l-365260 and Panic-Disorder

Topics: Adult; Agoraphobia; Arousal; Benzodiazepinones; Double-Blind Method; Female; Humans; Lactic Acid; Male; Middle Aged; Pain Measurement; Panic Disorder; Phenylurea Compounds; Receptor, Cholecystokinin B; Receptors, Cholecystokinin

The functional role of cholecystokinin in the central nervous system is unknown. The tetra peptide CCK-4 was previously observed to induce panic attacks in a majority of normal volunteers and patients with panic disorder. Furthermore, it had been demonstrated that pretreatment with 10-50 mg of L-365,260, a selective CCKB antagonist, blocked CCK-4 induced panic in patients with panic disorder. Therefore, the present multicenter, placebo-controlled, double-blind trial was designed to investigate the efficacy of L-365,260, a CCKB antagonist, in patients with panic disorder with or without agoraphobia. Following a 1-week, single-blind placebo period, 88 patients were randomized to double-blind treatment in which they received either L-365,260, 30 mg qid, or placebo for 6 weeks. At the dose tested, there were no clinically significant differences between L-365,260 and placebo in global improvement ratings, Hamilton anxiety rating scale scores, panic attack frequency, panic attack intensity, or disability measures. The possible reasons for lack of effect with L-365,260 are discussed.

Topics: Adult; Agoraphobia; Arousal; Benzodiazepinones; Double-Blind Method; Female; Humans; Male; Middle Aged; Panic Disorder; Personality Inventory; Phenylurea Compounds; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tetragastrin; Treatment Outcome

We investigated whether the selective brain cholecystokinin (CCKB) receptor antagonist, L-365,260, could antagonize the panicogenic effects of CCK-tetrapeptide (CCK-4) in patients with panic disorder.. The study employed a double-blind, placebo-controlled, two-period crossover design. Patients (N = 29) received a single oral dose of L-365,260 (10 or 50 mg) or placebo 90 minutes prior to injection of CCK-4. After a 1-week washout period, patients received a different dose of L-365,260 or placebo according to a balanced incomplete block design.. The 50-mg dose of L-365,260 was superior to placebo in reducing the number (P < .01) and sum intensity (P < .001) of symptoms induced with CCK-4. Panic attack frequency following CCK-4 injection was 88% for patients receiving placebo, 33% for those receiving the 10-mg dose, and 0% for those receiving the 50-mg dose. The difference between the effects of the 50-mg dose and placebo was statistically significant (P = .002). Increases in heart rate following CCK-4 injection were markedly reduced with both the 50-mg (P < .0001) and 10-mg (P < .01) doses compared with placebo.. These data suggest that CCKB receptors are an important site of action of exogenous CCK-4. It will be important to determine in future studies the efficacy of CCKB receptor antagonists as antipanic agents.

Topics: Administration, Oral; Adult; Benzodiazepinones; Dose-Response Relationship, Drug; Double-Blind Method; Drug Antagonism; Female; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Panic Disorder; Phenylurea Compounds; Placebos; Psychiatric Status Rating Scales; Receptors, Cholecystokinin; Severity of Illness Index; Tetragastrin