用于治疗精神病的痕量胺相关受体1（TAAR1）激动剂：对人类和非人类数据的实时系统评价和荟萃分析。

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.

作者信息

Siafis Spyridon, Chiocchia Virginia, Macleod Malcolm R, Austin Charlotte, Homiar Ava, Tinsdeall Francesca, Friedrich Claire, Ramage Fiona J, Kennett Jaycee, Nomura Nobuyuki, Maksym Olena, Rutigliano Grazia, Vano Luke J, McCutcheon Robert A, Gilbert David, Ostinelli Edoardo G, Stansfield Claire, Dehdarirad Hossein, Juma Damian Omari, Wright Simonne, Simple Ouma, Elugbadebo Olufisayo, Tonia Thomy, Mantas Ioannis, Howes Oliver D, Furukawa Toshi A, Milligan Lea, Moreno Carmen, Elliott Julian H, Hastings Janna, Thomas James, Michie Susan, Sena Emily S, Seedat Soraya, Egger Matthias, Potts Jennifer, Cipriani Andrea, Salanti Georgia, Leucht Stefan

机构信息

Department of Psychiatry and Psychotherapy, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.

German Center for Mental Health (DZPG), partner site München/Augsburg, Germany.

出版信息

Wellcome Open Res. 2024 Apr 11;9:182. doi: 10.12688/wellcomeopenres.21302.1. eCollection 2024.

DOI:10.12688/wellcomeopenres.21302.1

PMID:39036710

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11258611/

Abstract

BACKGROUND

Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies.

METHODS

We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses.

RESULTS

Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling.

CONCLUSIONS

TAAR1 agonists may be less efficacious than dopamine D receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted.

REGISTRATION

PROSPERO-ID: CRD42023451628.

摘要

背景

痕量胺相关受体1（TAAR1）激动剂在治疗精神病方面显示出前景，促使我们综合来自人类和非人类研究的数据。

方法

我们共同开展了一项关于在个体（有或无精神病/精神分裂症）及相关动物模型中研究TAAR1激动剂的对照研究的实时系统评价。两名独立评审员在多个电子数据库中检索研究（截至2023年11月17日），提取数据并评估偏倚风险。主要结局指标为人类研究中总体症状的标准化均值差（SMD）以及动物模型中的运动亢进。我们还研究了不良事件和神经递质信号传导。我们采用随机效应荟萃分析对数据进行综合分析。

结果

9项随机试验提供了两种TAAR1激动剂（乌洛托隆和雷米托隆）的数据，15项动物研究提供了10种TAAR1激动剂的数据。与安慰剂相比，乌洛托隆和雷米托隆在改善急性精神分裂症成人患者的总体症状方面差异不大（N = 4项研究，n = 1291名参与者；SMD = 0.15，95%CI：-0.05，0.34），且雷米托隆的疗效低于利培酮（N = 1项研究，n = 156名参与者，SMD = -0.53，95%CI：-0.86，-0.20）。在乌洛托隆的III期试验中观察到较大的安慰剂反应。有限的证据表明TAAR1激动剂的副作用相对较轻，尽管单剂量乌洛托隆后恶心和镇静较为常见。在动物研究中，与对照组相比，TAAR1激动剂改善了运动亢进（N = 13项研究，k = 41项实验，SMD = 1.01，95%CI：0.74，1.27），但与多巴胺D受体拮抗剂相比似乎疗效较差（N = 4项研究，k = 7项实验，SMD = -0.62，95%CI：-1.32，0.08）。有限的人类和动物数据表明TAAR1激动剂可能调节突触前多巴胺能信号传导。