628
BIOL PSYCHIATRY 1991 ;~:628- 630
Hypertonic Saline hffusion Induces Panic in Patients with Panic Disorder Carl F. Jensen, Elaine R. Peskind, Richard C. Veith, James Hughes, Deborah S. Cowley, Peter Roy-Byrne, and Murray A. Raskind
Introduction The mechanism by which sodium lactate (NaLAC) infusion induces panic remains obscure. That the standard 0.5 M NaLAC solution is a hypertonic sodium (Na) solution that produces a marked and rapid increase in plasma Na and osmolality (Osm) (George et al 1989) suggests that these rapid increases in plasma Na and Osm are involved in t?:e induction of panic. In this pilot study, we administered to par~ic disorder (PD) patients a hypertonic saline (HS) infusion (3% NaCI) designed to produce an increa~ in serum Na, Osm, and volume equal to the standard NaLAC infusion. We tested the hypothesis that increasing serum Osm and Na an equivalent amount with HS or NaLAC infusions would p ~ u c e panic ,~ymptoms of similar frequency and quality and that an equal volume infusion of normal saline (NS) would not produce panic symptoms.
Methods Subjects were 5 Caucasian men aged 36-63 who met DSM-III-R criteria for PD and were currently experiencing ~pontaneous panic attacks. From the Seattle VA Medical Center and Department of Psychiatry and Behavior,'tl Sciences, University of Washington School of Medicine, Seattle. WA. Address leprinl requests to Dr. Jensen, Seattle VA Medi-al Cente(116A), 1660 South Colu,•bian '~ay, Seattle, WA 98108. Received November 9, 1990; revised March 19, 1991.
© 1991 Society of Biological P s y c h i ~
Four had a history of alcohol dependence but had been free of alcohol for at least 3 wonths. Panic disorder was p~m..~_'3' in 3 of,,he 4. Subject 4 had no history of substance abuse. Subject 2 continued to experience spontaneous panic attacks even though maintaine2 on doxepin. He was also maintained on disulfiram and diphenylhydantoin. Subject 4 had spontaneous panic attacks despite maintenance on nortriptyline. Other subjects were free of prescribed medications for at least 3 weeks. Informed consent was obtained after procedures were fully explained. Thirty minutes prior to infusion, IV catheters were placed in each ann. infusions were administered between 9:00 AM and noon in double-blind fashion in randomized sequence at least 3 days apart. Solutions incivded 0.5 M NaLAC (1000 mEq/L), 3% NaCl (1026 mEq/L) (HS), and 0.9% NaCi (308 mEq/L) (NS), and were infused at l0 ml/kg over 20 min. Subjects were asked to abstain from food, caffeine, and tobacco from midnight prior to study. A urine sample was ¢btained prior to each infusion to screen for recent drug and alcohol use. Panic and anxiety were assessed by the Acute Panic Inventory (Dillon et al 1987), administered prior to infusion and at 5 min intervals for 40 min. At 15 min postinfusion, subjects globally rated the subjective quality and intensity of the experience compared to a spontaneous panic attack using a scale of 0 (totally unlike a panic attack) to l0 (exactly 0006-3223/91/$03.50
nlOL ~ ¥ c I ~ A ~ Y
Brief Reports
629
like a severe, spontaneous panic attack). A response was positive for "panic" if the subject met previously described criteria (Cowley et al 1989) and had a global panic rating of at least 5. Blood samples for serum Na and Osm were drawn from the noninfusion arm at baseline, immediately postinfusion, and at 15 rain intervals thereafter for 75 rain. Venous pH was measured at baseline and at end infusion in subjects 3, 4, and 5 only.
in subjects 3 and 4 with NaLAC (7.39-7.49 an~l 7.40-7.50) but not with HS (7.39-7.37 ~ 7.427.36) Subject 5 (HS o~y) had no increase in venous pH (" 38--7.~2). U ~ t o x k o ~ were negative for abused substarges excep: for subject I, whose urine was pop,rive for cocai~, tetra__hy&ocannabinol, and alcohol prior to ~ studies. Statistical an~ysis was restricted to the three subjects ( i, 3~ and 4) who met the criteria (completed ~ three infusions ~ achieved comparable Osm in HS and N ~ C conditions) necResults essary to test our a priori hypothesis. Due to Presence of panic, global panic ratings, APi small sample size, a ~rmumtion approach was scores at end infusion, and peak serum Na ~nd used (Miller 1986). A ~ d o m i z e d b l ~ k ~mlOsm are presented in Table 1. Subjects com- ys,s of variance was computed for each of the pleted all infusions except for subject 5 who had 216 permutations of each of three v ~ a b l e s a severe panic attack during his first infusion (in (presence or absence of ~ i c , global ~ i c rathis case, HS), and refused subsequent infusions. ings, and API scores); the p value was deterof ~ observed statistic among Four of four subjects were positive for panic mined by the ~ with NaLAC, four of five were positive for panic the 216 possible test statistics. There were no with HS, and none were positive with NS. The differences between HS and N ~ C conditions; subject positive for panic during NaLAC but not differences between-NS and Gae other two conHS attained a much higher Osm during NaLAC ditions are significant at p = 0.037 for all d~ree (324 mOsm&g, a 34 mOsm/kg increase over variables. baseline) than during HS (301 mOsm/kg, a 12 mOsm&g increase over baseline). The reason for this discrepancy was not apparent. In the D i s c u s s i o n three subjects who attained similar Na and Osm These preliminary data support the hypothesis with both NaLAC and HS, panic and anxiety that acutely increasing serum Na and/or Osm by w e ~ similar. Time-to-peak panic symptoms did either HS or NaLAC can induce p ~ c . Because not differ between HS (i7 ___3 mill) and NaLAC HS did induce p ~ c but did not produce ~ a (17 _+ 4 min) infusions. Venous pH increased losis, changes in acid base status may not be
Table 1. Panic Ratings, Acute Panic Inventory (API) Scores, Peak Serum Sodium (Na), ~ d Peak Osmolality (Osm) during Infusions of 0.5 M Sodium Lactate, Hypertonic S ~ e (3% NaCl), and Normal Saline (0.9% NaCI) Sodium lactate
Hypertonic saline
Normal saline
Subject
Panic
API
Na mEq/L
Osm mOsm/kg
Panic
API
Na mEq/L
Osm mOsm/kg
Panic
API
Na mEq/L
Osm mOsm/kg
! 2
+(8) +(10)
6 12
144 156
297 324
+ (6) - (0)
6 0
145 147
300 301
-(0) -(0)
1 !
141 140
288 291
3 4 5
+(10) 11 +(6) 19 . . .
147 148 .
311 303
+(10) + (7) + (8)
20 15 23
152 147 145
309 301 300
-(3) -(5)
5 5 --
141 141 --
289 291
~Presence or absence of panic indicated by + or - ; global panic rating in parentheses.
630
Brief Reports
BIOL PSYCHIATRY !991;30:628-630
central to the induction of panic by NaLAC. Subjects in whom 14S and NaLAC increased serum Na and Osm to the same degree experienced equivalent panic symptomatology with infusions. Subject 2, who failed to panic with HS, achieved a markedly smaller increase in serum Na and Osm during the HS infusion compared with the NaLAC infusion, and therefore may have received an inadequate stimulus for the induction of panic. Other studies have addressed a potential osmolar mechanism in panic induction. In a report in which serum Na and Osm were not measured, 3% HS induced panic in several subjects (RoyByme et al 19S9). In contrast, increasing serum Osm with a hyperosmolar glucose solution did not induce panic (Pitts and McClure 1967). However, hyperosmolar glucose is an ineffective stimulus for the hypothalamic osmostat-mediated release of arginine vasopressin (AVP), the human antidiuretic hormone (Zerbe and Robertson 1983), whereas both HS and NaLAC are potent osmotic stimuli for AVP release (Carr et al 1986). Recent studies suggest potential mechanisms by which an increase in body Na could produce panic and anxiety symptoms via corticotropin-releasing hormone or other neuroendocrine systems (Lightman and Young 1987; Rittmaster ¢t al 1987). The present pilot study must be interpreted cautiously because of the small number of sub~ects and the presence of a substance abuse history in several subjects. Also, our definition of a positive ~r~_nic response a;~'r~,.~a ,~,om " " " ^r some investigators because we did not require that a subject request that the infusion be stopped. Larger studies of uncomplicated PD and normal subjects are needed to confirm these findings, and to explore the effect of body Na and Osm on panic symptomatology and neuroendocrine systems relevant to arousal and anxiety.
The authors wish to thank Cart Sikkema, Gaff Gumbrecht, Shannon ~ n , Sharon Mmray, an0 Monique Chemer for the~ excellent technical assistance, and Maxine Comfier and Rebekah Rein for manuscril~ prepar~o~. This work
was supported by the Depam~nt of Veterans Affairs and NIH Grant AG08419.
References Cart DB, Fishman SM, Kasting NW, et al (1986): Vasopressin response to lactate ififusion in norm~s and patients with panic disorder. Funct New rol !: 123-127. Cowley DS, Jensen CF, Johannessen D, et al (1989): Response to sodium lactate infusion in alcoholics with panic attacks. Am J Psychiatry 146:!4791483. Dillon DJ, Gonnan J, Liebowitz MR, et al (1987): Measurement of lactate-induced panic and anxiety. Psychia.ny Res 20:97-105. ~ r g e DT, Nutt DJ, Waxman RP, et al (1989): Panic response to lactate administration in alcoholic and nonalcoholic patients with panic disorder. Am J Psychiatry 146:1161-1165. Lightman SL, Young W1 (1987): Changes in hypothalamic preproenkephalin A mRNA following stress and opiate withdraw~. Nmure 328:64.3645. Miller RG ( 1986): Beyond ANOVA, Basics of Applied Statistics. New York: Wiley. Pitts FN, McClure JN (1967): Lactate metabolism in anxiety neurosis. N Engl J Med 277:1329-1336. Ri.qmaster RS, Cutler GB, Gold PW, et al (1987): The relationship of saline-induced changes in vasopressin secretion to basal and corticotropm-releasing hormone-stimulated adrenocorticotropin mm Cu,u~, ~.a~;UUU in man. J Clin Endocrinoi Metab 64:371-376. Roy-Byrne PP, Schmidt P, Cannon RO, et al (1989): Microvascular angina and panic disorder, int l Psychiatry Med 19:315-326. Zerbe RL, Robertson GL (1983): Osmoregulation of thirst and vasopressin secretion in human subjects: Effect of various solutes. Am J Physio1244:E602E614.
BIOL PSYCHIATRY 1991 ;~:628- 630
Hypertonic Saline hffusion Induces Panic in Patients with Panic Disorder Carl F. Jensen, Elaine R. Peskind, Richard C. Veith, James Hughes, Deborah S. Cowley, Peter Roy-Byrne, and Murray A. Raskind
Introduction The mechanism by which sodium lactate (NaLAC) infusion induces panic remains obscure. That the standard 0.5 M NaLAC solution is a hypertonic sodium (Na) solution that produces a marked and rapid increase in plasma Na and osmolality (Osm) (George et al 1989) suggests that these rapid increases in plasma Na and Osm are involved in t?:e induction of panic. In this pilot study, we administered to par~ic disorder (PD) patients a hypertonic saline (HS) infusion (3% NaCI) designed to produce an increa~ in serum Na, Osm, and volume equal to the standard NaLAC infusion. We tested the hypothesis that increasing serum Osm and Na an equivalent amount with HS or NaLAC infusions would p ~ u c e panic ,~ymptoms of similar frequency and quality and that an equal volume infusion of normal saline (NS) would not produce panic symptoms.
Methods Subjects were 5 Caucasian men aged 36-63 who met DSM-III-R criteria for PD and were currently experiencing ~pontaneous panic attacks. From the Seattle VA Medical Center and Department of Psychiatry and Behavior,'tl Sciences, University of Washington School of Medicine, Seattle. WA. Address leprinl requests to Dr. Jensen, Seattle VA Medi-al Cente(116A), 1660 South Colu,•bian '~ay, Seattle, WA 98108. Received November 9, 1990; revised March 19, 1991.
© 1991 Society of Biological P s y c h i ~
Four had a history of alcohol dependence but had been free of alcohol for at least 3 wonths. Panic disorder was p~m..~_'3' in 3 of,,he 4. Subject 4 had no history of substance abuse. Subject 2 continued to experience spontaneous panic attacks even though maintaine2 on doxepin. He was also maintained on disulfiram and diphenylhydantoin. Subject 4 had spontaneous panic attacks despite maintenance on nortriptyline. Other subjects were free of prescribed medications for at least 3 weeks. Informed consent was obtained after procedures were fully explained. Thirty minutes prior to infusion, IV catheters were placed in each ann. infusions were administered between 9:00 AM and noon in double-blind fashion in randomized sequence at least 3 days apart. Solutions incivded 0.5 M NaLAC (1000 mEq/L), 3% NaCl (1026 mEq/L) (HS), and 0.9% NaCi (308 mEq/L) (NS), and were infused at l0 ml/kg over 20 min. Subjects were asked to abstain from food, caffeine, and tobacco from midnight prior to study. A urine sample was ¢btained prior to each infusion to screen for recent drug and alcohol use. Panic and anxiety were assessed by the Acute Panic Inventory (Dillon et al 1987), administered prior to infusion and at 5 min intervals for 40 min. At 15 min postinfusion, subjects globally rated the subjective quality and intensity of the experience compared to a spontaneous panic attack using a scale of 0 (totally unlike a panic attack) to l0 (exactly 0006-3223/91/$03.50
nlOL ~ ¥ c I ~ A ~ Y
Brief Reports
629
like a severe, spontaneous panic attack). A response was positive for "panic" if the subject met previously described criteria (Cowley et al 1989) and had a global panic rating of at least 5. Blood samples for serum Na and Osm were drawn from the noninfusion arm at baseline, immediately postinfusion, and at 15 rain intervals thereafter for 75 rain. Venous pH was measured at baseline and at end infusion in subjects 3, 4, and 5 only.
in subjects 3 and 4 with NaLAC (7.39-7.49 an~l 7.40-7.50) but not with HS (7.39-7.37 ~ 7.427.36) Subject 5 (HS o~y) had no increase in venous pH (" 38--7.~2). U ~ t o x k o ~ were negative for abused substarges excep: for subject I, whose urine was pop,rive for cocai~, tetra__hy&ocannabinol, and alcohol prior to ~ studies. Statistical an~ysis was restricted to the three subjects ( i, 3~ and 4) who met the criteria (completed ~ three infusions ~ achieved comparable Osm in HS and N ~ C conditions) necResults essary to test our a priori hypothesis. Due to Presence of panic, global panic ratings, APi small sample size, a ~rmumtion approach was scores at end infusion, and peak serum Na ~nd used (Miller 1986). A ~ d o m i z e d b l ~ k ~mlOsm are presented in Table 1. Subjects com- ys,s of variance was computed for each of the pleted all infusions except for subject 5 who had 216 permutations of each of three v ~ a b l e s a severe panic attack during his first infusion (in (presence or absence of ~ i c , global ~ i c rathis case, HS), and refused subsequent infusions. ings, and API scores); the p value was deterof ~ observed statistic among Four of four subjects were positive for panic mined by the ~ with NaLAC, four of five were positive for panic the 216 possible test statistics. There were no with HS, and none were positive with NS. The differences between HS and N ~ C conditions; subject positive for panic during NaLAC but not differences between-NS and Gae other two conHS attained a much higher Osm during NaLAC ditions are significant at p = 0.037 for all d~ree (324 mOsm&g, a 34 mOsm/kg increase over variables. baseline) than during HS (301 mOsm/kg, a 12 mOsm&g increase over baseline). The reason for this discrepancy was not apparent. In the D i s c u s s i o n three subjects who attained similar Na and Osm These preliminary data support the hypothesis with both NaLAC and HS, panic and anxiety that acutely increasing serum Na and/or Osm by w e ~ similar. Time-to-peak panic symptoms did either HS or NaLAC can induce p ~ c . Because not differ between HS (i7 ___3 mill) and NaLAC HS did induce p ~ c but did not produce ~ a (17 _+ 4 min) infusions. Venous pH increased losis, changes in acid base status may not be
Table 1. Panic Ratings, Acute Panic Inventory (API) Scores, Peak Serum Sodium (Na), ~ d Peak Osmolality (Osm) during Infusions of 0.5 M Sodium Lactate, Hypertonic S ~ e (3% NaCl), and Normal Saline (0.9% NaCI) Sodium lactate
Hypertonic saline
Normal saline
Subject
Panic
API
Na mEq/L
Osm mOsm/kg
Panic
API
Na mEq/L
Osm mOsm/kg
Panic
API
Na mEq/L
Osm mOsm/kg
! 2
+(8) +(10)
6 12
144 156
297 324
+ (6) - (0)
6 0
145 147
300 301
-(0) -(0)
1 !
141 140
288 291
3 4 5
+(10) 11 +(6) 19 . . .
147 148 .
311 303
+(10) + (7) + (8)
20 15 23
152 147 145
309 301 300
-(3) -(5)
5 5 --
141 141 --
289 291
~Presence or absence of panic indicated by + or - ; global panic rating in parentheses.
630
Brief Reports
BIOL PSYCHIATRY !991;30:628-630
central to the induction of panic by NaLAC. Subjects in whom 14S and NaLAC increased serum Na and Osm to the same degree experienced equivalent panic symptomatology with infusions. Subject 2, who failed to panic with HS, achieved a markedly smaller increase in serum Na and Osm during the HS infusion compared with the NaLAC infusion, and therefore may have received an inadequate stimulus for the induction of panic. Other studies have addressed a potential osmolar mechanism in panic induction. In a report in which serum Na and Osm were not measured, 3% HS induced panic in several subjects (RoyByme et al 19S9). In contrast, increasing serum Osm with a hyperosmolar glucose solution did not induce panic (Pitts and McClure 1967). However, hyperosmolar glucose is an ineffective stimulus for the hypothalamic osmostat-mediated release of arginine vasopressin (AVP), the human antidiuretic hormone (Zerbe and Robertson 1983), whereas both HS and NaLAC are potent osmotic stimuli for AVP release (Carr et al 1986). Recent studies suggest potential mechanisms by which an increase in body Na could produce panic and anxiety symptoms via corticotropin-releasing hormone or other neuroendocrine systems (Lightman and Young 1987; Rittmaster ¢t al 1987). The present pilot study must be interpreted cautiously because of the small number of sub~ects and the presence of a substance abuse history in several subjects. Also, our definition of a positive ~r~_nic response a;~'r~,.~a ,~,om " " " ^r some investigators because we did not require that a subject request that the infusion be stopped. Larger studies of uncomplicated PD and normal subjects are needed to confirm these findings, and to explore the effect of body Na and Osm on panic symptomatology and neuroendocrine systems relevant to arousal and anxiety.
The authors wish to thank Cart Sikkema, Gaff Gumbrecht, Shannon ~ n , Sharon Mmray, an0 Monique Chemer for the~ excellent technical assistance, and Maxine Comfier and Rebekah Rein for manuscril~ prepar~o~. This work
was supported by the Depam~nt of Veterans Affairs and NIH Grant AG08419.
References Cart DB, Fishman SM, Kasting NW, et al (1986): Vasopressin response to lactate ififusion in norm~s and patients with panic disorder. Funct New rol !: 123-127. Cowley DS, Jensen CF, Johannessen D, et al (1989): Response to sodium lactate infusion in alcoholics with panic attacks. Am J Psychiatry 146:!4791483. Dillon DJ, Gonnan J, Liebowitz MR, et al (1987): Measurement of lactate-induced panic and anxiety. Psychia.ny Res 20:97-105. ~ r g e DT, Nutt DJ, Waxman RP, et al (1989): Panic response to lactate administration in alcoholic and nonalcoholic patients with panic disorder. Am J Psychiatry 146:1161-1165. Lightman SL, Young W1 (1987): Changes in hypothalamic preproenkephalin A mRNA following stress and opiate withdraw~. Nmure 328:64.3645. Miller RG ( 1986): Beyond ANOVA, Basics of Applied Statistics. New York: Wiley. Pitts FN, McClure JN (1967): Lactate metabolism in anxiety neurosis. N Engl J Med 277:1329-1336. Ri.qmaster RS, Cutler GB, Gold PW, et al (1987): The relationship of saline-induced changes in vasopressin secretion to basal and corticotropm-releasing hormone-stimulated adrenocorticotropin mm Cu,u~, ~.a~;UUU in man. J Clin Endocrinoi Metab 64:371-376. Roy-Byrne PP, Schmidt P, Cannon RO, et al (1989): Microvascular angina and panic disorder, int l Psychiatry Med 19:315-326. Zerbe RL, Robertson GL (1983): Osmoregulation of thirst and vasopressin secretion in human subjects: Effect of various solutes. Am J Physio1244:E602E614.
