Initial phase 2 trial of a nicotinic agonist in schizophrenia
Initial phase 2 trial of a nicotinic agonist in schizophrenia
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DOI：
10.1176/appi.ajp.2008.07071135
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发表时间：
2008-08-01
影响因子：
17.7
通讯作者：
Kem, William R.
中科院分区：
文献类型：
--
作者：
Freedman, Robert;Olincy, Ann;Kem, William R.
目的：神经生物学和分子证据表明 α(7)-烟碱受体表达缺陷，表明烟碱乙酰胆碱受体是精神分裂症的可能治疗靶点。患者大量吸烟表明他们试图通过这种机制进行自我治疗。药物 3-(2,4-二甲氧基亚苄基) anabaseine (DMXB-A) 是部分 α(7)-烟碱激动剂，可以口服。一项 1 期试验显示了精神分裂症认知增强的证据。方法：在一项三臂、两个地点、双盲、交叉 2 期试验中，31 名精神分裂症受试者接受了两种不同剂量的 DMXB-A 和安慰剂，为期 4 周。 MATRICS 共识认知电池评估认知效果，阴性症状评估量表 (SANS) 和简明精神病评定量表 (BPRS) 评估临床效果。受试者在试验期间继续使用当前的抗精神病药物，并且不吸烟。结果：在三个治疗组中，DMXB-A 和安慰剂之间的 MATRICS 认知测量没有显着差异，但患者在较高 DMXB-A 剂量下的 SANS 总分有显着改善，并且 BPRS 总分有近乎显着的改善。 SANS 快感缺失和失语量表的改善最为显着。对第一个治疗组的检查显示，与基线相比，DMXB-A 对注意力/警觉性和工作记忆矩阵领域有影响。五名受试者在服用 DMXB-A 时出现轻度震颤，近一半受试者出现轻度恶心。结论：DMXB-A 是一种激活 α(7)-烟碱受体的烟碱激动剂，可改善通常对多巴胺拮抗剂抗精神病药物治疗耐药的阴性症状的临床评级。这种治疗的临床效用尚未确定。
Objective: Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.Method: Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.Results: There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.Conclusion: DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.