Luca Maria, Luca Antonina, Serretti Alessandro
Centre for Addiction, Adrano-Bronte, Adrano (CT), Italy.
Department of Medicine and Surgery, Kore University of Enna, Enna (EN), Italy.
Neuropsychiatr Dis Treat. 2024 Dec 27;20:2637-2649. doi: 10.2147/NDT.S501560. eCollection 2024.
Currently available antipsychotics, mainly targeting the dopaminergic pathway, fail to address the complexity of schizophrenic symptoms and can lead to burdening adverse events. The need for innovative pharmacological options remains critical and research is now focusing on the development of non-dopaminergic antipsychotics. This review aims to summarize the current literature on the most promising non-dopaminergic new APs (muscarinic agonists, Trace Amine Associated Receptor 1 agonists, Glycine Transporter Type 1 inhibitors and 5-HT2A antagonists) and provide a clinically oriented overview of their efficacy, safety and potential use in schizophrenia.
A preliminary search was conducted through the Clinical Trials Database, in order to identify a representative (at late-stage clinical development) for each pharmacological class. The following drugs were selected: bitopertin (GlyT-1 inhibitor), pimavanserin (5-HT2A antagonist), ulotaront (TAAR1 agonist) and xanomeline-trospium (muscarinic agonist). Then, a literature search was conducted through PubMed, in order to retrieve current literature focusing on the efficacy and safety of these drugs.
The clinical development of bitopertin and pimavanserin was halted despite the early promises. Xanomeline-trospium chloride was recently approved by the FDA for the treatment of schizophrenia. Ulotaront showed mixed results, although analysis is ongoing.
The findings of our review indicate that research on the treatment of schizophrenia is gaining momentum. However, it is crucial to remain cautious about over-optimism, as many compounds have failed to deliver the expected results. A balanced approach is recommended when dealing with new APs, whether under investigation or approved. In the latter case, clinicians should carefully evaluate the cost-benefit ratio. Since several agents are still being tested, there is hope that additional data may present new therapeutic opportunities.
目前可用的抗精神病药物主要作用于多巴胺能通路，无法解决精神分裂症症状的复杂性，还可能导致不良事件负担。对创新药物选择的需求仍然至关重要，目前研究正聚焦于非多巴胺能抗精神病药物的开发。本综述旨在总结关于最有前景的非多巴胺能新型抗精神病药物（毒蕈碱激动剂、痕量胺相关受体1激动剂、甘氨酸转运体1抑制剂和5-羟色胺2A拮抗剂）的当前文献，并提供其在精神分裂症中的疗效、安全性及潜在用途的临床导向概述。
通过临床试验数据库进行初步检索，以便为每个药理学类别确定一种具有代表性的（处于临床后期开发阶段）药物。选择了以下药物：比特丙肽（甘氨酸转运体1抑制剂）、匹莫范色林（5-羟色胺2A拮抗剂）、乌洛托品（痕量胺相关受体1激动剂）和占诺美林-曲司氯铵（毒蕈碱激动剂）。然后，通过PubMed进行文献检索，以获取关注这些药物疗效和安全性的当前文献。
尽管比特丙肽和匹莫范色林早期前景良好，但它们的临床开发已停止。氯化占诺美林-曲司氯铵最近已获美国食品药品监督管理局批准用于治疗精神分裂症。乌洛托品的结果喜忧参半，尽管分析仍在进行中。
我们综述的结果表明，精神分裂症治疗研究正在取得进展。然而，至关重要的是对过度乐观保持谨慎，因为许多化合物未能产生预期结果。在处理新型抗精神病药物时，无论处于研究阶段还是已获批准，都建议采取平衡的方法。对于已批准的药物，临床医生应仔细评估成本效益比。由于仍有几种药物正在测试中，有望获得更多数据带来新的治疗机会。
