Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin.

Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

A randomized trial of sertraline, self-administered cognitive behavior therapy, and their combination for panic disorder.

BACKGROUND: Self-administered cognitive behavior therapy (SCBT) has been shown to be an effective alternative to therapist-delivered treatment for panic disorder (PD). However, it is unknown whether combining SCBT and antidepressants can improve treatment. This trial evaluated the efficacy of SCBT and sertraline, alone or in combination, in PD. METHOD: Patients (n=251) were randomized to 12 weeks of either placebo drug, placebo drug plus SCBT, sertraline, or sertraline plus SCBT. Those who improved after 12 weeks of acute treatment received treatment for an additional 12 weeks. Outcome measures included core PD symptoms (panic attacks, anticipatory anxiety, agoraphobic avoidance), dysfunctional cognitions (fear of bodily sensations, agoraphobic cognitions), disability, and clinical global impression of severity and improvement. Efficacy data were analyzed using general and generalized linear mixed models. RESULTS: Primary analyses of trends over time revealed that sertraline/SCBT produced a significantly greater rate of decline in fear of bodily sensations compared to sertraline, placebo/SCBT and placebo. Trends in other outcomes were not significantly different over time. Secondary analyses of mean scores at week 12 revealed that sertraline/SCBT fared better on several outcomes than placebo, with improvement being maintained at the end of continuation treatment. Outcome did not differ between placebo and either sertraline monotherapy or placebo/SCBT. Moreover, few differences emerged between the active interventions. CONCLUSIONS: This trial suggests that sertraline combined with SCBT may be an effective treatment for PD. The study could not confirm the efficacy of sertraline monotherapy or SCBT without concomitant medication or therapist assistance in the treatment of PD.

Behavioral, neurochemical, anatomical and electrophysiological correlates of panic disorder: multiple transmitter interaction and neuropeptide colocalization.

Neurochemical accounts of panic disorder focus on peripheral indices of central transmitter activity, hormonal correlates and therapeutic efficacy. Anxiogenic agents augment norepinephrine activity, some anxiolytics increase serotonin neurotransmission while benzodiazepines and antidepressants influence catecholamine, indoleamine and gamma-aminobutyric acid turnover in infrahuman subjects. Reliable correlates of central transmitter activity in panic disorder are not in evidence. While animal models of anxiety may not mirror the symptom profile of panic, neurobiological accounts of panic disorder fail to consider extensive central colocalization of neurotransmitter and putative neurotransmitters. In effect, transmitter release in major ascending and descending transmitter systems is modulated by variable neuropeptide interfacing. The behavioral concomitants of psychological disturbance likely follow from variable neurochemical release induced by stimuli as well as conditioning and sensitization. The functional role of receptor sites associated with multiple neurochemical systems may vary and the sensitivity and/or density of receptor sites may be modified. Accordingly, the behavioral and neurochemical concomitants of acute and chronic pathology may be fundamentally different from one another. The present review argues that the symptoms of panic disorder and the etiology of the illness must be evaluated against a background of genetic, organismic and experiential factors. Such variables presumably underlie the diverse behavioral symptoms associated with panic disorder and variations in the therapeutic efficacy of pharmacological treatment.

CCK in animal and human research on anxiety.

Much data has accumulated over the past decade supporting the hypothesis that CCK plays a role in the neurobiology of anxiety and panic attacks. These data originated from animal studies and human studies that were initiated independently, but the conclusions are remarkably consistent. In this review, Jacques Bradwejn and colleagues examine the evidence for a role of CCK in anxiety and panic attacks, and highlight the consistencies between animal and human studies.

Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings.

We studied the action of cholecystokinin tetrapeptide (CCK-4) in patients with panic disorder and normal controls. Subjects received, in random order, one injection of CCK-4 and one injection of placebo (saline) on two separate days in a double-blind crossover design. Two doses of CCK-4, 50 and 25 micrograms, were administered to two different samples of subjects. The panic rate with 50 micrograms of CCK-4 was 100% (12/12) for patients and 47% (7/15) for controls. The panic rate with 25 micrograms of CCK-4 was 91% (10/11) for patients and 17% (2/12) for controls. Nine percent of patients compared with 0% of controls panicked with placebo. These findings concur with previous reports of a panicogenic effect of CCK-4 and suggest that patients with panic disorder are more sensitive to the panicogenic effect of the peptide than are normal controls.

The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with panic disorder.

BACKGROUND: 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. DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

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) antagonists 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 micrograms) or placebo on two separate occasions, in a balanced incomplete block design. Patients received in random order 10 micrograms (n = 12), 15 micrograms (n = 11), 20 micrograms (n = 12), or 25 micrograms (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 micrograms), 64% (15 micrograms), 75% (20 micrograms), and 75% (25 micrograms). 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 micrograms of CCK-4 (ED75) might be suitable for efficacy studies of CCKB antagonists and other potential antipanic drugs in patients with panic disorder.

Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers.

A randomized, placebo-controlled, double-blind, three-way crossover design was used to evaluate the effectiveness of single oral 100 mg doses of CI-988, a cholecystokinin B (CCKB) antagonist, in attenuating panic symptoms induced by intravenous injection of cholecystokinin-tetrapeptide (CCK-4). Thirty healthy men received the following treatments on three separate occasions: placebo capsules/placebo, placebo capsules/CCK-4, or CI-988 capsules/CCK-4. There was no marked difference in the number, time to onset, or duration of panic symptoms between CI-988/CCK-4 and placebo/CCK-4. There was, however, a 14% difference in sum intensity scores between these treatments that was statistically significant (p = 0.039). The symptoms most affected by CI-988 were cold chills/hot flushes, chest pain/discomfort, and anxiety/fear/apprehension. Panic attack frequency also decreased following CI-988 treatment (8/30 vs. 16/30; p = 0.035). This decrease, amid otherwise modest effects, could be explained by a preferential effect of CI-988 on the subjective experience of anxiety/fear/apprehension. Possible reasons for the relatively modest effects of CI-988 on CCK-4-induced panic symptoms are discussed.

Effect of acute tryptophan depletion on behavioral, cardiovascular, and hormonal sensitivity to cholecystokinin-tetrapeptide challenge in healthy volunteers.

Recent data suggest that serotonergic (5-HT) mechanisms may mediate the anxiogenic effects of cholecystokinin (CCK)-related peptides. Accordingly, we investigated the effect of lowering plasma tryptophan to the elicitation of behavioral, cardiovascular, and hormonal changes in healthy volunteers challenged with the tetrapeptide CCK agonist, CCK-4. Forty men without personal or family history of psychiatric disorders were randomly assigned to either a tryptophan-free amino acid mixture, which decreases central 5-HT concentrations, or a control mixture. Five hours after administration of the amino acid mixture, all subjects received a single intravenous injection of CCK-4. The main finding of the study was that acute depletion of tryptophan failed to modify the panicogenic and cardiovascular effects of CCK-4, although it did enhance CCK-4-mediated increases in ACTH/cortisol and prolactin secretion. While these findings suggest that at least part of the neuroendocrine action of CCK-4 is mediated through the 5-HT system, the locus of the 5-HT-CCK interaction and the specific 5-HT receptor subtype involved remains to be determined.

Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time points.

BACKGROUND: Several functional imaging studies have demonstrated increases of brain activity in the temporofrontal, cingulate, and claustrum regions during a pharmacologically induced panic attack when scanning was done at a single point in time. However, no study has evaluated changes in brain activity at two time points during a panic attack. We hypothesized that in response to a single bolus injection of the panicogen cholecystokinin-4 (CCK-4) in healthy volunteers, changes in regional cerebral blood flow (rCBF) might be different if scanning were done at two different time points. METHODS: To test this hypothesis, we conducted a single-blind study, using positron emission tomography (PET). To determine the time effect of panic attack on brain activity, we performed either early scan or late scan covering the first or the second minute after CCK-4 bolus injection, respectively. The PET images were analyzed by statistical parametric mapping (SPM) followed by region of interest (ROI) analysis. RESULTS: The results showed significant differences between the early and the late scan. The early effects of CCK-4 are accompanied by increases in rCBF in the hypothalamic region, whereas the late scan showed an increase in rCBF in the claustrum-insular region. Reductions in rCBF were observed for both time groups in the medial frontal region. A separate scan for anticipatory anxiety demonstrated rCBF increases in the anterior cingulate region and decreases in the occipital regions. CONCLUSIONS: These results may support the hypothesis that changes in rCBF as a function of time during CCK-4-induced panic might correspond to a neurocircuitry involved in panic attacks.

The role of the beta-noradrenergic system in cholecystokinin-tetrapeptide-induced panic symptoms.

BACKGROUND: The authors determined whether effective beta-adrenergic blockade could attenuate the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. METHODS: Subjects were randomly assigned to either a propranolol (n = 14) or placebo (n = 16) infusion. Ten minutes after completion of the infusion subjects received a bolus injection of CCK-4 (50 micrograms). RESULTS: Acute pretreatment with propranolol was more effective than placebo in decreasing behavioral and cardiovascular sensitivity. CONCLUSIONS: These preliminary results suggest that the panicogenic effects of CCK-4 are mediated, in part, through the beta-adrenergic system.

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.

Imipramine antagonism of the panicogenic effects of cholecystokinin tetrapeptide in panic disorder patients.

Eleven panic disorder patients who panicked in response to exogenous cholecystokinin tetrapeptide (CCK-4) were rechallenged after chronic treatment with imipramine. In the rechallenge the patients displayed a marked reduction in the number and intensity of panic symptoms, duration of symptoms, frequency of panic attacks, and cardiovascular responsiveness. This study demonstrates that imipramine can antagonize the panicogenic effects of CCK-4.

Anxiety sensitivity and response to cholecystokinin tetrapeptide in healthy volunteers.

The authors determined whether fear of anxiety symptoms mediates panicogenic responses to cholecystokinin tetrapeptide (CCK-4) in healthy subjects. Individuals with a preexisting high level of anxiety sensitivity (N = 10) experienced significantly more catastrophic cognitions and fear of somatic symptoms than did subjects with low (N = 9) or medium (N = 17) anxiety sensitivity, but they were not more susceptible to experiencing a panic attack. Thus, cognitive factors do not appear to be critical determinants of CCK-4-induced panic attacks.

Replication of action of cholecystokinin tetrapeptide in panic disorder: clinical and behavioral findings.

Eleven patients with panic disorder were challenged with cholecystokinin tetrapeptide (CCK-4) on two occasions. The effects of CCK-4 were consistent except symptom onset was more rapid with the second injection. Demonstrating that the effects of CCK-4 are reproducible in panic patients opens the doors for studies of the effects of drug treatment on CCK-4-induced panic.

Vitamin E in the treatment of tardive dyskinesia: a double-blind placebo-controlled study.

The authors compared vitamin E with placebo in a double-blind randomized crossover study of 27 patients with tardive dyskinesia. Each treatment period lasted for 6 weeks. Vitamin E showed no differences from placebo in the treatment of tardive dyskinesia.

Functional neuroanatomy of CCK4-induced anxiety in normal healthy volunteers.

OBJECTIVE: The authors tested the prediction of temporal cortex activation during experimentally induced anxiety by using positron emission tomography and the [15O]H2O bolus-subtraction method to determine regional cerebral blood flow (CBF) changes in normal volunteers challenged with a bolus injection of cholecystokinin tetrapeptide (CCK4). METHOD: Eight right-handed healthy subjects (five male, three female; mean age, 26.4 years) underwent four 60-second [15O]H2O scans separated by 15-minute intervals; each scan followed an intravenous bolus injection of either saline (placebo) or CCK4 (50 micrograms). Each subject received CCK4 once, as the first or second bolus, in a random-order, placebo-controlled, double-blind fashion. Two of the three placebo conditions were nominally identical, and the remaining placebo was used to control for anticipatory anxiety. Magnetic resonance imaging scans were obtained for subsequent anatomical correlation of blood flow changes. RESULTS: CCK4, but not placebo, elicited a marked anxiogenic response, reflected by robust increases in subjective anxiety ratings and heart rate. CCK4-induced anxiety was associated with 1) robust and bilateral increases in extracerebral blood flow in the vicinity of the superficial temporal artery territory and 2) CBF increases in the anterior cingulate gyrus, the claustrum-insular-amygdala region, and the cerebellar vermis. CONCLUSIONS: Some of the temporopolar cortex CBF activation peaks previously reported in humans in association with drug- and non-drug-induced anxiety, as well as the increase in regional CBF in the claustrum-insular-amygdala region, may be of vascular and/or muscular origin.

Effects of cholecystokinin tetrapeptide on respiratory function in healthy volunteers.

OBJECTIVE: The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. METHOD: Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions. RESULTS: 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. CONCLUSIONS: These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

Effect of aging on cholecystokinin-induced panic.

OBJECTIVE: Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). METHOD: The study used a double-blind, placebo-controlled design: 40 subjects 20-35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 micrograms of CCK-4 or normal saline. RESULTS: When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects. CONCLUSIONS: This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted.

Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder.

OBJECTIVE: The anxiogenic and panicogenic effects of peripheral administration of the cholecystokinin-B receptor agonist pentagastrin and placebo were evaluated in patients with generalized anxiety disorder and normal comparison subjects. METHODS: Seven patients with generalized anxiety disorder and seven age- and sex-matched normal subjects received an intravenous bolus of placebo and pentagastrin. RESULTS: Panic attacks occurred in five patients with generalized anxiety disorder (71%) and in one normal subject (14%). Patients with generalized anxiety disorder were more likely to report more nonpanic anxiety than were normal subjects. CONCLUSIONS: Patients with generalized anxiety disorder appear to exhibit greater subjective sensitivity to pentagastrin than do normal subjects.