Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists
Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists
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DOI：
10.1007/s00213-004-1794-x
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发表时间：
2004-06-01
影响因子：
3.4
通讯作者：
Friedman, JI
中科院分区：
文献类型：
--
作者：
Friedman, JI
理由。精神分裂症患者中枢胆碱能系统的改变，如皮质和海马中毒蕈碱和烟碱受体数量的减少，可能有助于精神分裂症的认知障碍。因此，增强中枢胆碱能功能的药物治疗可能有助于精神分裂症的认知增强。方法.对研究精神分裂症患者中枢胆碱能系统改变的文献进行检索。对靶向胆碱能系统的潜在认知增强化合物的动物和人体试验以及对精神分裂症患者进行的任何初步试验进行了额外的检索。结果目前可用的可能适用于此目的的治疗包括乙酰胆碱酯酶抑制剂、毒蕈碱激动剂、烟碱激动剂和烟碱受体功能的变构增效剂。尽管一些开放标签研究表明多奈哌齐治疗的精神分裂症患者的认知有适度改善，但来自盲法安慰剂对照研究的数据表明没有效果。来自加兰他敏（一种乙酰胆碱酯酶抑制剂和烟碱受体变构增效剂）对照试验的数据表明，这可能是一种有效的替代方案。此外，一些临床前数据表明，正在开发的选择性M-1毒蕈碱激动剂可能具有作为精神分裂症患者的认知增强剂和抗精神病治疗的潜力。结论.胆碱能方法改善精神分裂症的认知功能障碍似乎是可行的。有一些初步的数据，以支持联合乙酰胆碱酯酶抑制剂和变构增效剂的烟碱受体的疗效，而未来的试验正在等待目前正在开发的更具体的毒蕈碱激动剂。
Rationale. Alterations in the central cholinergic system of patients with schizophrenia such as reduced numbers of muscarinic and nicotinic receptors in the cortex and hippocampus may contribute to the cognitive impairment of schizophrenia. Therefore, pharmacological treatments that enhance central cholinergic function may be useful as cognitive enhancers in schizophrenia. Methods. Searches were conducted for articles which investigated alterations of central cholinergic systems in patients with schizophrenia. Additional searches were conducted for animal and human trials of potential cognitive enhancing compounds that target the cholinergic system and any preliminary trials conducted with schizophrenic patients. Results. Currently available treatments which are potentially suitable for this purpose include acetylcholinesterase inhibitors, muscarinic agonists, nicotinic agonists, and allosteric potentiators of nicotinic receptor function. Although some open label studies demonstrate modest cognitive improvements of schizophrenic patients treated with donepezil, data from a blinded, placebo controlled study demonstrate no effect. Data from a controlled trial of galantamine, a combined acetylcholinesterase inhibitor and allosteric potentiator of the nicotinic receptor, indicates that this may be an effective alternative. In addition, some preclinical data indicates that selective M-1 muscarinic agonists under development may have potential as cognitive enhancers and antipsychotic treatments for schizophrenic patients. Conclusions. A cholinergic approach to ameliorating the cognitive dysfunction of schizophrenia appears viable. There is some preliminary data to support the efficacy of combined acetylcholinesterase inhibitors and allosteric potentiators of the nicotinic receptor, whereas future trials are awaited for more specific muscarinic agonists currently under development.