clozapine has been implicated to cause catatonia when abruptly withdrawn. The data regarding clozapine withdrawal catatonia are scarce and are mostly available in the form of case reports and series. Aim: In this case series, we present three cases of clozapine withdrawal catatonia and review the available literature on clozapine withdrawal clozapine. Results: All the three patients developed catatonia within 48 h to 14 days of stoppage of clozapine in the doses of 100–350 mg/day. Two of the patients experiencing clozapine withdrawal improved with reinstitution of clozapine in the previous doses along with benzodiazepines. However, one patient additionally required electroconvulsive therapy (ECT) for the management of withdrawal catatonia. A review of literature showed that clozapine withdrawal catatonia has male preponderance and has been reported with withdrawal of clozapine doses of 50–550 mg/day. The catatonia usually starts in 48 h to 2 weeks of stopping clozapine. Available literature suggests that most of the patients have been managed with restarting of clozapine, along with lorazepam and occasional patients require ECT. Conclusions: To conclude our case series and the available review of literature suggests that sudden discontinuation of clozapine can lead to withdrawal catatonia. Our cases also highlight the importance of reviewing treatment history, especially of abrupt discontinuation of clozapine when a patient on clozapine present with catatonia. This can be very helpful in deciding about further management.

Abstract Background Clozapine is an off-label drug used in most countries to prevent suicide in individuals with schizophrenia. However, few studies have reported real-world prescription practices. This study aimed to explore the association between a history of suicidal behavior and clozapine prescribing during eight weeks of hospitalization for individuals with early-stage schizophrenia. Methods This observational cohort study used routine health data collected from a mental health hospital in Beijing, China. The study included 1057 inpatients who had schizophrenia onset within 3 years. History of suicidal behavior was coded from reviewing medical notes according to the Columbia Suicide Severity Rating Scale. Information on antipsychotic use during hospitalization was extracted from the prescription records. Time to clozapine use was analyzed using Cox regression models adjusted for sociodemographic and clinical covariates. Results The prevalence rates of self-harm, suicidal behavior, and suicide attempt were 12.3%, 7.5%, and 5.4%, respectively. A history of self-harm history was positively associated with clozapine uses upon admission (4.1% vs. 0.8%, exact p = 0.009). Among those who had not used clozapine and had no clozapine contraindication, A history of suicidal behavior increased the possibility of switch to clozapine within 56 days after admission (Hazard Ratio[95% CI], 6.09[2.08–17.83]) or during hospitalization (4.18[1.62–10.78]). Conclusion The use of clozapine for early-stage schizophrenia was more frequent among those with suicidal behavior than among those without suicidal behavior in China, although the drug instructions do not label its use for suicide risk.