Despite extensive research efforts aimed at discovering novel antipsychotic compounds, a satisfactory pharmacological strategy for schizophrenia treatment remains elusive. All the currently available drugs act by modulating dopaminergic neurotransmission, leading to insufficient management of the negative and cognitive symptoms of the disorder. Due to these challenges, several attempts have been made to design agents with innovative, non‐dopaminergic mechanisms of action. Consequently, a number of promising compounds are currently progressing through phases 2 and 3 of clinical trials. This review aims to examine the rationale behind the most promising of these strategies while simultaneously providing a comprehensive survey of study results. We describe the versatility behind the cholinergic neurotransmission modulation through the activation of M1 and M4 receptors, exemplified by the prospective drug candidate KarXT. Our discussion extends to the innovative approach of activating TAAR1 receptors via ulotaront, along with the promising outcomes of iclepertin, a GlyT‐1 inhibitor with the potential to become the first treatment option for cognitive impairment associated with schizophrenia. Finally, we evaluate the 5‐HT2A antagonist paradigm, assessing two recently developed serotonergic agents, pimavanserin and roluperidone. We present the latest advancements in developing novel solutions to the complex challenges posed by schizophrenia, offering an additional perspective on the diverse investigated drug candidates.

中文翻译：

---

超越多巴胺：精神分裂症治疗的新策略

尽管为了发现新型抗精神病化合物进行了广泛的研究工作，但令人满意的精神分裂症治疗药理学策略仍然难以实现。目前所有可用的药物都通过调节多巴胺能神经传递起作用，导致对该疾病的阴性和认知症状的管理不充分。由于这些挑战，人们进行了多次尝试来设计具有创新的、非多巴胺能作用机制的药物。因此，许多有前景的化合物目前正在进行临床试验的第二阶段和第三阶段。本综述旨在探讨这些最有前途的策略背后的基本原理，同时对研究结果进行全面调查。我们描述了通过激活 M 进行胆碱能神经传递调节背后的多功能性1和M4受体，以前瞻性候选药物 KarXT 为例。我们的讨论延伸到通过 ulotaront 激活 TAAR1 受体的创新方法，以及 iclepertin（一种 GlyT-1 抑制剂）的有希望的结果，有可能成为精神分裂症相关认知障碍的第一个治疗选择。最后，我们评估5-HT2A拮抗剂范例，评估两种最近开发的血清素能药物：pimavanserin 和 roluperidone。我们展示了针对精神分裂症带来的复杂挑战开发新颖解决方案的最新进展，为各种研究的候选药物提供了额外的视角。