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Brief Report   |    
Effect of Aging on Cholecystokinin-Induced Panic
Alastair J. Flint, M.B., Ch.B., F.R.C.P.(C), F.R.A.N.Z.C.P.; Diana Koszycki, Ph.D.; Franco J. Vaccarino, Ph.D.; Alain Cadieux, Ph.D.; Jean-Philippe Boulenger, M.D.; Jacques Bradwejn, M.D., F.R.C.P.(C)
Am J Psychiatry 1998;155:283-285.
Abstract

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 µg 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. (Am J Psychiatry 1998; 155:283–285)

Abstract Teaser
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Panic disorder has a peak age at onset in young adulthood; there is a marked decline in its incidence and prevalence in later life (1). The lower frequency of panic in old age has been attributed to age-related changes in the structure and function of neurotransmitter systems associated with this disorder, including the noradrenergic and serotonergic systems (1, 2). Age-related alterations in the cholecystokinin system could also contribute to the decline in panic in the elderly (1). Although little is known about the effect of aging on brain cholecystokinin, animal studies have found that the number of cholecystokinin receptor binding sites decreases with age (3).

In the light of these data, we wished to determine whether the elderly are less vulnerable to the behavioral and cardiovascular effects of the panicogenic agent cholecystokinin tetrapeptide (CCK-4). The precise mechanism of action of CCK-4 is not known, but its panicogenic effects may be linked to the interaction of cholecystokinin with other brain neurotransmitter systems (4). In younger adults, the intravenous administration of 50 µg of CCK-4 reliably provokes panic attacks in 100% of patients with panic disorder and approximately 50% of normal control subjects (5). We hypothesized that healthy older subjects would be less responsive than healthy younger individuals to CCK-4.

The study group consisted of 20 men and 20 women aged 20–35 years (mean=26.4, SD=4.6) and 20 men and 20 women aged 65 years and older (mean=71.0, SD=4.4). All were physically healthy volunteers, and none had a personal history of psychiatric disorder or panic attacks or a family history of depression, panic disorder, or agoraphobia in any first-degree relative. Subjects were not taking medications that could affect response to CCK-4, and they were not taking illicit drugs. After a complete description of the study to the subjects, written informed consent was obtained.

The study used a double-blind, placebo-controlled design. Within each age group, equal numbers of men and women were randomly assigned to receive either 50 µg of CCK-4 or placebo (0.9% saline). The subject sat in a reclining chair, a venous catheter was inserted into an antecubital vein, and a physiological saline drip was initiated. A blood pressure cuff with a pulse monitor attached to an automatic sphygmomanometer was applied to the other arm. CCK-4 or placebo was then injected in a bolus push. Heart rate and blood pressure were recorded at –1 minute and at 30-second intervals until 240 seconds after the injection. Subjects were asked to describe any symptoms they experienced after the injection, and the onset and duration of these symptoms were recorded.

Once the effects of the injection had abated, subjects were asked to rate each symptom on a panic symptom scale (5) derived from DSM-III-R on which 0=not present and 4=extremely severe. Two separate scores were obtained: 1) the total number of symptoms (number of items scored 1 or higher) and 2) the sum intensity of symptoms. To meet criteria for a panic attack, subjects had to achieve a score of 2 or higher on the anxiety/fear/apprehension item and a score of 1 or higher on each of at least four other items.

Two-way analysis of variance was used to analyze continuous data, and chi-square analysis was used for categorical data. Statistical significance was set at p≤0.05 (two-tailed).

At initial evaluation, subjects completed the Anxiety Sensitivity Index (6). Younger and older groups, respectively, had mean scores of 10.9 (SD=6.3) and 8.4 (SD=4.6) (t=2.02, df=78, p<0.05) (reference mean for normal subjects=19.0, SD=9.1) (6). Because anxiety sensitivity could have influenced subjects' behavioral responses to CCK-4, Anxiety Sensitivity Index scores were entered as a covariate in the analyses of behavioral data.

The results of the challenge appear in T1. Apart from time of onset of symptoms (F=13.13, df=1,75, p=0.001), older and younger subjects did not differ significantly in their behavioral responses to placebo. However, there was a significant difference between these two groups in the number of symptoms (F=59.39, df=1,75, p<0.001), the sum intensity of symptoms (F=31.95, df=1,75, p<0.001), and the duration of symptoms (F=11.67, df=1,75, p=0.001) induced by CCK-4. CCK-4 induced a panic attack in six of the 20 older subjects and nine of the 20 younger subjects (χ2=0.43, df=1, p=0.51).

When given placebo, younger and older groups did not differ in the maximum increase in heart rate from baseline. However, in response to CCK-4, the older group had significantly less of an increase in heart rate than did the younger group (F=10.79, df=1,76, p<0.01). At baseline, the older group had significantly higher mean systolic and diastolic blood pressures than the younger group (T1). Therefore, in comparing these groups on the maximum change of blood pressure following the challenge, we analyzed relative (%) change rather than absolute change. The groups did not differ in their blood pressure responses to placebo or CCK-4.

This study found an age-related change in responsiveness to CCK-4. Several explanations for this finding should be considered. First, the effects of CCK-4 are dose-dependent (5). Even though both age groups were given the same dose of CCK-4, it is possible that older subjects had a lower concentration of this peptide at its site of action. This is unlikely, however, because cholecystokinin is probably inactivated by enzymatic degradation (7) and there is no evidence that proteolytic enzyme activity increases with age (8). Second, symptomatic differences between younger and older subjects may have been due to differences in interpretation. However, Koszycki et al. (9) found that cognitive factors were not an important determinant of panicogenic responses to CCK-4 in healthy volunteers. Also, in our study, there was no meaningful clinical difference in baseline anxiety sensitivity between younger and older subjects, and Anxiety Sensitivity Index scores were not a significant covariate in the analyses of behavioral response. Therefore, these data do not suggest that younger subjects were more predisposed to fear or amplify anxiety symptoms. Finally, an age-associated functional decline in brain cholecystokinin and/or neurotransmitter systems that interact with cholecystokinin may have contributed to our results. This merits further exploration.

 

Presented at the 149th annual meeting of the American Psychiatric Association, New York, May 4–9, 1996. Received Dec. 13, 1996; revision received June 10, 1997; accepted July 17, 1997. From the Departments of Psychiatry and Psychology, University of Toronto, and the Departments of Psychiatry and Pharmacology, University of Sherbrooke, Quebec. Address reprint requests to Dr. Flint, The Toronto Hospital (General Division), 8 Eaton North, Rm. 238, 200 Elizabeth St., Toronto, Ont. M5G 2C4, Canada; aflint@torhosp.toronto.on.ca (e-mail). Supported by grant 7176004 from The Queen Elizabeth Hospital Research Institute. The authors thank Wendy Hiscox and Mary Knickle for their assistance with this research.

Flint AJ, Cook JM, Rabins PV: Why is panic disorder less frequent in late-life? Am J Geriatr Psychiatry  1996; 4:96–109
 
Charney DS, Woods SW, Nagy LM, Southwick SM, Krystal JH, Heninger GR: Noradrenergic function in panic disorder. J Clin Psychiatry  1990; 51:12(suppl A):5–11
 
Harro J, Oreland L: Age-related differences of cholecystokinin receptor binding in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry  1992; 16:369–375
[PubMed]
[CrossRef]
 
Harro J, Vasar E, Bradwejn J: CCK in animal and human research on anxiety. Trends Pharmacol Sci  1993; 14:244–249
[PubMed]
[CrossRef]
 
Bradwejn J, Koszycki D, Shriqui C: Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Arch Gen Psychiatry  1991; 48:603–610
[PubMed]
 
Peterson RA, Reiss S: Anxiety Sensitivity Index Revised Test Manual. Worthington, Ohio, International Diagnostic Services, 1992
 
Rehfeld JF, Nielsen FC: Molecular forms and regional distribution of cholecystokinin in the central nervous system, in Cholecystokinin and Anxiety: From Neuron to Behaviour. Edited by Bradwejn J, Vasar E. Austin, Tex, RG Landes, 1995, pp 33–56
 
Selkoe D, Kosik K: Neurochemical changes with aging, in Clinical Neurology of Aging. Edited by Albert M. New York, Oxford University Press, 1984, pp 53–75
 
Koszycki D, Cox BJ, Bradwejn J: Anxiety sensitivity and response to cholecystokinin tetrapeptide in healthy volunteers. Am J Psychiatry 1993; 150:1881–  1883
 
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References

Flint AJ, Cook JM, Rabins PV: Why is panic disorder less frequent in late-life? Am J Geriatr Psychiatry  1996; 4:96–109
 
Charney DS, Woods SW, Nagy LM, Southwick SM, Krystal JH, Heninger GR: Noradrenergic function in panic disorder. J Clin Psychiatry  1990; 51:12(suppl A):5–11
 
Harro J, Oreland L: Age-related differences of cholecystokinin receptor binding in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry  1992; 16:369–375
[PubMed]
[CrossRef]
 
Harro J, Vasar E, Bradwejn J: CCK in animal and human research on anxiety. Trends Pharmacol Sci  1993; 14:244–249
[PubMed]
[CrossRef]
 
Bradwejn J, Koszycki D, Shriqui C: Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Arch Gen Psychiatry  1991; 48:603–610
[PubMed]
 
Peterson RA, Reiss S: Anxiety Sensitivity Index Revised Test Manual. Worthington, Ohio, International Diagnostic Services, 1992
 
Rehfeld JF, Nielsen FC: Molecular forms and regional distribution of cholecystokinin in the central nervous system, in Cholecystokinin and Anxiety: From Neuron to Behaviour. Edited by Bradwejn J, Vasar E. Austin, Tex, RG Landes, 1995, pp 33–56
 
Selkoe D, Kosik K: Neurochemical changes with aging, in Clinical Neurology of Aging. Edited by Albert M. New York, Oxford University Press, 1984, pp 53–75
 
Koszycki D, Cox BJ, Bradwejn J: Anxiety sensitivity and response to cholecystokinin tetrapeptide in healthy volunteers. Am J Psychiatry 1993; 150:1881–  1883
 
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