Effects of the CCKB antagonist CI-988 on responses to mCPP in generalized anxiety disorder

In order to evaluate the effect of the CCK, antagonist CI-988 on behavioral , neuroendocrine, and physiologic responses to the mixed, post-synaptic ser otonin (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 an d the testing was conducted in double-blind fashion. In an initial dose-fin ding phase (N = 6) with a dose of CI-988 of 25 mg, there were no significan t 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 an other of patients (N = 10). CI-988 (100 mg) was well tolerated and had no s ignificant effects on pretest anticipatory anxiety. There was no significan t blunting of the anxiety response to mCPP as a result of CI-988 administra tion, nor did CI-988 affect physiologic or neuroendocrine measures. Correla tions between peak changes in plasma levels of CI-988 and mCPP-induced anxi ety in the high-dose patient group were not significant. Overall, these fin dings 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 in dependent of 5-HT function. However, follow-up studies using higher doses o f CI-988 are indicated to confirm this preliminary finding as are studies m ore closely evaluating the interrelationship between CCK and 5-HT function in GAD. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.