658
BIOL PSYCHIATRY 1991;29:658-664
The Effects of Physostigmine Infusion on Patients With Panic Disorder Mark Hyman Rapaport, S. Craig Risch, J. Christian Gillin, Shalu'ckh Golshan, and David Janowsky
Nine patients who met both DSM-III and RDC criteria for panic disorder and nine agematched normal controls received infusions of physostigmine. The patients and normal controls did not differ in either their self-reported or the observer-reported ratings of anxiety, mood, or activation. The two subject groups also did not differ in blood pressure, pulse, or cortisol responses to physosti~ine. Physostigmine did not provoke panic attacks in either the control or patients groups
Introduction During the past decade there have been extensive biological studies of panic disorder. These studies have increased our knowledge of the biology of panic disorder and stimulated the development of an increasing number of theoretical constructs concerning panic disorder. Neuroendocrine studies demonstrate an attenuated growth hormone response to both growth hormone-releasing factor and clonidine, but contradictory findings regarding cortisol responsiveness and thyroid function in panic disorder (Curtis et al 1982; Holsboer et al 1987; Lieberman et al 1983; Rapaport et al 1989a, 1989b; Stein and Uhde 1988a, 1988b; Uhde et al 1986, 1988; Roy-Byrne et al 1986). Genetic and epidemiologic studies have shown a comorbidity between panic and depressive disorders in certain individuals, and some investigators have even speculated that panic disorder and depressive disorder emerge from a common biological diathesis (Cohen et al 1988; Coryell et al 1988; Merikangas et al 1988; Weissman 1988). Challenge studies have consistently found that a variety of excitatory substances, including yohimbine, caffeine, sodium lactate, and isoproterenol, can provoke panic attacks in individuals with panic disorder (Pitts and McClure 1967; Charney et al 1984, 1985; Rainey et al 1984; Griez et al 1987). Other investigations have demonstrated that carbon dioxide challenge also induces panic attacks in panic disorder patients (Griez et al 1987). However, some researchers employ a more cognitive-behavioral model to explain panic disorder, and they contend that current biological approaches do not sufficien'dy explain etiology of panic attacks. In particular, many cognitive-behaviorists belie-Je that the panic attacks are. caused by a complex
From the Department of Psychiatry, University of California-San Diego, School of Medicine and Psychiatry Service, San Diego Veterans Affairs Medical Center (MHR, JCG, SG), the Department of Psychiatry, Emory University (SCR), and the Department of Psychiatry, University of North Carolina at Chapel Hill (DJ). Address reprint requests to Mark Hyman Rapaport, M.D., Department of Psychiatry, University of California-San Diego, School of Medicine, La Jolla, CA 92093. Received May 2, 1990; revised October 24, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
Physostigmine and Panic Disorder
toOL~sYcmAraY
659
interaction of the peripheral physiological changes with environmental cues, prev'v'v'v'v'v'v'v'v'v~ experiences, and baseline apprehension (Margraf et al 1986). This study investigates two questions posed by the current panic disorder literature. The first question is whether patients with panic disorder and normal controls respond differently to cholinergic challenges. The second question is whether individuals with panic disorder are more likely to respond to noxious stimulus with symptoms of panic than normal individuals. Physo~tigmine, a cholinesterase inhibitor, was used as the stimulus agent for this study because there is a long history in depression research that individuals with unipolar depression, bipolar depression, and schizoaffective disorder have profound changes in mood during physostigmine infusions (Janowsky et al 1972, 1973, 1985; Janowsky Risch 1987). Physostigmine typically induces an allergic syndrome characterized by depression, lethargy, apathy, and motor retardation during the immediate postirffusion period. These symptoms are profoundly more intense in patients with affective disorders than in normal controls (Janowsky et al 1972; Janowsky and Risch 1987). The secoM ratio.ale for the choice of physostigmine as a provocative agent for individuals with panic disorder was to ascertain if increases in the cholinergic tone, which is tradition~y viewed as modulating inhibitory behavioral effects, would evoke a similar type of anxiogenic response to that seen with challenges using excitatory agents such as yohimbine or sodium lactate.
Methods Nine medically healthy patients (four women and five men) who met DSM-ffl and RDC criteria for panic disorder as assessed by a SADS-L interview gave written informed consent to participate in a double-blind, counterbalanced crossover study. Two patients also met criteria for major depressive disorder, single episode, resolved, and one met criteria for alcoholism in rem;-ssion. All patients had been medication free for at least 2 weeks prior to the study and only one patient had regularly taken psychotropic medication during the previous year. Five male aged-matched controls participated in the doubleblind crossover part of the study. However, after three of the investigators had left the institution a normal control had a vasovagal episode and the study was terminated prematCrely. The data from four other age- but not sex-matched healthy male controls who had previousiy participated in a single-blind physostigmine challenge study were also IL. y. used to complete the control data set for"u n:~. . .~.t u u-'-" The mean age of the patient group (n = 9) was 28.2 years (range 21-50). The mean age of the control group was (n = 9) was 30 years (range 21-50). Eighty minutes prior to the initiation of the study an intravenous (IV) line was placed in the nondominant forearm space using a 22-gauge butterfly needle. The line was kept open with a heparin lock that was flushed prior to sample draws. The subjects were orally administered 45 mg propantheline bromide, in order to block the direct peripheral effects of increasing cholinergic tone, approximately 70 rain prior to the initiation of the study. Seventy minutes later each subject received 0.022 mg/kg IV of pbysostigmine salicylate during a 10-rain peri¢~l. Subjects had measures of blood pressure and pulse manually taken at the - 8 0 , - 3 0 , - 1, 0, + 10, + 20, + 30, + 45, and + 60 rain time points by a research nurse who had been responsible for these measurements in previous phys~ stigmine studies. The patients had cortisol samples drawn at the - 8 0 , - 3 0 , - 1 , + 10, + 20, + 30, + 45, and + 60 rain time points.
660
BIOL PSYCHIATRY 1991;29:658-664
M.H. Rapaport et al
Ratings were performed by both subjects and the observer raters in a double-blind fashion at the - 3 0 , - 15, + 10, +30, and + 6 0 rain time points. These ratings included the Beigel Murphy rating scale, the BPRS rating scale, the activation-inhibition rating scale, the POMS rating scale, the Beck depression rating scale, and the Hamilton rating scale (Beck et al 1961; Bunney and Hamburg 1963; Hamilton 1960; Overall and Gotham 1962). Blood samples were collected in polypropylene tubes with EDTA on ice, immediately centrifuged in a refrigerated centrifuge at 15,000 rpm for 20 rain, and stored at -80°(2 until assayed. Plasma cortisol concentrations were determined by radioimmunoassay (RIA) (Panter, Santa Monica, CA). The detection limit of the assay is 25 pg per tube and the intraassay and interassay coefficients of variation are 7% and 10%, respectively. The data were analyzed by analysis of variance (ANOVA) with repeated measures and analysis of covariance (ANCOVA). Appropriate post hoc t-tests were appfied to significant findings from the ANOVAs.
Results There were no baseline differences between groups in measurements of either the diastolic blood pressure, pulse, or cortisol, but the baseline measure of systolic blood pressure was highe(in the patients with panic disorder compared with controls (123.1 _+ 15.5 versus 109.6 _ 7.3 ~ g ; F - 5.62, df -- 1,16,p < 0.04). At baseline, panic disorder patients also had lower scores for grandiosity on the Beigel Murphy ratings scale (2.4 _ 1.3 versus 3.8 ± 0.5; F = 5.28, df = 1, ! 2, p - 0.04) and lower ratings of friendliness (13.89 _+ 8.7 versus 20.7 _ 3.6; F = 4.63, df - 1,16, p < 0.05) on the POMS ratings scale. Although the physostigndne infusion produced profound behavioral changes in both patients and controls, in none of these cases was the degree of change in the panic disorder group different from the controls (Table 1). Patients and controls also did not differ in their physiological response to physostigmine, as reflected in measurements of systolic blood pressure, diastolic blood pressure, pulse, and cortisol. Maximum changes in blood pressure and pulse occurred in both patient and control subjects !0 min after the infusion of physostigmine: diastolic blood pressure changed from a baseline of 77.5 _.+ 9.47 mmHg to 80.44 - 8.53 mmHg for the patients versus a baseline of 73.33 _+ 7.81 mmHg to 81.55 _+ 16.63 mmHg for controls (p = 0,74); the systolic blood Ixessure changed from a baseline of 123.10 -+ 15.50 mmHg to 127.78 _.+ 11.02 mmHg versus a baseline of 109.50 _+ 7.21 mmHg to 123.89 _+ 21.89 mrnHg for controls (p = 0.18); and the pulse measurement changed from a baseline of 74.00 -4- 9.53 beats/rain to 94.89 _+ 19.82 beats/rain for patients versus a baseline of 71.10 _+ 11.96 beats/min to 102.77 _+ 25.79 beats/rain for controls (p = 0.74). The maximum rise in cortisol levels occurred 45 min after infusion, and there were no significant differences between the patient and control values (baseline 14.48 _+ 5.32 p~g/dl and postinfusion 28.23 _+ 10.26/Lg/dl versus baseline 12.62 + 6.09 p~g/dl and postinfusion 30.89 _+ 14.43 p~g/dl;p = 0.92). Other analyses of the data using both the ANOVA with repeated measures techniques and an ANOVA of change scores (mean preinfusion values minus the postinfusion values at each time point) demonstrated no significant differences or trends between patients and controls.
Discussion At baseline the panic disorder patients bad increased systolic heart rates, lower scores on the grandiosity rating on the Beigel Murphy rating scale, and a lower rating of
mot. PS'*tCtt~TRy
Physostigmine and Panic Disorder
661
1991; 2 9 ~ 6 6 4
Table 1. Physostigndne-lnduced Mood and Energy Alterations in Patients and Controls~ Patients Measurement
Controls
- 1 5 min
Postinfusion
- 1 5 rain
Beigel Murphy Grandiosit3/' Total* Inhibitionb
2.41 _+ 1.28 6.71 - !.75 4.22 _ 0.29
!.15-*- 1.09 4.99 _ 2.5 7.41 _ 2.89
3.80-*-0.50 7.93 ~ 0.54 4.06 -*- 0.14
1.90-*- t.3 4.2 ± 2.18 5.8 "*" 1.8
BPRS Depressionb Psychosisb Total"
5.72 _ 1.94 8.23 -+ 0.43 27.78 _+ 4.55
7.85 +_ 2.73 10.25 -*- !.83 35.29 _+ 7.84
4.66 _ 0.94 8.20 _ 0.299 25.33 _ 1.22
5.31 ± 0.64 9.13 "*- 1.16 28.15 +_ 2.4
Rater measured Inhibition Activation Dysphoria
!.44 _ 1.88 6.44 _+ 1.66 0.255 ± 0.66
17.28 ± 13.42 3.78 -*- 2.31 1.33 ~ 1.36
i.86 ± 2.18 8.46 _ 0.76 0.40 ± 0.89
13.15 ± 9.00 6.22 -*- 2.53 1.42 ± 1.39
7.11 _ 8.63 8.33 - 4.76
2 0 . 4 6 _ 17.80 5.94 -+ 3.81
5 . 0 0 _ 6.00 12.44 _ 2.24
14.81 _ 12.17 8.24 +_ 5.06
14.11 4.44 3.33 10.44 20.66
7.50 6.85 5.09 6.01 13.57
Subject measured Inhibition~ Activationb POMS Vigor Fatigue Confusion Elation Friendly
I i.00 3.33 4.11 6.55 13.88
__ + +_ -+ -+
6.55 4.27 2.42 5.57 8.73
5.48 8.81 7.79 3.89 7.94
_ _+ .4_ _
5.48 6.94 3.57 3.56 5.41
~ 4.59 ± 3.84 +_ 2.50 _+ 5.17 __ 3.60
Postinf~
_ 6.26 _ 6.08 _+ 2.71 _ 6.00 _ 8.75
*Data reported as mean - SD. bValues for only five controls.
friendliness on the POMS. These findings may be interpreted as implying that the panic disorder patients were more anxious and guarded than the controls about participating in the study. This would be consistent with the clinical observation that panic disorder patients have problems with anticipatory anxiety, particularly in situations where they perceive themselves as potentially out of control. The baseline finding of an increase in systolic blood pressure is interesting, and may reflect a mild physiological response • .. ; . . . . . . a h . - . o ° n . . . . . . . a°a . . . . ; . , , h . . . . ; . . a;o..a.,, o , , h ; , ~ . . . , ~ 3 ~ s might be interpreted as a significant finding if considered within the context of the work by Lieberman et al (1983), who observed increases in baseline systolic cardiovascular measures in panic disorder patients who later experienced panic attacks during sodium lactate infusions. Thus this finding might be interpreted as suggesting that panic disorder patients in this study demonstrated a mild baseline systolic blood pressure increase that is usually masked because it falls within the normal range for blood pressure readings. However.: any enthusiasm over these findings must be tempered because of the dissimilarity between patient and control subjects (there were four women and five men i~ the patient group and nine men in the control sample), and the extremely small sample size of this study. There were no significant differences between patients and controls in the behavioral, physiological, or biological measures assessed after physostigrnine infusion. None of the panic disorder patients o, normal control subjects had a panic attack. This was assessed by asking each subject a direct question about the occurrence of panic attacks during the
662
BIOL PSYCHIATRY 1991:29:658-664
M.H. Rapaport et al
study and by objective evaluation of ratings of panic, anxiety, nervousness, terror, tension, and somatic symptoms on the Hamilton, POMS, and BPRS. However, both the panic disorder patients and the normal control subjects had behavioral and physiological changes in response to physostigmine infusion that were consistent with those p,-eviously reported for normal controls (Janowsky and Risch 1987). They demonstrated a mild form of the physostigmine anergic syndrome characterized by increased ratings of depression and dysphoria, lethargy and motor inhibition, and mild confusion (Table 1). It is intriguing to note that the panic disorder patients seemed to have a more attenuated physiological response to the infusions, with changes in blood pressure and pulse that were less than those of the control subjects. These results, again, must be tempered by several weaknesses in the design of the study. The major flaw in this study is that the control group is partially composed of a retrospective sample, and, at times, because of this, certain variables have a smaller control sample size. A second weakness in the study is that the rating scales used were more focused on assessment of affective disorders than anxiety disorders. This allows for comparison of this study with previous studies of the effects of cholinergic challenges with affective disorder patients, but means that subtle differences in measures of ~xiety may have been missed. A third limitation of this study is the paucity of biological variables evaluated, with measures of many potentially useful markers not having been assessed. In spite of these problems, the observation that neither the panic disorder patients nor control subjects developed panic attacks during the physostigmine infusion is intriguing. Physostigmine is a cholinesterase inhibitor, and thus increases the synaptic levels of this inhibitory neurotransmitter. This acute increase in acetylcholine causes profound physiological changes (Table 1). Thus, if patients with panic disorder were prone to panic because of perceived uncontrollable physiological aberration, it is likely that the extreme physiological and affective changes that occur with a physostigmine challenge would induce panic attacks. A second preliminary observation from this study is that the intensity of the physostigmine-induced anergic syndrome is similar for panic disorder patients and controls (Table 1). The similarity in the intensity of the anergic syndre'ne for these groups is markedly different from what one sees when one compares the response of individuals with affective disorders and controls to physostigmine challenge (Janowsky and Risch 1987). In comparison with controls, the patients with affective disorders rate themselves, and are rated by experienced research clinicians, as experiencing more feelings of depression, listlessness, apathy, lassitude, anergia, and liability after physostigmine challenge. This may be interpreted as indirect evidence that affective disorder and panic disorder might be distinct, at least in terms of the cholinergic nervous system. Such a supposition would not preclude either the development of secondary depression in individuals subject to panic attacks or the development of panic attacks in individuals suffering from depressive disorder. However, if this extrapolation is true, then it is more likely that panic disorder and affective disorder do not descend from a common biological diathesis. In conclusion, this study suggests that panic disorder patients have panic attacks only in response to specific biological agents and that physostigmine is not one of these agents. An ancillary finding is that panic disorder patients seem to respond differently than affective disorder patients have been reported to respond to physostigmine infusion. There are several weaknesses in the design of this study, including problems with the selection of the control population for the study, and the rating scales used. However, this preliminary information is of interest and we believe deserves further investigation.
Physostigmine and Panic Disorder
Brat. psYCmA'mY 1991 ;29:65~-664
663
This wo~ w~ supported in part b,, NIMH Grants MH 00393(SCR), MH 391 ~3(SCR), 30914(CRC), MH 18399 (training grant), MH 3o7.~8(SCG) and S.D.V.A.M.C. Research Service. The authors wish to t.'cankthe San Diego TERRAP Chapter for their help.
References Beck AT, Ward CH, Mendelsohn M, Mock J, Erbaugh J (1961): An inventory for measuring depression. Arch Gen P~,chiatry 4:561-571. Bunney WE Jr, Hamburg DA (1963): Methods for reliable longitudinal observations of behavior. Arch Gen Psychiatry 9:114-128. Charney D, Heninger G, Breier A (1984): Noradrenergic function in p ~ c anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:751-763. Charney D, Heninger G, Jatlow P (1985): Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233-243. Cohen LS, Biederman J (1988): Further evidence for an association between affective disorders and anxiety disorders: Review and case reports, l Clin Psychiatry 49:313-316. Coryell W, Endicott J, Andreasen NC, et al (1988): Depression and panic attacks: The s i ~ c a ~ e of overlap as reflected in follow-up and family study data. Am J Psychiatry 145:293-300, Curtis GC, Cameron OG, Nesse RM (1982): The Dexamethasone Suppression Test in panic disorder &nd agoraphobia. Am J Psychia,~' ! 39:1043-1046. Griez E, Lousberg H, van den Hour M, Van der Bolen G (1987): CO2 ~ e r a b ~ t y in panic disorder. Ps?~chiatry Res 20:87-95. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Holsboer F, yon Bardeleben U, Buller R, Heuser I, Steiger A (1987): Stimulation response to corticotropin-releasing hormone (CRH) in patients with depression, alcoholism, and pamc disorder. Horm Metab Res 16(suppl):8088. Janowsky DS, Risch SC (1987): Role of acetylcholine mechanisms in the affective disorders. In Meltzer HY (ed), Psychopharmacology: The Third Generation of Progress. New York: Raven, pp 527-533. Janowsky DS, EI-Yousef MK, Davis JM Seke;ke HI (1972): A cholinergic-adrenergic hypothesis of mania and depression. Lancet i:632-636. Janowsky DS, EI-Yousef MK, Davis JM, Sekerke HI (1973): Parasympathetic suppression of manic symptoms by physostigmine. Arch G,'~ Psychiatry 28:542-547. ~__~a.,3, --~,-~-,-,7;°~"°" ,,~A~'°~'--,,-,,.Effec~ of physo~ti~n;ne.,_.~ ... on Janowsk-y DS, Risch o,.., ,,r, Huey ,., , v~, K~,~,~j pulse, blood pressure, and serum epinephrine levels. Am 3 Psychiatry 142:738-739. Lieberman JA, Renner R, Lesser M, Coccaro E, Borenstein M, Kane JM (1983): Dexamethasone Suppression Tests in patients with panic disorder. Am 3 Psychiatry 140:917-919. Margraf J, El~ers A, Roth WT (1986): Sodium lactate infusions and panic attacks: A review and critique. Psychosom Med 48:23-51. Merikangas J, Prusoff BA, Weissman MM (1988): Parental concordance for affective disorders: Psychopathology in offspring. 3 Affective Disord 15:279-290. Overall JE, Gorham DR (1962): The brief psychiatric tati~g sc~e. Psychol Rep 10:799-812. Pitts FN, McClure JN (1967): Lactate metabolism in anxiety neurosis. N Engl J Med 277:13291336. Rainey JM, Pohl RB, Williams M, Knitter E, Freedman R, Ettedgui E (1984): A comparison of lactate and isoproterenol anxiety states. Psychopa:;~ology 17(suppl 1):74-82. Rapaport MH, Risch SC, Gillin JC, Golshan S, Janowsky DS (1989a): A blunted growth hormone response to peripheral infusion of human growth hormone releasing factor in patients with panic disorder. Am J Psychiatry 146:92-95.
664
BIOL PSYCHIATRY 1991 ;29:658-664
M.H. Rapaport et al
Rapaport MH, Risch SC, Golshan S, Gillin JC (1989b): NetLroendocrine effects of ovine corticotropin-releasing hormone in panic disorder patients. Biol Psychiatry 26:344-348. Roy-Byrne PP, Uhde T, Post R, Gallucci W, Chrousos GP, Gold PW (1986): The corticotropinreleasing hormone stimulation test in patients with panic disorder. Am J Psychiatry 143:896-899. Stein MB, Uhde TW (1988a): Panic disorder and major depression: A tale of two syndromes. Psychiatr Clin North Am l 1:441-461. Stein MB, Uhde TW (1988b): Cortisol response to clonidine in panic disorder: Comparison with depressed patients and normal controls. J Nerv Ment Dis 176:431-439. Uhde T, Vittone BJ, Siever LJ, Kaye WH, Post RM (1986): Blunted growth hormone response to clonidine in panic disorder patients. Biol Psychiatry 21:!081-1085. Uhde T, Joffe RT, Jimerson DC, Post RM (1988): Normal urinary free cortisol and plasma MHPG in panic disorder: Clinical and theoretical implications. Biol Psychiatry 23:575-585. Weissman MM (1988): The epidemiology of anxiety disorders: Rates, risks and familial patterns. J Psvchiatr Res 22(suppl 1):99-114.
BIOL PSYCHIATRY 1991;29:658-664
The Effects of Physostigmine Infusion on Patients With Panic Disorder Mark Hyman Rapaport, S. Craig Risch, J. Christian Gillin, Shalu'ckh Golshan, and David Janowsky
Nine patients who met both DSM-III and RDC criteria for panic disorder and nine agematched normal controls received infusions of physostigmine. The patients and normal controls did not differ in either their self-reported or the observer-reported ratings of anxiety, mood, or activation. The two subject groups also did not differ in blood pressure, pulse, or cortisol responses to physosti~ine. Physostigmine did not provoke panic attacks in either the control or patients groups
Introduction During the past decade there have been extensive biological studies of panic disorder. These studies have increased our knowledge of the biology of panic disorder and stimulated the development of an increasing number of theoretical constructs concerning panic disorder. Neuroendocrine studies demonstrate an attenuated growth hormone response to both growth hormone-releasing factor and clonidine, but contradictory findings regarding cortisol responsiveness and thyroid function in panic disorder (Curtis et al 1982; Holsboer et al 1987; Lieberman et al 1983; Rapaport et al 1989a, 1989b; Stein and Uhde 1988a, 1988b; Uhde et al 1986, 1988; Roy-Byrne et al 1986). Genetic and epidemiologic studies have shown a comorbidity between panic and depressive disorders in certain individuals, and some investigators have even speculated that panic disorder and depressive disorder emerge from a common biological diathesis (Cohen et al 1988; Coryell et al 1988; Merikangas et al 1988; Weissman 1988). Challenge studies have consistently found that a variety of excitatory substances, including yohimbine, caffeine, sodium lactate, and isoproterenol, can provoke panic attacks in individuals with panic disorder (Pitts and McClure 1967; Charney et al 1984, 1985; Rainey et al 1984; Griez et al 1987). Other investigations have demonstrated that carbon dioxide challenge also induces panic attacks in panic disorder patients (Griez et al 1987). However, some researchers employ a more cognitive-behavioral model to explain panic disorder, and they contend that current biological approaches do not sufficien'dy explain etiology of panic attacks. In particular, many cognitive-behaviorists belie-Je that the panic attacks are. caused by a complex
From the Department of Psychiatry, University of California-San Diego, School of Medicine and Psychiatry Service, San Diego Veterans Affairs Medical Center (MHR, JCG, SG), the Department of Psychiatry, Emory University (SCR), and the Department of Psychiatry, University of North Carolina at Chapel Hill (DJ). Address reprint requests to Mark Hyman Rapaport, M.D., Department of Psychiatry, University of California-San Diego, School of Medicine, La Jolla, CA 92093. Received May 2, 1990; revised October 24, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
Physostigmine and Panic Disorder
toOL~sYcmAraY
659
interaction of the peripheral physiological changes with environmental cues, prev'v'v'v'v'v'v'v'v'v~ experiences, and baseline apprehension (Margraf et al 1986). This study investigates two questions posed by the current panic disorder literature. The first question is whether patients with panic disorder and normal controls respond differently to cholinergic challenges. The second question is whether individuals with panic disorder are more likely to respond to noxious stimulus with symptoms of panic than normal individuals. Physo~tigmine, a cholinesterase inhibitor, was used as the stimulus agent for this study because there is a long history in depression research that individuals with unipolar depression, bipolar depression, and schizoaffective disorder have profound changes in mood during physostigmine infusions (Janowsky et al 1972, 1973, 1985; Janowsky Risch 1987). Physostigmine typically induces an allergic syndrome characterized by depression, lethargy, apathy, and motor retardation during the immediate postirffusion period. These symptoms are profoundly more intense in patients with affective disorders than in normal controls (Janowsky et al 1972; Janowsky and Risch 1987). The secoM ratio.ale for the choice of physostigmine as a provocative agent for individuals with panic disorder was to ascertain if increases in the cholinergic tone, which is tradition~y viewed as modulating inhibitory behavioral effects, would evoke a similar type of anxiogenic response to that seen with challenges using excitatory agents such as yohimbine or sodium lactate.
Methods Nine medically healthy patients (four women and five men) who met DSM-ffl and RDC criteria for panic disorder as assessed by a SADS-L interview gave written informed consent to participate in a double-blind, counterbalanced crossover study. Two patients also met criteria for major depressive disorder, single episode, resolved, and one met criteria for alcoholism in rem;-ssion. All patients had been medication free for at least 2 weeks prior to the study and only one patient had regularly taken psychotropic medication during the previous year. Five male aged-matched controls participated in the doubleblind crossover part of the study. However, after three of the investigators had left the institution a normal control had a vasovagal episode and the study was terminated prematCrely. The data from four other age- but not sex-matched healthy male controls who had previousiy participated in a single-blind physostigmine challenge study were also IL. y. used to complete the control data set for"u n:~. . .~.t u u-'-" The mean age of the patient group (n = 9) was 28.2 years (range 21-50). The mean age of the control group was (n = 9) was 30 years (range 21-50). Eighty minutes prior to the initiation of the study an intravenous (IV) line was placed in the nondominant forearm space using a 22-gauge butterfly needle. The line was kept open with a heparin lock that was flushed prior to sample draws. The subjects were orally administered 45 mg propantheline bromide, in order to block the direct peripheral effects of increasing cholinergic tone, approximately 70 rain prior to the initiation of the study. Seventy minutes later each subject received 0.022 mg/kg IV of pbysostigmine salicylate during a 10-rain peri¢~l. Subjects had measures of blood pressure and pulse manually taken at the - 8 0 , - 3 0 , - 1, 0, + 10, + 20, + 30, + 45, and + 60 rain time points by a research nurse who had been responsible for these measurements in previous phys~ stigmine studies. The patients had cortisol samples drawn at the - 8 0 , - 3 0 , - 1 , + 10, + 20, + 30, + 45, and + 60 rain time points.
660
BIOL PSYCHIATRY 1991;29:658-664
M.H. Rapaport et al
Ratings were performed by both subjects and the observer raters in a double-blind fashion at the - 3 0 , - 15, + 10, +30, and + 6 0 rain time points. These ratings included the Beigel Murphy rating scale, the BPRS rating scale, the activation-inhibition rating scale, the POMS rating scale, the Beck depression rating scale, and the Hamilton rating scale (Beck et al 1961; Bunney and Hamburg 1963; Hamilton 1960; Overall and Gotham 1962). Blood samples were collected in polypropylene tubes with EDTA on ice, immediately centrifuged in a refrigerated centrifuge at 15,000 rpm for 20 rain, and stored at -80°(2 until assayed. Plasma cortisol concentrations were determined by radioimmunoassay (RIA) (Panter, Santa Monica, CA). The detection limit of the assay is 25 pg per tube and the intraassay and interassay coefficients of variation are 7% and 10%, respectively. The data were analyzed by analysis of variance (ANOVA) with repeated measures and analysis of covariance (ANCOVA). Appropriate post hoc t-tests were appfied to significant findings from the ANOVAs.
Results There were no baseline differences between groups in measurements of either the diastolic blood pressure, pulse, or cortisol, but the baseline measure of systolic blood pressure was highe(in the patients with panic disorder compared with controls (123.1 _+ 15.5 versus 109.6 _ 7.3 ~ g ; F - 5.62, df -- 1,16,p < 0.04). At baseline, panic disorder patients also had lower scores for grandiosity on the Beigel Murphy ratings scale (2.4 _ 1.3 versus 3.8 ± 0.5; F = 5.28, df = 1, ! 2, p - 0.04) and lower ratings of friendliness (13.89 _+ 8.7 versus 20.7 _ 3.6; F = 4.63, df - 1,16, p < 0.05) on the POMS ratings scale. Although the physostigndne infusion produced profound behavioral changes in both patients and controls, in none of these cases was the degree of change in the panic disorder group different from the controls (Table 1). Patients and controls also did not differ in their physiological response to physostigmine, as reflected in measurements of systolic blood pressure, diastolic blood pressure, pulse, and cortisol. Maximum changes in blood pressure and pulse occurred in both patient and control subjects !0 min after the infusion of physostigmine: diastolic blood pressure changed from a baseline of 77.5 _.+ 9.47 mmHg to 80.44 - 8.53 mmHg for the patients versus a baseline of 73.33 _+ 7.81 mmHg to 81.55 _+ 16.63 mmHg for controls (p = 0,74); the systolic blood Ixessure changed from a baseline of 123.10 -+ 15.50 mmHg to 127.78 _.+ 11.02 mmHg versus a baseline of 109.50 _+ 7.21 mmHg to 123.89 _+ 21.89 mrnHg for controls (p = 0.18); and the pulse measurement changed from a baseline of 74.00 -4- 9.53 beats/rain to 94.89 _+ 19.82 beats/rain for patients versus a baseline of 71.10 _+ 11.96 beats/min to 102.77 _+ 25.79 beats/rain for controls (p = 0.74). The maximum rise in cortisol levels occurred 45 min after infusion, and there were no significant differences between the patient and control values (baseline 14.48 _+ 5.32 p~g/dl and postinfusion 28.23 _+ 10.26/Lg/dl versus baseline 12.62 + 6.09 p~g/dl and postinfusion 30.89 _+ 14.43 p~g/dl;p = 0.92). Other analyses of the data using both the ANOVA with repeated measures techniques and an ANOVA of change scores (mean preinfusion values minus the postinfusion values at each time point) demonstrated no significant differences or trends between patients and controls.
Discussion At baseline the panic disorder patients bad increased systolic heart rates, lower scores on the grandiosity rating on the Beigel Murphy rating scale, and a lower rating of
mot. PS'*tCtt~TRy
Physostigmine and Panic Disorder
661
1991; 2 9 ~ 6 6 4
Table 1. Physostigndne-lnduced Mood and Energy Alterations in Patients and Controls~ Patients Measurement
Controls
- 1 5 min
Postinfusion
- 1 5 rain
Beigel Murphy Grandiosit3/' Total* Inhibitionb
2.41 _+ 1.28 6.71 - !.75 4.22 _ 0.29
!.15-*- 1.09 4.99 _ 2.5 7.41 _ 2.89
3.80-*-0.50 7.93 ~ 0.54 4.06 -*- 0.14
1.90-*- t.3 4.2 ± 2.18 5.8 "*" 1.8
BPRS Depressionb Psychosisb Total"
5.72 _ 1.94 8.23 -+ 0.43 27.78 _+ 4.55
7.85 +_ 2.73 10.25 -*- !.83 35.29 _+ 7.84
4.66 _ 0.94 8.20 _ 0.299 25.33 _ 1.22
5.31 ± 0.64 9.13 "*- 1.16 28.15 +_ 2.4
Rater measured Inhibition Activation Dysphoria
!.44 _ 1.88 6.44 _+ 1.66 0.255 ± 0.66
17.28 ± 13.42 3.78 -*- 2.31 1.33 ~ 1.36
i.86 ± 2.18 8.46 _ 0.76 0.40 ± 0.89
13.15 ± 9.00 6.22 -*- 2.53 1.42 ± 1.39
7.11 _ 8.63 8.33 - 4.76
2 0 . 4 6 _ 17.80 5.94 -+ 3.81
5 . 0 0 _ 6.00 12.44 _ 2.24
14.81 _ 12.17 8.24 +_ 5.06
14.11 4.44 3.33 10.44 20.66
7.50 6.85 5.09 6.01 13.57
Subject measured Inhibition~ Activationb POMS Vigor Fatigue Confusion Elation Friendly
I i.00 3.33 4.11 6.55 13.88
__ + +_ -+ -+
6.55 4.27 2.42 5.57 8.73
5.48 8.81 7.79 3.89 7.94
_ _+ .4_ _
5.48 6.94 3.57 3.56 5.41
~ 4.59 ± 3.84 +_ 2.50 _+ 5.17 __ 3.60
Postinf~
_ 6.26 _ 6.08 _+ 2.71 _ 6.00 _ 8.75
*Data reported as mean - SD. bValues for only five controls.
friendliness on the POMS. These findings may be interpreted as implying that the panic disorder patients were more anxious and guarded than the controls about participating in the study. This would be consistent with the clinical observation that panic disorder patients have problems with anticipatory anxiety, particularly in situations where they perceive themselves as potentially out of control. The baseline finding of an increase in systolic blood pressure is interesting, and may reflect a mild physiological response • .. ; . . . . . . a h . - . o ° n . . . . . . . a°a . . . . ; . , , h . . . . ; . . a;o..a.,, o , , h ; , ~ . . . , ~ 3 ~ s might be interpreted as a significant finding if considered within the context of the work by Lieberman et al (1983), who observed increases in baseline systolic cardiovascular measures in panic disorder patients who later experienced panic attacks during sodium lactate infusions. Thus this finding might be interpreted as suggesting that panic disorder patients in this study demonstrated a mild baseline systolic blood pressure increase that is usually masked because it falls within the normal range for blood pressure readings. However.: any enthusiasm over these findings must be tempered because of the dissimilarity between patient and control subjects (there were four women and five men i~ the patient group and nine men in the control sample), and the extremely small sample size of this study. There were no significant differences between patients and controls in the behavioral, physiological, or biological measures assessed after physostigrnine infusion. None of the panic disorder patients o, normal control subjects had a panic attack. This was assessed by asking each subject a direct question about the occurrence of panic attacks during the
662
BIOL PSYCHIATRY 1991:29:658-664
M.H. Rapaport et al
study and by objective evaluation of ratings of panic, anxiety, nervousness, terror, tension, and somatic symptoms on the Hamilton, POMS, and BPRS. However, both the panic disorder patients and the normal control subjects had behavioral and physiological changes in response to physostigmine infusion that were consistent with those p,-eviously reported for normal controls (Janowsky and Risch 1987). They demonstrated a mild form of the physostigmine anergic syndrome characterized by increased ratings of depression and dysphoria, lethargy and motor inhibition, and mild confusion (Table 1). It is intriguing to note that the panic disorder patients seemed to have a more attenuated physiological response to the infusions, with changes in blood pressure and pulse that were less than those of the control subjects. These results, again, must be tempered by several weaknesses in the design of the study. The major flaw in this study is that the control group is partially composed of a retrospective sample, and, at times, because of this, certain variables have a smaller control sample size. A second weakness in the study is that the rating scales used were more focused on assessment of affective disorders than anxiety disorders. This allows for comparison of this study with previous studies of the effects of cholinergic challenges with affective disorder patients, but means that subtle differences in measures of ~xiety may have been missed. A third limitation of this study is the paucity of biological variables evaluated, with measures of many potentially useful markers not having been assessed. In spite of these problems, the observation that neither the panic disorder patients nor control subjects developed panic attacks during the physostigmine infusion is intriguing. Physostigmine is a cholinesterase inhibitor, and thus increases the synaptic levels of this inhibitory neurotransmitter. This acute increase in acetylcholine causes profound physiological changes (Table 1). Thus, if patients with panic disorder were prone to panic because of perceived uncontrollable physiological aberration, it is likely that the extreme physiological and affective changes that occur with a physostigmine challenge would induce panic attacks. A second preliminary observation from this study is that the intensity of the physostigmine-induced anergic syndrome is similar for panic disorder patients and controls (Table 1). The similarity in the intensity of the anergic syndre'ne for these groups is markedly different from what one sees when one compares the response of individuals with affective disorders and controls to physostigmine challenge (Janowsky and Risch 1987). In comparison with controls, the patients with affective disorders rate themselves, and are rated by experienced research clinicians, as experiencing more feelings of depression, listlessness, apathy, lassitude, anergia, and liability after physostigmine challenge. This may be interpreted as indirect evidence that affective disorder and panic disorder might be distinct, at least in terms of the cholinergic nervous system. Such a supposition would not preclude either the development of secondary depression in individuals subject to panic attacks or the development of panic attacks in individuals suffering from depressive disorder. However, if this extrapolation is true, then it is more likely that panic disorder and affective disorder do not descend from a common biological diathesis. In conclusion, this study suggests that panic disorder patients have panic attacks only in response to specific biological agents and that physostigmine is not one of these agents. An ancillary finding is that panic disorder patients seem to respond differently than affective disorder patients have been reported to respond to physostigmine infusion. There are several weaknesses in the design of this study, including problems with the selection of the control population for the study, and the rating scales used. However, this preliminary information is of interest and we believe deserves further investigation.
Physostigmine and Panic Disorder
Brat. psYCmA'mY 1991 ;29:65~-664
663
This wo~ w~ supported in part b,, NIMH Grants MH 00393(SCR), MH 391 ~3(SCR), 30914(CRC), MH 18399 (training grant), MH 3o7.~8(SCG) and S.D.V.A.M.C. Research Service. The authors wish to t.'cankthe San Diego TERRAP Chapter for their help.
References Beck AT, Ward CH, Mendelsohn M, Mock J, Erbaugh J (1961): An inventory for measuring depression. Arch Gen P~,chiatry 4:561-571. Bunney WE Jr, Hamburg DA (1963): Methods for reliable longitudinal observations of behavior. Arch Gen Psychiatry 9:114-128. Charney D, Heninger G, Breier A (1984): Noradrenergic function in p ~ c anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:751-763. Charney D, Heninger G, Jatlow P (1985): Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233-243. Cohen LS, Biederman J (1988): Further evidence for an association between affective disorders and anxiety disorders: Review and case reports, l Clin Psychiatry 49:313-316. Coryell W, Endicott J, Andreasen NC, et al (1988): Depression and panic attacks: The s i ~ c a ~ e of overlap as reflected in follow-up and family study data. Am J Psychiatry 145:293-300, Curtis GC, Cameron OG, Nesse RM (1982): The Dexamethasone Suppression Test in panic disorder &nd agoraphobia. Am J Psychia,~' ! 39:1043-1046. Griez E, Lousberg H, van den Hour M, Van der Bolen G (1987): CO2 ~ e r a b ~ t y in panic disorder. Ps?~chiatry Res 20:87-95. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Holsboer F, yon Bardeleben U, Buller R, Heuser I, Steiger A (1987): Stimulation response to corticotropin-releasing hormone (CRH) in patients with depression, alcoholism, and pamc disorder. Horm Metab Res 16(suppl):8088. Janowsky DS, Risch SC (1987): Role of acetylcholine mechanisms in the affective disorders. In Meltzer HY (ed), Psychopharmacology: The Third Generation of Progress. New York: Raven, pp 527-533. Janowsky DS, EI-Yousef MK, Davis JM Seke;ke HI (1972): A cholinergic-adrenergic hypothesis of mania and depression. Lancet i:632-636. Janowsky DS, EI-Yousef MK, Davis JM, Sekerke HI (1973): Parasympathetic suppression of manic symptoms by physostigmine. Arch G,'~ Psychiatry 28:542-547. ~__~a.,3, --~,-~-,-,7;°~"°" ,,~A~'°~'--,,-,,.Effec~ of physo~ti~n;ne.,_.~ ... on Janowsk-y DS, Risch o,.., ,,r, Huey ,., , v~, K~,~,~j pulse, blood pressure, and serum epinephrine levels. Am 3 Psychiatry 142:738-739. Lieberman JA, Renner R, Lesser M, Coccaro E, Borenstein M, Kane JM (1983): Dexamethasone Suppression Tests in patients with panic disorder. Am 3 Psychiatry 140:917-919. Margraf J, El~ers A, Roth WT (1986): Sodium lactate infusions and panic attacks: A review and critique. Psychosom Med 48:23-51. Merikangas J, Prusoff BA, Weissman MM (1988): Parental concordance for affective disorders: Psychopathology in offspring. 3 Affective Disord 15:279-290. Overall JE, Gorham DR (1962): The brief psychiatric tati~g sc~e. Psychol Rep 10:799-812. Pitts FN, McClure JN (1967): Lactate metabolism in anxiety neurosis. N Engl J Med 277:13291336. Rainey JM, Pohl RB, Williams M, Knitter E, Freedman R, Ettedgui E (1984): A comparison of lactate and isoproterenol anxiety states. Psychopa:;~ology 17(suppl 1):74-82. Rapaport MH, Risch SC, Gillin JC, Golshan S, Janowsky DS (1989a): A blunted growth hormone response to peripheral infusion of human growth hormone releasing factor in patients with panic disorder. Am J Psychiatry 146:92-95.
664
BIOL PSYCHIATRY 1991 ;29:658-664
M.H. Rapaport et al
Rapaport MH, Risch SC, Golshan S, Gillin JC (1989b): NetLroendocrine effects of ovine corticotropin-releasing hormone in panic disorder patients. Biol Psychiatry 26:344-348. Roy-Byrne PP, Uhde T, Post R, Gallucci W, Chrousos GP, Gold PW (1986): The corticotropinreleasing hormone stimulation test in patients with panic disorder. Am J Psychiatry 143:896-899. Stein MB, Uhde TW (1988a): Panic disorder and major depression: A tale of two syndromes. Psychiatr Clin North Am l 1:441-461. Stein MB, Uhde TW (1988b): Cortisol response to clonidine in panic disorder: Comparison with depressed patients and normal controls. J Nerv Ment Dis 176:431-439. Uhde T, Vittone BJ, Siever LJ, Kaye WH, Post RM (1986): Blunted growth hormone response to clonidine in panic disorder patients. Biol Psychiatry 21:!081-1085. Uhde T, Joffe RT, Jimerson DC, Post RM (1988): Normal urinary free cortisol and plasma MHPG in panic disorder: Clinical and theoretical implications. Biol Psychiatry 23:575-585. Weissman MM (1988): The epidemiology of anxiety disorders: Rates, risks and familial patterns. J Psvchiatr Res 22(suppl 1):99-114.
