Effects of the CCK(B) antagonist CI-988 on responses to mCPP in generalized anxiety disorder

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.