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TOP統合失調症および関連する精神病クロザピンの副作用クロザピン：通常はみられない稀な副作用

クロザピン：通常はみられない稀な副作用

副作用 経過 コメント
無顆粒球症/好中球減少（遅発性）1-4 開始後3ヵ月間に起こりやすいが，いつでも起こる可能性がある 治療開始から1年経過しても，クロザピンと関連する血液障害の報告が散見される。最長9年間リスクが増加する可能性がある5。一部の症例では，クロザピンが原因ではない可能性もある6, 7。血液学的副作用に関する項を参照のこと
大腸炎/消化管壊死8-15 通常は開始後1ヵ月以内に生じるが，いつでも起こる可能性がある16 症例報告が増えている。重症または慢性の下痢を認める際には，死亡リスクが明らかなので専門医に紹介すべきである。抗コリン薬の使用は，おそらく大腸炎や壊死のリスクを増加させる17
せん妄18-20 いつでも起こる まずまずの頻度（8-10％18, 21）でみられるという報告があるが，実臨床においては，慎重に増量し，血漿中濃度を測定していれば稀である。高齢であることと身体合併症がせん妄のリスクを増加させる。せん妄のよくある原因を確実に治療する（せん妄に関する項を参照）
好酸球増加22-24 開始後数週間に起こる25, 26 ある程度みられるが，その意義に関しては不明である。好中球減少の予測因子となるという意見もあるが異論もある。通常は良性であるが，炎症性臓器障害の徴候について調査すること27（心筋炎28，間質性腎炎26, 29，間質性肺疾患，肝炎，膵炎30）。大腸炎やその症状と関連する可能性がある15, 31。DRESS症候群の症例報告が6件ある32。臓器の炎症がなければ再投与が奏効する可能性もある33。抗うつ薬を併用するとリスクが増加する可能性がある34, 35
熱中症36, 37 いつでも起こる 症例報告が2件あり，いずれも猛暑中に発現していた。NMSと誤診する可能性がある（どちらの場合もCKが上昇した）
肝不全/酵素異常38-44 開始後数ヵ月間に起こる LFTでは良性の変化がよくみられるが（症例の50％にみられることもある），劇症肝不全のリスクもわずかながらあるため，モニタリングが有用である45。皮疹が，クロザピン関連の肝炎に伴ってみられる可能性がある46。肝障害に関する項を参照のこと
低体温症47 いつでも起こる ファーマコビジランスデータベースに数件の症例報告と事象報告がある。死に至ることもある
間質性腎炎29, 48-56 通常は開始後3週間に生じるが，最長3ヵ月間は可能性がある26, 57 少数ではあるが，クロザピンの関与を示唆する報告がある。免疫介在性である。数回の投与後に発症することもある。症状としては，発熱，頻脈，悪心，嘔吐，下痢，クレアチニン上昇，排尿困難，好酸球増加がみられる。典型的な腎炎に伴う皮疹はみられない場合がある26。クロザピン再開が成功した症例の報告はない26
間質性肺疾患 通常は開始後数ヵ月間に起こるが，その後の投与中に生じる可能性もある 症例報告が6件ある58。原因は誤嚥または免疫反応と考えられる。症状は非特異的で，息切れ，発熱，咳嗽，疲労等である。肺炎も報告されている59
眼への影響 いつでも起こる 眼の色素沈着の症例報告が1件60，眼窩周囲浮腫の症例報告が5件61ある。クロザピンがドライアイ症候群を惹起する可能性がある62
膵炎63-70 通常は開始後6週間に起こるが，その後の投与中に生じる可能性もある71 無症候性および症候性の膵炎が数件報告されている。症状としては，発熱，腹痛および腹部膨満，悪心および嘔吐，CRP上昇，リパーゼおよび/またはアミラーゼ上昇等がみられる。バルプロ酸ナトリウムがリスクを増加させる可能性がある26。クロザピン再開の試みは大半が不成功に終わるが66, 72-74，成功例1例が報告されている75
耳下腺腫大76-82 通常は開始後数週間に起こるが，それ以降に生じることもある83 いくつかの症例報告がある。発症機序は明らかではないが，免疫学的機序または唾液の濃縮によるカルシウム析出の可能性がある。再発する可能性がある。自然に軽快することもある84。テラゾシンとbenzatropineを併用して流涎過多を治療すると奏効する場合がある
心膜炎および心膜液貯留85-93 いつでも起こる いくつかの文献報告がある。疲労，胸痛，呼吸困難，頻脈等の症状があるが，症状がないこともある94。徴候は炎症性マーカー（特にトロポニンI）およびpro-BNP値の上昇である95。心エコー検査を行って心膜液貯留の有無を確認する。再投与が奏効する可能性もある96, 97
吃音98-106 いつでも起こる 症例報告がある。EPSまたはてんかん様活動の結果かもしれない。血漿中濃度を確認し，減量または抗けいれん薬の投与を考慮する。差し迫った全般発作の警告徴候である可能性もある107
血小板減少症108-111 開始後3ヵ月間に起こる データはほとんどないが，まずまずの頻度でみられるようである（発現率は年間3％112から8％113）。一過性で臨床的意義は少ないかもしれないが，遷延する場合114, 115や，クロザピンを再開すると再発する場合116もある。血小板増加症も報告されている117
皮膚反応118 いつでも起こる 一般に統合失調症患者では皮膚疾患の有病率が高い119。下肢に融合性の紅斑性皮疹が生じたとする血管炎の報告が4件ある120-123。スティーブンス・ジョンソン症候群の報告が1件124，バラ色粃糠疹の報告が2件125, 126，丘疹の報告が1件127，発疹性膿疱症の報告が1件128，スウィート症候群の死亡例が1件ある129。皮疹はDRESS症候群でよく報告される32
血栓塞栓症130-134 いつでも起こる135 体重増加と鎮静が血栓塞栓症のリスクに寄与している可能性がある。5-HT2A受容体刺激作用による血小板凝集の増加が，機序であるかもしれない136。クロザピンは肺血栓塞栓症のリスクを一般集団と比べて28倍増加させる137。リスクは用量依存性である可能性がある138。他の危険因子（手術，不動状態）が存在する場合は，予防的抗血栓療法の閾値を低くすべきである。塞栓症後の治療の継続は可能と考えられるが139，予防的抗血栓療法を行わないと再発する可能性があるため，血液専門医に相談すること140, 141

（水野　裕也）

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