精神醫學的臨床試驗：焦聚於抗精神病藥物的研發

Clinical Trials in Psychiatry: Focusing on Antipsychotic Development

臨床試驗是以病人為對象的臨床研究，針對一種疾病或障礙症施行包括藥物、疫苗、飲 食選擇、營養補充或醫療儀器的介入是否產生效果，並且觀察其副作用的症狀與程度。本綜 說回顧抗精神病藥物發展過程中的臨床試驗。當今精神疾患的治療以藥物為主，但在早期則 有許多有趣而奇怪的治療方式。這些包括瘧疾發燒，胰島素引發昏迷與抽搐，pentylenetetrazole 和電氣引發抽搐及大腦額葉切除來治療各種精神病。Lithium，chlorpromazine，imipramine，chlordiazepoxide 和 iproniazid 則是在研究者細心的觀察下，意外發現其治療效果，成 為現代精神藥理學的磐石。經過數十年的演變，目前新藥要上市都必需通過嚴格規範與嚴謹 設計的臨床試驗。在本綜說中，作者將介紹新近上市的 lurasidone，brexpiprazole，cariprazine 與 blonanserin，它們具有不同的接受器結合與副作用。認知強化劑則利用麩胺酸系統調節 劑，磷酸二酯抑制劑和尼古丁受體促動劑機轉研發中，用來治療思覺失調症相關的認知障 礙。作者也在本綜說中，回顧台灣相關的臨床試驗與臨床藥物研究。未來精準醫療，即在正 確診斷的病人，適時給予適切的治療，也適用於精神疾患。臨床試驗則必需建立在生物、心 理與社會文化的差異上，才可達到精準醫學的要求。

Clinical trial is referred to an experiment to investigate novel therapies including drug, vaccines, dietary choices, dietary supplements, and medical devices or other intervention to a certain disease or illness, and to assess the contingent side effects. This overview is to focus on the clinical trial in the development of antipsychotic drugs. Pharmacotherapy is the mainstay of treatment for mental disorders in modern medicine, while there were many interesting and strange therapies implemented in the early days. These therapies include malaria-induced fever to treat neurosyphilitic paresis, insulin-induced coma and convulsions to treat schizophrenia, pentylenetetrazole-induced convulsions and electroconvulsive shock therapy to treat schizophrenia and affective psychoses, and prefrontal lobotomy to treat psychosis and personality disorder. Lithium, chlorpromazine, imipramine, chlordiazepoxide, and iproniazid (MAOI) were developed serendipitously by careful clinical researchers and became the founders of modern psychopharmacology. Currently there are strict regulations and paradigms for clinical trial after decades of evolution. Recently approved antipsychotic drugs such as lurasidone, brexpiprazole, cariprazine and blonanserin are introduced. They have different receptor affinity and carry different side effect profiles. Cognition enhancers are developed using the mechanism of glutamate system modulation, phosphodiesterase inhibition and nicotinic receptor agonism. Inverse agonist in an old concept and a new antipsychotic has been developed using this concept. Also the clinical trials and clinical pharmacological studies in psychiatric field done in Taiwan are reviewed. In the future, precise medicine as getting the right treatment at the right time to the right person is also important for mental disorders. More precise diagnostic categories based on biological, psychological, and socio-cultural variables, which need many kinds of data to reach precision of a clinical trial.