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Exercise Tolerance in Panic Disorder Patients Jonathan M. Stein, Laszlo A. Papp, Donald F. Klein, Susannah Cohen, Joshua Simon, Donald Ross, Jose Martinez, and Jack M. Gorman
Sixteen panic patients and fifteen normal controls performed submaximal exercise testing on a bicycle ergometer. Only one patient subject panicked. Biochemical, physiological, and psychological data showed similar exercise tolerance in both patients and controls. Exercise.induced distress and lactate increment do not appear to cause panic attacks.
Introduction In 1950 Cohen and White found that "neurocirculatory asthenia" patients--an earlier diagnostic category that resembles panic disorder--did not last as long, developed a lower absolute maximum lactate level, and had higher pulse rates during moderate exercise than normals. However, the patients had significantly higher values than controls of "lactate per cubic centimeter of blood per second of running time." This suggested a restricted ability for aerobic metabolism in the patients (Homgren and S|rom 1959). However, no patient experienced significant anxiety or panic during exercise. A possible association between elevated lactate levels and anxiety prompted Pitts and McClure (1967) to test whether sodium lactate infusion would provoke panic attacks in panic disorder patients. Sodium lactate infusion has become an important tool in the investigation of panic disorder although how it induces panic is still unclear. Because no study has systemically evaluated the level of anxiety, meo,alred lactate levels, and assessed the occurrence of panic during exercise in currently defined panic patients we conducted exercise tolerance tests in panic patients and normal controls. We posed the following questions: (1) Is non-specific physiological distress, such as provoked by standard exercise, sufficient to induce significant anxiety or panic in panic disorder patients? (2) Do patients with panic disorder have reduced exercise tolerance? (3) Do patients and controls differ in the rate of biological changes, such as the rate of endogenous lactate increment, during exercise?
From the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, the Biological Studies Unit, New York State Psychiatric Institute, and Hillside Hospital, New York. Address reprint requests to Dr. Laszlo A. Papp, 722 W. 168 Street, New York, N.Y. 10032. $upporled in part by MHg03.COO3I, MH33422-08, MH37592-04, Scientist Development Award for Clinicians MH.00858 (LAP), Research Scientist Development Award MH00416 OMG) from the National Institute of Mental Health, and by Biomedical Research Support Grant 903E-704R. Received June 24, 1991; revised April 11, 1992.
© 1992 Society of Biological Psychiatry
0006.3223/92/$05.00
282
BlOt.PSYCHIATRY
J.M.
Stein et al
1992;32:281-287
Methods Nine male and seven female patients meeting DSM-III-R criteria for panic disorder (n = 9) or agoraphobia with panic attacks (n = 7) (without any other Axis I pathology) and six aaale and nine female controls free of any Axis I psychiatric disorder were recruited via professional referral or advertisement. The diagnoses were established with semistructured interviews conducted by experienced research psychiatrists. Subjects were tested in the Biological Studies Unit of the New York State Psychiatric Institute after a 12-hr period of abstinence from food, alcohol, caffeine, and cigarettes. They had been free of psychotropic medications for at least 2 weeks. After signing an informed consent, each subject performed a modified version of the Astrand-Rhyming submaximal bicycle ergometer test (Astrand and Rodahl 1977). The subject began the exercise with a moderately hard, constant workload as opposed to an incremental test starting with very light work. If the subjects were only allowed to exercise up to their own determined limit, they presumably would have stopped exercising before getting anxious. Exercise testing with a predetermined fraction of maximal power output may have missed the onset of anxiety symptoms. Therefore, it was necessary to start with a relatively high "dose" that was still submaximal. Pilot work showed that the selected level of workload was well tolerated by normals and rated to be of moderate difficulty by them. Heart rate and EKG were recorded via electrodes on a Grass polygraph throughout the procedure. A heparinized venous catheter was placed in an antecubital vein in each subject. After a 30-min rest, baseline blood samples were drawn for measurement of plasma lactate, pyruvate, phosphate, epinephrine and norepinephrine levels, and blood gases. Two more blood samples were obtained during the procedure, one immediately upon completion of the exercise test, and another 3 min later. The purpose of the last sample was to detect a lactate peak in the blood as it diffuses from muscle. In some individuals maximum values of lactate do not appear in the blood until 3 min after cessation of exercise (Linko 1950). Methods for the anal~ ;~ of biochemical measures as well as validity and reliability data for our lactate assay have been described elsewhere (Liebowitz et al 1985). The test began with a workload of 120 Watts (2 kiloponds of resistance, 60 revolutions per rain) for men ai~d 100 Watts (2 kiloponds of resistance, 50 revolutions per rain) for women using a Monark 668 bicycle ergometer. Cadence was determined by an electronic metronome. The subject was told that the test would terminate when any one of three criteria had been met: (1) the subject could go on no longer and asked that the test be stopped; (2) following the guidelines for submaximal testing (Astrand and Rodahl 1977) the subject reached a heart rate that exceeded submaximal level or reached a "target zone" heart rate and maintained it for a period of 1 min; or (3) 24 rain of exercise has been completed. No other instruction was given to the subject. During the test the Borg Rating of Perceived Exertion Scale (Astrand and Rodahl 797~) was administered every 3 rain to measure subjective work perception. The Borg Scale provides a scoring system of 6 to 20, according to how the subject feels while exercising. A rating of 13 corresponds to "somewhat hard exertion," a level of 15 corresponds to "hard exertion." The 28-item Acute Panic Inventory (API), a measure of anxiety and panic attack symptoms (Dillon et al 1986), was administered three times. For the initial administration of the API the subject was asked to describe his or her symptoms during a typical panic attack. Controls were asked to respond to the initial
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APl scale by recording symptoms commonly experienced during their own greatest periods of anxiety. The second API was e, baseline measurement of symptoms on the morning of the test. Finally, the scale was readministered immediately after completion of the test to record symptoms produced by the exercise. The observing psychiatrist determined whether the subject had a panic attack, defined as a discrete period of apprehension or fear, and at least four of the typical panic=associated crescendo-type symptoms listed in DSM Ill. The psychiatrist was not blind to the diagnosis of the subjects.
Results
Baseline Differences Baseline differences between patients and controls were evaluated with analysis of variance. Analysis of Rating of Perceived Exertion scores, age, and baseline heart rate were done with Student's t-test. All significance levels are two-tailed. There were no significant differences in mean age (35.4 +_ 7.7 versus 32.2 _ 7.8.) or in sex distribution between patients and controls. Analysis of API scores showed significant group effects such that patients scored significantly higher than controls on mean total score (F = 11.11; df = 1,27; p < 0.003), and on the following individual items: faintness (F = 4.72, df - 1,27; p < 0.039), fear in general (F -- 12.29 (If = 1,27;p < 0.002), dizziness (F = 11.93; df - 1,27;p < 0.002), confusion (F - 4.50; df = 1,27; p < 0.044), inability to do a job (F = 8.99; df = 1,27; p < 0.006), chest pain (F -= 6.20; df = 1,27; p < 0.02), and weakness (F -- 19.25; df -- 1,27; p < 0.001). Patients had significantly higher heart rate at baseline than controls (78.6 _ 8,5 versus 70.9 - 10.7; t = -2.22; df = 29; p "~ 0.03). No differences were found in blood pressure. The biochemistry data are listed in Table 1. Patients had higher pyruvate values (F = 12,87; df = 1,22;p < 0.002) and lower bicarbonate levels (F -- 4.45, df - 1,21; p < 0.005) than controls and a trend for lower pCO2 (F = 3.48; df =- 1,21; p < 0.08). The only significant baseline sex differences were higher bicarbonate (F -- 17.45, df = 1,21;p < 0.0005) and pCO2 levels (F -- 9.28, p < 0.01) for men compared to women. No baseline group or sex differences were found for pH, lactate, epinephrine, norepinephrine, or phosphate levels. No group-by-sex interactions were present for any of the variables.
Effects of Exercise The differential rate of panic attacks and the rate of premature termination of the test between patients and controls were compared by chi-square (uncorrected). Ten of the sixteen patients and five of the fifteen controls stopped the test prematurely due to physical discomfort and fatigue. Four of the sixteen patients and ten of the fifteen controls were stopped by the investigators because they either exceeded submaximal heart ram or maintained a "~rget zone" heart rate for I min. One patient but none of the controls had a panic attack during exercise. Only one patient and no control completed the full 24min exercise. The overall two (patients versus controls) by four (stopped by self, stopped by staff, panic, completer) chi-square was not significant (chi=square = 6.21, NS).
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Table 1. Biochemistry Means ( ± SD) for Three Timepoints
Variable time
Patients male (n = 7)
Patients female (n = 5)
Controls
Controls
male (n = 5)
female (n = 8)
7.377 ± 0.030 7.332 .4- 0.028 7.328 ± 0.031
7.382 .4- 0.015 7.343 ± 0.016 7.358 ± 0.027
7.380 ± 0.023 7.305 ± 0.032 7.296 ± 0.017
7.367 ± 0.024 7.322 ± 0.032 7.321 ± 0.037
47.44 ± 6,27 47.21 ± 6,30 45.40 ± 6.05
41.04 ± 1.04 43.50 ± 5.45 38.28 .4- 5.14
49.12 ± 3.50 54.52 ± 5.50 49.32 ± 8.39
45.50 ± 2.71 46.50 ± 4.55 42.01 ± 5.93
27,34 24,53 23.40 male
24.08 ± 0.86 23.14 ± 2,20 21.16 ± 2.64 female (n = 5)
28.66 ± 1.32 26.48 ± 1.79 23.46 ± 3.76 male (n -- 5)
25.84 ± 23.72 ± 21.36 ± female (n
8.35 _ 2.05 22.56 ± 6.23 33.20 ± 15.03
6.48 ± 0.79 36.06 ± 9.16 44.87 ± 19.89
7.89 ± 1.90 27.89 ± 8,43 36.41 ± 11.96
0.51 ± 0.21 0.60 ± 0.27 0.84 ± 0.69
0.28 ± 0.10 0.53 ± 0.29 0.66 ± 0.58
0.40 ± 0.11 0.52 ± 0.22 0.63 ± 0.33
33.3 ± 31.0 89.7 __. 34,7 130.7 ± 28.0
59.3 ± 59.0 158.0 ± 74.0 106.3 ± 45.4
19.6 ± 7.1 67.8 ± 16.8 59.2 ± 28,8
pH Baseline Term Term + 3 rain pCOz (mmHg) Baseline Term Term + 3 rain Bicarbonate (nmol/L) Baseline Term Term + 3 min
4. ± ± (n
2.34 3.26 3.43 = 7)
Lactate (mg/dl) Baseline 9.09 -~..: 3.15 Term 33.22 ± 13.86 Term + 3 min 38.59 ± 17.10 Pymvate (mg/dl) Baseline 0.62 ± 0.18 Term 0,67 ± 0,26 Term + 3 min 0.84 ± 0.35 Epinephrine (pg/ml plasma) Baseline 55.3 ± 21.6 Term 138,0 ± 42.9 Term + 3min 104,8 ± 52.t Norepinephrine (pg/ml plasma) (n = 4) Baseline 261,0 ± 92.2 Ter~ 903,3 ± 111.5 Term + 3 rain 799,8 -*- ~il.0 Phosphate (mg/dl) (n ~ 7 ) Baseline 2.93 ± 0.59 Term 3,57 --. 0.50 Term + 3 rain 3.52 ± 5.54 pO2 (mmH8) (n = 7) Baseline 32,09 -*- 13.32 Term 40,79 ± 20,62 Term + 3rain 42,66 ± 17.97
(n 120.0 511.0 531.3
= ± ± ±
3) 52.2 220,4 234,5
(n~-4) 3,33 ± 0.65 3 Jl ± 0.53 3.67 ± 0.47 (n 38,12 46.22 54,10
= ± ± ±
5) 10,94 18.20 18,53
(n 222.5 1039,5 854,8
= ± ± ±
4) 83.7 81.0 198.8
(n=5) 3.11 ± 0,65 3.54 ± 0.40 3.49 ± 0.33 (n 31.36 21.64 33,10
= ± ± ±
5) 7.47 10.63 17.49
(n 224.8 978.0 796.8
= ± ± ±
1.85 2.94 3.31 = 9)
5) 79.5 415.1 302.6
(n=9) 3.50 - 0.58 3.78 ± 0.67 3.68 ± 0.57 (n 32.95 3".-~.57 44.81
= ± ± ±
8) 10.34 20.35 19,03
However, significantly more controls than patients were stopped by the staff (Fisher's exact, p < 0.03, two-tailed). Whereas more patients than controls stopped early due to fatigue, the difference did not reach significance. The mean ( ± SD) time of exercise was 6.7 (__ 6.4) rain for patients, and 6.4 ± 3.9 rain for controls (t = .24, df -- 29; NS). Overall, women tended to stop earlier (4.6 rain) than men (8.9 min). Women patients only exercised for a mean of 2.9 min, but there was no group-by-sex interaction for the time of exercise. Data for API, Borg score, and biochemistry were included for a subject only when
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measurements for every sampling period were obtained. Changes in subjective parameters (API, Borg score) were assessed by analysis of variance with repeated measures. API scores for both patients and controls increased significantly over time for mean total score (F = 24.23; df = 1,27; p < 0.001), and on the following items: palpitations (F = 17.20; df -- 1,27; p < 0.001), difficulty breathing (F = 24.05; df = 1,27; p < 0.001), dizziness (F - 6.24; df = 1,27;p < 0.019), sweating (F = 30.12; df = 1,27;p < 0.001), difficulty speaking (F = 9.94; df - 1,27;p < 0.004), impaired ability to do a job (F = 11.28; df = 1,27; p < 0.003), difficulty swallowing (F = 10.97; df = 1,27;p < 0.003), and dry mouth (F = 35.84; df - 1,27;p < 0.001). No groupby-time interaodons were found for total score. Only one individual API item, a feeling of weakness, showed a group-by-time interaction (F = 4.37; df -- 1,27; p < 0.05), indicating that patients felt weaker than controls after exercise. The level of perceived exertion (Borg score) at the end of exercise was not significantly different between the two groups when compared by t-test ipatients = 14.6 _ $D 2.9, controls = 14.1 ± $D 1.3, t = -0,626, df - 29; N$). The differential effects of the exercise test on the biochemistry of patients and controls were evaluated with analysis of variance for three time points: "baseline," "termination of exercise," and "3 min after termination of exercise" with group and sex as factors. In order to account for the varying duration of exercise, the "termination of exercise" value was standardized to the level at 1 min after the start of exercise. This was calculated as the sum of baseline and the difference between the termination and the baseline value divided by the time of exercise (base + [{termination - base}/time of exercise]). The "3 min postexercise" value was also standardized to 1 min after the exercise termination point by calculating the sum of termination and the difference between the 3-min post and the termination value divided by three (termination + [{3 min posttermination value termination}/3]). This calculation enabled us to compare the increments per minute in each epoch using groups and time as repeated measure factors. When adjusted for the variable time of exercise the ANOVAR revealed that th~ only group difference between patients and controls was in epinephrine levels (F = 9.14, df - 1,12; p - 0.05). Patients increased their epinephrine levels more than controls during exereise. $igvificant time effects were found for pH (F -- 20.32, df = 1,21;p < 0.0001), bicarbonate iF = 38.20, df = 1,21; p < 0.0001, epinephrine (F = 13.77, df = 1,12, p < 0.005), norepinephrine iF = 15.2; df = 1,12; p < 0.005), lactate (F = 52.02, df = 1,22;p < 0.0001), phosphate iF - 12.28; df = 1,22;p < 0.005), and pyruvate iF - 12.09, df = 1,21; p < 0.002). pH, bicarbonate, and phosphate dropped while lactate, pyruvate, epinephrine, and norepinephrine increased over time. There was no time effect for PCO2. Removal of the single panicking patient from all the analyses did not alter these results.
Analysis of Rate of Lactate Rise Per Minute No significant difference in the mean rate of lactate rise per minute of exercise was found between groups (controls IN = 14]: 5.1 - 2.9 mg/dl/min; patients [N = 12], 5.3 _ 3.5 mg/dl/min). The single panicking subject had a baseline lactate level of 6.9 mg/dl (compared to a mean of 9.0 - 2.7 for 11 non-panicking patients). He reached 21.2 mg/dl at the point of panic, after 2.7 min of exercise time (c,~mpared to the mean of 29.5 mg/dl 4- 12.6
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for non-panickers). Three minutes after termination his lactate level was 47.9 mg/dl (compared to a mean of 35.3 +_ 16.1 mg/dl for non-panickers).
Discussion Overall, panic patients and controls had similar responses to submaximal exercise. Only one patient out of 16 panicked during exercise. With the exception of this single patient, none of the subjects experienced significant anxiety during the test. The Acute Panic Inventory items that changed over time in both groups were primarily normal physiological accompaniments of exercise such as increased sweating, breathing, dry mouth, and palpitations. Patients and controls showed a parallel increase in API symptoms and in the Borg Scale of Perceived Exertion. These findings are consistent with Cohen and White's 1950 study which reported no panic attacks or increase in subjective anxiety level in the patients studied. The changes in biochemistry and physiology were consistent with vigorous exercise. The absence of group-by-time interactions across all parameters indicates again that patients and controls respond to exercise similarly. In contrast to Cohen and White (1950), we did not find group differences for lactate level rate of change during exercise. It is possible that their population included a broader spectrum of anxiety disorders that are not comparable to our homogenous group of panic disorder patients. Exercise-induced anxiety, if it exists at all, may be unrelated to elevated ~actate levels. Lactate levels in our only panicking patient were close to the non-panicking patient group means. Mean lactate levels at the termination of exercise were also comparable to those achieved during intravenous infusion of racemic sodium lactate (Liebowitz et al 1985). The rate of lactate increment (mg of lactate/dl/min) during exercise was actually much higher during exercise than during lactate infusion (5.3 versus 2.6 in patients; 5.1 versus 2.9 in controls). We found no change in pCO2 from baseline to exercise termination in either group. This was expected, as moderate exercise has been shown to be isocapnic (Wasserman et el 1967). On the other hand, several groups have shown that CO2 inhalation causes panic attacks in patients with panic disorder (German et al 1984, Griez et al 1984, Woods et al 1986), Hence, hypercapnic rather than isocapnic stress may be essential in causing panic attacks. This possibility is also compatible with cognitive/behavioral theories conceptualizing panic as a misattribution of interoceptive cues. Panic patients may not catastrophize if they can explain the source of discomfort as exercise. However, it should be noted that infusions of physostigmine, insulin, and TRH, while producing unfamiliar anxiety like sensations, nonetheless do not cause panic. Patients felt weaker, had higher baseline heart rate, tended to terminate the test due to fatigue earlier, but were not more anxious compared to controls, suggesting that premature cessation of exercise in patients was caused by poor conditioning and not anxiety. Unfortunately, we did not collect information regarding pre-test exercise habits. Selecting panic patients who specifically avoid exercise due to "exercise sensitivity" and Fating their anxiety blindly may have yielded different findings. While no actual panic attacks were reported, retrospective self-rating of anxiety at various exercise levels were found higher in panic disorder patients than controls or patients with other anxiety disorders (Cameron and Hudson 1986). Nevertheless, in view of our results and the finding that panic disorder patients have higher cardiovascular
Exercise Tolerance in PD Patients
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\ mortality than controls (Coryell et al 1982, Weissman ct al 1 ~ ) , moderate exercise is not contraindicated and should be encouraged in this patient population.
References Astrand P, Rodahl K (1977): Textbook of Work Physiology: Physiological Bases of Exercise, New York, McGraw-Hill, pp 33-361. Barlow DH (1988): Anxiety and its Disorders: The Nature and Treatment of Anxiety and Panic. New York, Guilford. Cameron OG, Hudson CJ (1986): Influence of exercise on anxiety level in patients with anxiety disorders. Psychosomatics 27:720-723. Cohen ME, White PD (1950): Life situations, emotions and neurocirculatory asthenia (anxiety neurosis, neurasthenia, effort syndrome). Research Nerv and Meat Dis Proc 29:832-869. Coryell W, Noyes R, Clancy J (1982): Excess mortality in panic disorder. Arch Gen Psychiatry 39:701-703. Dillon D, (3orman JM, Liebowitz MR, Fyer AJ, Klein DF (1986): The measurement of lactateinduced panic and anxiety. Psychiatry Res 20:97-105. (3ormanJM, Askanazi J, Liebowitz MR, Fyer AJ, Stein JM, Kinney JM, Klein DF (1984): Response to hyperventilation in a group of patients with panic disorder. Am J Psychiatry 41(7):857-861. (3riez E, Van denHout M (1984): Panic attack symptoms after inhalation of carbon dioxide. Br J Psychiatry 144:503-507. Homgrcn A, Strom (3 (1959): Blood lactate concentration in relation to absolute and relative work load in normal men, and in mitral stenosis, atrial septal defect and vasoregulatory asthenia. Acre Medica Scandinavica 163:185. Liebowitz MR, Gorman JM, Fyer AJ, Levitt M, Dillon D, Levy G, Appleby IL, Anderson S, Palij M, Davies SO, Klein DF (1985): Lactate provocation of panic attacks II: Biochemical and physiological findings. Arch Gen Psychiatry 42:709-719. Linko E (1950): Lactic acid response to muscular exercise in neurocirculatory asthenia. Ann M Fennia 39:161-176. Pitts FN, McClure JN (1967): Lactate metabolism in anxiety neurosis. N Engl J Med 277:13291336. Siuyor D, S,:hwartz S, et al (1983): Aerobic fitness level and reactivity to psychosocial stress: Physiological, biochemical, and subjective measures. Psychosomatic Med 45:205-217. Wasserman }~, Van Kessel AL, Burton (3(3 (! 967): Interactions of physiologicalmechanisms during exercise. J Appl Physiol 22(I):71-85. Weissman MM, Markowitz JS, Oulette R, (3reenwald S, Kahn JP (1990): Panic disorder and cardiovasL:nlar/c~rebrovascularproblems: results from a community survey. Am J Psychiatry 147:1504--i 508. Woods SW, Charney DS, Lake J, Goodman WK, Redmond DE, Heninger DR (1986): Carbon dioxide s msitivity in panic anxiety: Ventilatory and anxiogenic response to carbon dioxide in healthy subjects and panic anxiety patients before and after alprazolam treatment. Arch Gen Psychiat~~ 43:900-909.
281
Exercise Tolerance in Panic Disorder Patients Jonathan M. Stein, Laszlo A. Papp, Donald F. Klein, Susannah Cohen, Joshua Simon, Donald Ross, Jose Martinez, and Jack M. Gorman
Sixteen panic patients and fifteen normal controls performed submaximal exercise testing on a bicycle ergometer. Only one patient subject panicked. Biochemical, physiological, and psychological data showed similar exercise tolerance in both patients and controls. Exercise.induced distress and lactate increment do not appear to cause panic attacks.
Introduction In 1950 Cohen and White found that "neurocirculatory asthenia" patients--an earlier diagnostic category that resembles panic disorder--did not last as long, developed a lower absolute maximum lactate level, and had higher pulse rates during moderate exercise than normals. However, the patients had significantly higher values than controls of "lactate per cubic centimeter of blood per second of running time." This suggested a restricted ability for aerobic metabolism in the patients (Homgren and S|rom 1959). However, no patient experienced significant anxiety or panic during exercise. A possible association between elevated lactate levels and anxiety prompted Pitts and McClure (1967) to test whether sodium lactate infusion would provoke panic attacks in panic disorder patients. Sodium lactate infusion has become an important tool in the investigation of panic disorder although how it induces panic is still unclear. Because no study has systemically evaluated the level of anxiety, meo,alred lactate levels, and assessed the occurrence of panic during exercise in currently defined panic patients we conducted exercise tolerance tests in panic patients and normal controls. We posed the following questions: (1) Is non-specific physiological distress, such as provoked by standard exercise, sufficient to induce significant anxiety or panic in panic disorder patients? (2) Do patients with panic disorder have reduced exercise tolerance? (3) Do patients and controls differ in the rate of biological changes, such as the rate of endogenous lactate increment, during exercise?
From the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, the Biological Studies Unit, New York State Psychiatric Institute, and Hillside Hospital, New York. Address reprint requests to Dr. Laszlo A. Papp, 722 W. 168 Street, New York, N.Y. 10032. $upporled in part by MHg03.COO3I, MH33422-08, MH37592-04, Scientist Development Award for Clinicians MH.00858 (LAP), Research Scientist Development Award MH00416 OMG) from the National Institute of Mental Health, and by Biomedical Research Support Grant 903E-704R. Received June 24, 1991; revised April 11, 1992.
© 1992 Society of Biological Psychiatry
0006.3223/92/$05.00
282
BlOt.PSYCHIATRY
J.M.
Stein et al
1992;32:281-287
Methods Nine male and seven female patients meeting DSM-III-R criteria for panic disorder (n = 9) or agoraphobia with panic attacks (n = 7) (without any other Axis I pathology) and six aaale and nine female controls free of any Axis I psychiatric disorder were recruited via professional referral or advertisement. The diagnoses were established with semistructured interviews conducted by experienced research psychiatrists. Subjects were tested in the Biological Studies Unit of the New York State Psychiatric Institute after a 12-hr period of abstinence from food, alcohol, caffeine, and cigarettes. They had been free of psychotropic medications for at least 2 weeks. After signing an informed consent, each subject performed a modified version of the Astrand-Rhyming submaximal bicycle ergometer test (Astrand and Rodahl 1977). The subject began the exercise with a moderately hard, constant workload as opposed to an incremental test starting with very light work. If the subjects were only allowed to exercise up to their own determined limit, they presumably would have stopped exercising before getting anxious. Exercise testing with a predetermined fraction of maximal power output may have missed the onset of anxiety symptoms. Therefore, it was necessary to start with a relatively high "dose" that was still submaximal. Pilot work showed that the selected level of workload was well tolerated by normals and rated to be of moderate difficulty by them. Heart rate and EKG were recorded via electrodes on a Grass polygraph throughout the procedure. A heparinized venous catheter was placed in an antecubital vein in each subject. After a 30-min rest, baseline blood samples were drawn for measurement of plasma lactate, pyruvate, phosphate, epinephrine and norepinephrine levels, and blood gases. Two more blood samples were obtained during the procedure, one immediately upon completion of the exercise test, and another 3 min later. The purpose of the last sample was to detect a lactate peak in the blood as it diffuses from muscle. In some individuals maximum values of lactate do not appear in the blood until 3 min after cessation of exercise (Linko 1950). Methods for the anal~ ;~ of biochemical measures as well as validity and reliability data for our lactate assay have been described elsewhere (Liebowitz et al 1985). The test began with a workload of 120 Watts (2 kiloponds of resistance, 60 revolutions per rain) for men ai~d 100 Watts (2 kiloponds of resistance, 50 revolutions per rain) for women using a Monark 668 bicycle ergometer. Cadence was determined by an electronic metronome. The subject was told that the test would terminate when any one of three criteria had been met: (1) the subject could go on no longer and asked that the test be stopped; (2) following the guidelines for submaximal testing (Astrand and Rodahl 1977) the subject reached a heart rate that exceeded submaximal level or reached a "target zone" heart rate and maintained it for a period of 1 min; or (3) 24 rain of exercise has been completed. No other instruction was given to the subject. During the test the Borg Rating of Perceived Exertion Scale (Astrand and Rodahl 797~) was administered every 3 rain to measure subjective work perception. The Borg Scale provides a scoring system of 6 to 20, according to how the subject feels while exercising. A rating of 13 corresponds to "somewhat hard exertion," a level of 15 corresponds to "hard exertion." The 28-item Acute Panic Inventory (API), a measure of anxiety and panic attack symptoms (Dillon et al 1986), was administered three times. For the initial administration of the API the subject was asked to describe his or her symptoms during a typical panic attack. Controls were asked to respond to the initial
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APl scale by recording symptoms commonly experienced during their own greatest periods of anxiety. The second API was e, baseline measurement of symptoms on the morning of the test. Finally, the scale was readministered immediately after completion of the test to record symptoms produced by the exercise. The observing psychiatrist determined whether the subject had a panic attack, defined as a discrete period of apprehension or fear, and at least four of the typical panic=associated crescendo-type symptoms listed in DSM Ill. The psychiatrist was not blind to the diagnosis of the subjects.
Results
Baseline Differences Baseline differences between patients and controls were evaluated with analysis of variance. Analysis of Rating of Perceived Exertion scores, age, and baseline heart rate were done with Student's t-test. All significance levels are two-tailed. There were no significant differences in mean age (35.4 +_ 7.7 versus 32.2 _ 7.8.) or in sex distribution between patients and controls. Analysis of API scores showed significant group effects such that patients scored significantly higher than controls on mean total score (F = 11.11; df = 1,27; p < 0.003), and on the following individual items: faintness (F = 4.72, df - 1,27; p < 0.039), fear in general (F -- 12.29 (If = 1,27;p < 0.002), dizziness (F = 11.93; df - 1,27;p < 0.002), confusion (F - 4.50; df = 1,27; p < 0.044), inability to do a job (F = 8.99; df = 1,27; p < 0.006), chest pain (F -= 6.20; df = 1,27; p < 0.02), and weakness (F -- 19.25; df -- 1,27; p < 0.001). Patients had significantly higher heart rate at baseline than controls (78.6 _ 8,5 versus 70.9 - 10.7; t = -2.22; df = 29; p "~ 0.03). No differences were found in blood pressure. The biochemistry data are listed in Table 1. Patients had higher pyruvate values (F = 12,87; df = 1,22;p < 0.002) and lower bicarbonate levels (F -- 4.45, df - 1,21; p < 0.005) than controls and a trend for lower pCO2 (F = 3.48; df =- 1,21; p < 0.08). The only significant baseline sex differences were higher bicarbonate (F -- 17.45, df = 1,21;p < 0.0005) and pCO2 levels (F -- 9.28, p < 0.01) for men compared to women. No baseline group or sex differences were found for pH, lactate, epinephrine, norepinephrine, or phosphate levels. No group-by-sex interactions were present for any of the variables.
Effects of Exercise The differential rate of panic attacks and the rate of premature termination of the test between patients and controls were compared by chi-square (uncorrected). Ten of the sixteen patients and five of the fifteen controls stopped the test prematurely due to physical discomfort and fatigue. Four of the sixteen patients and ten of the fifteen controls were stopped by the investigators because they either exceeded submaximal heart ram or maintained a "~rget zone" heart rate for I min. One patient but none of the controls had a panic attack during exercise. Only one patient and no control completed the full 24min exercise. The overall two (patients versus controls) by four (stopped by self, stopped by staff, panic, completer) chi-square was not significant (chi=square = 6.21, NS).
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Table 1. Biochemistry Means ( ± SD) for Three Timepoints
Variable time
Patients male (n = 7)
Patients female (n = 5)
Controls
Controls
male (n = 5)
female (n = 8)
7.377 ± 0.030 7.332 .4- 0.028 7.328 ± 0.031
7.382 .4- 0.015 7.343 ± 0.016 7.358 ± 0.027
7.380 ± 0.023 7.305 ± 0.032 7.296 ± 0.017
7.367 ± 0.024 7.322 ± 0.032 7.321 ± 0.037
47.44 ± 6,27 47.21 ± 6,30 45.40 ± 6.05
41.04 ± 1.04 43.50 ± 5.45 38.28 .4- 5.14
49.12 ± 3.50 54.52 ± 5.50 49.32 ± 8.39
45.50 ± 2.71 46.50 ± 4.55 42.01 ± 5.93
27,34 24,53 23.40 male
24.08 ± 0.86 23.14 ± 2,20 21.16 ± 2.64 female (n = 5)
28.66 ± 1.32 26.48 ± 1.79 23.46 ± 3.76 male (n -- 5)
25.84 ± 23.72 ± 21.36 ± female (n
8.35 _ 2.05 22.56 ± 6.23 33.20 ± 15.03
6.48 ± 0.79 36.06 ± 9.16 44.87 ± 19.89
7.89 ± 1.90 27.89 ± 8,43 36.41 ± 11.96
0.51 ± 0.21 0.60 ± 0.27 0.84 ± 0.69
0.28 ± 0.10 0.53 ± 0.29 0.66 ± 0.58
0.40 ± 0.11 0.52 ± 0.22 0.63 ± 0.33
33.3 ± 31.0 89.7 __. 34,7 130.7 ± 28.0
59.3 ± 59.0 158.0 ± 74.0 106.3 ± 45.4
19.6 ± 7.1 67.8 ± 16.8 59.2 ± 28,8
pH Baseline Term Term + 3 rain pCOz (mmHg) Baseline Term Term + 3 rain Bicarbonate (nmol/L) Baseline Term Term + 3 min
4. ± ± (n
2.34 3.26 3.43 = 7)
Lactate (mg/dl) Baseline 9.09 -~..: 3.15 Term 33.22 ± 13.86 Term + 3 min 38.59 ± 17.10 Pymvate (mg/dl) Baseline 0.62 ± 0.18 Term 0,67 ± 0,26 Term + 3 min 0.84 ± 0.35 Epinephrine (pg/ml plasma) Baseline 55.3 ± 21.6 Term 138,0 ± 42.9 Term + 3min 104,8 ± 52.t Norepinephrine (pg/ml plasma) (n = 4) Baseline 261,0 ± 92.2 Ter~ 903,3 ± 111.5 Term + 3 rain 799,8 -*- ~il.0 Phosphate (mg/dl) (n ~ 7 ) Baseline 2.93 ± 0.59 Term 3,57 --. 0.50 Term + 3 rain 3.52 ± 5.54 pO2 (mmH8) (n = 7) Baseline 32,09 -*- 13.32 Term 40,79 ± 20,62 Term + 3rain 42,66 ± 17.97
(n 120.0 511.0 531.3
= ± ± ±
3) 52.2 220,4 234,5
(n~-4) 3,33 ± 0.65 3 Jl ± 0.53 3.67 ± 0.47 (n 38,12 46.22 54,10
= ± ± ±
5) 10,94 18.20 18,53
(n 222.5 1039,5 854,8
= ± ± ±
4) 83.7 81.0 198.8
(n=5) 3.11 ± 0,65 3.54 ± 0.40 3.49 ± 0.33 (n 31.36 21.64 33,10
= ± ± ±
5) 7.47 10.63 17.49
(n 224.8 978.0 796.8
= ± ± ±
1.85 2.94 3.31 = 9)
5) 79.5 415.1 302.6
(n=9) 3.50 - 0.58 3.78 ± 0.67 3.68 ± 0.57 (n 32.95 3".-~.57 44.81
= ± ± ±
8) 10.34 20.35 19,03
However, significantly more controls than patients were stopped by the staff (Fisher's exact, p < 0.03, two-tailed). Whereas more patients than controls stopped early due to fatigue, the difference did not reach significance. The mean ( ± SD) time of exercise was 6.7 (__ 6.4) rain for patients, and 6.4 ± 3.9 rain for controls (t = .24, df -- 29; NS). Overall, women tended to stop earlier (4.6 rain) than men (8.9 min). Women patients only exercised for a mean of 2.9 min, but there was no group-by-sex interaction for the time of exercise. Data for API, Borg score, and biochemistry were included for a subject only when
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measurements for every sampling period were obtained. Changes in subjective parameters (API, Borg score) were assessed by analysis of variance with repeated measures. API scores for both patients and controls increased significantly over time for mean total score (F = 24.23; df = 1,27; p < 0.001), and on the following items: palpitations (F = 17.20; df -- 1,27; p < 0.001), difficulty breathing (F = 24.05; df = 1,27; p < 0.001), dizziness (F - 6.24; df = 1,27;p < 0.019), sweating (F = 30.12; df = 1,27;p < 0.001), difficulty speaking (F = 9.94; df - 1,27;p < 0.004), impaired ability to do a job (F = 11.28; df = 1,27; p < 0.003), difficulty swallowing (F = 10.97; df = 1,27;p < 0.003), and dry mouth (F = 35.84; df - 1,27;p < 0.001). No groupby-time interaodons were found for total score. Only one individual API item, a feeling of weakness, showed a group-by-time interaction (F = 4.37; df -- 1,27; p < 0.05), indicating that patients felt weaker than controls after exercise. The level of perceived exertion (Borg score) at the end of exercise was not significantly different between the two groups when compared by t-test ipatients = 14.6 _ $D 2.9, controls = 14.1 ± $D 1.3, t = -0,626, df - 29; N$). The differential effects of the exercise test on the biochemistry of patients and controls were evaluated with analysis of variance for three time points: "baseline," "termination of exercise," and "3 min after termination of exercise" with group and sex as factors. In order to account for the varying duration of exercise, the "termination of exercise" value was standardized to the level at 1 min after the start of exercise. This was calculated as the sum of baseline and the difference between the termination and the baseline value divided by the time of exercise (base + [{termination - base}/time of exercise]). The "3 min postexercise" value was also standardized to 1 min after the exercise termination point by calculating the sum of termination and the difference between the 3-min post and the termination value divided by three (termination + [{3 min posttermination value termination}/3]). This calculation enabled us to compare the increments per minute in each epoch using groups and time as repeated measure factors. When adjusted for the variable time of exercise the ANOVAR revealed that th~ only group difference between patients and controls was in epinephrine levels (F = 9.14, df - 1,12; p - 0.05). Patients increased their epinephrine levels more than controls during exereise. $igvificant time effects were found for pH (F -- 20.32, df = 1,21;p < 0.0001), bicarbonate iF = 38.20, df = 1,21; p < 0.0001, epinephrine (F = 13.77, df = 1,12, p < 0.005), norepinephrine iF = 15.2; df = 1,12; p < 0.005), lactate (F = 52.02, df = 1,22;p < 0.0001), phosphate iF - 12.28; df = 1,22;p < 0.005), and pyruvate iF - 12.09, df = 1,21; p < 0.002). pH, bicarbonate, and phosphate dropped while lactate, pyruvate, epinephrine, and norepinephrine increased over time. There was no time effect for PCO2. Removal of the single panicking patient from all the analyses did not alter these results.
Analysis of Rate of Lactate Rise Per Minute No significant difference in the mean rate of lactate rise per minute of exercise was found between groups (controls IN = 14]: 5.1 - 2.9 mg/dl/min; patients [N = 12], 5.3 _ 3.5 mg/dl/min). The single panicking subject had a baseline lactate level of 6.9 mg/dl (compared to a mean of 9.0 - 2.7 for 11 non-panicking patients). He reached 21.2 mg/dl at the point of panic, after 2.7 min of exercise time (c,~mpared to the mean of 29.5 mg/dl 4- 12.6
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for non-panickers). Three minutes after termination his lactate level was 47.9 mg/dl (compared to a mean of 35.3 +_ 16.1 mg/dl for non-panickers).
Discussion Overall, panic patients and controls had similar responses to submaximal exercise. Only one patient out of 16 panicked during exercise. With the exception of this single patient, none of the subjects experienced significant anxiety during the test. The Acute Panic Inventory items that changed over time in both groups were primarily normal physiological accompaniments of exercise such as increased sweating, breathing, dry mouth, and palpitations. Patients and controls showed a parallel increase in API symptoms and in the Borg Scale of Perceived Exertion. These findings are consistent with Cohen and White's 1950 study which reported no panic attacks or increase in subjective anxiety level in the patients studied. The changes in biochemistry and physiology were consistent with vigorous exercise. The absence of group-by-time interactions across all parameters indicates again that patients and controls respond to exercise similarly. In contrast to Cohen and White (1950), we did not find group differences for lactate level rate of change during exercise. It is possible that their population included a broader spectrum of anxiety disorders that are not comparable to our homogenous group of panic disorder patients. Exercise-induced anxiety, if it exists at all, may be unrelated to elevated ~actate levels. Lactate levels in our only panicking patient were close to the non-panicking patient group means. Mean lactate levels at the termination of exercise were also comparable to those achieved during intravenous infusion of racemic sodium lactate (Liebowitz et al 1985). The rate of lactate increment (mg of lactate/dl/min) during exercise was actually much higher during exercise than during lactate infusion (5.3 versus 2.6 in patients; 5.1 versus 2.9 in controls). We found no change in pCO2 from baseline to exercise termination in either group. This was expected, as moderate exercise has been shown to be isocapnic (Wasserman et el 1967). On the other hand, several groups have shown that CO2 inhalation causes panic attacks in patients with panic disorder (German et al 1984, Griez et al 1984, Woods et al 1986), Hence, hypercapnic rather than isocapnic stress may be essential in causing panic attacks. This possibility is also compatible with cognitive/behavioral theories conceptualizing panic as a misattribution of interoceptive cues. Panic patients may not catastrophize if they can explain the source of discomfort as exercise. However, it should be noted that infusions of physostigmine, insulin, and TRH, while producing unfamiliar anxiety like sensations, nonetheless do not cause panic. Patients felt weaker, had higher baseline heart rate, tended to terminate the test due to fatigue earlier, but were not more anxious compared to controls, suggesting that premature cessation of exercise in patients was caused by poor conditioning and not anxiety. Unfortunately, we did not collect information regarding pre-test exercise habits. Selecting panic patients who specifically avoid exercise due to "exercise sensitivity" and Fating their anxiety blindly may have yielded different findings. While no actual panic attacks were reported, retrospective self-rating of anxiety at various exercise levels were found higher in panic disorder patients than controls or patients with other anxiety disorders (Cameron and Hudson 1986). Nevertheless, in view of our results and the finding that panic disorder patients have higher cardiovascular
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\ mortality than controls (Coryell et al 1982, Weissman ct al 1 ~ ) , moderate exercise is not contraindicated and should be encouraged in this patient population.
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