Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals
Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and c...
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Veröffentlicht in: | British journal of psychiatry 2024-11, Vol.225 (5), p.492-498 |
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creator | Kikuchi, Yuki Kurosawa, Masahiro Sakata, Mutsumi Takahashi, Yu Yamamoto, Kyohei Tomita, Hiroaki Yoshio, Takashi Yasui-Furukori, Norio |
description | Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation.
We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date.
We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days.
Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset.
A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications. |
doi_str_mv | 10.1192/bjp.2024.113 |
format | Article |
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We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date.
We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days.
Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset.
A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.</description><identifier>ISSN: 0007-1250</identifier><identifier>ISSN: 1472-1465</identifier><identifier>EISSN: 1472-1465</identifier><identifier>DOI: 10.1192/bjp.2024.113</identifier><identifier>PMID: 39104017</identifier><language>eng</language><publisher>Cambridge, UK: Cambridge University Press</publisher><subject>Acids ; Adult ; Antipsychotic Agents - adverse effects ; Antipsychotics ; Anxiolytics ; Benzodiazepines ; Case-Control Studies ; Clozapine ; Clozapine - adverse effects ; Drug dosages ; Drugs ; East Asian People ; Electroconvulsive therapy ; Female ; Fever ; Fever - chemically induced ; Gender ; Heart diseases ; Hospitals ; Humans ; Hypnotics ; Inflammation ; Japan - epidemiology ; Lithium ; Male ; Medical records ; Mental disorders ; Middle Aged ; Multivariate analysis ; Myocarditis ; Obesity ; Obesity - chemically induced ; Obesity - epidemiology ; Olanzapine ; Orexins ; Original Article ; Overweight ; Pneumonia ; Psychotropic drugs ; Quetiapine ; Regression analysis ; Retrospective Studies ; Risk Factors ; Schizophrenia ; Schizophrenia - drug therapy ; Schizophrenia, Treatment-Resistant - chemically induced ; Schizophrenia, Treatment-Resistant - drug therapy ; Sex Factors ; Side effects ; Time Factors ; Titration ; Valproic acid</subject><ispartof>British journal of psychiatry, 2024-11, Vol.225 (5), p.492-498</ispartof><rights>Copyright © The Author(s), 2024. Published by Cambridge University Press on behalf of Royal College of Psychiatrists</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c245t-855a0ff3f836174a0adbd931accf4c897b2d3ed3da3044b4c2b53e9e360561d53</cites><orcidid>0000-0002-4414-3770 ; 0000-0002-1184-8918</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.cambridge.org/core/product/identifier/S0007125024001132/type/journal_article$$EHTML$$P50$$Gcambridge$$H</linktohtml><link.rule.ids>164,314,780,784,27924,27925,30999,55628</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39104017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kikuchi, Yuki</creatorcontrib><creatorcontrib>Kurosawa, Masahiro</creatorcontrib><creatorcontrib>Sakata, Mutsumi</creatorcontrib><creatorcontrib>Takahashi, Yu</creatorcontrib><creatorcontrib>Yamamoto, Kyohei</creatorcontrib><creatorcontrib>Tomita, Hiroaki</creatorcontrib><creatorcontrib>Yoshio, Takashi</creatorcontrib><creatorcontrib>Yasui-Furukori, Norio</creatorcontrib><title>Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals</title><title>British journal of psychiatry</title><addtitle>Br J Psychiatry</addtitle><description>Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation.
We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date.
We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days.
Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset.
A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.</description><subject>Acids</subject><subject>Adult</subject><subject>Antipsychotic Agents - adverse effects</subject><subject>Antipsychotics</subject><subject>Anxiolytics</subject><subject>Benzodiazepines</subject><subject>Case-Control Studies</subject><subject>Clozapine</subject><subject>Clozapine - adverse effects</subject><subject>Drug dosages</subject><subject>Drugs</subject><subject>East Asian People</subject><subject>Electroconvulsive therapy</subject><subject>Female</subject><subject>Fever</subject><subject>Fever - chemically induced</subject><subject>Gender</subject><subject>Heart diseases</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hypnotics</subject><subject>Inflammation</subject><subject>Japan - epidemiology</subject><subject>Lithium</subject><subject>Male</subject><subject>Medical records</subject><subject>Mental disorders</subject><subject>Middle Aged</subject><subject>Multivariate analysis</subject><subject>Myocarditis</subject><subject>Obesity</subject><subject>Obesity - chemically induced</subject><subject>Obesity - epidemiology</subject><subject>Olanzapine</subject><subject>Orexins</subject><subject>Original Article</subject><subject>Overweight</subject><subject>Pneumonia</subject><subject>Psychotropic drugs</subject><subject>Quetiapine</subject><subject>Regression analysis</subject><subject>Retrospective Studies</subject><subject>Risk Factors</subject><subject>Schizophrenia</subject><subject>Schizophrenia - drug therapy</subject><subject>Schizophrenia, Treatment-Resistant - chemically induced</subject><subject>Schizophrenia, Treatment-Resistant - drug therapy</subject><subject>Sex Factors</subject><subject>Side effects</subject><subject>Time Factors</subject><subject>Titration</subject><subject>Valproic acid</subject><issn>0007-1250</issn><issn>1472-1465</issn><issn>1472-1465</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>7QJ</sourceid><recordid>eNptkU1vEzEQhi0EoqFw44wsceGQDf7abJZbVZUWVIkLnFdee5x1yNqL7aRq_yv_hUkaQEKcrLGeeWZGLyGvOVtw3or3_WZaCCYUVvIJmXHViIqrZf2UzBhjTcVFzc7Ii5w3WEolmufkTLacKcabGfl55RyYkml0tPiSdPEx0DwB2DldQ7CQ5jT2kH25pzpYamIwcfRFh0JHsN4cO7A_0DIATT5_P3L4BwWVIxzUZhsf9OQDVDrnaLwuYKmDPSSqxxjW9LOedIAMdEIfBFzozpeBZjP4hzgNCYLXH2iCkiIuZ4rf4yzYe7g76gedsMWlOFLB6YAMbrjNL8kzhw-8Or3n5NvHq6-XN9Xtl-tPlxe3lRGqLtWqrjVzTrqVXPJGaaZtb1vJtTFOmVXb9MJKsNJqyZTqlRF9LaEFuWT1kttanpN3j94pxR87yKUbfTaw3eJNcZc7yVZtzRVrBKJv_0E3cZcCbtdJrsSq4Q1vkZo_UgbvzQlcNyU_6nTfcdYdYu8w9u4QO1YS8Tcn6a7HUP7Av3NGYHHy6bFP3q7h79j_Gn8B3xW84g</recordid><startdate>202411</startdate><enddate>202411</enddate><creator>Kikuchi, Yuki</creator><creator>Kurosawa, Masahiro</creator><creator>Sakata, Mutsumi</creator><creator>Takahashi, Yu</creator><creator>Yamamoto, Kyohei</creator><creator>Tomita, Hiroaki</creator><creator>Yoshio, Takashi</creator><creator>Yasui-Furukori, Norio</creator><general>Cambridge University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QJ</scope><scope>7TK</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4414-3770</orcidid><orcidid>https://orcid.org/0000-0002-1184-8918</orcidid></search><sort><creationdate>202411</creationdate><title>Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals</title><author>Kikuchi, Yuki ; Kurosawa, Masahiro ; Sakata, Mutsumi ; Takahashi, Yu ; Yamamoto, Kyohei ; Tomita, Hiroaki ; Yoshio, Takashi ; Yasui-Furukori, Norio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c245t-855a0ff3f836174a0adbd931accf4c897b2d3ed3da3044b4c2b53e9e360561d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Acids</topic><topic>Adult</topic><topic>Antipsychotic Agents - adverse effects</topic><topic>Antipsychotics</topic><topic>Anxiolytics</topic><topic>Benzodiazepines</topic><topic>Case-Control Studies</topic><topic>Clozapine</topic><topic>Clozapine - adverse effects</topic><topic>Drug dosages</topic><topic>Drugs</topic><topic>East Asian People</topic><topic>Electroconvulsive therapy</topic><topic>Female</topic><topic>Fever</topic><topic>Fever - chemically induced</topic><topic>Gender</topic><topic>Heart diseases</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Hypnotics</topic><topic>Inflammation</topic><topic>Japan - epidemiology</topic><topic>Lithium</topic><topic>Male</topic><topic>Medical records</topic><topic>Mental disorders</topic><topic>Middle Aged</topic><topic>Multivariate analysis</topic><topic>Myocarditis</topic><topic>Obesity</topic><topic>Obesity - chemically induced</topic><topic>Obesity - epidemiology</topic><topic>Olanzapine</topic><topic>Orexins</topic><topic>Original Article</topic><topic>Overweight</topic><topic>Pneumonia</topic><topic>Psychotropic drugs</topic><topic>Quetiapine</topic><topic>Regression analysis</topic><topic>Retrospective Studies</topic><topic>Risk Factors</topic><topic>Schizophrenia</topic><topic>Schizophrenia - drug therapy</topic><topic>Schizophrenia, Treatment-Resistant - chemically induced</topic><topic>Schizophrenia, Treatment-Resistant - drug therapy</topic><topic>Sex Factors</topic><topic>Side effects</topic><topic>Time Factors</topic><topic>Titration</topic><topic>Valproic acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kikuchi, Yuki</creatorcontrib><creatorcontrib>Kurosawa, Masahiro</creatorcontrib><creatorcontrib>Sakata, Mutsumi</creatorcontrib><creatorcontrib>Takahashi, Yu</creatorcontrib><creatorcontrib>Yamamoto, Kyohei</creatorcontrib><creatorcontrib>Tomita, Hiroaki</creatorcontrib><creatorcontrib>Yoshio, Takashi</creatorcontrib><creatorcontrib>Yasui-Furukori, Norio</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Applied Social Sciences Index & Abstracts (ASSIA)</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>British journal of psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kikuchi, Yuki</au><au>Kurosawa, Masahiro</au><au>Sakata, Mutsumi</au><au>Takahashi, Yu</au><au>Yamamoto, Kyohei</au><au>Tomita, Hiroaki</au><au>Yoshio, Takashi</au><au>Yasui-Furukori, Norio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals</atitle><jtitle>British journal of psychiatry</jtitle><addtitle>Br J Psychiatry</addtitle><date>2024-11</date><risdate>2024</risdate><volume>225</volume><issue>5</issue><spage>492</spage><epage>498</epage><pages>492-498</pages><issn>0007-1250</issn><issn>1472-1465</issn><eissn>1472-1465</eissn><abstract>Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation.
We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date.
We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days.
Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset.
A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.</abstract><cop>Cambridge, UK</cop><pub>Cambridge University Press</pub><pmid>39104017</pmid><doi>10.1192/bjp.2024.113</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-4414-3770</orcidid><orcidid>https://orcid.org/0000-0002-1184-8918</orcidid></addata></record> |
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subjects | Acids Adult Antipsychotic Agents - adverse effects Antipsychotics Anxiolytics Benzodiazepines Case-Control Studies Clozapine Clozapine - adverse effects Drug dosages Drugs East Asian People Electroconvulsive therapy Female Fever Fever - chemically induced Gender Heart diseases Hospitals Humans Hypnotics Inflammation Japan - epidemiology Lithium Male Medical records Mental disorders Middle Aged Multivariate analysis Myocarditis Obesity Obesity - chemically induced Obesity - epidemiology Olanzapine Orexins Original Article Overweight Pneumonia Psychotropic drugs Quetiapine Regression analysis Retrospective Studies Risk Factors Schizophrenia Schizophrenia - drug therapy Schizophrenia, Treatment-Resistant - chemically induced Schizophrenia, Treatment-Resistant - drug therapy Sex Factors Side effects Time Factors Titration Valproic acid |
title | Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals |
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