Dunlop John, Brandon Nicholas J
AstraZeneca Neuroscience iMed, Cambridge, MA, USA
AstraZeneca Neuroscience iMed, Cambridge, MA, USA.
J Psychopharmacol. 2015 Feb;29(2):230-8. doi: 10.1177/0269881114565806. Epub 2015 Jan 13.
Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.
目前用于治疗精神分裂症的药物，即典型和非典型抗精神病药物，主要通过拮抗多巴胺D2受体亚型发挥治疗作用，对该疾病的阳性症状有显著临床疗效，但对阴性症状和认知障碍的影响有限或几乎没有影响。鉴于当前治疗方法存在这些局限性，以及认识到多巴胺能系统之外的递质系统，特别是谷氨酸能传递，在精神分裂症病因中起作用，最近人们付出了巨大努力，致力于发现和开发作用机制与现有药物不同的新型精神分裂症治疗药物。具体而言，选择性靶向代谢型谷氨酸受体2/3亚型、磷酸二酯酶10亚型、甘氨酸转运体1亚型和α7烟碱型乙酰胆碱受体的化合物，一直是药物研发的重点。在此，我们回顾了针对这些新机制的最先进候选药物的近期临床经验，并讨论这些新药是否达到了预期。
