Goddard A W, Woods S W, Money R, Pande A C, Charney D S, Goodman W K, Heninger G R, Price L H
Yale University Department of Psychiatry, Connecticut Mental Health Center, New Haven 06519, USA.
Psychiatry Res. 1999 Mar 22;85(3):225-40. doi: 10.1016/s0165-1781(99)00015-3.
In order to evaluate the effect of the CCK(B) antagonist CI-988 on behavioral, neuroendocrine, and physiologic responses to the mixed, post-synaptic serotonin (5-HT) agonist/antagonist mCPP, 16 patients with a principal DSM-III-R diagnosis of generalized anxiety disorder (GAD) were enrolled in a study that involved two challenge tests. On one day, patients received a single oral dose of CI-988 followed 30 min later by an i.v. infusion of 0.1 mg/kg mCPP. On a second test day patients received placebo CI-988 followed 30 min later by active i.v. mCPP. The sequence of CI-988 was randomly assigned and the testing was conducted in double-blind fashion. In an initial dose-finding phase (N = 6) with a dose of CI-988 of 25 mg, there were no significant between-test differences in behavioral response to mCPP. Accordingly, the second phase of the study was conducted with a CI-988 dose of 100 mg in another of patients (N = 10). CI-988 (100 mg) was well tolerated and had no significant effects on pretest anticipatory anxiety. There was no significant blunting of the anxiety response to mCPP as a result of CI-988 administration, nor did CI-988 affect physiologic or neuroendocrine measures. Correlations between peak changes in plasma levels of CI-988 and mCPP-induced anxiety in the high-dose patient group were not significant. Overall, these findings did not provide evidence of anxiolytic effects of CI-988 in patients with GAD. The lack of effect of CI-988 on neuroendocrine and physiological measures further suggests that CI-988's pharmacological effects could be independent of 5-HT function. However, follow-up studies using higher doses of CI-988 are indicated to confirm this preliminary finding as are studies more closely evaluating the interrelationship between CCK and 5-HT function in GAD.
为了评估胆囊收缩素（CCK）（B）拮抗剂CI - 988对混合的突触后5 - 羟色胺（5 - HT）激动剂/拮抗剂mCPP的行为、神经内分泌和生理反应的影响，16例主要依据《精神疾病诊断与统计手册》第三版修订本（DSM - III - R）诊断为广泛性焦虑症（GAD）的患者参与了一项包含两项激发试验的研究。在某一天，患者口服单次剂量的CI - 988，30分钟后静脉输注0.1mg/kg的mCPP。在第二个试验日，患者接受安慰剂CI - 988，30分钟后静脉输注活性mCPP。CI - 988的给药顺序随机分配，试验采用双盲方式进行。在初始剂量探索阶段（N = 6），CI - 988剂量为25mg，对mCPP的行为反应在不同试验之间没有显著差异。因此，研究的第二阶段在另外10例患者中采用100mg的CI - 988剂量进行。CI - 988（100mg）耐受性良好，对试验前预期焦虑没有显著影响。给予CI - 988并没有显著减弱对mCPP的焦虑反应，CI - 988也未影响生理或神经内分泌指标。高剂量患者组中CI - 988血浆水平的峰值变化与mCPP诱导的焦虑之间的相关性不显著。总体而言，这些发现没有提供CI - 988对GAD患者有抗焦虑作用的证据。CI - 988对神经内分泌和生理指标缺乏影响进一步表明，CI - 988的药理作用可能独立于5 - HT功能。然而，需要使用更高剂量的CI - 988进行后续研究以证实这一初步发现，同时也需要更密切评估GAD中CCK与5 - HT功能之间相互关系的研究。
