253
Psychiatry Research, 431253-262
Elsevier
Smoking in Patients With Panic Disorder Robert Pohl, Vikram K. Yeragani, Ren6e McBride Received
January
16. 1992; revised
Richard Balon, Helene Lycaki, and
version received
May 5, 1992; accepted
July 25, 1992.
Abstract. We compared smoking prevalence in 217 patients with panic disorder with that in 217 age- and sex-matched control subjects who were obtained by telephone survey from the same neighborhoods. Data were obtained for current smoking habits and smoking status at either the onset of illness (patients) or 10 years previously (control subjects). Patients had been ill for 10.6 (SD = 10.0) years. Female patients with panic disorder had a significantly higher smoking prevalence at the onset of their illness than did control subjects 10 years previously (54% vs. 35%). The current smoking prevalence for female patients
was also significantly higher than that of control subjects (40% vs. 25%). Male smoking rates did not differ between patients and control subjects. Caffeine use did not appear to explain these findings. These data suggest a link between smoking behavior and panic disorder in women. Key Words. Anxiety,
caffeine, gender, nicotine.
The relationship between smoking and panic attacks is controversial. There are anecdotal reports that smoking relieves panic attacks (Brodsky, 1985) although self-reports by patients with panic disorder on the effect of smoking on panic vary (Yeragani et al., 1988), and it is possible that amelioration of panic-anxiety by smoking is an attenuation of smoking withdrawal symptoms (Dilsaver, 1987). The pharmacological effects of nicotine suggest that smoking exacerbates anxiety symptoms. Smoking increases pulse rate and blood pressure, and increases plasma norepinephrine and epinephrine (Cryer et al., 1976). Some evidence points to a link between smoking and anxiety disorders. Smokers as a group are more anxious than nonsmokers on the basis of a personality inventory (Williams et al., 1982). In a study of patients with anxiety-related problems, 55% smoked, while only 35% of a sex-matched nurse control group smoked (Tilley, 1987). Ninth graders with a history of panic attacks are more likely to have tried smoking, although the temporal relationship between smoking and the onset of panic attacks in this population is not known (Hayward et al., 1989).
An earlier version of this report was presented at the 145th Annual Meeting of the American Psychiatric Association, Washington, DC, May 2-7, 1992. Robert Pohl, M.D., is Professor; Vikram K. Yeragani, M.D., Richard Balon, M.D., and Helene Lycaki, Ph.D., are Associate Professors; and RenCe McBride, B.S., is Research Assistant, Department of Psychiatry, Wayne State University School of Medicine, Detroit, Ml. All authors are at the Lafayette Clinic, Detroit, MI. (Reprint requests to Dr. R. Pohl, Lafayette Clinic, 951 East Lafayette, Detroit. Ml 48207, USA.) 0165-1781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd
254
More recent studies also support a relationship between smoking and anxiety disorders. Glassman et al. (1990) in a study of 3,213 randomly interviewed subjects in the St. Louis Epidemiologic Catchment Area Survey, found that the odds ratio for ever smoking in patients with panic disorder was 2.13. This ratio was not statistically significant (95% confidence interval: 0.81-5.65) but it suggests a potential link between panic disorder and smoking given that the prevalence of panic disorder in the St. Louis Survey was only 0.9%, or about 30 subjects (Myers et al., 1984). Breslau et al. (1991) found in a random sample of 1,007 young adults in the Detroit area that nicotine dependence was associated with anxiety disorders. The strength of this relationship varied by the level of nicotine dependence-the greater the nicotine dependence, the higher the association of smoking with anxiety disorders. The odds ratio of panic disorder in moderately dependent subjects was 2.86 (95% confidence interval: 1.04-7.90), and the likelihood for any anxiety disorder in moderate nicotine dependence was more than four times higher than in persons with no nicotine dependence. Neither of these studies addressed whether smoking was present at the onset of illness. In this study, the smoking status of 217 patients with panic disorder was determined and compared with that of 217 age- and sex-matched control subjects from the same neighborhoods. Because caffeine can provoke panic (Uhde, 1990) and might act as a confounding variable, caffeine consumption data were collected from 95 of the panic disorder subjects and also compared with data from 95 matching control subjects. Data were obtained for both current habits and for smoking and caffeine use at the onset of panic attacks or, in the case of control subjects, habits 10 years previous to the interview. Our hypothesis was that smoking is a risk factor for the development of panic disorder. If true, we would expect to find an increased prevalence of smoking before the onset of panic disorder as well as an increased prevalence of current smoking in patients.
Methods Subjects. Data for current smoking behavior and smoking at the time of onset of illness were collected during 1988 through 1990 from consecutive patients at two sites in metropolitan Detroit: an urban research clinic with free treatment and a suburban fee-for-service private practice office. Clinic patients were often self-referred in response to advertisements for while office patients were often referred from other health care research subjects, professionals. Most patients (76%) were obtained from the office site. The mean duration of illness in patients with panic disorder was 10.6 (SD = 10.0) years, with a mean onset of illness at 26.8 (SD = 11.9) years. All patients were seen by experienced research psychiatrists who worked primarily with anxiety disorder patients. Interviews were unstructured but documented panic attack symptoms that met DSM-III criteria for panic disorder or agoraphobia with panic attacks (American Psychiatric Association, 1980). Patients with concomitant diagnoses of affective or eating disorders were excluded. All eligible patients agreed to participate. At the office site, consecutive patients were prospectively asked about their smoking habits, both at present and at the onset of illness, by the treating physician. At the clinic site, data about smoking were obtained from structured interviews with research assistants. Smoking was defined as the regular daily use of cigarettes. Midway through the study, it became apparent that patients had a higher rate of smoking than did the general population, and the study design was strengthened by adding caffeine
255 data and a control group. No change was made in the patient data collection procedures other than asking questions about caffeine consumption. Caffeine consumption was estimated in cups per day, but information on the number of cigarettes smoked each day was not obtained. Caffeine consumption of beverages other than regular coffee was estimated by counting 0.3 cups per cup of tea, 0.4 cups per 335-ml container of cola, 0.2 per cup of cocoa, and 0.2 per chocolate bar. These estimates are modeled after the caffeine data provided by Gilbert (1976). No attempt was made to differentiate between brewed, percolated, or instant coffee, as the source of caffeine intake might vary from day to day. Control subjects were obtained in 1990 by a telephone survey to matching phone exchanges (the first three digits of a phone number) using random dialing. The survey was conducted with a structured interview that asked about current smoking, smoking IO years before the interview, past psychiatric treatment, psychiatric hospitalization, depression that required treatment, any past history of anxiety attacks. and caffeine use. Caffeine consumption was measured because it may be associated with smoking. Both current and past caffeine use from all sources was estimated in numbers of cups per day of regular coffee. If the phone number was not a residence, another number from a random numbers table was dialed using the same exchange. If there was no answer, the number was dialed twice more at different times of day during the week, and then finally dialed in the evening or on the weekend. If there was no response, or the resident refused the interview, another randomly chosen number was dialed from the same phone exchange. Interviewees who had an age group or sex match to a panic disorder patient were then included in the study. Control subjects with any history of psychiatric treatment or hospitalization, a history of depression that required treatment, or a history of anxiety attacks were excluded. More than 95% of the original patient group was matched with a control. Final elimination of unmatched patients (IO males) resulted in 217 subjects in each group. Seventy percent of the subjects (151 in each group) were women. Statistics.
Current smoking status and caffeine consumption data are compared between patients with panic disorder and control subjects both as a group and for men and women separately, since the frequency of smoking in the population varies by gender. Smoking and caffeine habits for control subjects IO years before the interview are compared with the smoking and caffeine habits in patients at the onset of illness, as onset of illness was a mean IO.6 years before the interview. Frequency data are compared by means of contingency tables, and reported as a x2 value with the exact probability. The amount of caffeine consumed is compared in the two groups with a two-tailed t test.
Results Subjects resided in 140 different phone exchange areas in the Detroit metropolitan area, an area with over 330 phone exchanges. Ninety-one percent of the subjects were white, 870 black, and < 1% Asian. There was a significant difference in racial distribution between control subjects and patients (x2 = 6.95, p = 0.03), but the absolute numbers were small (i.e., 12 black patients vs. 23 black control subjects) and the correlation between race and onset or current smoking status was negligible (r = 0.05 and r = 0.02, respectively). The mean ages of patients and control subjects were almost identical (patients: mean = 37.4 years, SD = 11.9; control subjects: mean = 38.1 years, SD = 12.2) and remained almost identical after the subjects were grouped by gender. Smoking. The 51.6% rate of smoking in the 217 patients with panic disorder at the onset of their illness was significantly higher than the 38.3% rate in the 217 control subjects one decade ago (Fig. 1, x2 = 7.83, p = 0.005). There was also a trend for
256 Fig. 1. Prevalence of smoking in 217 patients matched group of control subjects
with panic disorder
and a
100 -
s p 2
90
-
H PATIENTS W CONTROLS
60-
7060-
p-0 005
p-0 07
ONSET ALL
CURRENT
SUWECTS (n = 434)
The smoking prevalence at the onset of illness III patients is compared with the smoking rates in control subjects 10 years before the interview.
panic disorder subjects as a group to have a higher rate of current smoking &? = 3.39, p = 0.07). Men and women had similar durations of illness (men: mean = 11.8 years, SD = 9.5; women: mean = IO. 1 years. SD = 10.2; t = I. 18, c/f= 215, p = 0.24). and were examined separately. Among women, patients had higher smoking rates than control subjects. The difference is significant for both smoking at the onset of illness (Fig. 2, 53.69(, vs. 35.1%, ~2 = 10.52, p = 0.001) and for current smoking (39.7% vs. 24.5%;, x2 = 8.03, p = 0.005). On the other hand. smoking rates in male patients and Fig. 2. Prevalence of smoking in 151 female patients with panic disorder and a matched group of control subjects 100 90 g
60-
p
70-
2
g
6050
2
40
W PATIENTS W CONTROLS p-o 001 (53 61
p-o 005
0 H 3o cn 20 10 0 ONSET
CURRENT
FEMALE SUBJECTS (n= 302) The smoking prevalence at the onset of illness in patients IS compared with the smokmg rates m control subjects 10 years before the intervtew.
257 control subjects were similar. There is almost an identical rate for smoking at the onset of illness compared with 10 years previously (Fig. 3, 47.0% vs. 45.5%, x2 = 0.03, p = 0.86), and fewer male patients smoked at present than did control subjects, although this difference was nonsignificant (30.3% vs. 37.9%, x2 = 0.84, p = 0.36). The prevalence of smoking in patients with panic disorder did not vary by site. At the clinic site, 42.3% of patients were current smokers, compared with 35.1% at the office site h* = 0.87, p = 0.35). Smoking prevalence at the onset of illness was almost identical at the clinic (50%) and office (52.1%) sites b2 = 0.07, p = 0.79). While the high prevalence of smoking in patients with panic disorder at the onset of illness suggests that smoking antedates the illness, the possibility remains that some symptoms of anxiety, perhaps in a mild or prodromal form, led to smoking. However, it appeared unlikely that prodromal symptoms led to smoking because of a large time difference between the age by which most smokers develop the habit and the age of onset for panic disorder in smokers. Most smokers develop the habit by the age of 20 years (Smoking and Health, 1987). Patients who smoked at the onset of their illness had a mean age of onset of illness of 29.7 (SD = 10.1) years, significantly higher than the mean age of onset of 23.7 (SD = 12.9) years for those who did not smoke (t = 3.84, df= 215, p = 0.0002). In addition, if symptoms of panic lead patients to smoke, one would expect that patients who were too young to smoke when they became ill would become smokers as adults. Twenty-nine of the patients (62% were women) had an onset of illness at or before the age of 14 (mean = 10.8, SD = 2.6 years). The current age of this group (mean = 31.9, SD = 10.6 years) was well above the the usual age for regular smoking to begin. One of these 29 patients was an onset smoker, and 3 (10.3%) of the 29 were current smokers, a percentage significantly lower than the prevalence in other patients &2 = 8.84, p = 0.003) and a prevalence lower than that in control subjects, though not significantly so b2 = 3.48, p = 0.06).
Fig. 3. Prevalence of smoking in 66 male patients with panic disorder and a matched group of control subjects W W
PATIENTS CONTROLS
0
ONSET
CURRENT
MALE SUELECTS (n = 132) The smoking prevalence at the onset of illness in patients is compared with the smoking rates in control subjects 10 years before the interview.
258
Caffeine. During the second half of the study, caffeine data were systematically collected for 95 of the 2 17 patients. These patients were age and sex matched to 95 of the control subjects. The subgroup with caffeine data was similar to those patients without caffeine data in age (mean + SD = 38.3 f 12.2 vs. 36.6 I 11.7 years, respectively), gender (69% men vs. 70% women), and age of onset of illness (mean f SD = 26.2 AZ 11.6 vs. 27.1 f 12.2 years, respectively). There is a significant correlation between caffeine consumption and smoking status at the onset of the illness (r = 0.38, p = O.OOOl), but the slope of this relationship was small (0.05, 95% confidence intervals: 0.03-0.07), and the correlation would explain only 1470 of the variance. There was a negligible correlation between current caffeine consumption and current smoking status (r = 0.14). The caffeine consumption in patients did not significantly differ from that of control subjects (Fig. 4). Women patients tended to drink less than men did (mean f SD = 2.8 AZ3.3 cups vs. 4.1 f 6.0 cups, I = I .37, df= 93, p = 0.17)at the onset of their illness. Fig. 4. Caffeine consumption in 95 patients matched group of control subjects
with
panic
disorder
and a
0
ONSET
CURRENT
CAFFEINE SUBSAMPLE (n = 190) Caffeine consumption before the interwew.
at the onset of illness in patients is compared with the consumption
in control subjects 10 years
Discussion In this study, the smoking rates in women with panic disorder were significantly higher than the rates in age- and sex-matched control subjects from the same neighborhoods. The difference was especially striking when the number of women patients who smoked at the onset of their illness was compared with the smoking rates of women control subjects 10 years ago. Rates of smoking are known to vary depending on education (Pierce et al., 1989) race, and employment status (Brackbill et al., 1988). However, because of the geographical matching, the socioeconomic class of the control subjects is likely to be similar to that of the patients. In the general population, men smoke more than women (Hammond and
259 Garfinkel, 1961; Report of the Surgeon General, 1980) although these rates are converging (Fiore et al., 1989). Male control subjects smoked more than female control subjects in our sample, but smoking in male patients with panic disorder was not different from smoking prevalence in male control subjects. There is no ready explanation for this gender difference. Smoking in patients with panic disorder preceded the onset of the illness, rather than the reverse. Over one-half of the patients reported that they were smoking before the onset of illness. Consistent with this, the average age of onset of illness in this panic disorder population (29.7 f SD 10.1 years) was 10 years older than the age by which most smokers develop a smoking habit (Smoking and Health, 1987). There was no evidence within this data set that panic symptoms led to smoking behavior. Panic disorder symptoms can begin in childhood (Moreau et al., 1989) and patients in this study with an onset of attacks at or below the age of 14 have a low current smoking prevalence. The finding that patients with a very early onset of illness are likely to remain nonsmokers may explain why nonsmokers in this study had on average a significantly earlier onset of illness. Nonsmokers were also reported to have an earlier onset of illness in a study of the prevalence of smoking among patients with various anxiety disorders (Himle et al., 1988) although the difference failed to reach statistical significance (p = 0.59). Our data cannot address the’diagnostic specificity of the association between smoking and panic disorder because of the lack of psychiatric control groups. The prevalence of current smoking in a study of psychiatric outpatients was increased across all diagnostic groups (Hughes and Hatsukami, 1986) but was associated with a history of hospitalization for psychiatric symptoms. Only 38% of patients who had not been hospitalized were smokers. Our impression is that a history of psychiatric hospitalization is rare in our patient group. In another uncontrolled study of anxiety disorder patients with various diagnoses, the highest incidence of smoking occurred among patients with agoraphobia (57%) panic disorder (47%), and simple phobia (47%) and the lowest prevalence occurred in obsessive-compulsive disorder (9%) (Himle et al., 1988). It is unlikely that smoking in outpatients is associated with anxiety disorders only, as there is strong evidence from recent studies that smoking is also associated with depression (Glassman et al., 1990; Breslau et al., 1991). Caffeine use was a potentially confounding variable in this study. Although patients tended to have a higher caffeine intake at the onset of their illness compared with control subjects, this difference was not statistically significant and amounted to less than one cup of coffee daily. The difference is further minimized because patients were more likely than control subjects to smoke; smokers metabolize caffeine at a higher rate, and have a much greater clearance of caffeine, compared with nonsmokers (Parsons and Neims, 1978; Kotake et al., 1982; Brown et al., 1988). Moreover, female patients tended to drink less than males at the onset of their illness, the opposite of what one would expect if concomitant caffeine consumption explained the association between smoking and panic disorder in women. Since smoking behavior precedes the development of panic disorder and is associated with the disorder, are there biological mechanisms that may link smoking to panic disorder? Although the pathophysiology of panic is inadequately
260 understood, there is a body of evidence for noradrenergic dysregulation in panic disorder (Charney et al., 1990), and adrenergic drugs provoke panic attacks (Charney et al., 1984; Pyke and Greenberg, 1986; Pohl et al., 1988). A variety of other physiologically activating or stimulating drugs also provoke panic attacks (Cowley and Arana, 1990; Uhde, 1990). Smoking has marked adrenergic effects, and increases pulse rate, blood pressure, and blood lactate/pyruvate ratios. These increases are blocked by adrenergic blockade with intravenous phentolamine and propranolol, and precede smokinginduced increases in plasma norepinephrine and epinephrine, suggesting that they are the result of local release of norepinephrine in tissues (Cryer et al., 1976). Nicotine readily crosses the blood-brain barrier (Hansson and Schmiterliiw, 1962; Oldendorf, 1974), and activates a number of central nervous system pathways, leading to the release of norepinephrine, as well as acetylcholine, dopamine, and serotonin (Pomerleau and Pomerleau, 1984; Benowitz, 1988). Smoking stimulates the central nervous system (Domino, 1967, 1973), and increases cerebral oxygen consumption (Wennmalm, 1982). In a well-controlled metabolic study, smoking increased 24-hour energy expenditure by approximately IO%, increased average heart rate 20%, and increased the urinary excretion of norepinephrine by 45% (Hofstetter et al., 1986). Since women had smoking rates significantly higher than matched control subjects at the onset of their illness, it is possible that smoking may be a risk factor for the development of panic disorder in women. However, this finding needs to be replicated at other sites. In addition, while there are theoretical reasons to suspect that nicotine would have a deleterious effect on panic disorder, the lack of an association in male patients with panic disorder remains unexplained. It is possible that the relationship between smoking and panic disorder is not a causal one. In any event, the association between smoking and panic disorder points to a significant public health problem (Hayward et al., 1990), and suggests that psychiatrists should take a more active role in helping patients with smoking cessation. Acknowledgment. This research was supported Health, State of Michigan.
in part
by the Department
of Mental
References American Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Press, 1980. Benowitz, N.L. Pharmacologic aspects of cigarette smoking and nicotine addiction. NeM: England Journal of Medicine, 3 19: 13 I8- 1330, 1988. Brackbill, R.; Frazier, T.; and Shilling, S. Smoking characteristics of US workers, 19781980. American Journal of Industrial Medicine, I3:5-4 1, 1988. Breslau, N.; Kilbey, M.; and Andreski, P. Nicotine dependence, major depression, and anxiety in young adults. Archives of General Psychiatry, 48:1069-1074, 1991. Brodsky, L. Can nicotine control panic attacks? American Journal of Psychiatry, 142:524, 1985. Brown, C.R.; Jacob, P. III; Wilson, M.; and Benowitz, N.L. Changes in rate and pattern of caffeine metabolism after cigarette abstinence. Clinical Pharmacology and Therapeutics, 43:488-491. 1988.
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Charney, D.S.; Heninger, G.R.; and Breier, A. Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Archives of General Psychiatry, 41:75 l-763, 1984. Charney, D.S.; Woods, S. W.; Price, L.H.; Goodman, W.K.; Glazer, W.M.; and Heninger, G.R. Noradrenergic dystegulation in panic disorder. In: Ballenger, J.C., ed. Neurobiology of Panic Disorder. New York: Wiley-Liss, 1990. pp. 91-105. Cowley, D.S., and Arana, G.W. The diagnostic utility of lactate sensitivity in panic disorder. Archives of General Psychiatry, 47:277-284, 1990. and Cryer, P.E.; Haymond, M.W.; Santiago, J.V.; and Shah, S.D. Norepinephrine epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. New England Journal of Medicine, 2951573-577, 1976. Dilsaver, S.C. Nicotine and panic attacks. American Journalof Psychiatry, 14411245-1246, 1987. Domino, E.F. Electroencephalographic and behavioral arousal effects of small doses of nicotine: A neuropsychopharmacological study. Annals of the New York Academy of Sciences, 142:216-244, 1967. Domino, E.F. Neuropsychopharmacology of nicotine and tobacco smoking. In: Dunn, W.L., ed. Smoking Behavior: Motives and Incentives. Washington, DC: V.H. Winston, 1973. Fiore, M.C.; Novotny, T.E.; and Pierce, J.P. Trends in cigarette smoking in the United States: The changing influence of gender and race. Journal of the American Medical Association, 261149-55, 1989. Gilbert, R.M. Caffeine as a drug of abuse. In: Gibbins, R.J.;Israel, Y.; Kalant, H.; and Andal, E., eds. Research Advances in Alcoholand Drug Problems. New York: John Wiley & Sons Inc., 1976. pp. 49-102. Glassman, A.; Helzer, J.; Covey, L.; Cottler, L.; Stetner, F.; Tipp, J.; and Johnson, J. Smoking, smoking cessation, and major depression. Journal of the American Medical Association, 264: 1546-1549, 1990. Hammond, E.C., and Garfinkel, L. Smoking habits of men and women. Journal of the National Cancer Institute, 271419-442, 1961. Hansson, E., and Schmiterlow, C.G. Physiological disposition and fate of C14-labeled nicotine in mice and rats. Journal of Pharmacology and Experimental Therapeutics, 137:91102, 1962. Hayward, C.; Clark, D.B.; and Taylor, C.B. Panic disorder, anxiety, and cardiovascular risk. In: Ballenger, J.C., ed. Clinical Aspects of Panic Disorder. New York: John Wiley & Sons, Inc., 1990. pp. 99-l IO. Hayward, C.; Killen, J.D.; and Taylor, C.B. Panic attacks in young adolescents. American Journal of Psychiatry, 146:1061-1062, 1989. Himle, J.; Thyer, B.A.; and Fischer, D.J. Prevalence of smoking among anxious outpatients. Phobia Practice and Research Journal, 1:25-31, 1988. Hofstetter, A.; Schutz, Y.; Jequier, E.; and Wahren, J. Increased 24-hour energy expenditure in cigarette smokers. New England Journal of Medicine, 314:79-82: 1986. Hughes, J.R., and Hatsukami, K. Signs and symptoms of tabacco withdrawal. Archives of General Psychiatry, 43:289-294, 1986. Kotake, A.N.; Schoeller, D.A.; Lamber, G.H.; Baker, A.L.; Schaffer, D.D.; and Josephs, H. The caffeine CO2 breath test: Dose-response and amount of N-demethylation in smokers and nonsmokers. Clinical Pharmacology and Therapeutics, 32:261-269, 1982. Moreau, D.L.; Weissman, M.; and Warner, V. Panic disorder in children at high risk for depression. American Journal of Psychiatry, 146: 1059-1060, 1989. Myers, J.K.; Weissman, M.M.; Tischler, G.L.; Holzer, C.E.; Leaf, P.J.; Orvaschel, H.; Anthony, J.C.; Boyd, J.H.; Burke, J. D.; Kramer, M.; and Stoltzman, R. Six-month prevalence of psychiatric disorders in three communities: 1980 to 1982. Archives of Generul Psychiatry, 41:959-967, 1984. Oldendorf, W.H. Lipid solubility and drug penetrations in the blood-brain barrier. Proceedings of the Society for Experimental Biology and Medicine, I47:8 13-8 15, 1974.
262 Parsons, W.D., and Neims, A.H. Effect of smoking on caffeine clearance. Clinical Pharmacology and Therapeutics, 2440-45, 1978. Pierce, J.P.; Fiore, M.C.; Novotny, T.E.; Hatziandreu, E.J.; and Davis, R.M. Trends in cigarette smoking in the United States: Educational differences are increasing. Journal ofthe American Medical Association, 261:56-60, 1989. Pohl, R.; Yeragani, V.K.; Balon, R.; Rainey, J.M.; Lycaki, H.; Ortiz, A.; Berchou, R.; and Weinberg, P. Isoproterenol-induced panic attacks. Biological Psychiatry, 24:891-902, 1988. Pomerleau, O.F., and Pomerleau, C.S. Neuroregulators and the reinforcement of smoking: Towards a behavioral explanation. Neuroscience and Biobehavioral Reviews, 8:503-5 13, 1984. Pyke, R.E., and Greenberg, H.S. Norepinephrine challenges in panic patients. Journal of Clinical Psychopharmacology, 6:279-285, 1986. Report of the Surgeon General. The Health Consequences of Smoking for Women: A Report of the Surgeon General. Rockville, MD: Office on Smoking and Health, 1980. Smoking and Health: A national status report. Leads from the MMWR. Journal of the American Medical Association, 257~17-18, 1987. Tilley, S. Alcohol, other drugs and tobacco use and anxiolytic effectiveness: A comparison of anxious patients and psychiatric nurses. British Journal of Psychiatry, 15 1:389-392, 1987. Uhde, T.W. Caffeine provocation of panic: A focus on biological mechanisms. In: Ballenger, J.C., ed. Neurobiology of Panic Disorder. New York: Wiley-Liss, 1990. pp. 219-242. Wennmalm, A. Effect of cigarette smoking on basal and carbon dioxide stimulated cerebral blood flow in man. Clinical Physiology, 2:529-535, 1982. Williams, S.G.; Hudson, A.; and Redd, C. Cigarette smoking, manifest anxiety and somatic symptoms. Addictive Behaviors, 7:427-428, 1982. Yeragani, V.K.; Pohl, R.; Balon, R.; and Jankowski, W. Nicotine: Is it useful for panic attacks? Biological Psychiatry, 24:365-366, 1988.
Psychiatry Research, 431253-262
Elsevier
Smoking in Patients With Panic Disorder Robert Pohl, Vikram K. Yeragani, Ren6e McBride Received
January
16. 1992; revised
Richard Balon, Helene Lycaki, and
version received
May 5, 1992; accepted
July 25, 1992.
Abstract. We compared smoking prevalence in 217 patients with panic disorder with that in 217 age- and sex-matched control subjects who were obtained by telephone survey from the same neighborhoods. Data were obtained for current smoking habits and smoking status at either the onset of illness (patients) or 10 years previously (control subjects). Patients had been ill for 10.6 (SD = 10.0) years. Female patients with panic disorder had a significantly higher smoking prevalence at the onset of their illness than did control subjects 10 years previously (54% vs. 35%). The current smoking prevalence for female patients
was also significantly higher than that of control subjects (40% vs. 25%). Male smoking rates did not differ between patients and control subjects. Caffeine use did not appear to explain these findings. These data suggest a link between smoking behavior and panic disorder in women. Key Words. Anxiety,
caffeine, gender, nicotine.
The relationship between smoking and panic attacks is controversial. There are anecdotal reports that smoking relieves panic attacks (Brodsky, 1985) although self-reports by patients with panic disorder on the effect of smoking on panic vary (Yeragani et al., 1988), and it is possible that amelioration of panic-anxiety by smoking is an attenuation of smoking withdrawal symptoms (Dilsaver, 1987). The pharmacological effects of nicotine suggest that smoking exacerbates anxiety symptoms. Smoking increases pulse rate and blood pressure, and increases plasma norepinephrine and epinephrine (Cryer et al., 1976). Some evidence points to a link between smoking and anxiety disorders. Smokers as a group are more anxious than nonsmokers on the basis of a personality inventory (Williams et al., 1982). In a study of patients with anxiety-related problems, 55% smoked, while only 35% of a sex-matched nurse control group smoked (Tilley, 1987). Ninth graders with a history of panic attacks are more likely to have tried smoking, although the temporal relationship between smoking and the onset of panic attacks in this population is not known (Hayward et al., 1989).
An earlier version of this report was presented at the 145th Annual Meeting of the American Psychiatric Association, Washington, DC, May 2-7, 1992. Robert Pohl, M.D., is Professor; Vikram K. Yeragani, M.D., Richard Balon, M.D., and Helene Lycaki, Ph.D., are Associate Professors; and RenCe McBride, B.S., is Research Assistant, Department of Psychiatry, Wayne State University School of Medicine, Detroit, Ml. All authors are at the Lafayette Clinic, Detroit, MI. (Reprint requests to Dr. R. Pohl, Lafayette Clinic, 951 East Lafayette, Detroit. Ml 48207, USA.) 0165-1781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd
254
More recent studies also support a relationship between smoking and anxiety disorders. Glassman et al. (1990) in a study of 3,213 randomly interviewed subjects in the St. Louis Epidemiologic Catchment Area Survey, found that the odds ratio for ever smoking in patients with panic disorder was 2.13. This ratio was not statistically significant (95% confidence interval: 0.81-5.65) but it suggests a potential link between panic disorder and smoking given that the prevalence of panic disorder in the St. Louis Survey was only 0.9%, or about 30 subjects (Myers et al., 1984). Breslau et al. (1991) found in a random sample of 1,007 young adults in the Detroit area that nicotine dependence was associated with anxiety disorders. The strength of this relationship varied by the level of nicotine dependence-the greater the nicotine dependence, the higher the association of smoking with anxiety disorders. The odds ratio of panic disorder in moderately dependent subjects was 2.86 (95% confidence interval: 1.04-7.90), and the likelihood for any anxiety disorder in moderate nicotine dependence was more than four times higher than in persons with no nicotine dependence. Neither of these studies addressed whether smoking was present at the onset of illness. In this study, the smoking status of 217 patients with panic disorder was determined and compared with that of 217 age- and sex-matched control subjects from the same neighborhoods. Because caffeine can provoke panic (Uhde, 1990) and might act as a confounding variable, caffeine consumption data were collected from 95 of the panic disorder subjects and also compared with data from 95 matching control subjects. Data were obtained for both current habits and for smoking and caffeine use at the onset of panic attacks or, in the case of control subjects, habits 10 years previous to the interview. Our hypothesis was that smoking is a risk factor for the development of panic disorder. If true, we would expect to find an increased prevalence of smoking before the onset of panic disorder as well as an increased prevalence of current smoking in patients.
Methods Subjects. Data for current smoking behavior and smoking at the time of onset of illness were collected during 1988 through 1990 from consecutive patients at two sites in metropolitan Detroit: an urban research clinic with free treatment and a suburban fee-for-service private practice office. Clinic patients were often self-referred in response to advertisements for while office patients were often referred from other health care research subjects, professionals. Most patients (76%) were obtained from the office site. The mean duration of illness in patients with panic disorder was 10.6 (SD = 10.0) years, with a mean onset of illness at 26.8 (SD = 11.9) years. All patients were seen by experienced research psychiatrists who worked primarily with anxiety disorder patients. Interviews were unstructured but documented panic attack symptoms that met DSM-III criteria for panic disorder or agoraphobia with panic attacks (American Psychiatric Association, 1980). Patients with concomitant diagnoses of affective or eating disorders were excluded. All eligible patients agreed to participate. At the office site, consecutive patients were prospectively asked about their smoking habits, both at present and at the onset of illness, by the treating physician. At the clinic site, data about smoking were obtained from structured interviews with research assistants. Smoking was defined as the regular daily use of cigarettes. Midway through the study, it became apparent that patients had a higher rate of smoking than did the general population, and the study design was strengthened by adding caffeine
255 data and a control group. No change was made in the patient data collection procedures other than asking questions about caffeine consumption. Caffeine consumption was estimated in cups per day, but information on the number of cigarettes smoked each day was not obtained. Caffeine consumption of beverages other than regular coffee was estimated by counting 0.3 cups per cup of tea, 0.4 cups per 335-ml container of cola, 0.2 per cup of cocoa, and 0.2 per chocolate bar. These estimates are modeled after the caffeine data provided by Gilbert (1976). No attempt was made to differentiate between brewed, percolated, or instant coffee, as the source of caffeine intake might vary from day to day. Control subjects were obtained in 1990 by a telephone survey to matching phone exchanges (the first three digits of a phone number) using random dialing. The survey was conducted with a structured interview that asked about current smoking, smoking IO years before the interview, past psychiatric treatment, psychiatric hospitalization, depression that required treatment, any past history of anxiety attacks. and caffeine use. Caffeine consumption was measured because it may be associated with smoking. Both current and past caffeine use from all sources was estimated in numbers of cups per day of regular coffee. If the phone number was not a residence, another number from a random numbers table was dialed using the same exchange. If there was no answer, the number was dialed twice more at different times of day during the week, and then finally dialed in the evening or on the weekend. If there was no response, or the resident refused the interview, another randomly chosen number was dialed from the same phone exchange. Interviewees who had an age group or sex match to a panic disorder patient were then included in the study. Control subjects with any history of psychiatric treatment or hospitalization, a history of depression that required treatment, or a history of anxiety attacks were excluded. More than 95% of the original patient group was matched with a control. Final elimination of unmatched patients (IO males) resulted in 217 subjects in each group. Seventy percent of the subjects (151 in each group) were women. Statistics.
Current smoking status and caffeine consumption data are compared between patients with panic disorder and control subjects both as a group and for men and women separately, since the frequency of smoking in the population varies by gender. Smoking and caffeine habits for control subjects IO years before the interview are compared with the smoking and caffeine habits in patients at the onset of illness, as onset of illness was a mean IO.6 years before the interview. Frequency data are compared by means of contingency tables, and reported as a x2 value with the exact probability. The amount of caffeine consumed is compared in the two groups with a two-tailed t test.
Results Subjects resided in 140 different phone exchange areas in the Detroit metropolitan area, an area with over 330 phone exchanges. Ninety-one percent of the subjects were white, 870 black, and < 1% Asian. There was a significant difference in racial distribution between control subjects and patients (x2 = 6.95, p = 0.03), but the absolute numbers were small (i.e., 12 black patients vs. 23 black control subjects) and the correlation between race and onset or current smoking status was negligible (r = 0.05 and r = 0.02, respectively). The mean ages of patients and control subjects were almost identical (patients: mean = 37.4 years, SD = 11.9; control subjects: mean = 38.1 years, SD = 12.2) and remained almost identical after the subjects were grouped by gender. Smoking. The 51.6% rate of smoking in the 217 patients with panic disorder at the onset of their illness was significantly higher than the 38.3% rate in the 217 control subjects one decade ago (Fig. 1, x2 = 7.83, p = 0.005). There was also a trend for
256 Fig. 1. Prevalence of smoking in 217 patients matched group of control subjects
with panic disorder
and a
100 -
s p 2
90
-
H PATIENTS W CONTROLS
60-
7060-
p-0 005
p-0 07
ONSET ALL
CURRENT
SUWECTS (n = 434)
The smoking prevalence at the onset of illness III patients is compared with the smoking rates in control subjects 10 years before the interview.
panic disorder subjects as a group to have a higher rate of current smoking &? = 3.39, p = 0.07). Men and women had similar durations of illness (men: mean = 11.8 years, SD = 9.5; women: mean = IO. 1 years. SD = 10.2; t = I. 18, c/f= 215, p = 0.24). and were examined separately. Among women, patients had higher smoking rates than control subjects. The difference is significant for both smoking at the onset of illness (Fig. 2, 53.69(, vs. 35.1%, ~2 = 10.52, p = 0.001) and for current smoking (39.7% vs. 24.5%;, x2 = 8.03, p = 0.005). On the other hand. smoking rates in male patients and Fig. 2. Prevalence of smoking in 151 female patients with panic disorder and a matched group of control subjects 100 90 g
60-
p
70-
2
g
6050
2
40
W PATIENTS W CONTROLS p-o 001 (53 61
p-o 005
0 H 3o cn 20 10 0 ONSET
CURRENT
FEMALE SUBJECTS (n= 302) The smoking prevalence at the onset of illness in patients IS compared with the smokmg rates m control subjects 10 years before the intervtew.
257 control subjects were similar. There is almost an identical rate for smoking at the onset of illness compared with 10 years previously (Fig. 3, 47.0% vs. 45.5%, x2 = 0.03, p = 0.86), and fewer male patients smoked at present than did control subjects, although this difference was nonsignificant (30.3% vs. 37.9%, x2 = 0.84, p = 0.36). The prevalence of smoking in patients with panic disorder did not vary by site. At the clinic site, 42.3% of patients were current smokers, compared with 35.1% at the office site h* = 0.87, p = 0.35). Smoking prevalence at the onset of illness was almost identical at the clinic (50%) and office (52.1%) sites b2 = 0.07, p = 0.79). While the high prevalence of smoking in patients with panic disorder at the onset of illness suggests that smoking antedates the illness, the possibility remains that some symptoms of anxiety, perhaps in a mild or prodromal form, led to smoking. However, it appeared unlikely that prodromal symptoms led to smoking because of a large time difference between the age by which most smokers develop the habit and the age of onset for panic disorder in smokers. Most smokers develop the habit by the age of 20 years (Smoking and Health, 1987). Patients who smoked at the onset of their illness had a mean age of onset of illness of 29.7 (SD = 10.1) years, significantly higher than the mean age of onset of 23.7 (SD = 12.9) years for those who did not smoke (t = 3.84, df= 215, p = 0.0002). In addition, if symptoms of panic lead patients to smoke, one would expect that patients who were too young to smoke when they became ill would become smokers as adults. Twenty-nine of the patients (62% were women) had an onset of illness at or before the age of 14 (mean = 10.8, SD = 2.6 years). The current age of this group (mean = 31.9, SD = 10.6 years) was well above the the usual age for regular smoking to begin. One of these 29 patients was an onset smoker, and 3 (10.3%) of the 29 were current smokers, a percentage significantly lower than the prevalence in other patients &2 = 8.84, p = 0.003) and a prevalence lower than that in control subjects, though not significantly so b2 = 3.48, p = 0.06).
Fig. 3. Prevalence of smoking in 66 male patients with panic disorder and a matched group of control subjects W W
PATIENTS CONTROLS
0
ONSET
CURRENT
MALE SUELECTS (n = 132) The smoking prevalence at the onset of illness in patients is compared with the smoking rates in control subjects 10 years before the interview.
258
Caffeine. During the second half of the study, caffeine data were systematically collected for 95 of the 2 17 patients. These patients were age and sex matched to 95 of the control subjects. The subgroup with caffeine data was similar to those patients without caffeine data in age (mean + SD = 38.3 f 12.2 vs. 36.6 I 11.7 years, respectively), gender (69% men vs. 70% women), and age of onset of illness (mean f SD = 26.2 AZ 11.6 vs. 27.1 f 12.2 years, respectively). There is a significant correlation between caffeine consumption and smoking status at the onset of the illness (r = 0.38, p = O.OOOl), but the slope of this relationship was small (0.05, 95% confidence intervals: 0.03-0.07), and the correlation would explain only 1470 of the variance. There was a negligible correlation between current caffeine consumption and current smoking status (r = 0.14). The caffeine consumption in patients did not significantly differ from that of control subjects (Fig. 4). Women patients tended to drink less than men did (mean f SD = 2.8 AZ3.3 cups vs. 4.1 f 6.0 cups, I = I .37, df= 93, p = 0.17)at the onset of their illness. Fig. 4. Caffeine consumption in 95 patients matched group of control subjects
with
panic
disorder
and a
0
ONSET
CURRENT
CAFFEINE SUBSAMPLE (n = 190) Caffeine consumption before the interwew.
at the onset of illness in patients is compared with the consumption
in control subjects 10 years
Discussion In this study, the smoking rates in women with panic disorder were significantly higher than the rates in age- and sex-matched control subjects from the same neighborhoods. The difference was especially striking when the number of women patients who smoked at the onset of their illness was compared with the smoking rates of women control subjects 10 years ago. Rates of smoking are known to vary depending on education (Pierce et al., 1989) race, and employment status (Brackbill et al., 1988). However, because of the geographical matching, the socioeconomic class of the control subjects is likely to be similar to that of the patients. In the general population, men smoke more than women (Hammond and
259 Garfinkel, 1961; Report of the Surgeon General, 1980) although these rates are converging (Fiore et al., 1989). Male control subjects smoked more than female control subjects in our sample, but smoking in male patients with panic disorder was not different from smoking prevalence in male control subjects. There is no ready explanation for this gender difference. Smoking in patients with panic disorder preceded the onset of the illness, rather than the reverse. Over one-half of the patients reported that they were smoking before the onset of illness. Consistent with this, the average age of onset of illness in this panic disorder population (29.7 f SD 10.1 years) was 10 years older than the age by which most smokers develop a smoking habit (Smoking and Health, 1987). There was no evidence within this data set that panic symptoms led to smoking behavior. Panic disorder symptoms can begin in childhood (Moreau et al., 1989) and patients in this study with an onset of attacks at or below the age of 14 have a low current smoking prevalence. The finding that patients with a very early onset of illness are likely to remain nonsmokers may explain why nonsmokers in this study had on average a significantly earlier onset of illness. Nonsmokers were also reported to have an earlier onset of illness in a study of the prevalence of smoking among patients with various anxiety disorders (Himle et al., 1988) although the difference failed to reach statistical significance (p = 0.59). Our data cannot address the’diagnostic specificity of the association between smoking and panic disorder because of the lack of psychiatric control groups. The prevalence of current smoking in a study of psychiatric outpatients was increased across all diagnostic groups (Hughes and Hatsukami, 1986) but was associated with a history of hospitalization for psychiatric symptoms. Only 38% of patients who had not been hospitalized were smokers. Our impression is that a history of psychiatric hospitalization is rare in our patient group. In another uncontrolled study of anxiety disorder patients with various diagnoses, the highest incidence of smoking occurred among patients with agoraphobia (57%) panic disorder (47%), and simple phobia (47%) and the lowest prevalence occurred in obsessive-compulsive disorder (9%) (Himle et al., 1988). It is unlikely that smoking in outpatients is associated with anxiety disorders only, as there is strong evidence from recent studies that smoking is also associated with depression (Glassman et al., 1990; Breslau et al., 1991). Caffeine use was a potentially confounding variable in this study. Although patients tended to have a higher caffeine intake at the onset of their illness compared with control subjects, this difference was not statistically significant and amounted to less than one cup of coffee daily. The difference is further minimized because patients were more likely than control subjects to smoke; smokers metabolize caffeine at a higher rate, and have a much greater clearance of caffeine, compared with nonsmokers (Parsons and Neims, 1978; Kotake et al., 1982; Brown et al., 1988). Moreover, female patients tended to drink less than males at the onset of their illness, the opposite of what one would expect if concomitant caffeine consumption explained the association between smoking and panic disorder in women. Since smoking behavior precedes the development of panic disorder and is associated with the disorder, are there biological mechanisms that may link smoking to panic disorder? Although the pathophysiology of panic is inadequately
260 understood, there is a body of evidence for noradrenergic dysregulation in panic disorder (Charney et al., 1990), and adrenergic drugs provoke panic attacks (Charney et al., 1984; Pyke and Greenberg, 1986; Pohl et al., 1988). A variety of other physiologically activating or stimulating drugs also provoke panic attacks (Cowley and Arana, 1990; Uhde, 1990). Smoking has marked adrenergic effects, and increases pulse rate, blood pressure, and blood lactate/pyruvate ratios. These increases are blocked by adrenergic blockade with intravenous phentolamine and propranolol, and precede smokinginduced increases in plasma norepinephrine and epinephrine, suggesting that they are the result of local release of norepinephrine in tissues (Cryer et al., 1976). Nicotine readily crosses the blood-brain barrier (Hansson and Schmiterliiw, 1962; Oldendorf, 1974), and activates a number of central nervous system pathways, leading to the release of norepinephrine, as well as acetylcholine, dopamine, and serotonin (Pomerleau and Pomerleau, 1984; Benowitz, 1988). Smoking stimulates the central nervous system (Domino, 1967, 1973), and increases cerebral oxygen consumption (Wennmalm, 1982). In a well-controlled metabolic study, smoking increased 24-hour energy expenditure by approximately IO%, increased average heart rate 20%, and increased the urinary excretion of norepinephrine by 45% (Hofstetter et al., 1986). Since women had smoking rates significantly higher than matched control subjects at the onset of their illness, it is possible that smoking may be a risk factor for the development of panic disorder in women. However, this finding needs to be replicated at other sites. In addition, while there are theoretical reasons to suspect that nicotine would have a deleterious effect on panic disorder, the lack of an association in male patients with panic disorder remains unexplained. It is possible that the relationship between smoking and panic disorder is not a causal one. In any event, the association between smoking and panic disorder points to a significant public health problem (Hayward et al., 1990), and suggests that psychiatrists should take a more active role in helping patients with smoking cessation. Acknowledgment. This research was supported Health, State of Michigan.
in part
by the Department
of Mental
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