プレプリント / バージョン1

うつ病のメカニズムと抗うつ作用に関する近年の動物研究の動向

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DOI:

https://doi.org/10.51094/jxiv.2493

キーワード:

うつ病、 モノアミン、 動物モデル、 炎症、 幻覚剤、 神経回路

抄録

うつ病は生涯にわたり発症し得る有病率の高い精神疾患であるが、その病態生理は依然として十分には解明されていない。これまでの基礎研究および臨床研究の蓄積により、モノアミン神経伝達の異常がうつ病の発症に関与することが示唆され、この知見に基づいて、選択的セロトニン再取り込み阻害薬やセロトニン・ノルアドレナリン再取り込み阻害薬などの抗うつ薬が開発され、広く臨床に用いられてきた。しかし、これら従来型抗うつ薬は効果発現までに数週間を要し、長期的な服用が必要であるにもかかわらず、約3割の患者では十分な治療効果が得られないことが知られている。加えて、一部の患者においては自殺念慮の増加など重篤な副作用も報告されており、有効性および安全性の両面から、新規治療戦略の確立が喫緊の課題となっている。近年、ケタミンや幻覚薬に代表される薬物が即効性かつ持続的な抗うつ効果を示すことが明らかとなり、従来のモノアミン仮説のみでは説明し得ない新たな病態メカニズムに注目が集まっている。これらの知見は、グルタミン酸神経伝達、シナプス可塑性、さらには免疫—脳相互作用など、多様な生物学的機構が抗うつ作用に不可欠であることを示唆すると同時に、長年支持されてきた神経伝達物質異常仮説を再検討する契機ともなっている。さらに、脳回路レベルでの機序解明を含む基礎研究の進展は、うつ病の新たな治療戦略の構築に大きく寄与しつつある。本総説では、抗うつ薬開発の歴史的背景と近年の新規作用機序に関する再評価を概観するとともに、主要なうつ病動物モデルの特性とモデル研究の意義を整理し、基礎研究から臨床応用へと接続する橋渡し研究の最新動向について概説する。

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生物学・生命科学・基礎医学