Cholecystokinin-Tetrapeptide Induces Panic Attacks in Patients with Panic Disorder* JACQUES BRADWEJN, M.D. I, DIANA KOSZYCKI, M.A. 2 AND GREG METERISSIAN, M.D. 3

Cholecystokinin-tetrapeptide (CCK-4) and placebo were injected to 11 panic disorder patients. CCK-4 induced a panic attack identical to spontaneous panic attacks in all patients; placebo did not induce any attacks. The role of CCK-4 in anxiety disorders is discussed.

attacks the week prior to the injections was 6.45 (± 0.93). All patients were drug free at the time of the injections Double-blind intravenous injections of CCK-4 and of placebo were carried out one to three days apart. CCK-4 (50 ug in 2.5 ml of NaCI 0.9%), consisted of an amino acid chain of TRP-MET-ASP-PHE-NH 2 . Placebo consisted of 2.5 ml of NaCL 0.9%. Each injection was administered in less than five seconds. Patients were evaluated using an inventory based on DSM-llI symptoms of a panic attack. Patients rated each symptom on a five point scale ranging from absent to extremely severe and compared their reaction to their spontaneous panic attacks.

C

holecystokinin (CCK) is a peptide found in high concentrations in the limbic system of the mammalian CNS (1). Studies suggest that CCK might act as a CNS neurotransmitter (2). It is synthesized and stored in nerve terminals and cell bodies (3); it is released by depolarization; it has specific binding sites (4); it can affect the firing rate of other CNS neurons (5); and its effects can be interfered with by analogues (6). CCK might be involved in anxiety. Benzodiazepine receptor agonists have been reported to antagonize CCKinduced activation of rat hippocampal pyramidal neurons, and to antagonize the effect of CCK in the periphery (7,8). Long term treatment with benzodiazepines reduce the effectiveness of CCK in the rat CNS (de Montigny - personal communication). Administration of CCK-tetrapeptide (CCK-4) to healthy volunteers has been reported to elicit fear and anxiety or tension (9, and Rehfeld - personal communication) . The present study examined the effect of CCK-4 in patients with panic disorder.

Results CCK-4 induced a reaction reported to be a panic attack by all II patients. The mean time of onset of the attacks following the injections was 20 ± 3 seconds (range: 10 to 50 seconds) and their mean duration was 20.7 ± 7.6 minutes (range: 6 to 93 minutes). The symptoms and intensity of symptoms induced by CCK-4 are listed in Table I. The mean number of symptoms per patient was 12.6 ± 0.6 (range: 10 to 16 symptoms). There was no significant difference in the mean number of symptoms reported by males and females (12 ± 0.9 and 13.4 ± 0.7 respectively). Compared to spontaneous panic attacks, the CCK-induced attacks started more abruptly, but were judged by patients to be identical in type, number, and sequence of appearance of symptoms. Four patients reported a new symptom (see Table I) which was of a brief duration and which was overshadowed by the global experience of the CCK-4-induced panic attack. Ten of II patients received placebo. One patient experienced a panic attack of such intensity with CCK-4 that the subsequent placebo injection was refused. None of the patients who received placebo reported a panic attack. Six patients reported isolated symptoms listed in Table I. The mean number of symptoms per patient was 1.8 ± 0.6 (range: o to 6 symptoms).

Method Eleven caucasian outpatients (six men; five women) fulfilling the DSM-III criteria for panic disorder gave voluntary written informed consent for their participation. Their age ranged from 20 to 51 years (33.45 ± 3.56 years; mean ± SEM). The duration of their illnesses ranged from 0.2 to 12 years (3.61 ± 1.07 years). The mean number of panic *Supported in part by the St. Mary's Hospital Psychopharmacology Fund and St. Mary's Hospital Foundation. Read in part at the Annual Meeting of the Canadian Psychiatric Association. Halifax. N.S., September 29 1988. Manuscript received December 1988; revised April 1989. I Assistant Professor of Psychiatry. McGill University; Director of Psychopharmacology. St. Mary's Hospital. Montreal. Quebec. 2Ph.D student in Psychology. Carleton University. Ottawa, Ontario. 3Staff Psychiatrist. St. Mary's Hospital. Montreal. Quebec. Address reprint requests to: Dr. J. Bradwejn, Department of Psychiatry. St. Mary's Hospital. 3830 Lacombe Ave .• Montreal. Quebec H3T I M5

Discussion These preliminary results suggest that CCK-4 might be panicogenic. It remains to be shown whether CCK-4-induced panic attacks via a direct CNS action. It is unknown whether CCK-4 crosses the blood-brain barrier. Larger forms ofCCK may cross the blood-brain barrier in amounts sufficient to

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Table I Symptoms Induced by CCK-4 and by Placebo Symptom Dyspnea Palpitation, rapid heart Sweating Faintness Dizziness, vertigo Apprehension Chest pain, discomfort Paresthesias Hot/cold flashes Fear of going crazy Fear of losing control Fear of dying Trembling, shaking Choking Nausea, abdominal distress Feeling detached, unreal Stiffness, cramps Headache Tinnitus Blurred vision* Warmth in chest* Warmth in throat* Bitter taste* Prickling in throat* Tickling in throat*

CCK-4 Mean ± SEM (n= II) 3.5 ± 0.2 2.1 ± 0.4 2.5 ± 0.3 1.2 ± 0.4 2.3 ± 0.3 2.3 ± 0.4 2.4 ± 0.3 2.3 ± 0.3 2.4 ± 0.3 1.4 ± 0.4 1.7 ± 0.4 0.3 ± 0.1 2.1 ± 0.4 0.7 ± 0.1 1.9 ± 0.4 0.9 ± 0.4 0.5 ± 0.3 0.4 ± 0.3 0.1 ± 0.1 0.3 ± 0.2 0.3 ± 0.3 0.1 ± 0.1 0.4 ± 0.3 0.2 ± 0.2 0.0 ± 0

(n) (11) (9) (10) (6)

(11) (9) (10) (10)

(10) (6)

(8) (3) (8) (3) (9) (4) (3) (2)

(1)

(2)

(1)

(1)

(1) (1) (1)

Placebo, Mean ± SEM (n= 10)

o± 0 o± 0

0.3 ± 0.1 o± 0 0.2 ± 0.1 o± 0 o± 0 0.3 ± 0.1 0.2 ± 0.1 o± 0 o± 0 o± 0 0.2 ± 0.2 o± 0 0.3 ± 0.1 o± 0 0.1 ;:l: 0.1 0.1 ± 0.1 o± 0 0.1 ± 0.1 o± 0 o± 0 0.1 ± 0.1 o± 0 0.1 ± 0.1

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Cholecystokinin-tetrapeptide induces panic attacks in patients with panic disorder.

Cholecystokinin-tetrapeptide (CCK-4) and placebo were injected to 11 panic disorder patients. CCK-4 induced a panic attack identical to spontaneous pa...
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