- Email: [email protected]
Measurement of lactate-induced panic and anxiety
97
Ps.vchiafr>, Research. 20. 97-105
Elsevier
Measurement
of Lactate-Induced
Donald J. Dillon, Jack M. Gorman, Donald F. Klein
Michael
Received January 31, 1986;
received
revised
version
Panic and Anxiety R. Liebowitt,
April
16, 1986;
Abby J. Fyer, and
ac~crpfed
April
,7/.
1986.
Abstract. Acute Panic Inventory (API) scores were obtained from 26 normal controls and 89 patients with either panic disorder or agoraphobia with panic attacks before and during lactate infusions. Retrospective ratings of the patients’ usual spontaneous attacks were much higher, by API, than ratings of moments of severe stress by the controls. Point of panic API scores, as well as increments of panic scores over prelactate scores, were higher for patients who experienced lactate panics than for both controls and patients who did not panic. Key Words.
Acute Panic Inventory,
lactate infusions, agoraphobia.
There are many instruments available to the clinician and researcher for characterizing the nature and severity of anxiety (e.g., Taylor, 1953; Zuckerman, 1960; Spielberger et al., 1970). With increasing realization that panic attacks are among the most common and important forms of anxiety reaction, and that they are distinct from generalized anxiety, the need for a measurement specific to panic has become apparent. Ideally, such an instrument would have the following features: (I) Be rapidly administered, since panic attacks are fairly evanescent events and consequently must be assessed in a matter of minutes. (2) Differentiate a true panic attack as experienced by a patient with panic disorder from the anxiety of patients with generalized anxiety disorder or the anxiety of stress reactions experienced by normal individuals. (3) Demonstrate a clear incremental increase in symptoms and severity from baseline to the point of an attack. (4) Establish an absolute level score or absolute change from baseline score that reliably distinguishes a panic attack from other forms of anxiety reaction. In connection with our ongoing sodium lactate infusion experiment (Liebowitz et al., 1984), we used a rating scale called the Acute Panic Inventory (API), an instrument developed at Hillside Hospital and modified for inclusion in our lactate studies. The API was specifically designed to measure the severity of symptoms that typically occur during the spontaneous panic attacks of patients with panic disorder.
Donald J. Dillon, Ph.D., is Associate Research Scientist (Psychology);
Jack M. Gorman. M.D.. Michael are Assistant Professors ofClinical Psychiatry; and Donald F. Klein, M.D., is Director ofResearch and Professor of Psychiatry, New York State Psychjatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia tlniversity. (Reprint requests to Dr. D.J. Dillon, N.Y. S. State Psychiatric Institute, 722 W. 168 St., New York, NY 10032. USA.) R. Liebowitz,
M.D.,
0165-1781/87/$03.50
and Abby J. Fyer, M.D.,
@ 1987 Elsevier Science Publishers R.V
98 Each of the I7 items on the scale represents one common symptom of a panic attack and is rated on a 4-point scale: zero (symptom not experienced); I.0 (slight experience); 2.0 (moderate experience); 3.0 (severe experience of symptom). The API can be administered in minutes and yields a total score from 0 to 51. Subjects can be asked to respond to the questions as if they were currently undergoing a typical panic attack, as if they were currently undergoing a period of marked stress, or as they feel at the moment. Presumably, if the API measures panic over and above anticipatory anxiety, it will yield high scores for patients with panic disorder responding as if they were having a typical panic attack and for patients actually experiencing panic attacks. Lower scores should be obtained by patients responding at times when they were not having a panic attack and by controls responding as if they were simply undergoing moments of acute stress. It is now well known that many patients with panic disorder experience an acute panic attack during sodium lactate infusion (Pitts and McClure, 1967; Bonn et al., 1971; Kelly et al., 1971; Rifkin et al., 1981). In studies already published (Appleby et al., 1980; Dillon et al., 1982; Liebowitz et al., 1984), we have shown that API scores are higher for patients experiencing an acute, lactate-induced panic attack than for patients or normal controls who do not panic during the infusion. Furthermore, the point-of-panic API scores during the infusion are very similar to the scores obtained from the same patients when describing their typical attacks. Several other issues with respect to both the sodium lactate infusion and the API need clarification: (I) Is the increment in API score from baseline to point of panic during a lactate infusion greater than the increment in API score from baseline to similar time points during a lactate infusion for nonpanicking patients and controls? Such an incremental difference would indicate that patients having a lactate-induced panic attack actually experience a quantitatively unique experience during the infusion. This argues against a hypothesis that lactate infusions elevate anxiety levels similarly in all individuals, and the lactate-induced panic/anxiety simply reflects higher levels of prelactate anxiety. (2) Is there an absolute score on the API or a specific increment in score from baseline that reliably identifies patients who actually experience a panic attack during a lactate infusion? If so, then standardization of the judgment of patient responses to lactate across laboratories would be possible.
Methods Eighty-nine
patients with panic disorder or agoraphobia
with panic attacks according to
DSM-I//criteria (American Psychiatric Association, 1980) underwent sodium lactate infusion in our laboratory. The patients were 39 men and 50 women with a mean age of 33. I (SD 7.6) years. In addition, we infused 26 normal volunteers, 17 men and 9 women, with a mean age of 28.6 (SD 7.0 years). (See Table I .) Subjects were recruited by media presentations, advertisements, medical referrals, and word of mouth. All subjects were in good medical health. Patients were excluded if they had concurrent major depressive disorder or current psychoactive drug use that could not be discontinued at least 2 weeks before infusion. Controls were excluded if any psychopathological state was evident on semistructured interview or if any first degree relative had a history of panic disorder. All consecutive subjects whose infusions were without procedural difficulty have been included in this report. Such procedural difficulties included extended infusions with lactate
99
Table 1. Mean (k SD) ages of controls, nonpanic patients (NP), early panic patients (EP), and late panic patients (LP) by sex Controls Sex n Mean+SD
Male 17 29.0+6.6
NP
Female
Male
Female
12
22
9 28.9zt8.2
32.5k8.0
LP
EP
33.0f8.0
Male 6 32.Ok6.8
Female
Male
19
19
32.1+7.6
33.0f7.1
Female 11 35.8f7.5
(> 22.5 minutes), the occurrence of panic during the preliminary saline or dextrose placebo infusion, or i.v. infiltration. The procedure used for sodium lactate infusion has been described in detail elsewhere (Liebowitz et al., 1984). Briefly, the subject first receives a slow i.v. infusion of either dextrose in water or normal saline for 30 minutes to test the response to placebo. Then, under singleblind conditions, the infusion is switched to half-molar racemic sodium lactate IO cc/ kg. This is continued for 20 minutes unless the subject has a panic attack, at which point the procedure is terminated. The API is administered serially throughout the procedure. The individual items of the API are presented in Table 2. On the day before the actual infusion, all subjects are asked by one investigator to respond verbally to the API items in two ways. First, the patients are asked to rate the items as experienced during a typical panic attack, while the controls are asked to rate themselves as if they were undergoing a period of severe stress-the “usual” score. Second, all subjects are asked to rate themselves as they feel at the moment-the “baseline” score. On the day of the infusion, the same investigator, who although not blind as to patient status, was not involved in judging the infusion result, asked the subjects again to rate themselves at the point just before the i.v. catheter is inserted (preneedle score), at the end of the placebo infusion (prelactate score), IO minutes after the lactate infusion is begun (first half score), and at the end of the infusion at 20 minutes (second half score). The API was also obtained immediately at the point of a panic attack, if one occurred. If the panic occurred in the first IO minutes of lactate infusion, the point-of-panic rating is used as the first half score. In that case, no second half score is collected.
Table 2. The 17 items of the Acute Panic Inventory Do you feel faint? Are you afraid of dying? Are you generally fearful? Do you have heart palpitations? Do you have any difficulty in breathing, or are you breathing rapidly? Do you have the urge to urinate? Do you have the urge to defecate? Do you feel dizzy or light-headed? Do you feel confused? Do you have a sense of unreality? Do you feel detached from part or all of your body? Is it difficult for you to concentrate? Are you sweating? Is it difficult for you to speak? Would it be difficult for you to do a job? Do you feel any shakiness, trembling, or twitching? Do vou feel nauseous? Ratings were: not at all (O),slight (l), moderate (2), or severe (3)
100 The clinical designation of panic during the infusion was based on the attending psychiatrist’s observation of an abrupt escalation of fear and distress accompanied by the typical physical symptoms of an attack. Physical symptoms alone were not sufficient to judge the occurrence of an attack. API scores for patients who had attacks within the first IO minutes of the infusion were compared to the first half score obtained at the end of IO minutes of the infusion for the nonpanicking patients and the controls. Similarly, API scores for patients who had attacks between IO and 20 minutes of the infusion were compared to the second half score for the nonpanicking patients and controls. Because of the ordinal nature of the data, nonparametric tests were used for statistical analysis. These included Wilcoxon and Mann-Whitney tests.
Results Fifty-five
of the 89 patients
lactate infusion. and are referred
with
Twenty-five to as “early
panic
disorder
had acute
of these had their attacks panickers.” The remaining
panic
within
attacks the first
during
the
IO minutes
30 had their attacks in the last 10 minutes of the infusion and are referred to as “late panickers.” Thirty-four of the patients and all 26 of the normal controls received the full 20-minute dose of lactate without experiencing an attack. There were no relationships between the occurrence of lactate-induced panic and sex, age, or the presence of agoraphobia within the patients. The API items were summed for each subject at each administration of the instrument to yield a single score per subject per administration. Medians for the four groups (presented in Fig. I, Tables 3 and 4) were calculated at each point of administration: controls, patients who did not panic (NP), early panickers (EP), and late panickers (LP). Scores obtained from all three patient groups (NP, EP, and LP)
Fig. 1. Acute Panic Inventory (API) scores before and during lactate infusions and when rating stress or panic attacks retrospectively
Pafienb
Early Panic pfn=251 !. /
Putients: Late Panic fn =301 Patients:. n rJlon%
Controls
Bose
PreNeedle
PreLocfate
IOI
Table 3. Medians and semi-interquartile ranges of total weighted Acute Panic Inventory scores at each administration of the test for each of the 4 groups Baseline Preneadle Prelactate 1st half 2nd half Usual Controls (n = 26)
3.0 + 3.0
0.0 k 0.5
0.0 + 1 .o
1 .o + 1 .o
2.5 k 3.0
4.5 f 3.5
23.5 f 4.5
2.0 + 2.5
4.0 + 4.0
3.5 k 2.5
9.0 + 5.0
14.0 f 6.5
25.0 +- 3.5
4.0 + 2.5
6.0 f 3.5
8.0 f 3.5
23.0 f 3.5
26.0 f 6.5
3.0 + 2.5
4.0 * 2.0
7.0 + 3.5
12.5 f 3.5
Nonpanic patients (n = 34) Early panic patients (n = 25)
--
Late panic patients (n = 30)
20.0 f 0.5
Table 4. Levels of significance (2-tailed) of intergroup comparisons (MannWhitney U tests) at each administration of the Acute Panic Inventory for data in Table 3 Usual
Baseline Preneedle Prelactate 1st half
2nd half
Controls:NP
0.000
0.006
0.000
0.000
0.001
Control:EP
0.000
0.000
0.000
0.000
0.000
--
Control:LP
0.000
0.000
0.000
0.000
0.000
0.000
0.000
NP:EP
NS
NS
NS
0.010
0.000
--
NP:LP
NS
0.027
NS
0.040
0.003
0.001
EP:LP
NS
NS
NS
NS
0.000
--
NP = Nonpanic patients. EP = Early panic patients. LP = Late panic patients.
when describing their usual panic attacks were significantly higher than the scores obtained by controls describing the experience of extreme stress, with no differences among the patient groups. When rating themselves on the basis of how they felt at the moment on baseline day, all three patient groups achieved scores slightly but significantly higher than controls but essentially indistinguishable from each other. This was also the case for the preneedle assessment on the actual infusion day. At the prelactate point, not only did all three patient groups have a higher score than the controls, but the two patient groups that would go on to panic (EP and LP) now obtained higher scores than the group of patients that would not go on to panic (NP). However, only five of the patients in the EP and LP groups achieved scores greater than the highest score obtained by NP patients. Therefore, it was not possible to predict which patients would subsequently panic from the prelactate API score. The point-of-panic API score for the EP group was higher than the first half score for the LP and NP patients, and for the controls. The score for the NP group was greater than for the controls. Similarly, the point-of-panic score for the LP group was higher than the second half score for the NP patients and the controls. The NP group also attained higher scores than the controls at the second half administration. Point-of-panic scores for the EP group were almost indistinguishable from their scores when rating their usual panic attack. The LP group, however, had a point-ofpanic score significantly (Wilcoxon test, two-tailed) lower than their usual score. The
102 NP usual score was considerably and significantly higher than either of the NP scores obtained during the infusion. It is possible that the high API scores at the point of panic for the EP and LP groups merely reflect the relatively high scores obtained by these groups before starting the infusion. In this case, the increase in API score for the EP and LP group would simply parallel the increase for the NP and control groups. Instead of measuring a panic attack, the API would be reflecting some form of increased arousal or anxiety common to all subjects who undergo a lactate infusion (see Margraf et al., 1981). Therefore, the increments in API over the prelactate score were computed for all four groups (Tables 5 and 6). The patients who had panic attacks had significantly greater increments than the control group, as well as the patients who did not panic. There was no significant difference between the increments of the controls and the nonpanickers.
Table 5. Medians and semi-interquartile ranges of increments in Acute Panic Inventory scores at point of panic or 1st or 2nd half scores over prelactate scores for the 4 groups Increments over prelactate
Controls
NP
Panic or 1st half
2.0 f 2.5
3.0 f 2.5
Panic or 2nd half
3.0 + 3.0
7.5 * 4.5
EP 16.0 + 2.5 --
LP 5.5 k 2.5 15.0 Ik 5.0
NP = Nonpanic patients. EP = Early panic patients. LP = Late panic patients.
Table 6. Levels of significance (2-tailed) of intergroup comparisons (Mann-Whitney U tests) for increments in Table 5 Increments over Prelactate Panic or 1st half Panic or 2nd half
C:NP NS NS
C:LP
C:EP
0.000 0.000
0.000 --
NP:LP LP:EP NP:EP 0.014 0.014
0 200 --
0.000 --
C = Control. NP = Nonpanic patients. EP = Early panic patients. LP = Late panic patients
We attempted to find either an absolute level API score or increment in API score from prelactate to infusion termination that would distinguish the panicking patients from the nonpanickers. A first half score > 20, or an increment of the first half scores over prelactate scores > 13 completely separated the early panickers from the nonpanickers and the controls, and from 24 of the late panickers. However, these criteria falsely identified 6 of the 30 LP patients as early panickers. The sensitivity in distinguishing early panickers from nonpanickers and controls was 84% and the specificity was 100%. When these same criteria of 20 and 13 were applied to the second half scores, six nonpanicking patients and no controls were misidentified as late panickers, whereas 18 of the 30 late panickers were correctly identified. Relative to the nonpanicking
103 patients, the sensitivity was 82%.
for the LP group with this cutoff was 60% and the specificity
Discussion The Acute Panic Inventory appears robust in differentiating panic attacks from other forms of stress and anxiety. In this study, the API differentiated the typical panic attacks of patients with panic disorder from the stress reactions of normal controls and demonstrated that the lactate-induced attacks were quite similar to those typical attacks. Although the API yielded higher scores for patients about to have a lactateinduced attack than for patients or controls who were not about to panic (i.e., the prelactate scores), these scores were not so high as achieved during the attack itself. The prelactate scores did not correlate well with actually having an attack during the lactate infusion, and therefore did not serve as good actuarial predictors of those who would go on to panic. It appears, then, that the API is a valid instrument for rating a panic attack, and separating panic from anticipatory anxiety. Therefore, we can usefully turn to the question of what it tells us about the characteristics of a lactate-induced attack. Using the API in these lactate infusion experiments yields five main observations: I. Patients who will go on to panic during a lactate infusion show heightened anticipatory anxiety in the minutes ‘before lactate infusion is started. The level of anticipatory anxiety (prelactate API) is, however, a significant but poor predictor of panic occurrence. 2. A lactate-induced panic attack has the same overall severity of symptoms as do naturally occurring panic attacks. Thus, scores achieved by early panickers (but not the late panickers) during the panic attack are virtually identical to those the patients give themselves when retrospectively characterizing a usual panic attack. On the other hand, patients who do not panic during the infusion do not achieve API scores that approximate what they obtain when retrospectively characterizing their usual attacks. The physical symptoms associated with the lactate infusion alone-increased heart rate, tremulousness, urinary urgency and dry mouth-are not enough to increase the API score into the “panic” range. 3. Even though patients start out with higher API scores just before lactate than normal controls (presumably because of increased anticipatory anxiety), the high API score obtained during a panic attack is not simply a reflection of higher prelactate anxiety. The increase in API scores from prelactate to termination of the infusion is not parallel in patients who panic and subjects who do not panic, Because the increment in score from prelactate is significantly greater for the subjects who panic, we can conclude that the panic attack is a qualitatively and quantitatively distinct phenomenon. 4. There appears to be a difference between panic attacks that occur in the first IO minutes of a lactate infusion and attacks that occur in the last IO minutes. We were able to find an absolute API score and an increment in API score over baseline that completely distinguished the early panickers from controls and patients who did not
104
panic during the first half of the infusion (both NP and LP groups). This was not so clear cut for the late panickers. The difference appears due to the increase in symptomatology after 20 minutes of lactate infusion in the nonpanicking patients, which substantially exceeds the increment in the controls. The fact that the second half scores were significantly lower than the usual scores for the LP group also suggests that the later panic reactions to the lactate may differ from those occurring during the first 10 minutes. 5. Since the symptomatology by API score of the nonpanickers at 20 minutes far exceeds that of the controls but is lower than their own reported usual panic API score, it appears that lactate is active in the nonpanicking patients even though it does not cause frank panic. This is especially true of the lactate effects seen in the LP patients during the first half of the infusion. We have hypothesized that the clinical panic attack consists of two stages: an initial increase in tension (probably accompanied by hyperventilation) followed by an abrupt crescendo. Panic patients receiving lactate regularly seem to experience the first stage, although controls do not. If the crescendo phase is triggered early in the infusion, then our symptom inventory clearly picks this up. If the crescendo occurs late, then the smaller panic report combined with the increased symptoms of the nonpanickers compromises the ability of the API to detect panic. The NP patients seem to be experiencing the initial increase in tension, perhaps of a magnitude insufficient to trigger the abrupt crescendo necessary for a lactate panic. If this differentiation between early and late panicking patients is correct, other measures of panic such as heart rate, minute ventilation, and skin conductance might be similarly affected. Hence, a sudden burst in heart rate would be expected to occur in patients panicking during the first 10 minutes of a lactate infusion, but because heart rate might be so high in all subjects by 20 minutes into the infusion, no further increase in heart rate would be detected in patients panicking late in the infusion. We are currently investigating this possibility using these other dependent measures of panic anxiety. Acknowledgment. The research reported was supported in part by MH-903-1163G and MH-CR903C006 from the National Institute of Mental Health and by Research Scientist Development Award MH-000416 to Dr. Gorman. The authors thank Samuel Anderson, Ph.D., and Andrew Levin, M.D., for their suggestions, as well as Gail Levy, Ph.D., Michael Palij, Barry Cohen, and John Pavlos for data-analytic assistance.
References American
Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. APA, Washington, DC (1980). Appleby, I.L., Klein, D.F., Sachar, E.J., and Levitt, M. Biochemical indices of lactateinduced panic: A preliminary report paper. Presented at the Annual Meeting of the American Psychopathological Association, Washington, DC, March (1980). Bonn, J.A., Harrison, J., and Rees, W.L. Lactate-induced anxiety: Therapeutic applications. British Journal of Psychiatry, 119,460 (1971). Dillon, D.J., Levitt, M., Klein, D.F., and Danielson, E. Some physiological, biochemical and psychological concomitants of lactate-induced panic. In: Maletesha, R.N., and Hartlage, L.C., eds. Neuropsychology and Cognition. Vol. II. Nijhoff, The Hague/ Boston/ London, p. 651 (1982).
105
Kelly, D., Mitchell-Heggs, N., and Sherman, D. Anxiety and the effects of sodium lactate assessed clinically and physiologically. &iris/r Journal qf Psychiatry. 119, I29 ( I97 I). Liebowitz, M.R., Fyer, A.J., Gorman, J.M., Dillon, D.J., Appleby, I.L., Levy, G., Anderson, S., Levitt, M., Palij, M., and Davies, S.O. Lactate provocation of panic attacks: I. Clinical and behavioral findings. Archives qfGenera/ Psychiatry. 41, 764 (1984). Margraf, J., Ehlers, A., and Roth, W.T. Current biological models of panic disorder: A look at the evidence. Unpublished manuscript (1981). Pitt% F.N., Jr., and McClure, J.N., Jr, Lactate metabolism in anxiety neurosis. N~JM England Journal of Medicine, 277, I320 ( 1967). Rifkin, A., Klein, D.F., Drllon, D., and Levitt, M. Blockade by imipramine or desipramine of panic induced by sodium lactate. American Journal oj’P.s,vc.hiatry. 138, 767 ( I98 I). Spielberger, C.D., Gorsuch, R.L., and Lushene, R.E. The State-Trait Anxiet_v /nventor_l~: Test Manua/fijr Form X. Consulting Psychologists Press, Palo Alto, CA (1970). Taylor, J.A. A personality test of manifest anxiety. Journal of Abnormal and Skial Psychology, 48, 285 (I 953). Zuckerman, M. The development of an affect adjective checklist for the measurement of anxiety. Journal of’Con.wlting Psychology. 24, 457 ( 1960).
Ps.vchiafr>, Research. 20. 97-105
Elsevier
Measurement
of Lactate-Induced
Donald J. Dillon, Jack M. Gorman, Donald F. Klein
Michael
Received January 31, 1986;
received
revised
version
Panic and Anxiety R. Liebowitt,
April
16, 1986;
Abby J. Fyer, and
ac~crpfed
April
,7/.
1986.
Abstract. Acute Panic Inventory (API) scores were obtained from 26 normal controls and 89 patients with either panic disorder or agoraphobia with panic attacks before and during lactate infusions. Retrospective ratings of the patients’ usual spontaneous attacks were much higher, by API, than ratings of moments of severe stress by the controls. Point of panic API scores, as well as increments of panic scores over prelactate scores, were higher for patients who experienced lactate panics than for both controls and patients who did not panic. Key Words.
Acute Panic Inventory,
lactate infusions, agoraphobia.
There are many instruments available to the clinician and researcher for characterizing the nature and severity of anxiety (e.g., Taylor, 1953; Zuckerman, 1960; Spielberger et al., 1970). With increasing realization that panic attacks are among the most common and important forms of anxiety reaction, and that they are distinct from generalized anxiety, the need for a measurement specific to panic has become apparent. Ideally, such an instrument would have the following features: (I) Be rapidly administered, since panic attacks are fairly evanescent events and consequently must be assessed in a matter of minutes. (2) Differentiate a true panic attack as experienced by a patient with panic disorder from the anxiety of patients with generalized anxiety disorder or the anxiety of stress reactions experienced by normal individuals. (3) Demonstrate a clear incremental increase in symptoms and severity from baseline to the point of an attack. (4) Establish an absolute level score or absolute change from baseline score that reliably distinguishes a panic attack from other forms of anxiety reaction. In connection with our ongoing sodium lactate infusion experiment (Liebowitz et al., 1984), we used a rating scale called the Acute Panic Inventory (API), an instrument developed at Hillside Hospital and modified for inclusion in our lactate studies. The API was specifically designed to measure the severity of symptoms that typically occur during the spontaneous panic attacks of patients with panic disorder.
Donald J. Dillon, Ph.D., is Associate Research Scientist (Psychology);
Jack M. Gorman. M.D.. Michael are Assistant Professors ofClinical Psychiatry; and Donald F. Klein, M.D., is Director ofResearch and Professor of Psychiatry, New York State Psychjatric Institute and the Department of Psychiatry, College of Physicians and Surgeons, Columbia tlniversity. (Reprint requests to Dr. D.J. Dillon, N.Y. S. State Psychiatric Institute, 722 W. 168 St., New York, NY 10032. USA.) R. Liebowitz,
M.D.,
0165-1781/87/$03.50
and Abby J. Fyer, M.D.,
@ 1987 Elsevier Science Publishers R.V
98 Each of the I7 items on the scale represents one common symptom of a panic attack and is rated on a 4-point scale: zero (symptom not experienced); I.0 (slight experience); 2.0 (moderate experience); 3.0 (severe experience of symptom). The API can be administered in minutes and yields a total score from 0 to 51. Subjects can be asked to respond to the questions as if they were currently undergoing a typical panic attack, as if they were currently undergoing a period of marked stress, or as they feel at the moment. Presumably, if the API measures panic over and above anticipatory anxiety, it will yield high scores for patients with panic disorder responding as if they were having a typical panic attack and for patients actually experiencing panic attacks. Lower scores should be obtained by patients responding at times when they were not having a panic attack and by controls responding as if they were simply undergoing moments of acute stress. It is now well known that many patients with panic disorder experience an acute panic attack during sodium lactate infusion (Pitts and McClure, 1967; Bonn et al., 1971; Kelly et al., 1971; Rifkin et al., 1981). In studies already published (Appleby et al., 1980; Dillon et al., 1982; Liebowitz et al., 1984), we have shown that API scores are higher for patients experiencing an acute, lactate-induced panic attack than for patients or normal controls who do not panic during the infusion. Furthermore, the point-of-panic API scores during the infusion are very similar to the scores obtained from the same patients when describing their typical attacks. Several other issues with respect to both the sodium lactate infusion and the API need clarification: (I) Is the increment in API score from baseline to point of panic during a lactate infusion greater than the increment in API score from baseline to similar time points during a lactate infusion for nonpanicking patients and controls? Such an incremental difference would indicate that patients having a lactate-induced panic attack actually experience a quantitatively unique experience during the infusion. This argues against a hypothesis that lactate infusions elevate anxiety levels similarly in all individuals, and the lactate-induced panic/anxiety simply reflects higher levels of prelactate anxiety. (2) Is there an absolute score on the API or a specific increment in score from baseline that reliably identifies patients who actually experience a panic attack during a lactate infusion? If so, then standardization of the judgment of patient responses to lactate across laboratories would be possible.
Methods Eighty-nine
patients with panic disorder or agoraphobia
with panic attacks according to
DSM-I//criteria (American Psychiatric Association, 1980) underwent sodium lactate infusion in our laboratory. The patients were 39 men and 50 women with a mean age of 33. I (SD 7.6) years. In addition, we infused 26 normal volunteers, 17 men and 9 women, with a mean age of 28.6 (SD 7.0 years). (See Table I .) Subjects were recruited by media presentations, advertisements, medical referrals, and word of mouth. All subjects were in good medical health. Patients were excluded if they had concurrent major depressive disorder or current psychoactive drug use that could not be discontinued at least 2 weeks before infusion. Controls were excluded if any psychopathological state was evident on semistructured interview or if any first degree relative had a history of panic disorder. All consecutive subjects whose infusions were without procedural difficulty have been included in this report. Such procedural difficulties included extended infusions with lactate
99
Table 1. Mean (k SD) ages of controls, nonpanic patients (NP), early panic patients (EP), and late panic patients (LP) by sex Controls Sex n Mean+SD
Male 17 29.0+6.6
NP
Female
Male
Female
12
22
9 28.9zt8.2
32.5k8.0
LP
EP
33.0f8.0
Male 6 32.Ok6.8
Female
Male
19
19
32.1+7.6
33.0f7.1
Female 11 35.8f7.5
(> 22.5 minutes), the occurrence of panic during the preliminary saline or dextrose placebo infusion, or i.v. infiltration. The procedure used for sodium lactate infusion has been described in detail elsewhere (Liebowitz et al., 1984). Briefly, the subject first receives a slow i.v. infusion of either dextrose in water or normal saline for 30 minutes to test the response to placebo. Then, under singleblind conditions, the infusion is switched to half-molar racemic sodium lactate IO cc/ kg. This is continued for 20 minutes unless the subject has a panic attack, at which point the procedure is terminated. The API is administered serially throughout the procedure. The individual items of the API are presented in Table 2. On the day before the actual infusion, all subjects are asked by one investigator to respond verbally to the API items in two ways. First, the patients are asked to rate the items as experienced during a typical panic attack, while the controls are asked to rate themselves as if they were undergoing a period of severe stress-the “usual” score. Second, all subjects are asked to rate themselves as they feel at the moment-the “baseline” score. On the day of the infusion, the same investigator, who although not blind as to patient status, was not involved in judging the infusion result, asked the subjects again to rate themselves at the point just before the i.v. catheter is inserted (preneedle score), at the end of the placebo infusion (prelactate score), IO minutes after the lactate infusion is begun (first half score), and at the end of the infusion at 20 minutes (second half score). The API was also obtained immediately at the point of a panic attack, if one occurred. If the panic occurred in the first IO minutes of lactate infusion, the point-of-panic rating is used as the first half score. In that case, no second half score is collected.
Table 2. The 17 items of the Acute Panic Inventory Do you feel faint? Are you afraid of dying? Are you generally fearful? Do you have heart palpitations? Do you have any difficulty in breathing, or are you breathing rapidly? Do you have the urge to urinate? Do you have the urge to defecate? Do you feel dizzy or light-headed? Do you feel confused? Do you have a sense of unreality? Do you feel detached from part or all of your body? Is it difficult for you to concentrate? Are you sweating? Is it difficult for you to speak? Would it be difficult for you to do a job? Do you feel any shakiness, trembling, or twitching? Do vou feel nauseous? Ratings were: not at all (O),slight (l), moderate (2), or severe (3)
100 The clinical designation of panic during the infusion was based on the attending psychiatrist’s observation of an abrupt escalation of fear and distress accompanied by the typical physical symptoms of an attack. Physical symptoms alone were not sufficient to judge the occurrence of an attack. API scores for patients who had attacks within the first IO minutes of the infusion were compared to the first half score obtained at the end of IO minutes of the infusion for the nonpanicking patients and the controls. Similarly, API scores for patients who had attacks between IO and 20 minutes of the infusion were compared to the second half score for the nonpanicking patients and controls. Because of the ordinal nature of the data, nonparametric tests were used for statistical analysis. These included Wilcoxon and Mann-Whitney tests.
Results Fifty-five
of the 89 patients
lactate infusion. and are referred
with
Twenty-five to as “early
panic
disorder
had acute
of these had their attacks panickers.” The remaining
panic
within
attacks the first
during
the
IO minutes
30 had their attacks in the last 10 minutes of the infusion and are referred to as “late panickers.” Thirty-four of the patients and all 26 of the normal controls received the full 20-minute dose of lactate without experiencing an attack. There were no relationships between the occurrence of lactate-induced panic and sex, age, or the presence of agoraphobia within the patients. The API items were summed for each subject at each administration of the instrument to yield a single score per subject per administration. Medians for the four groups (presented in Fig. I, Tables 3 and 4) were calculated at each point of administration: controls, patients who did not panic (NP), early panickers (EP), and late panickers (LP). Scores obtained from all three patient groups (NP, EP, and LP)
Fig. 1. Acute Panic Inventory (API) scores before and during lactate infusions and when rating stress or panic attacks retrospectively
Pafienb
Early Panic pfn=251 !. /
Putients: Late Panic fn =301 Patients:. n rJlon%
Controls
Bose
PreNeedle
PreLocfate
IOI
Table 3. Medians and semi-interquartile ranges of total weighted Acute Panic Inventory scores at each administration of the test for each of the 4 groups Baseline Preneadle Prelactate 1st half 2nd half Usual Controls (n = 26)
3.0 + 3.0
0.0 k 0.5
0.0 + 1 .o
1 .o + 1 .o
2.5 k 3.0
4.5 f 3.5
23.5 f 4.5
2.0 + 2.5
4.0 + 4.0
3.5 k 2.5
9.0 + 5.0
14.0 f 6.5
25.0 +- 3.5
4.0 + 2.5
6.0 f 3.5
8.0 f 3.5
23.0 f 3.5
26.0 f 6.5
3.0 + 2.5
4.0 * 2.0
7.0 + 3.5
12.5 f 3.5
Nonpanic patients (n = 34) Early panic patients (n = 25)
--
Late panic patients (n = 30)
20.0 f 0.5
Table 4. Levels of significance (2-tailed) of intergroup comparisons (MannWhitney U tests) at each administration of the Acute Panic Inventory for data in Table 3 Usual
Baseline Preneedle Prelactate 1st half
2nd half
Controls:NP
0.000
0.006
0.000
0.000
0.001
Control:EP
0.000
0.000
0.000
0.000
0.000
--
Control:LP
0.000
0.000
0.000
0.000
0.000
0.000
0.000
NP:EP
NS
NS
NS
0.010
0.000
--
NP:LP
NS
0.027
NS
0.040
0.003
0.001
EP:LP
NS
NS
NS
NS
0.000
--
NP = Nonpanic patients. EP = Early panic patients. LP = Late panic patients.
when describing their usual panic attacks were significantly higher than the scores obtained by controls describing the experience of extreme stress, with no differences among the patient groups. When rating themselves on the basis of how they felt at the moment on baseline day, all three patient groups achieved scores slightly but significantly higher than controls but essentially indistinguishable from each other. This was also the case for the preneedle assessment on the actual infusion day. At the prelactate point, not only did all three patient groups have a higher score than the controls, but the two patient groups that would go on to panic (EP and LP) now obtained higher scores than the group of patients that would not go on to panic (NP). However, only five of the patients in the EP and LP groups achieved scores greater than the highest score obtained by NP patients. Therefore, it was not possible to predict which patients would subsequently panic from the prelactate API score. The point-of-panic API score for the EP group was higher than the first half score for the LP and NP patients, and for the controls. The score for the NP group was greater than for the controls. Similarly, the point-of-panic score for the LP group was higher than the second half score for the NP patients and the controls. The NP group also attained higher scores than the controls at the second half administration. Point-of-panic scores for the EP group were almost indistinguishable from their scores when rating their usual panic attack. The LP group, however, had a point-ofpanic score significantly (Wilcoxon test, two-tailed) lower than their usual score. The
102 NP usual score was considerably and significantly higher than either of the NP scores obtained during the infusion. It is possible that the high API scores at the point of panic for the EP and LP groups merely reflect the relatively high scores obtained by these groups before starting the infusion. In this case, the increase in API score for the EP and LP group would simply parallel the increase for the NP and control groups. Instead of measuring a panic attack, the API would be reflecting some form of increased arousal or anxiety common to all subjects who undergo a lactate infusion (see Margraf et al., 1981). Therefore, the increments in API over the prelactate score were computed for all four groups (Tables 5 and 6). The patients who had panic attacks had significantly greater increments than the control group, as well as the patients who did not panic. There was no significant difference between the increments of the controls and the nonpanickers.
Table 5. Medians and semi-interquartile ranges of increments in Acute Panic Inventory scores at point of panic or 1st or 2nd half scores over prelactate scores for the 4 groups Increments over prelactate
Controls
NP
Panic or 1st half
2.0 f 2.5
3.0 f 2.5
Panic or 2nd half
3.0 + 3.0
7.5 * 4.5
EP 16.0 + 2.5 --
LP 5.5 k 2.5 15.0 Ik 5.0
NP = Nonpanic patients. EP = Early panic patients. LP = Late panic patients.
Table 6. Levels of significance (2-tailed) of intergroup comparisons (Mann-Whitney U tests) for increments in Table 5 Increments over Prelactate Panic or 1st half Panic or 2nd half
C:NP NS NS
C:LP
C:EP
0.000 0.000
0.000 --
NP:LP LP:EP NP:EP 0.014 0.014
0 200 --
0.000 --
C = Control. NP = Nonpanic patients. EP = Early panic patients. LP = Late panic patients
We attempted to find either an absolute level API score or increment in API score from prelactate to infusion termination that would distinguish the panicking patients from the nonpanickers. A first half score > 20, or an increment of the first half scores over prelactate scores > 13 completely separated the early panickers from the nonpanickers and the controls, and from 24 of the late panickers. However, these criteria falsely identified 6 of the 30 LP patients as early panickers. The sensitivity in distinguishing early panickers from nonpanickers and controls was 84% and the specificity was 100%. When these same criteria of 20 and 13 were applied to the second half scores, six nonpanicking patients and no controls were misidentified as late panickers, whereas 18 of the 30 late panickers were correctly identified. Relative to the nonpanicking
103 patients, the sensitivity was 82%.
for the LP group with this cutoff was 60% and the specificity
Discussion The Acute Panic Inventory appears robust in differentiating panic attacks from other forms of stress and anxiety. In this study, the API differentiated the typical panic attacks of patients with panic disorder from the stress reactions of normal controls and demonstrated that the lactate-induced attacks were quite similar to those typical attacks. Although the API yielded higher scores for patients about to have a lactateinduced attack than for patients or controls who were not about to panic (i.e., the prelactate scores), these scores were not so high as achieved during the attack itself. The prelactate scores did not correlate well with actually having an attack during the lactate infusion, and therefore did not serve as good actuarial predictors of those who would go on to panic. It appears, then, that the API is a valid instrument for rating a panic attack, and separating panic from anticipatory anxiety. Therefore, we can usefully turn to the question of what it tells us about the characteristics of a lactate-induced attack. Using the API in these lactate infusion experiments yields five main observations: I. Patients who will go on to panic during a lactate infusion show heightened anticipatory anxiety in the minutes ‘before lactate infusion is started. The level of anticipatory anxiety (prelactate API) is, however, a significant but poor predictor of panic occurrence. 2. A lactate-induced panic attack has the same overall severity of symptoms as do naturally occurring panic attacks. Thus, scores achieved by early panickers (but not the late panickers) during the panic attack are virtually identical to those the patients give themselves when retrospectively characterizing a usual panic attack. On the other hand, patients who do not panic during the infusion do not achieve API scores that approximate what they obtain when retrospectively characterizing their usual attacks. The physical symptoms associated with the lactate infusion alone-increased heart rate, tremulousness, urinary urgency and dry mouth-are not enough to increase the API score into the “panic” range. 3. Even though patients start out with higher API scores just before lactate than normal controls (presumably because of increased anticipatory anxiety), the high API score obtained during a panic attack is not simply a reflection of higher prelactate anxiety. The increase in API scores from prelactate to termination of the infusion is not parallel in patients who panic and subjects who do not panic, Because the increment in score from prelactate is significantly greater for the subjects who panic, we can conclude that the panic attack is a qualitatively and quantitatively distinct phenomenon. 4. There appears to be a difference between panic attacks that occur in the first IO minutes of a lactate infusion and attacks that occur in the last IO minutes. We were able to find an absolute API score and an increment in API score over baseline that completely distinguished the early panickers from controls and patients who did not
104
panic during the first half of the infusion (both NP and LP groups). This was not so clear cut for the late panickers. The difference appears due to the increase in symptomatology after 20 minutes of lactate infusion in the nonpanicking patients, which substantially exceeds the increment in the controls. The fact that the second half scores were significantly lower than the usual scores for the LP group also suggests that the later panic reactions to the lactate may differ from those occurring during the first 10 minutes. 5. Since the symptomatology by API score of the nonpanickers at 20 minutes far exceeds that of the controls but is lower than their own reported usual panic API score, it appears that lactate is active in the nonpanicking patients even though it does not cause frank panic. This is especially true of the lactate effects seen in the LP patients during the first half of the infusion. We have hypothesized that the clinical panic attack consists of two stages: an initial increase in tension (probably accompanied by hyperventilation) followed by an abrupt crescendo. Panic patients receiving lactate regularly seem to experience the first stage, although controls do not. If the crescendo phase is triggered early in the infusion, then our symptom inventory clearly picks this up. If the crescendo occurs late, then the smaller panic report combined with the increased symptoms of the nonpanickers compromises the ability of the API to detect panic. The NP patients seem to be experiencing the initial increase in tension, perhaps of a magnitude insufficient to trigger the abrupt crescendo necessary for a lactate panic. If this differentiation between early and late panicking patients is correct, other measures of panic such as heart rate, minute ventilation, and skin conductance might be similarly affected. Hence, a sudden burst in heart rate would be expected to occur in patients panicking during the first 10 minutes of a lactate infusion, but because heart rate might be so high in all subjects by 20 minutes into the infusion, no further increase in heart rate would be detected in patients panicking late in the infusion. We are currently investigating this possibility using these other dependent measures of panic anxiety. Acknowledgment. The research reported was supported in part by MH-903-1163G and MH-CR903C006 from the National Institute of Mental Health and by Research Scientist Development Award MH-000416 to Dr. Gorman. The authors thank Samuel Anderson, Ph.D., and Andrew Levin, M.D., for their suggestions, as well as Gail Levy, Ph.D., Michael Palij, Barry Cohen, and John Pavlos for data-analytic assistance.
References American
Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. APA, Washington, DC (1980). Appleby, I.L., Klein, D.F., Sachar, E.J., and Levitt, M. Biochemical indices of lactateinduced panic: A preliminary report paper. Presented at the Annual Meeting of the American Psychopathological Association, Washington, DC, March (1980). Bonn, J.A., Harrison, J., and Rees, W.L. Lactate-induced anxiety: Therapeutic applications. British Journal of Psychiatry, 119,460 (1971). Dillon, D.J., Levitt, M., Klein, D.F., and Danielson, E. Some physiological, biochemical and psychological concomitants of lactate-induced panic. In: Maletesha, R.N., and Hartlage, L.C., eds. Neuropsychology and Cognition. Vol. II. Nijhoff, The Hague/ Boston/ London, p. 651 (1982).
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Kelly, D., Mitchell-Heggs, N., and Sherman, D. Anxiety and the effects of sodium lactate assessed clinically and physiologically. &iris/r Journal qf Psychiatry. 119, I29 ( I97 I). Liebowitz, M.R., Fyer, A.J., Gorman, J.M., Dillon, D.J., Appleby, I.L., Levy, G., Anderson, S., Levitt, M., Palij, M., and Davies, S.O. Lactate provocation of panic attacks: I. Clinical and behavioral findings. Archives qfGenera/ Psychiatry. 41, 764 (1984). Margraf, J., Ehlers, A., and Roth, W.T. Current biological models of panic disorder: A look at the evidence. Unpublished manuscript (1981). Pitt% F.N., Jr., and McClure, J.N., Jr, Lactate metabolism in anxiety neurosis. N~JM England Journal of Medicine, 277, I320 ( 1967). Rifkin, A., Klein, D.F., Drllon, D., and Levitt, M. Blockade by imipramine or desipramine of panic induced by sodium lactate. American Journal oj’P.s,vc.hiatry. 138, 767 ( I98 I). Spielberger, C.D., Gorsuch, R.L., and Lushene, R.E. The State-Trait Anxiet_v /nventor_l~: Test Manua/fijr Form X. Consulting Psychologists Press, Palo Alto, CA (1970). Taylor, J.A. A personality test of manifest anxiety. Journal of Abnormal and Skial Psychology, 48, 285 (I 953). Zuckerman, M. The development of an affect adjective checklist for the measurement of anxiety. Journal of’Con.wlting Psychology. 24, 457 ( 1960).