RESUMO
BACKGROUND: Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation. AIMS: We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date. METHOD: We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days. RESULTS: Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset. CONCLUSION: A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.
RESUMO
AIMS: It has been recommended that for patients with schizophrenia, antipsychotics should be prescribed simply, using an optimal dose. However, pro re nata (p.r.n., meaning to use on an as-needed basis) antipsychotics may increase the risk of excessive dosing (defined as mean chlorpromazine-equivalent doses above 1000 mg) and polypharmacy (combination use of different antipsychotics). This study aimed to investigate the increased risk caused by p.r.n. antipsychotics. METHOD: The subjects included 413 patients with schizophrenia from 17 acute psychiatric wards in nine hospitals. Over a 24-h period on a survey day, data on regular medication and the use of p.r.n. were collected. The analysis focused on p.r.n. antipsychotics in agitated patients. We used McNemar's test to evaluate differences in the proportions of patients prescribed antipsychotics with excessive dosing or polypharmacy before (i.e., regular medication only) and after prescribed p.r.n. antipsychotics were added to regular medication (i.e., regular medication plus p.r.n. antipsychotics). RESULTS: Of 413 patients, 312 (75.5%) were prescribed p.r.n. for agitated status. Of those, 281 (90.1%) were prescribed p.r.n. antipsychotics. The total doses were significantly higher and more compounded in case patients prescribed p.r.n. antipsychotics than in those who were not. Seventeen patients (4.1%) were actually administered p.r.n. antipsychotics. Their total medication, including p.r.n. on the current day, represented excessive dosing or polypharmacy of antipsychotics. CONCLUSION: The use of p.r.n. antipsychotics may cause hidden excessive dosing and polypharmacy. Our results indicate the importance of careful monitoring of p.r.n. antipsychotics to agitated patients with schizophrenia.