nlOLPSYCtHATRY
539
1992:32:539-542
BRIEF REPORTS
Lactate Sensitivity in Sleeping Panic Disorder Patients and Healthy Controls Harold W. Koenigsberg, Charles P. Pollak, Jeffrey Fine, and Tatsu Kakuma
Introduction In spite of a series of careful physiological and neuroendocrine studies of sodium lactate-induced panic attacks in Panic Disorder (PD) patients, the mechanism of panic induction remains poorly understood. To further explore this mechanism, we administered sodium lactate infusions to PD patients and normal controls during sleep, taking advantage of the opportunity that sleep provides for closely monitoring shifts in state of arousal. In previous work (Koenigsberg et al 1987) we reported that sodium lactate but not dextrose-saline infusions, administered during stage 3-4 sleep, induced prompt awakenings in panic disorder (PD) patients.
Methods Subjects were 15 PD patients and 12 normal controls between the ages of 20 and 59 years. The groups did not differ significantly in mean age or gender ratio. Diagnoses of subjects and family psychiatric history were obtained using
From the Department of Psychi,~try, Comell University Medical College and the New York H~ital----Cornell Medical Center, Westchester Diviston. This work was supported by a grant from the National Institute of Mental Health (ROI MI4 42805). Address reprint requests to Dr. Koenigsberg, The New York Hospital--Comell Medical Center, Westchester Division. 21 Bloommgdale Road. White Plains, N.Y. 10605. Received December 12, 1991; revised February 11. 1992.
© 1992 Society of Biological Psychiatry
the SCID-P and Family Interview Schedule Criteria (FISC) interviews, respectively. For inclusion, PD subjects were required to meet DSMIII-R criteria for Panic Disorder and to have no current diagnoses of major depression, substance use disorders, or history of psychotic or organic mental disorders. Normal control subjects had no DSM-III-R axis I disorder and no family history of PD. All subjects were in good physical health and gave informed consent. They had been free of psychotropic medications for 2 weeks. All of the normal controls and seven of the PD subjects were studied in the present protocol. We have also included findings on eight PD subjects studied in an earlier protocol (Koenigsberg 1987). Inspection showed no difference in lactate response in the two PD samples. Subjects spent an accommodation night followed by au infusion night in the sleep laboratory. Sleep stages were rated in 30-sec epochs using standard criteria (Rechtschaffen and Kales 1968). Awakening was defined as a Iransition to sleep stage 0. Raters were blind to diagnosis and infusion type. On the infusion night, either 1.0 mol/L sodium lactate or 5% dextrose and 0.9% saline (D5NS) was infused intravenously during stage 3-4 sleep. Multiple infusions were given whenever possible, alternating between lactate and D5NS, with a random choice of the first infusion. Infusions continued until a 2-min awakening had occurred or until the maximum total dose 0006-3223/92/$05.00
540
BIOL PSYCHIATRY 1992;32:539-542
of 5 ml/kg of solution had been delivered. PD subjects studied in the earlier protocol received a waking lactate challenge during the day, did not spend an accommodation night in the sleep lab, and received 0.5 mol/L rather than 1.0 mol/L sodium lactate to a maximum nighttime dose of 10 ml/kg. We used the 1.0moFL concentration, of Bonn et al (1971) and others, in the present study to increase the likelihood of inducing panic directly from sleep. Responses to lactate and D5NS were measured by changes in median sleep stage and by frequency of awakening. To calculate median sleep stage, the 30-see sleep-stage ratings were treated as ordinal data, setting stage 4 equal to 4, etc. ItEM sleep was rare around times of infusion and was omitted from the analysis. Medians of the ordinal values assigned to sleep stages were calculated for each successive 2.5min interval, from 10 min before to 30 min after the start of each infusion given during stage 34 sleep. Medians were taken over multiple infusions of each substance in each subject, and then over subjects in each group (Figure 1). Ordinal logit analysis (McKelvey and Zavoina 1975) was used to test for significant differeflces.
The number of awakenings occurring during successive 10-rain intervals, from 10 min before
Brief
to 30 min after each stage 3-4 infusion, were averaged over subjects in each group. Likelihood ratio statistics based on the Poisson distribution were used to test for significance. Pairwise comparisons were carried out using a onetailed Wald test (Rao 1965). Results Comparing percent delta sleep and wake plus movement time between the 5 PD patients and twelve normals for whom we have accommodation night data, we found no significant difference in depth of sleep between the groups. Median sleep stages are displayed in Figure 1. Between 2.5 and 5.0 rain after lactate infusions, but not DSNS, PD subjects lightened to a median sleep stage of 2, whereas normals did not show this lightening response until l0 rain after the infusion. This PD versus normals difference is significant for all intervals from 2.5 to 10 rain (X~w > 3.25, df = 1, p < 0.05). By 10 rain after the infusion, lactate began to be significantly more arousogenic than DSNS in normals as well, and this effect is significant for all intervals from 10 to 20 min after the infusion (X~,ad > 2.92, df = 1, p < 0.05). Whereas the sleep of PD patients following DSNS appears to be somewhat lighter than that of nonnals, this difference does not reach significance in six of
1
a)
-io
Reports
0
o io TI~ from lnfustan (mln)
b)
-1o
L
o
Io
T|me frm InfUsion (rain)
Figure 1. Median sleep stages preceding and following infusions for: a) Panic Disorder Patients and b) Normal Controls. Heavylines indicate sodiumlactate infusions;thin lines indicate DSNS infusions.
Brief Reports
BIOL PSYCHIATRY 1992;32:539-542
541
Table 1. Sensitivity of Individual Subjects to Lactate as Measured by Number of Awakenings Within 10 Min of Challenge Panic Disorder Patients
Subject Pi* P2* P3* P4* P5* P6* PT* P8 P9 Pl0 Pl I P12 P13
Age
Sex
No. Infusions Received in 3-4 Sleep
27 40 27 42 38 38 28 28 36 25 22 47 38
F M M F F F M M F F F M M
I 1 2 1 1 1 I 2 2 I I 1 1
Healthy Controls
No. Awakenings Within 10 Min ! ! 2 0 1 1 1 2 2 I I 0 2
Subject
Age
Sex
No. Infusions Received in 3--4 Sleep
NI N2 N3 N4 N5 N6 N7 N8 N9
59 22 23 23 32 27 20 34 42
F F M M F F M M F
2 2 1 1 3 1 2 I I
No. Awakenings Within 10 Min 1 2 0 0 2 2 0 ! 0
Subjects indicated by asterisk received O.S.mol/Linfusions; all others received l.O-mol/L infusions. (Two panic disorder subjects and three healthy centrals are not included, as they received no lactate infesions during stage 3.-4 sleep.)
the seven 2.5-min post-infvsion intervals compared. During the first 10 min after infusion, PD subjects had significantly more awakenings with lactate than with D5NS infusions (X2~d -- 2.87, df - 1, p < 0.05). This was not the case for the normals. Comparing PD subjects and normals, lactate tended to induce more awakenings in the PD patients (X2~d ffi 1.2~, df ffi l , p ffi 0.13) in the first 10 min. During the second 10min interval, lactate tended to induce more awakenings in normals than in PD patients (X2w~d ffi 1.56, df ffi 1, p ffi 0.11). This is probably because PD patients had already been awakened by lactate in the previous interval. Although more awakenings also followed D5NS in PD patients than in normals, this difference was not significant for any interval. The sensitivity of individual subjects to lactate challenge is displayed in Table 1. As in our prior study, the lactate infusions did not trigger panic attacks directly from sleep in any subjects. This may be because awakening occurred long before the usual panicogenic dose of lactate had been reached.
Discussion Our findings suggest that PD subjects are more sensitive than controls to the arousogenic property of sodium lactate. One possible explanation is that PD subjexts are lighter sleepers than normal controls, ~rtd therefore may be more prone to arouse from any stimulus. There is no evidence, however, in our comparison or in the work of Mellman and Uhde (1990) that stage 3-4 sleep is lighter in PD subjects than normals. Comparisons of stage 3-4 EEG spectra and thresholds for arousal to other stimuli ate needed, however, to role out this possibility.
References Bonn JA, Harrison J, Rees WL (1971): Lactate Induced Anxiety: Therapeutic Application, Br J Psychiatry ! 19:468-471. Koenigsberg HW, Pollak C, Sullivan T (1987): The Sleep Lactate Infusion: Arousal and the Panic Mechanism. Biological Psychiatry 789-791. McKelvey RD, Zavoina W (1975): A statistical model for the analysis of ordinal level dependent variables. J Mathematical 5ociology 4:103-120.
542
BIOLPSYCHIATRY 1992;32:539-542
Mellman TA, Uhde TW (1990): Sleep in Panic and Generalized Anxiety Disorders, in Ballenger JC (ed), Neurobiology of Panic Disorder. New York, Wiley-Liss. Rao CR (1965): Linear Statistical Inference and Its Applications (2nd edition). New York, John Wiley & Sons, p 417.
Brief Reports
Rechtschaffen A, Kales A (1968): A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects, publication 234. Washington, D.C., Department of Health, Education and Welfare.
539
1992:32:539-542
BRIEF REPORTS
Lactate Sensitivity in Sleeping Panic Disorder Patients and Healthy Controls Harold W. Koenigsberg, Charles P. Pollak, Jeffrey Fine, and Tatsu Kakuma
Introduction In spite of a series of careful physiological and neuroendocrine studies of sodium lactate-induced panic attacks in Panic Disorder (PD) patients, the mechanism of panic induction remains poorly understood. To further explore this mechanism, we administered sodium lactate infusions to PD patients and normal controls during sleep, taking advantage of the opportunity that sleep provides for closely monitoring shifts in state of arousal. In previous work (Koenigsberg et al 1987) we reported that sodium lactate but not dextrose-saline infusions, administered during stage 3-4 sleep, induced prompt awakenings in panic disorder (PD) patients.
Methods Subjects were 15 PD patients and 12 normal controls between the ages of 20 and 59 years. The groups did not differ significantly in mean age or gender ratio. Diagnoses of subjects and family psychiatric history were obtained using
From the Department of Psychi,~try, Comell University Medical College and the New York H~ital----Cornell Medical Center, Westchester Diviston. This work was supported by a grant from the National Institute of Mental Health (ROI MI4 42805). Address reprint requests to Dr. Koenigsberg, The New York Hospital--Comell Medical Center, Westchester Division. 21 Bloommgdale Road. White Plains, N.Y. 10605. Received December 12, 1991; revised February 11. 1992.
© 1992 Society of Biological Psychiatry
the SCID-P and Family Interview Schedule Criteria (FISC) interviews, respectively. For inclusion, PD subjects were required to meet DSMIII-R criteria for Panic Disorder and to have no current diagnoses of major depression, substance use disorders, or history of psychotic or organic mental disorders. Normal control subjects had no DSM-III-R axis I disorder and no family history of PD. All subjects were in good physical health and gave informed consent. They had been free of psychotropic medications for 2 weeks. All of the normal controls and seven of the PD subjects were studied in the present protocol. We have also included findings on eight PD subjects studied in an earlier protocol (Koenigsberg 1987). Inspection showed no difference in lactate response in the two PD samples. Subjects spent an accommodation night followed by au infusion night in the sleep laboratory. Sleep stages were rated in 30-sec epochs using standard criteria (Rechtschaffen and Kales 1968). Awakening was defined as a Iransition to sleep stage 0. Raters were blind to diagnosis and infusion type. On the infusion night, either 1.0 mol/L sodium lactate or 5% dextrose and 0.9% saline (D5NS) was infused intravenously during stage 3-4 sleep. Multiple infusions were given whenever possible, alternating between lactate and D5NS, with a random choice of the first infusion. Infusions continued until a 2-min awakening had occurred or until the maximum total dose 0006-3223/92/$05.00
540
BIOL PSYCHIATRY 1992;32:539-542
of 5 ml/kg of solution had been delivered. PD subjects studied in the earlier protocol received a waking lactate challenge during the day, did not spend an accommodation night in the sleep lab, and received 0.5 mol/L rather than 1.0 mol/L sodium lactate to a maximum nighttime dose of 10 ml/kg. We used the 1.0moFL concentration, of Bonn et al (1971) and others, in the present study to increase the likelihood of inducing panic directly from sleep. Responses to lactate and D5NS were measured by changes in median sleep stage and by frequency of awakening. To calculate median sleep stage, the 30-see sleep-stage ratings were treated as ordinal data, setting stage 4 equal to 4, etc. ItEM sleep was rare around times of infusion and was omitted from the analysis. Medians of the ordinal values assigned to sleep stages were calculated for each successive 2.5min interval, from 10 min before to 30 min after the start of each infusion given during stage 34 sleep. Medians were taken over multiple infusions of each substance in each subject, and then over subjects in each group (Figure 1). Ordinal logit analysis (McKelvey and Zavoina 1975) was used to test for significant differeflces.
The number of awakenings occurring during successive 10-rain intervals, from 10 min before
Brief
to 30 min after each stage 3-4 infusion, were averaged over subjects in each group. Likelihood ratio statistics based on the Poisson distribution were used to test for significance. Pairwise comparisons were carried out using a onetailed Wald test (Rao 1965). Results Comparing percent delta sleep and wake plus movement time between the 5 PD patients and twelve normals for whom we have accommodation night data, we found no significant difference in depth of sleep between the groups. Median sleep stages are displayed in Figure 1. Between 2.5 and 5.0 rain after lactate infusions, but not DSNS, PD subjects lightened to a median sleep stage of 2, whereas normals did not show this lightening response until l0 rain after the infusion. This PD versus normals difference is significant for all intervals from 2.5 to 10 rain (X~w > 3.25, df = 1, p < 0.05). By 10 rain after the infusion, lactate began to be significantly more arousogenic than DSNS in normals as well, and this effect is significant for all intervals from 10 to 20 min after the infusion (X~,ad > 2.92, df = 1, p < 0.05). Whereas the sleep of PD patients following DSNS appears to be somewhat lighter than that of nonnals, this difference does not reach significance in six of
1
a)
-io
Reports
0
o io TI~ from lnfustan (mln)
b)
-1o
L
o
Io
T|me frm InfUsion (rain)
Figure 1. Median sleep stages preceding and following infusions for: a) Panic Disorder Patients and b) Normal Controls. Heavylines indicate sodiumlactate infusions;thin lines indicate DSNS infusions.
Brief Reports
BIOL PSYCHIATRY 1992;32:539-542
541
Table 1. Sensitivity of Individual Subjects to Lactate as Measured by Number of Awakenings Within 10 Min of Challenge Panic Disorder Patients
Subject Pi* P2* P3* P4* P5* P6* PT* P8 P9 Pl0 Pl I P12 P13
Age
Sex
No. Infusions Received in 3-4 Sleep
27 40 27 42 38 38 28 28 36 25 22 47 38
F M M F F F M M F F F M M
I 1 2 1 1 1 I 2 2 I I 1 1
Healthy Controls
No. Awakenings Within 10 Min ! ! 2 0 1 1 1 2 2 I I 0 2
Subject
Age
Sex
No. Infusions Received in 3--4 Sleep
NI N2 N3 N4 N5 N6 N7 N8 N9
59 22 23 23 32 27 20 34 42
F F M M F F M M F
2 2 1 1 3 1 2 I I
No. Awakenings Within 10 Min 1 2 0 0 2 2 0 ! 0
Subjects indicated by asterisk received O.S.mol/Linfusions; all others received l.O-mol/L infusions. (Two panic disorder subjects and three healthy centrals are not included, as they received no lactate infesions during stage 3.-4 sleep.)
the seven 2.5-min post-infvsion intervals compared. During the first 10 min after infusion, PD subjects had significantly more awakenings with lactate than with D5NS infusions (X2~d -- 2.87, df - 1, p < 0.05). This was not the case for the normals. Comparing PD subjects and normals, lactate tended to induce more awakenings in the PD patients (X2~d ffi 1.2~, df ffi l , p ffi 0.13) in the first 10 min. During the second 10min interval, lactate tended to induce more awakenings in normals than in PD patients (X2w~d ffi 1.56, df ffi 1, p ffi 0.11). This is probably because PD patients had already been awakened by lactate in the previous interval. Although more awakenings also followed D5NS in PD patients than in normals, this difference was not significant for any interval. The sensitivity of individual subjects to lactate challenge is displayed in Table 1. As in our prior study, the lactate infusions did not trigger panic attacks directly from sleep in any subjects. This may be because awakening occurred long before the usual panicogenic dose of lactate had been reached.
Discussion Our findings suggest that PD subjects are more sensitive than controls to the arousogenic property of sodium lactate. One possible explanation is that PD subjexts are lighter sleepers than normal controls, ~rtd therefore may be more prone to arouse from any stimulus. There is no evidence, however, in our comparison or in the work of Mellman and Uhde (1990) that stage 3-4 sleep is lighter in PD subjects than normals. Comparisons of stage 3-4 EEG spectra and thresholds for arousal to other stimuli ate needed, however, to role out this possibility.
References Bonn JA, Harrison J, Rees WL (1971): Lactate Induced Anxiety: Therapeutic Application, Br J Psychiatry ! 19:468-471. Koenigsberg HW, Pollak C, Sullivan T (1987): The Sleep Lactate Infusion: Arousal and the Panic Mechanism. Biological Psychiatry 789-791. McKelvey RD, Zavoina W (1975): A statistical model for the analysis of ordinal level dependent variables. J Mathematical 5ociology 4:103-120.
542
BIOLPSYCHIATRY 1992;32:539-542
Mellman TA, Uhde TW (1990): Sleep in Panic and Generalized Anxiety Disorders, in Ballenger JC (ed), Neurobiology of Panic Disorder. New York, Wiley-Liss. Rao CR (1965): Linear Statistical Inference and Its Applications (2nd edition). New York, John Wiley & Sons, p 417.
Brief Reports
Rechtschaffen A, Kales A (1968): A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects, publication 234. Washington, D.C., Department of Health, Education and Welfare.
