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.
Goddard
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AW
Yale University Department of Psychiatry, Connecticut Mental Health Center, New Haven 06519, USA. andrew.goddard@yale.edu
Woods
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Money
R
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Pande
A C
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Charney
D S
DS
Goodman
W K
WK
Heninger
G R
GR
Price
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LH
D000328:Adult; D000339:Affect; D000704:Analysis of Variance; D014151:Anti-Anxiety Agents / Q000097:blood / Q000494:pharmacology*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000503:physiopathology; D001794:Blood Pressure; D005260:Female; D006339:Heart Rate; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007211:Indoles / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D011388:Prolactin / Q000097:blood; D011569:Psychiatric Status Rating Scales; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D007211:Indoles; D010879:Piperazines; D017366:Serotonin Receptor Agonists; D019382:Human Growth Hormone; C065599:PD 134308; D008536:Meglumine; D011388:Prolactin; C015068:1-(3-chlorophenyl)piperazine; D006854:Hydrocortisone