103
Ps,hiatr_v Research. 32: IO3-I I2 Elsevier
Somatic and Psychological Symptoms Isoproterenol-Induced Panic Attacks Richard Balon, Vikram Richard Berchou Received 1989.
K. Yeragani,
Robert
May 18. 1989; revised version received November
During
Pohl,
John
Muench,
IO, 1989; accepted
and
December 20.
Abstract. To determine which symptoms characterized isoproterenol-induced panic attacks, we analyzed the presence of panic attacks in 54 panic disorder patients who panicked, 24 patients who did not panic, and 37 controls who did not panic during isoproterenol infusions. The increases over the baseline of the symptoms shortness of breath and fear of going crazy were highly associated with panicking patients when compared to nonpanicking patients and nonpanicking controls. The increases of the symptoms trembling and shaking, generally nervous, and fear of going crazy were highly associated with patients when compared to controls. The possibility of a cognitive theory of panic attacks is discussed. Key Words. theory.
Isoproterenol,
panic
attack,
panic
disorder
patients,
cognitive
Panic attacks are episodes of intense anxiety accompanied by other symptoms such as heart pounding, chest pain or tightness, shortness of breath, sweating, and faintness (American Psychiatric Association, 1987). Some symptoms of panic attacks are similar to the symptoms of j?-adrenergic activation-namely, heart pounding, shortness of breath, sweating, and tremulousness. Various laboratory methods of provocation of panic attacks have been reported, with sodium lactate being the most studied one (Liebowitz and Hollander, 1989). We reported on panic attacks induced by isoproterenol, a &agonist, in panic disorder patients (Rainey et al., 1984; Pohl et al., 1985, 1988; Balon et al., 1988a, 19886). Panic disorder patients are more sensitive than controls to the effect of isoproterenol (Pohl et al., 1988). Isoproterenol was less sensitive, but more specific than lactate in the induction of panic attacks in panic disorder patients (Balon et al., 1988~). Phenomenological analysis revealed a similarity of isoproterenol-induced panic attacks to presumably spontaneous panic attacks during dextrose (placebo) infusion
Richard
Balon, M.D., is Assistant Professor of Psychiatry, Wayne State University, and Staff Psychiatrist, Adult Outpatient Department, Lafayette Clinic, Detroit, Ml. Vikram K. Yeragani, M.D., is Associate Professor of Psychiatry, Wayne State University, and Assistant Director, Outpatient Department, Lafayette Clinic, Detroit, MI. Robert Pohl, M.D., is Associate Professor of Psychiatry, Wayne State University, and Director, Outpatient Department, Lafayette Clinic, Detroit, MI. John Muench, M.D., was a medical student at Wayne State University School of Medicine when this research was carried out. Richard Berchou, Pharm.D., is Research Scientist, Lafayette Clinic. (Reprint requests to Dr. R. Balon, Lafayette Clinic, 95 I E. Lafayette, Detroit, MI 48207, USA.) 0165-I 781/90/$03.50
@ 1990 Elsevier Scientific
Publishers Ireland
Ltd.
104 (Balon et al., 19886). The symptom analysis of lactate-induced panic attacks (Yeragani et al., 1989) revealed that symptoms of shortness of breath, feeling frightened, feeling dizzy, and fear of losing control were significantly associated with lactate-induced panic and also that cognitive symptoms of fear of losing control and fear of going crazy appeared to be important determinants of lactate-induced panic. Clark (1986), in his review of a cognitive approach to panic attacks, postulated that panic attacks are the result of a catastrophic misinterpretation of certain bodily sensations. lsoproterenol produces panic attacks similar to the spontaneous attacks, and some of the peripheral symptoms (e.g., heart pounding) characteristic for isoproterenol-induced panic attacks are similar to the somatic symptoms of spontaneous panic attacks. We infused 86 patients and 45 healthy controls with isoproterenol. These were the same subjects as in our previous report on lactate and isoproterenol infusions (Balon et al., 1988a), but two of the patients are different individuals from 2 of the 86 patients described in another report on isoproterenol infusions (Pohl et al., 1988). In this study we analyzed which symptoms are most frequently associated with isoproterenol-induced panic attacks. We also examined the relationship of somatic symptoms of isoproterenol-induced panic attacks to psychological symptoms.
Methods Subjects.
All subjects were voluntary participants in our Anxiety Disorder Research Program at Lafayette Clinic. All patients met Research Diagnostic Criteria (RDC; Spitzer et al., 1978) for panic disorder and were actively symptomatic with an average of at least one panic attack per week. Nonpsychiatric controls reported no history of panic disorder or other mental disorder. All subjects did not take any psychotropic medication for at least 2 weeks before and throughout the infusion procedures. Subjects with a history of endocrine, respiratory, hepatic, renal, or cardiac disease other than mitral valve prolapse, and psychiatric illnesses other than panic disorder and agoraphobia with panic attacks were excluded from the study. Each subject had a complete physical examination, blood chemistry tests, blood count, urinalysis, and an electrocardiogram. We obtained complete isoproterenol infusion data on the Panic Description Scale (Rainey et al., 1984) for 78 patients and 41 controls. Of these, there were 54 panicking patients (I6 males and 38 females; mean age = 32.2 years; SD = 7.5; range 20-48) and 24 nonpanicking patients( I4 males and IO females; mean age = 33.0 years; SD = 7.9; range 18-51). Thirtyseven controls did not panic (23 males and I4 females; mean age= 29.3 years; SD = 6.6; range 22-48) and four did (I male and 3 females; mean age = 30.5 years; SD = I .8; range 29-32). We did not use the group of controls who panicked with isoproterenol for any analysis as the number of subjects (4) in this group was too small for any meaningful comparison. Procedure.
This communication is a part of a double-blind, placebo-controlled study of randomized infusions of sodium lactate, isoproterenol, and dextrose in panic disorder patients. The procedure has been described in detail elsewhere (Balon et al., 1988~). All subjects were infused with 20 ,ug of isoproterenol in D5W; the flow was adjusted by gravity feed to deliver a volume of 6 ml/kg over 20 min. The infusion rates (in pg/min/ kg) were 13.9 + 4.9 for patient panickers, I I. I + 3.9 for patient nonpanickers, and 13.3 * 3.9 for control nonpanickers. The Panic Description Scale (PDS), a 2l-item self-rating panic scale (Rainey et al., 1984) constructed from the RDC (Spitzer et al., 1978) criteria for panic disorder, was used to identify panic attacks. The PDS was administered during the baseline and every 2 min throughout the infusion. Each symptom was rated in intensity from 0
105
to 4 (not present-mild-moderate-severe-very severe). Infusions were stopped when a patient met the following criteria for a panic attack: the development of at least four symptoms from the PDS or an increase in intensity of symptoms present at baseline; and an increase in subjective apprehension or fear that had to be of at least moderate intensity. Scores on the PDS were further subdivided into psychological symptoms of anxiety (PDS-A, which includes items l-5 of the PDS) and somatic symptoms of anxiety (PDS-9, which includes the remaining symptoms of the PDS without the symptom of general nervousness; see Table I). Raters did not know the nature of the infusion given to the subject but were usually aware whether the subject was a patient or a control. Subjects did not know the nature of the experimental solution they received, but they knew that they had a one in three chance to receive lactate, isoproterenol, or placebo, and that lactate and isoproterenol may cause anxiety. Subjects were not told when the placebo (dextrose) lead-in was switched to the experimental infusion, but were told when the infusion was stopped. Statistics. The x2 test was used to compare sex distribution in the groups of panicking patients, nonpanicking patients, and nonpanicking controls. The x2 test was also used to compare the frequency of symptoms which increased first from baseline among the groups. One-way analysis of variance (ANOVA) was used to compare age, the rate of isoproterenol infusion, A values (A value = peak value minus baseline value) of total PDS scores; A values of PDS-A; A values of PDS-9; and A values of each individual symptom for all three groups. Newman-Keuls tests were used for post hoc comparison of individual cells. Two-tailed t tests were used for comparison of A values of some individual symptoms between panicking and nonpanicking patients when values in the control group equaled zero. A stepwise multiple regression analysis (SMRA) was done using the A values of PDS items to determine which items were significantly associated with isoproterenol-induced panic attacks in patients. Panic vs. nonpanic or patient vs. control was used as the criterion variable, and the PDS symptoms were used as predictor variables. These analyses were performed in panicking patients vs. nonpanicking patients, panicking patients vs. nonpanicking controls, and nonpanicking patients vs. nonpanicking controls. Pearson’s product-moment correlations were obtained to examine the relationship between individual psychological symptoms and PDS-B (total of somatic symptoms) and between psychological symptoms and specific somatic symptoms from PDS-B characteristic of adrenergic activation such as heart pounding, shortness of breath, sweating, and tremulousness in each group. Two-tailed t tests were used to compare the correlation coefficients of panicking and nonpanicking patients when these were significant. A probability value of 0.01 for correlation coefficients in at least one group was chosen due to the large number of comparisons. Nonpanicking controls were not used for this comparison as the majority of their correlation coefficients were not meaningful (both values equal 0).
Results There was an overall significant difference in sex distribution among the three groups h2 = 11.2, df= 2, p < 0.01): females were significantly more represented among panicking patients than among nonpanicking patients and nonpanicking controls. The difference in age was not significant (F= 2.4; df= 2, 114; NS). There was an overall significant difference in isoproterenol infusion rates among the three groups (F= 3.5; df = 2, 114;~ < 0.05). The infusion rate of panicking patients was significantly higher than the rate of nonpanicking patients (Q = 3.8, df = 1 12, p < 0.05), and the infusion rate of nonpanicking controls was higher than the rate of nonpanicking patients (Q= 3.0, df = 112,~ < 0.05). The difference between rates of
106 panicking patients and nonpanicking controls was not significant NS). Table I summarizes the results of ANOVA of A PDS items. usually had significantly higher A values of PDS items or totals patients and nonpanicking controls. For some symptoms (things fears of dying, losing control, or going crazy; and paralyzed and
(Q=
0.8, C-/J= I 12,
Panicking patients than nonpanicking do not seem real; going blind) there
Table 1. Comparison of A Panic Description Scale (PDS) of patient panickers, patient nonpanickers, and control nonpanickers Patient panickers (n = 54) (mean f SD)
Patient nonpanickers (n = 24) (mean f SD)
Control nonpanickers (n = 37) (mean f SD)
Analysis of variance (c/f always 2,114)
PDS-A (psychological symptoms)
1.Feeling
1.1 f
l.l’Tf
0.5 f
2. Things don’t seem real
0.7 f
1.0
0.3 + 0.6
o+o
t = 1.8. NS
3. Afraid of dying
0.4 f
0.8
0.1 + 0.4
Of0
t =
4. Afraid of losing control
0.9 f
1.2
0.1 f
Of0
t = 3.3, p < 0.01
5. Afraid of going crazy
0.5 f
1.1
0.2 + 0.5
3.3 +
3.8”TT
0.8 f
frightened
or afraid
Total A PDS-A PDS-B (somatic
1.40
0.03
0.5
+ 0.2
1.8, NS
t = 1.2, NS
o+o
1.3
F-14.o,p
Ps,hiatr_v Research. 32: IO3-I I2 Elsevier
Somatic and Psychological Symptoms Isoproterenol-Induced Panic Attacks Richard Balon, Vikram Richard Berchou Received 1989.
K. Yeragani,
Robert
May 18. 1989; revised version received November
During
Pohl,
John
Muench,
IO, 1989; accepted
and
December 20.
Abstract. To determine which symptoms characterized isoproterenol-induced panic attacks, we analyzed the presence of panic attacks in 54 panic disorder patients who panicked, 24 patients who did not panic, and 37 controls who did not panic during isoproterenol infusions. The increases over the baseline of the symptoms shortness of breath and fear of going crazy were highly associated with panicking patients when compared to nonpanicking patients and nonpanicking controls. The increases of the symptoms trembling and shaking, generally nervous, and fear of going crazy were highly associated with patients when compared to controls. The possibility of a cognitive theory of panic attacks is discussed. Key Words. theory.
Isoproterenol,
panic
attack,
panic
disorder
patients,
cognitive
Panic attacks are episodes of intense anxiety accompanied by other symptoms such as heart pounding, chest pain or tightness, shortness of breath, sweating, and faintness (American Psychiatric Association, 1987). Some symptoms of panic attacks are similar to the symptoms of j?-adrenergic activation-namely, heart pounding, shortness of breath, sweating, and tremulousness. Various laboratory methods of provocation of panic attacks have been reported, with sodium lactate being the most studied one (Liebowitz and Hollander, 1989). We reported on panic attacks induced by isoproterenol, a &agonist, in panic disorder patients (Rainey et al., 1984; Pohl et al., 1985, 1988; Balon et al., 1988a, 19886). Panic disorder patients are more sensitive than controls to the effect of isoproterenol (Pohl et al., 1988). Isoproterenol was less sensitive, but more specific than lactate in the induction of panic attacks in panic disorder patients (Balon et al., 1988~). Phenomenological analysis revealed a similarity of isoproterenol-induced panic attacks to presumably spontaneous panic attacks during dextrose (placebo) infusion
Richard
Balon, M.D., is Assistant Professor of Psychiatry, Wayne State University, and Staff Psychiatrist, Adult Outpatient Department, Lafayette Clinic, Detroit, Ml. Vikram K. Yeragani, M.D., is Associate Professor of Psychiatry, Wayne State University, and Assistant Director, Outpatient Department, Lafayette Clinic, Detroit, MI. Robert Pohl, M.D., is Associate Professor of Psychiatry, Wayne State University, and Director, Outpatient Department, Lafayette Clinic, Detroit, MI. John Muench, M.D., was a medical student at Wayne State University School of Medicine when this research was carried out. Richard Berchou, Pharm.D., is Research Scientist, Lafayette Clinic. (Reprint requests to Dr. R. Balon, Lafayette Clinic, 95 I E. Lafayette, Detroit, MI 48207, USA.) 0165-I 781/90/$03.50
@ 1990 Elsevier Scientific
Publishers Ireland
Ltd.
104 (Balon et al., 19886). The symptom analysis of lactate-induced panic attacks (Yeragani et al., 1989) revealed that symptoms of shortness of breath, feeling frightened, feeling dizzy, and fear of losing control were significantly associated with lactate-induced panic and also that cognitive symptoms of fear of losing control and fear of going crazy appeared to be important determinants of lactate-induced panic. Clark (1986), in his review of a cognitive approach to panic attacks, postulated that panic attacks are the result of a catastrophic misinterpretation of certain bodily sensations. lsoproterenol produces panic attacks similar to the spontaneous attacks, and some of the peripheral symptoms (e.g., heart pounding) characteristic for isoproterenol-induced panic attacks are similar to the somatic symptoms of spontaneous panic attacks. We infused 86 patients and 45 healthy controls with isoproterenol. These were the same subjects as in our previous report on lactate and isoproterenol infusions (Balon et al., 1988a), but two of the patients are different individuals from 2 of the 86 patients described in another report on isoproterenol infusions (Pohl et al., 1988). In this study we analyzed which symptoms are most frequently associated with isoproterenol-induced panic attacks. We also examined the relationship of somatic symptoms of isoproterenol-induced panic attacks to psychological symptoms.
Methods Subjects.
All subjects were voluntary participants in our Anxiety Disorder Research Program at Lafayette Clinic. All patients met Research Diagnostic Criteria (RDC; Spitzer et al., 1978) for panic disorder and were actively symptomatic with an average of at least one panic attack per week. Nonpsychiatric controls reported no history of panic disorder or other mental disorder. All subjects did not take any psychotropic medication for at least 2 weeks before and throughout the infusion procedures. Subjects with a history of endocrine, respiratory, hepatic, renal, or cardiac disease other than mitral valve prolapse, and psychiatric illnesses other than panic disorder and agoraphobia with panic attacks were excluded from the study. Each subject had a complete physical examination, blood chemistry tests, blood count, urinalysis, and an electrocardiogram. We obtained complete isoproterenol infusion data on the Panic Description Scale (Rainey et al., 1984) for 78 patients and 41 controls. Of these, there were 54 panicking patients (I6 males and 38 females; mean age = 32.2 years; SD = 7.5; range 20-48) and 24 nonpanicking patients( I4 males and IO females; mean age = 33.0 years; SD = 7.9; range 18-51). Thirtyseven controls did not panic (23 males and I4 females; mean age= 29.3 years; SD = 6.6; range 22-48) and four did (I male and 3 females; mean age = 30.5 years; SD = I .8; range 29-32). We did not use the group of controls who panicked with isoproterenol for any analysis as the number of subjects (4) in this group was too small for any meaningful comparison. Procedure.
This communication is a part of a double-blind, placebo-controlled study of randomized infusions of sodium lactate, isoproterenol, and dextrose in panic disorder patients. The procedure has been described in detail elsewhere (Balon et al., 1988~). All subjects were infused with 20 ,ug of isoproterenol in D5W; the flow was adjusted by gravity feed to deliver a volume of 6 ml/kg over 20 min. The infusion rates (in pg/min/ kg) were 13.9 + 4.9 for patient panickers, I I. I + 3.9 for patient nonpanickers, and 13.3 * 3.9 for control nonpanickers. The Panic Description Scale (PDS), a 2l-item self-rating panic scale (Rainey et al., 1984) constructed from the RDC (Spitzer et al., 1978) criteria for panic disorder, was used to identify panic attacks. The PDS was administered during the baseline and every 2 min throughout the infusion. Each symptom was rated in intensity from 0
105
to 4 (not present-mild-moderate-severe-very severe). Infusions were stopped when a patient met the following criteria for a panic attack: the development of at least four symptoms from the PDS or an increase in intensity of symptoms present at baseline; and an increase in subjective apprehension or fear that had to be of at least moderate intensity. Scores on the PDS were further subdivided into psychological symptoms of anxiety (PDS-A, which includes items l-5 of the PDS) and somatic symptoms of anxiety (PDS-9, which includes the remaining symptoms of the PDS without the symptom of general nervousness; see Table I). Raters did not know the nature of the infusion given to the subject but were usually aware whether the subject was a patient or a control. Subjects did not know the nature of the experimental solution they received, but they knew that they had a one in three chance to receive lactate, isoproterenol, or placebo, and that lactate and isoproterenol may cause anxiety. Subjects were not told when the placebo (dextrose) lead-in was switched to the experimental infusion, but were told when the infusion was stopped. Statistics. The x2 test was used to compare sex distribution in the groups of panicking patients, nonpanicking patients, and nonpanicking controls. The x2 test was also used to compare the frequency of symptoms which increased first from baseline among the groups. One-way analysis of variance (ANOVA) was used to compare age, the rate of isoproterenol infusion, A values (A value = peak value minus baseline value) of total PDS scores; A values of PDS-A; A values of PDS-9; and A values of each individual symptom for all three groups. Newman-Keuls tests were used for post hoc comparison of individual cells. Two-tailed t tests were used for comparison of A values of some individual symptoms between panicking and nonpanicking patients when values in the control group equaled zero. A stepwise multiple regression analysis (SMRA) was done using the A values of PDS items to determine which items were significantly associated with isoproterenol-induced panic attacks in patients. Panic vs. nonpanic or patient vs. control was used as the criterion variable, and the PDS symptoms were used as predictor variables. These analyses were performed in panicking patients vs. nonpanicking patients, panicking patients vs. nonpanicking controls, and nonpanicking patients vs. nonpanicking controls. Pearson’s product-moment correlations were obtained to examine the relationship between individual psychological symptoms and PDS-B (total of somatic symptoms) and between psychological symptoms and specific somatic symptoms from PDS-B characteristic of adrenergic activation such as heart pounding, shortness of breath, sweating, and tremulousness in each group. Two-tailed t tests were used to compare the correlation coefficients of panicking and nonpanicking patients when these were significant. A probability value of 0.01 for correlation coefficients in at least one group was chosen due to the large number of comparisons. Nonpanicking controls were not used for this comparison as the majority of their correlation coefficients were not meaningful (both values equal 0).
Results There was an overall significant difference in sex distribution among the three groups h2 = 11.2, df= 2, p < 0.01): females were significantly more represented among panicking patients than among nonpanicking patients and nonpanicking controls. The difference in age was not significant (F= 2.4; df= 2, 114; NS). There was an overall significant difference in isoproterenol infusion rates among the three groups (F= 3.5; df = 2, 114;~ < 0.05). The infusion rate of panicking patients was significantly higher than the rate of nonpanicking patients (Q = 3.8, df = 1 12, p < 0.05), and the infusion rate of nonpanicking controls was higher than the rate of nonpanicking patients (Q= 3.0, df = 112,~ < 0.05). The difference between rates of
106 panicking patients and nonpanicking controls was not significant NS). Table I summarizes the results of ANOVA of A PDS items. usually had significantly higher A values of PDS items or totals patients and nonpanicking controls. For some symptoms (things fears of dying, losing control, or going crazy; and paralyzed and
(Q=
0.8, C-/J= I 12,
Panicking patients than nonpanicking do not seem real; going blind) there
Table 1. Comparison of A Panic Description Scale (PDS) of patient panickers, patient nonpanickers, and control nonpanickers Patient panickers (n = 54) (mean f SD)
Patient nonpanickers (n = 24) (mean f SD)
Control nonpanickers (n = 37) (mean f SD)
Analysis of variance (c/f always 2,114)
PDS-A (psychological symptoms)
1.Feeling
1.1 f
l.l’Tf
0.5 f
2. Things don’t seem real
0.7 f
1.0
0.3 + 0.6
o+o
t = 1.8. NS
3. Afraid of dying
0.4 f
0.8
0.1 + 0.4
Of0
t =
4. Afraid of losing control
0.9 f
1.2
0.1 f
Of0
t = 3.3, p < 0.01
5. Afraid of going crazy
0.5 f
1.1
0.2 + 0.5
3.3 +
3.8”TT
0.8 f
frightened
or afraid
Total A PDS-A PDS-B (somatic
1.40
0.03
0.5
+ 0.2
1.8, NS
t = 1.2, NS
o+o
1.3
F-14.o,p
