CCK-4 Challenge Research Articles

The influence of Type A behavior pattern on the response to the panicogenic agent CCK-4

Objectives: Review of the literature equivocally suggests that subjects with Type A behavioral pattern (TABP) compared to subjects with Type B behavioral pattern display an increased sympathetic activity, a condition associated with sudden cardiac death. The objective of this study was to determine whether healthy subjects classified as Type A or Type B differed in their reactivity to the β1 and β2 receptor agonist isoproterenol and to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4). By comparing reactivity to CCK-4 after pretreatment with placebo or propranolol, a β1 and β2 receptor antagonist, the role of the β adrenergic system in the hypothesized increased response of Type A subjects to CCK-4 was also assessed. Methods: The study used a randomized, double-blind, placebo-controlled design. Twenty-seven Type A or B subjects were included in the study. The reactivity to isoproterenol was assessed with the CD25 of isoproterenol (i.e., the intravenous dose of isoproterenol necessary to increase the heart rate of 25 bpm). The panic symptom response and the cardiovascular response to bolus injection of 50 μg of CCK-4 was assessed in subjects pretreated with either propranolol or placebo infusions prior to the CCK-4 challenge. An additional group of subjects was recruited and these subjects received a placebo infusion pretreatment before an injection of placebo. Results: The CD25 was significantly greater in Type A subjects than in Type B subjects. No difference was found among the groups on behavioral sensitivity to the CCK-4 challenge. However, CCK-4-induced maximum increase in heart rate was greater in Type A subjects. Conclusion: Our finding that Type A subjects exhibited greater CD25 of isoproterenol and greater increases in heart rate following CCK-4 administration compared to Type B subjects suggests that peripheral β-receptor sensitivity may be increased in individuals with TABP.

Effects of Cholecystokinin Tetrapeptide on Respiratory Function in Healthy Volunteers

The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions. Dyspnea was reported by all of the subjects who received CCK-4 but only one subject who received placebo. CCK-4 caused a significant increase in tidal volume and minute ventilation but had no effect on breathing frequency. Placebo had no effect on any of the respiratory measures. These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

Behavioral, cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: A comparison of panickers and nonpanickers

Healthy subjects who panic following systemic cholecystokinin-tetrapeptide (CCK-4) challenge typically exhibit a symptom profile reminiscent of that evident among panic patients. However, the biological concomitants of CCK-4-induced panic in healthy subjects remain obscure. Accordingly, we evaluated the behavioral, cardiovascular, and neuroendocrine effects of CCK-4 in panickers and nonpanickers. Predictably, subjects who panicked with CCK-4 experienced more intense symptoms of panic and greater increases in ratings of fearful and anxious mood than did subjects who did not panic. CCK-4-induced increases in diastolic blood pressure, adrenocorticotropic hormone, prolactin, and growth hormone secretion were also significantly enhanced in subjects who panicked. The results of this study demonstrate that the behavioral experience of CCK-4-induced panic in healthy individuals is accompanied by marked biological changes and provide confirmation that CCK-4 is a useful model of panic for research among nonclinical subjects.

Psychological predictors of CCK4-induced panic-like symptoms

The present study investigated whether psychosomatic reaction to panicogenic CCK4 administration can be predicted based on basal and pre-administration psychological traits and characteristics. Sixteen healthy volunteers participated in a double-blind, placebo-controlled cross-over experiment in which they were subjected to CCK4 and placebo challenge. One week prior to experimentation, they completed a battery of self-administered psychological inventories, including the trait form of State-Trait Anxiety Inventory (STAI-T), Chambless Anxious Cognitions Inventory (CACI), Beck Depression Inventory (BDI) and the Symptom Checklist 90 (SCL-90). The state form of STAI (STAI-S) was administered before and after the injections of CCK4 (25 μg i.v.) and placebo. Various elements of the panic-like experience (latency and duration of symptoms, number and intensity of symptoms, fear of symptoms, and post-administration state anxiety) were recorded after both injections. The results of multiple regression analyses suggest that basal STAI-S, STAI-T and BDI are very good predictors of the number and intensity of CCK4-induced symptoms, the fear reaction to panic symptoms and post-injection state-anxiety. The SCL-90 scores were retained as the best predictor of placebo-induced panic-like symptoms. We conclude that substantial portions of variability in CCK4 and placebo-induced panic-like reaction can be explained by basal psychological characteristics. © 1998 John Wiley & Sons, Ltd.

The effect of cholecystokinin tetrapeptide on respiratory resistance in healthy volunteers

The effects of cholecystokinin tetrapeptide (CCK-4) on respiratory resistance were studied in 14 healthy volunteers by the registration of slow vital capacity and flow volume loop during forced respiration test. The administration of CCK-4 (50 micrograms) was performed in a double-blind and placebo-controlled design. Injections of CCK-4 induced prominent and time-limited paniclike symptoms in all healthy volunteers. Four volunteers (29%) experienced a panic attack. Subjective dyspnea was experienced by the majority of subjects at the peak of CCK-4 effect and seemed related to a diminution in vital capacity parameters; however, the forced respiration test did not reveal bronchoconstriction after CCK-4 challenge. Administration of CCK-4 also induced a short-lasting increase in heart rate and skin blood flow. This study suggests that dyspnea induced by CCK-4 is not related to changes in respiratory resistance.

P-10-18 - CCK-4 in cerebrospinal fluid: A pilot study in healthy male volunteers

Despite continuing efforts to determine genetic vulnerability to panic disorder (PD), the studies of candidate genes in this disorder have produced inconsistent or negative, results. Laboratory panic induction may have a potential in testing genetic substrate of PD. In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. The study sample consisted of 110 healthy volunteers (47 males and 63 females, mean age 22.2 ± 5.2) who participated in CCK-4 challenge test. Nine gene-candidates, including 5-HTTLPR, MAO-A VNTR, TPH2 rs1386494, 5-HTR1A −1019C–G, 5-HTR2A 102T–C, CCKR1 246G–A, CCKR2 −215C–A, DRD1 −94G–A and COMT Val158Met, were selected for genotyping based on previous positive findings from genetic association studies in PD. After CCK-4 challenge, 39 (35.5%) subjects experienced a panic attack, while 71 subjects were defined as non-panickers. We detected significant differences for both genotypic and allelic frequencies of 1386494A/G polymorphism in TPH2 gene between panic and non-panic groups with the frequencies of G/G genotype and G allele significantly higher in panickers. None of the other candidate loci were significantly associated with CCK-4-induced panic attacks in healthy subjects. In line with our previous association study in patients with PD, we detected a possible association between TPH2 rs1386494 polymorphism and susceptibility to panic attacks. Other polymorphisms previously associated with PD were unrelated to CCK-4-induced panic attacks, probably due to the differences between complex nature of PD and laboratory panic model.

A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder

Recent animal studies have shown that pretreatment with centrally active cholecystokinin (CCK) anatagonists blocks the anxiogenic effects of CCK-tetrapeptide (CCK-4). In order to determine whether pretreatment with these antagonists can block the anxiogenic effects of CCK-4 in patients with panic disorder, a suitable challenge dose of CCK-4 must be selected. Thus, we conducted a dose range study in which patients with panic disorder ( n = 29) were challenged with CCK-4 (10, 15, 20, or 25 μg) or placebo on two separate occasions, in a balanced incomplete block design. Patients received in random order 10 μg ( n = 12), 15 μg ( n = 11), 20 μg ( n = 12), or 25 μg ( n = 12) of CCK-4 or placebo ( n = 11). CCK-4 induced anxiety and panic responses in a dose-dependent fashion. The incidence of panic attacks following the CCK-4 challenge was 17% (10 μg), 64% (15 μg), 75% (20 μg), and 75% (25 μg). None of the patients panicked with placebo. Moreover, a strong linear relationship between CCK-4 and increases in heart rate and diastolic blood pressure was found. The findings of this study suggest that a dose of 20 μg of CCK-4 (ED 75) might be suitable for efficacy studies of CCK B antagonists and other potential antipanic drugs in patients with panic disorder.