CNS Biology, AstraZeneca Pharmaceutical, Wilmington, DE, USA.
Pharmacol Ther. 2010 May;126(2):173-85. doi: 10.1016/j.pharmthera.2010.02.001. Epub 2010 Feb 19.
Schizophrenia, bipolar disorder and unipolar depression are multi-dimensional and severely disabling psychiatric diseases with a strong need for improved pharmacotherapies with better adherence, long-term outcome and patient functionality. Progress has been achieved with the emergence of tailored multi-target agents (MTAs), such as second-generation antipsychotics for schizophrenia, with expanding clinical utility in bipolar disorder and depression. Better understanding of how these MTAs exert their beneficial and undesirable clinical effects in terms of receptor interaction remains an area for further elucidation, which may provide insight towards a new generation of individualized, and optimized therapies. This review explores to what extent the receptor signature of MTAs informs about their clinical action and therapeutic utility. Compelling clinical validation exists only for a limited number of molecular targets (e.g. D(2) receptor blockade, serotonin transport inhibition), indicating overall high attrition and poor translation of predictive preclinical pharmacology. Nevertheless, recent advances have identified promising novel approaches for schizophrenia, bipolar disorder and depression that require further clinical validation. It is hoped that the expanding clinical and mechanistic knowledge garnered from the use of existing MTAs will provide additional opportunities for "reverse translation" and towards target validation. There is considerable scope for further developing and applying the knowledge linking receptor signature to clinical activity to drive stronger target validation, and ultimately support rational development of the next generation of MTAs for the improved treatment of schizophrenia and mood disorders.
精神分裂症、双相情感障碍和单相抑郁症是多维的、严重致残的精神疾病，迫切需要改善药物治疗，提高患者的依从性、长期疗效和生活功能。随着针对精神分裂症的第二代抗精神病药物等多靶标药物（MTAs）的出现，已经取得了进展，这些药物在双相情感障碍和抑郁症方面的临床应用也在不断扩大。更好地了解这些 MTA 通过受体相互作用产生有益和不良临床效果的机制仍然是一个需要进一步阐明的领域，这可能为新一代个体化和优化治疗提供启示。本文探讨了 MTA 的受体特征在多大程度上可以反映其临床作用和治疗效果。只有少数分子靶点（如 D2 受体阻断、血清素转运抑制）具有令人信服的临床验证，这表明预测性临床前药理学的总体高淘汰率和转化效果不佳。然而，最近的进展为精神分裂症、双相情感障碍和抑郁症确定了有前途的新方法，需要进一步的临床验证。希望从现有 MTA 的使用中获得的不断扩大的临床和机制知识将为“反向转化”和目标验证提供额外的机会。将受体特征与临床活性联系起来以推动更强的目标验证的知识还有很大的发展和应用空间，并最终支持为改善精神分裂症和心境障碍的治疗而开发下一代 MTA 的合理发展。
