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Biologic findings in panic disorder:
Biologic Findings in Panic Disorder: Neuroendocrine
and Sleep-Related
Abnormalities
PETER P. ROY-BYRNE. M.D.
THOMAS A. MELLMAN.
Abstract-Studies
of neuroendocrine function. sleep physiology and
sleep deprivation tients
show
contrast.
in patients
a variety
ities in EEG
with
while
few
panic attacks.
association
with
nocturnal is either
anxiety
or a cumulative
findings
may be more
more result
are reviewed.
abnormalities.
These
closely
related
of repetitive
related
have findings
to sleep deprivation.
In
to occur
in
seem to occur
in
found
suggest
to background panic
to the actual
to pa-
been
EEG sleep patterns
attacks.
response
At baseline.
but fail to show abnormal-
response
abnormalities
characteristic
panic
closely
disorder
or a therapeutic
neuroendocrinr
with
dysfunction
panic
of neuroendocrine
sleep architecture
association crine
M.D. ANDTHOMAS W. UHDE. M.D.
attacks,
panic
that
neuroendo-
(“anticipatory”) while
attacks
EEG
sleep
themselves.
The notion that panic attacks have a significant biological basis has been fueled by evidence that they can be provoked by a variety of discrete pharmacologic stimuli (see Woods and Charney this issue). that they can be blocked by medications not traditionally considered to have prominent anxiolytic properties (Sheehan, Ballenger, & Jacobsen, 1980), and that they occur more frequently in family members of individuals suffering from them than from other psychiatric disorders (Crowe, Noyes, Pauls, & Slymen, 1983). Evidence that panic and major depressive disorders often co-occur in the same individual, and share important similarities in phenomenology, family history, and treatment response (Breier, Charney, & Heninger, 198.5), and evidence that cortisol nonsuppression following dexamethasone (Carroll, 1984) and shortened REM latency during sleep EGG recordings (Kupfer & Thase, 1983) are the biological abnormalities most consistently found in depressed patients, has Address Psychiatry Seattle.
correspondence and Behavioral
and reprint Sciences,
requests
to Dr.
Peter
P. Roy-Byrne.
RP-IO. University of Washington,
WA 98195. I7
Department
School
of Medicine,
of
18
P.
P. ROY-BYRNE.
T.
A.
MELLMAN,
ANDT.
W.
UHDE
prompted investigators to explore neuroendocrine and sleep-related parameters in patients with panic disorder. This paper will review the ecidence for neuroendocrine and sleep-related abnormalities in these patients and discuss how these lindings might clarify the relation between panic and major depressive disorders. as well as relate to proposed patho-physiologic mechanisms in panic disorder. NEUROENDOCRINE
FUNCTION
Although there is a rather extensive literature examining changes in endocrine function as a consequence/correlate of “stress,” with particular emphasis on the hypothalamic-pituitary-adrenal axis, until recently there has been relatively little attention paid to neuroendocrine function in anxiety disorders. This review will focus on the pituitary-adrenal and pituitary-thyroid axes, and on the secretion of growth hormone and prolactin. Although we are focusing on panic disorder, we will also include studies of endocrine function during exposure to feared situations in patients with simple phobias since there is evidence these patients experience fear similar in both intensity and temporal characteristics to a panic attack at this time. Finally, we will briefly discuss the possible implications of any abnormalities with regard to various neurotransmitter and receptor dysregulation hypotheses about panic disorder. Hypothalamic-Pituitac-Adrenal
(HPA) Ark
Although still quite preliminary. the greatest amount of data generated in panic disorder patients involved various measures of HPA function. Initial studies indicated that basal cortisol levels obtained in the morning, usually prior to infusion studies, were normal, whereas, subsequent investigators found elevated levels of cortisol in patients who were studied in the afternoon (Goldstein, Halbreich, Asnis, Endicott, & Alvir, 1987: Nesse, Cameron, Curtis, McCann, & Huber-Smith, 1984) and early evening (Roy-Byrne, Uhde, Post, et al., 1986). The late-afternooniearly-evening timing of these abnormalities is of some interest in view of a recent pilot study suggesting that the frequency of panic attacks is greatest in the early evening (Cameron, Lee, Kotun, & Murphy, 1986). However, since Halbreich, Asnis, Schindledecker, Zumoff, and Nathan (1985) have shown that the mean plasma cortisol levels between 1:00 and 4:00 p.m. are highly correlated with mean 24-hour plasma cortisol levels, these abnormalities may just reflect a time of day at which discrete sampling is a better reflection of overall HPA activity. Despite some evidence of cortisol hypersecretion, none of ten studies examining the dexamethasone suppression test in patients with panic disorder (Avery, et al., 1985; Bridges, Yeragani, Rainey, & Pohl, 1986; Coryell, Noyes, Clancy, Crowe, & Chaudrey, 1985; Curtis, Cameron, & Nesse, 1982; Goldstein et al., 1987; Lieberman et al., 1983; Peterson et
BIOLOGIC
FINDINGS
IN PANIC
DISORDER
19
al., 1985; Roy-Byrne, Bierer. PCUhde. 1985; Sheehan et al., 1983; Whiteford & Evans, 1984) found an incidence of cortisol nonsuppression approaching the average 45% figure seen in patients with major depression. Because the incidence found in some of these studies is higher than the accepted 5% figure for normals, and because two studies (Avery et al.. 1985; Coryell et al., 1985) that included a control group of outpatient depressives found comparable rates of nonsuppression in both patient groups, some investigators have suggested that it may still be “abnormal.” However, the three studies (Bridges et al., 1986: Goldstein et al., 1987; Roy-Byrne et al., 1985) including a normal control group tested under identical clinical and laboratory conditions failed to find that the incidence of nonsuppression in patients was significantly different than in controls. Although Goldstein et al. (1987) did find that post-dexamethasone cortisol levels were significantly higher in panic disorder patients than controls, both groups had low rates of suppression. This suggests that patients have, at the most, a subtle abnormality in feedback regulation. It should be noted that the combination of normal cortisol suppression following dexamethasone (normal feedback regulation) and basal cortisol hypersecretion, has been found in a subgroup of depressed patients (Halbreich et al., 1985). Unfortunately. there is currently no published data to determine whether patients in this subgroup share phenomenologic or treatment response characteristics with panic disorder patients. Additional evidence for HPA axis abnormality in panic disorder comes from a pilot study of ACTH and cortisol response to the hypothalamic peptide corticotropin releasing hormone (CRH) (Roy-Byrne, Uhde, Post et al., 1986). This study, performed in the early evening showed the elevated basal ACTH and cortisol levels mentioned earlier, with a pattern (the first of two basal ACTH levels was much greater than the second) suggesting an CICM,Zincrease in XCTH. More importantly. there was a decreased ACTH response to CRH and an inverse correlation between the basal cortisol level and ACTH response suggesting intact feedback with the pituitary responding normally to high cortisol levels by reducing its ACTH response to CRH. Finally. patients showed a markedly decreased ratio of ACTHicortisol secretion in response to CRH (more cortisol was being secreted per unit of secreted ACTH) suggesting an element of chronic hypercortisolemia (adrenal hypertrophy/hyperplasia as has been produced experimentally in animals by prolonged hyperstimulation of the adrenal cortex by ACTH (Symington, Dugvid. & Davidson. 1955)). These findings bring up the intriguing possibility that patients may episodically secrete CRH in response to “stress” and perhaps at times of panic. Regarding this latter possibility, it is interesting that the patient with the highest basal ACTH and lowest ACTH response to CRH, reported repeated attacks in the 30 minutes before and first 20 or so minutes after CRH administration. In addition, lactate has been shown to release CRH from cell culture (Gold et al., 1986) in vitro and CRH has been shown to increase locus ceruleus activity in animals (Valentino,
20
P.
P.
ROY-BYRNE.
T.
A.
MELLMAN.
ANDT.
W.
UHDE
Foote. & Aston-Jones, 1983). suggesting that CRH might play a role in mediating both the lactate-vulnerability and CY_? noradrenergic receptor dysregulation seen in patients with panic disorder. However, studies of panic disorder patients have failed to find consistent increases in cortisol or ACTH during lactate-induced panic attacks (Carr et al., 1986; Liebowitz et al., 1985) and during “situational” panic attacks (Woods, Charney, McPherson, Gradman. & Heninger, 1987). On the other hand, a small study of “spontaneous” panic attacks in four patients (Cameron, Lee, Curtis, & McCann, in press) and a larger study of panic-like states accompanying exposure to feared situations in patients with simple phobia (Nesse et al., 1985) have shown cortisol increases associated with panic attacks or panic-like states. However. these increases were not as consistent across individuals and often not as sustained or intense as the subjectively rated fear responses themselves. These findings are similar to those in the stress literature where normal subjects show great variability both within the same individual and between different individuals in the cortisol response to stress (Stokes. 1985). Although this evidence suggests that panic states themselves are not always accompanied by CRH increases. it is possible, as suggested by Woods et al. (1987), that initial attacks are indeed accompanied by elevation, but that later in the course of the illness (when most patients are studied) an adaptation takes place with down-regulation of the pituitary’s responsiveness to limbic-hypothalamic stimulation. This is consistent with animal evidence that the HPA axis is particularly likely, compared with other endocrine systems, to adapt to chronic stress by decreasing its responsivity (Armario. Lopez-Calderon, John, & Balasch, 1986) and with the reduced ACTH response to CRH seen in patients with panic disorder (Roy-Byrne, Uhde, Post et al.. 1986). Alternatively, if panic attacks are unlikely to be accompanied by greater activation of the HPA axis as compared with the times between attacks, increases in CRHiACTHicortisol may be more closely related to “anticipatory” anxiety. In fact, several investigators have suggested that higher or increasing levels of “background” anxiety in the basal state are sometimes related to the occurrence of both drug-induced and naturally occurring panic. This is consistent with findings that benzodiazepines reduce both HPA activity (Gram & Christensen, 1986) and anticipatory anxiety. Furthermore, the response-attenuating (i.e., anxiogenic) effects of centrally administered CRH in the Geller-Seifler conflict paradigm in rats and the ability of benzodiazepines to reverse this effect (Britton. Morgan, Rivier, Vale, & Koob, 1984) suggests that various behavioral aspects of anticipatory anxiety might be mediated by increased CRH secretions in other (i.e., extra-hypothalamic) areas of the CNS. Hypothalamic-Pitllitory-Thyroid
Although hyperthyroid attacks and generalized
Axis
states have been associated with both panic anxiety, (Katerndahl & Vande Creek, 1983:
BIOLOGIC
FINDINGS
IN PANIC DISORDER
‘I
Kathol & Delahunt, 1986) three studies failed to find evidence of abnormally increased thyroid hormone levels (i.e., hyperthyroidism) in panic disorder patients (Fishman, Sheehan, & Cat-r, 1985; Lesser, Rubin, Lydiard, Swinson, & Pecknold, in press; Pariser. Jones, Pinat, Young, & Fontana, 1979). However, one study (Adams, Wahby, Geller, & Mason, 1985), showed that panic disorder patients compared with a control group had significantly higher levels of free T3 and T4, although levels were still in the normal range. Furthermore, the study by Fishman et al. (1985) did TSH levels in show a high incidence of very low (i.e., “undetectable”) patients. These preliminary studies suggest the possibility of relative increases in thyroid function in panic disorder patients. Such a finding would be consistent with evidence that the increased adrenergic activity often seen in panic disorder patients (Charney & Heninger. 1986) may increase synthesis of thyroid hormone (Spaulding & North, 1975). Consistent with this possibility, three studies found reduced (“blunted”) TSH responses to TRH, in panic disorder patients. RoyByrne, Uhde, Rubinow, and Post (1986) found that patients had a significantly lower mean TSH response to TRH, with 5 of 15 patients (33%) having a maximal TSH response less than 7 ).rIU/ml (a rate of “blunting” comparable to many studies of depressed patients). Although basal TSH levels were also significantly lower in patients, the levels of both patients and controls were at the lower limits of assay sensitivity, compromising the validity of this finding. Although levels of T3 and T4 were within normal limits, there was a trend correlation (p < .lO) between T4 and the maximal TSH response suggesting that the blunted responses may be physiologically appropriate and that relative increases in free thyroid hormone, such as those found in the study by Adams et al. (1985), could be contributing to the reduced TSH responses. There were no clinicalendocrine correlations. Hamlin and Pottash (1986) also found reduced TSH responses to TRH with a 40% incidence of blunted responses (8 of 20 patients). In a separate study, Hamlin (1987) has shown that patients with prominent symptoms of dizziness and vertigo have much higher TSH responses than those without these symptoms. Finally, Schweizer. Winokur, and Rickels (1985) reported a 30% incidence of blunted TSH response and also noted a 10% incidence of augmented TSH response. Because increased hypophyseal dopamine can reduce the TSH response to TRH, Roy-Byrne, Uhde, Sack, Linnoila, & Post (1986) also measured basal plasma HVA levels in 15 patients just prior to TRH administration. Basal HVA levels were bimodally distributed in patients and those in the higher HVA mode were more anxious at the time of sampling and had significantly more panic attacks in the previous year and less time asymptomatic (free of panic attacks) overall. However, HVA was not correlated with TSH response. Although plasma HVA only reflects a small proportion of CNS dopamine, these findings are consistent with a recent study in which reduced TSH responses to TRH in depressed patients were unaffected by neuroleptic treatment (Loosen, Garbutt, & Tipermas. 1986) and suggest that tuberoinfindibular dopamine probably does not play a role in the reduced TSH responses seen in some
22
P. P. ROY-BYRNE,
T.
A.
MELLMAN,
ANDT.
W.
UHDE
psychiatric patients. Although some in vitro studies have suggested that increases in norepinephrine may cause TRH release, plasma MHPG, one commonly employed measure of central noradrenergic function was also measured at baseline in the Roy-Byrne, Uhde, Sack et al. (1986) study and was unrelated to TSH response. Although some studies suggest that hypercortisolemia can reduce the TSH response to TRH, Roy-Byrne and Uhde (unpublished observations) showed that TSH responses to TRH, and ACTH responses to CRH were unrelated in the eight patients who received both tests. Finally, despite some reports of TSH increases associated with “stress” in normals, TSH levels do not increase in simple phobics exposed to feared stimuli (Nesse, Curtis, & Brown, 1982) and were not elevated at baseline in one patient who had a panic attack just prior to TRH infusion (Roy-Byrne, Uhde, Rubinow et al.. 1986). The absence of any evidence of TSH stress responsivity as opposed to the variable increases in HPA activity in response to stress and the absence of any relation between TRH and CRH test results in the studies of Roy-Byrne, Uhde, Rubnow, et al. (1986) and Roy-Byrne, Uhde, Sack, et al. (1986), suggests that the abnormality in this system may be pathophysiologically distinct from the HPA axis abnormalities previously discussed. Growth Hormone Several studies have shown elevations in plasma growth hormone (GH) levels in response to a variety of “stressful” situations. Because GH secretion occurs episodically without clear-cut precipitants, as well as in response to specific stimuli (Rose, 1984), interpretation of the effects of stress on GH is complicated. Like cortisol and ACTH, GH increases at times may be greater during anticipation of an upcoming stress as opposed to at the time of stress (Rose, 1984). However, GH and cortisol responses are often dissociated, and some studies suggest that GH secretion may require a more intense stimulus compared with cortisol and may also be more likely to occur in subjects with certain coping styles (Kosten, Jacobs, Mason, Wahby, & Atkins, 1984). A number of investigators have identified basal growth hormone elevations in some panic disorder patients (Charney & Heninger, 1986; Uhde, Vittone, Siever, Kaye, & Post, 1986), although the relevance of this finding (based on only one or two samples) for pathologically anxious states is unclear. The above two studies have also found reduced GH receptor effect, and is consistent with other data implicating c+receptor dysregulation in this illness. Although some psychiatric patients have shown pathologic GH response to TRH, panic disorder patients have not (Roy-Byrne & Uhde, unpublished observations). Although GH is not increased in lactate-induced panic states (Carr et al., 1986), and was increased during spontaneous panic attacks in only one of four patients tested (Cameron et al., in press), it was the only hormone showing an increase in simple phobics exposed to feared situations (Woods et al., 1987).
BIOLOGIC
FINDINGS
IN PANIC DISORDER
23
an increase in simple phobics exposed to feared situations (Woods et al., 1987). Prolactin Numerous studies in normal subjects have documented prolactin increases in response to physical stressors such as surgery and exercise (Rose, 1984). A smaller body of literature shows increases in response to psychological stressors which can be dissociated from both cortisol and GH responses and, like GH, may also require a provocative stimulus of greater magnitude than required for cortisol. Although one study has shown a 40% incidence of increased PL responses to TRH at baseline (Schweizer, Winokur, & Rickels, 1985) in panic disorder patients, another study showed that patients have reduced prolactin responses to TRH (Roy-Byrne et al., 1985). Furthermore, prolactin levels do not increase in simple phobics exposed to feared stimuli (Nesse, Curtis, Brown, & Rubin, 1980) in panic disorder patients undergoing a cold presser test (Grunhaus, Gloger, Birmacher, Palmer, & Ben-David, 19831, or in panic disorder patients during lactate-induced panic (Carr et al., 1986). However, Cameron et al. (in press) found prolactin increases, compared with changes in other hormones, to be most consistently related to spontaneous panic attacks. Furthermore, the degree of elevation was highly correlated with the severity of the panic attack. SLEEP PHYSIOLOGY
AND SLEEP DEPRIVATION
Disturbed sleep patterns are frequent complaints in both primary anxiety and depressive states. Certain sleep EEG variables have been shown to have relative specificity for depression, although these features have also been reported in other conditions possibly related to the affective spectrum. Thus, assessment of these variables in panic disorder and other anxiety states could provide clues toward overlapping or non-overlapping mechanisms for these disorders. Furthermore, the psychobiological disturbances of psychiatric disorders, including anxiety states, are seldom restricted to waking and the state of sleep provides a means for studying these conditions with reduced conscious and environmental influence. Finally, assessment of the actual effects of sleep deprivation on mood and behavior in panic disorder patients, compared with depressed patients and controls, can clarify anecdotal reports of clinical deterioration in anxious patients following reduced, distrubed, or broken sleep, as well as determine whether panic disorder patients might manifest the paradoxical elevation of mood in response to sleep deprivation seen in some depressed patients. EEG Sleep Physiology Numerous studies have shown that reduced REM latency and increased early REM activity are relatively specific for depression, while
z-1
P. P. ROY-BYRNE.
T. A. MELLMAN.
AND-C.
W. UHDE
decreased delta sleep and decreased sleep continuity appear to occur in other psychiatric conditions besides depression. Only recently have several studies investigated these parameters in patient groups with anxiety disorders. Three studies have found that reduced REM latency and increased REM percent discriminated depressed outpatients from those with generalized anxiety (Reynolds. Shaw. Newton, Coble, & Kupfer, 1983) and from heterogeneous groups with both generalized anxiety and panic disorder (Akiskal et al., 1984; Sitaram, Dube, Jones, Pohl, & Gershon, 1984). In general, these studies have shown that anxious patients have equal (Reynolds et al., 1983) or greater (Akiskal et al., 1984) difficulty in initiating and maintaining sleep. Another small study demonstrated a substantial increase in movement time during the sleep recording, perhaps indicating hyperarousal despite the absence of environmental or conscious intluence (Uhde et al., 1984). Finally, unpublished data from the Unit on Anxiety and Affective Disorders at the National Institute of Mental Health (NIMH), involving I3 panic patients shows a large variability in REM latencies, reduced REM latencies tending to occur in patients with moderate concomitant depressive symptoms, and a trend for movement time to be lower on nights when panic attacks occurred during sleep. Of further interest with regard to panic disorder is the accumulating evidence that panic attacks can occur during sleep. Anecdotal reports have noted that nocturnal panic attacks often occur, awakening patients from sleep. In a recent survey from our unit at NIMH, 22 of 31 (71%) of non-hospitalized panic patients reported nocturnal panic attacks to have occurred at least once, and two of these patients reported sleep panic as a typical or frequent feature of their illness. Scattered reports suggest that these events are preceded by non-REM sleep. We have now recorded six nocturnal panic attacks occurring during all night sleep EEG recordings. To date all of the awakenings that were associated with panic symptoms were preceded by non-REM sleep that could be characterized as a transition from stage 2 to stage 3. In one subject where cardiac monitoring was available, a 20 beat per minute increase in heart rate occurred in the minute preceding the awakening. Time awake was brief for these events. Two preceded and four followed the first REM period and all events were relatively proximate to the first REM period. Of interest, there was a significant increase in REM latency associated with “panicking” nights compared to other “non-panicking” nights in the same patients. This delayed REM was also evidenced when comparing between groups of patients with and without nocturnal panic attacks and controls. Panic attacks occurring from sleep may provide a useful model for elucidating mechanisms of panic. These findings would support the observation that some panic attacks can occur spontaneously and suggest that they might be physiologically triggered. The association with nonREM sleep and autonomic activation preceding awakening renders it difficult to invoke cognitive factors as primary to these sleep-related events. It is also of interest that despite overlap in the phenomenology and bi-
BIOLOGIC
FINDINGS
IN PANIC
DISORDER
‘5 -_
ology of anxiety and depression, anxiety disorders including panic generally do not feature reduced REM latencies and that nocturnal panic appears to be associated with prolongation of the first non-RElM period. Finally, the fact that increased movement time is most prominent on nonpanic attack nights suggests it might be, paradoxically, a protective mechanism that somehow counteracts, rather than promotes, panic attacks. Response
to One-Night’s
Sleep Deprivation
Because of anecdotal reports that some panic disorder patients experience an exacerbation of their symptoms with lack of sleep, because some psychosensory symptoms in these patients resemble those seen in complex partial seizure disorder, and because it is well established that sleep deprivation can exacerbate EEG abnormalities. Roy-Byrne, Uhde, and Post (1986) investigated the effects of one night’s sleep deprivation on mood and behavior in panic disorder patients. In contrast to the improvement in symptoms of anxiety and depression shown by the majority of depressed patients, these patients did not improve and a subgroup (40%) experienced exacerbation of anxiety and panic attacks on the day following sleep deprivation. None of these 12 patients had abnormalities on EEG recordings with nasopharyngeal electrodes done the day following sleep deprivation, which would suggest evidence of temporal lobe seizure activity. This study suggests the possibility that sleep deprivation is either a non-specific stress that lowers the threshold for panic, or interacts more intimately with some underlying pathophysiologic abnormality. Recent findings that sleep deprivation may cause increases in TSH as well as peripheral thyroid hormones (Palmblad, Akerstedt, Froberg, Melander, SCVon Schenck, 1979) may provide an avenue for future investigations of possible underlying mechanisms. CONCLUSION
The neuroendocrine findings noted here in panic disorder patients show a large degree of overlap with those observed both in depressed patients and in naturally occurring and experimentally induced states of stress in humans and animals. The HPA axis may be activated more by the state of chronic anxiety seen in most panic disorder patients than by the panic attacks themselves (although the former often increase the likelihood of the latter), such that there is adaptation in the axis’ response to more acute perturbations (i.e., panic). The causes of reduced TSH and prolactin responses to TRH are unclear, although they may also represent adaptations to excess ongoing secretions of TRH, perhaps associated with chronic anxiety. Relative increases in T4 may play a role in the reduced TSH response. The relatively unique association of prolactin increases with spontaneous panic attacks is consistent with animal studies showing less adaptation in the response of this system to experi-
26
P. P. ROY-BYRNE,
T. A. MELLMAN,
ANDT.
W. UHDE
mental stress. Overall, these neuroendocrine findings are consistent with hypotheses implicating both noradrenergic and benzodiazepine abnormalities in the pathophysiology of anxious states, although they cannot be explained exclusively by them. In contrast to the neuroendocrine findings, the sleep findings provide more evidence of a biologic distinction between panic and major depressive disorders. The occurrence of specific sleep EEG changes preceding the occurrence of nocturnal panic attacks suggest that understanding individual variations in EEG sleep topography associated with specific clinical findings (i.e., nocturnal panic) may be more helpful in elucidating the pathophysiology of panic disorder. It remains to be demonstrated whether the sleep deprivation findings (i.e., clinical deterioration in panic disorder patients) are nonspecific, much like the overall sleep EEG findings documenting disturbances in sleep initiation and maintenance, or, like specific EEG findings occurring on the night of nocturnal panic, may be more initimately related to the underlying pathophysiology of the disorder.
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Liebowitz. M. R.. Gorman, J. M., Fyer, A. J., Levitt, M., Dillon, D., Levy, G., Appleby, I. L., Anderson, S., Palij, IM., Davies, S. O., & Klein, D. F. (1985). Lactate provocation of panic attacks, II: Biochemical and physiological findings. Archirjes of General Psychiatry, 42, 709-719. Loosen. P. T., Garbutt. J. C.. & Tipermas, A. (1986). The TRH test during dopamine receptor blockade in depressed patients. Psychoneuroendocrinology, 11, 327-336.
P.
25 Nesse.
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ROY-BYRNE,
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T.
0. G..
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Curtis.
G. C..
in patients
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ANDT.
McCann.
W.
CHDE
D. S.. & Huber-Smith.
panic anxiety.
%I. J.
of Gene&
,-trchire.\
Psxclri-
carp. 41. 771-776.
Nesse. R. M.. Curtis. G. C.. & Brown. G. M. (1982). Phobic anxiety does not affect plasma levels of thyroid stimulating hormone in man. P~~cl2o,zrlrroentl~~~i~~~~~~~~. 7, 69-7-t. Nesse.
R. M.,
Curtis,
flooding therapy
G. C..
Brown.
G. hl..
Medicine. 42 1 ?5-3 I. Nesse, R. M., Curtis. G. C.. Thyer. R. F. (1985).
rmfic
Endocrine
Mrdicinr,
Palmblad.
& Rubin.
R. T. (19801.
for phobias does not elicit prolactin B. A..
secretory
McCann,
and cardiovascular
Anxiety
induced
by
response.
Ps~cltosorntrric
D. S.. Huber-Smith.
Xl. J.. Knopf.
responses
Psycho~o-
during phobic anxiety.
47, 320.
.I.. Akerstedt.
T.. Froberg,
and adrenomedullary
reactions
J., Melander,
A., & Von Schenck,
durin g sleep
deprivation.
H. (1979). Thyroid
Acrcl End~crinIyrrtr.
90,
233-239. Pariser,
S. E, Jones.
attacks:
B. A..
Diagnostic
Pinat,
evaluation
E. R.. of
Young.
17 patients.
E. A..
& Fontana.
M. E. (1979).
Panic
Arnericc~rz Journcd c!f Ps?clrictrp.
136,
lO4- 106. Peterson.
G. A., Ballenger.
Trockman.
J. C.. Cou,
(1985).The
C.
D. P., Hucek,
devamethasone
A..
Lydiard.
suppression
R. B.. Laraia.
test in agroaphobia.
.Ll. T.. R: Jonrrrcrl (t/
Clinictr[ Psv~ll~,p/rclrr,rcl~~~~[~,~~. 5, IOO- 102. Reynolds.
C. F.. Shaw,
D. H..
sleep in outpatients outpatients.
Neuton.
T. F.. Cable.
with generalized
anxiety:
R: Kupfer.
D. J. (19x3).
comparison
EEG
uith depressed
Ps~chicltr~ Rescwrch. 8, 81-89.
Rose. R. >l. (198-t). Overview
of endocrinology
docrirro/og.v crnd ps.vchicrlric thorder Roy-Byrne.
P. A.,
A preliminary
P. P.. Bierer.
test in panic
L. hl..
disorder:
of stress. In G. b1. Brown
(pp. 95- 1221. New York: Raven
& Uhde.
Comparison
T. W. (19851.
with
normal
(Ed.).
The denamethasone
Biologicr~l
controls.
.L’rlrrorrr-
Press. wppression
P.\~ci~ic~rtyv.20.
1237- 1210. Roy-Byrne.
P. P.. Uhde.
T. W.. S; Post. R. M. (1986).
tion on mood and behavior
in patients
Effects
of one night’s sleep depriva-
Archi\,r.s oJ’Gctrc~,nl P~\.chi-
with panic disorder.
P. P.. Uhde.
(1986).
order. American Roy-Byrne.
responses
G. P.. ~9:Gold.
test in patient5
uith
P. N.
panic dis-
D. R., 8: Post. R. M. (1986).
in patients
Reduced
TSH
and
Americclrt Jcurrfrcll o~jP_t~clzi-
with panic disorder.
143, 503-507.
Roy-Byrne, HVA
W.. Chrousos.
stimulation
143, X96-899.
T. W.. Rubinow.
to TRH
Gallucci.
hormone
Jmrrnrrl ofPJyc/ticlrty,
P. P.. Uhde.
prolactin
fq.
7. W.. Post. R. M..
The corticotropin-releasing
P. P.. Uhde.
and anxiety
Schweizer.
T. W.. Sack,
in patients
E.. Winokur.
disorder. Dallas,
D. A.,
M..
& Post. R. M. (1986).
Plasma
Biological Psvchicitr~. 21. 847-849. K. (1985. May). ivrltrorNdoo;nefi~~l~riorl in pclnit
A.. & Rickels.
Paper presented
Linnoila.
with panic disorder.
at the Annual
Meeting
of the Biological
Psychiatry
Society.
TX.
Sheehan,
D. V., Ballenger.
phobic,
hysterical
J.. & Jacobsen.
G. (1980). Treatment
and hypochondrical
symptoms.
ofendogenous
anxiety
Arch\~rs of Grrwrcrl P~xcltitrrry,
with
37,
51-39. Sheehan.
D. V.. Claycomb.
Panic attacks
B.. Surman.
and dexamethasone
0. S.. Baer, L.. Coleman. suppression
J.. & Gelles.
test. Awwriccln Joumcll
L. (1983).
of P.rqchicrtn.
140, 1063. Sitaram.
N..
renergic 17(Suppl. Spaulding.
Clinics
Dube.
S., Jones.
sensitivity
D.. Pohl. R., Sr Gershon.
in the separation
of depression
S. (198-t). Acetylcholine and anxiety.
and Z-ad-
Ps~chopctri~o/og.
31, 21-39. S. W..
0flVorth
&
North,
Americcr.
R. H.
(1975).
59, ll23-
1131.
Thyroid-catecholamine
interactions.
.Wrdiccd
BlOLOGlC
Stokes.
P. (1985).
Anxiep Symington.
T.. Dugvid.
tihde.
during
T. W..
adrenal
NJ:
P. P.. Gillin. The
J. C..
Mendelsohn.
sleep of patients
with
(Eds.).
Erlbaum.
of exogenouscorticotropin
Effect cortex
and a comparison
c
Jo/rr~trl
R. M. (198-t).
A. H. Tuma & J. D. Maser
Hillsdale.
J. N. (1955).
of the human
‘9
& Mertrbolism. W..
Bonlenger.
panic
disorder.
with
the
16, 5X0-598. J. P.. Vittone. Psxclriclr~
Re-
12 . ‘5 - I-259.
stwd1. Uhde.
stress.
Roy-Byrne.
B. J., s( Post.
(pp. 53-76).
W. P.. & Davidson. pattern
IN PANIC DISORDER
of anxiety. In
The neuroendocrinology
untl the trn.rirlF rlisorders
on the histochemical changes
FINDINGS
T. W..
growth
Vittone.
hormone
B. J.. Siever. response
L. J..
to clonidine
Kaye.
W. K..
in panic disorder
Sr Post patients.
R. M.
(1986).
Blunted
Biohgiccd P~~clric~rry.
21, 1081-1081. V’alentino.
R. J.. Fotte.
vates Whiteford. test. Woods,
H. A..
tion.
neurons
8: Evans.
of the locus
L. (198-t).
G. (1983). coeruleus.
S. W.. Charney. Situational
D. S..
panic
Agoraphobia
McPherson.
attacks:
Behavioral.
Architvs of‘Grtrrr_cl/Psychirrrt?. C. hl..
exposure
Klein. in viva
D. E. & Woerner. and imipramine.
C. A..
Corticotropin-releasing
factor
R~~srcwch. 270.
Brc7in
and the dexamethasone
Ausrrtrlicr ,k’e~. Zurltr~rd Jorrructl of P.ychicrr/?.
(1987). Zitrin.
S. L.. & Aston-Jones.
noradrenergic
acti-
363-367. suppression
18. 374.
Gradman.
physiologic
A. H.,
&
Heninger.
and biochemical
G. R.
characteriza-
44. 365-376.
M. G. (1980).
Treatment
of agoraphobia
Arc/rit~e.sofGenrrtr/ Ps~clritrr~~. 37,
63-72.
with
group
and Sleep-Related
Abnormalities
PETER P. ROY-BYRNE. M.D.
THOMAS A. MELLMAN.
Abstract-Studies
of neuroendocrine function. sleep physiology and
sleep deprivation tients
show
contrast.
in patients
a variety
ities in EEG
with
while
few
panic attacks.
association
with
nocturnal is either
anxiety
or a cumulative
findings
may be more
more result
are reviewed.
abnormalities.
These
closely
related
of repetitive
related
have findings
to sleep deprivation.
In
to occur
in
seem to occur
in
found
suggest
to background panic
to the actual
to pa-
been
EEG sleep patterns
attacks.
response
At baseline.
but fail to show abnormal-
response
abnormalities
characteristic
panic
closely
disorder
or a therapeutic
neuroendocrinr
with
dysfunction
panic
of neuroendocrine
sleep architecture
association crine
M.D. ANDTHOMAS W. UHDE. M.D.
attacks,
panic
that
neuroendo-
(“anticipatory”) while
attacks
EEG
sleep
themselves.
The notion that panic attacks have a significant biological basis has been fueled by evidence that they can be provoked by a variety of discrete pharmacologic stimuli (see Woods and Charney this issue). that they can be blocked by medications not traditionally considered to have prominent anxiolytic properties (Sheehan, Ballenger, & Jacobsen, 1980), and that they occur more frequently in family members of individuals suffering from them than from other psychiatric disorders (Crowe, Noyes, Pauls, & Slymen, 1983). Evidence that panic and major depressive disorders often co-occur in the same individual, and share important similarities in phenomenology, family history, and treatment response (Breier, Charney, & Heninger, 198.5), and evidence that cortisol nonsuppression following dexamethasone (Carroll, 1984) and shortened REM latency during sleep EGG recordings (Kupfer & Thase, 1983) are the biological abnormalities most consistently found in depressed patients, has Address Psychiatry Seattle.
correspondence and Behavioral
and reprint Sciences,
requests
to Dr.
Peter
P. Roy-Byrne.
RP-IO. University of Washington,
WA 98195. I7
Department
School
of Medicine,
of
18
P.
P. ROY-BYRNE.
T.
A.
MELLMAN,
ANDT.
W.
UHDE
prompted investigators to explore neuroendocrine and sleep-related parameters in patients with panic disorder. This paper will review the ecidence for neuroendocrine and sleep-related abnormalities in these patients and discuss how these lindings might clarify the relation between panic and major depressive disorders. as well as relate to proposed patho-physiologic mechanisms in panic disorder. NEUROENDOCRINE
FUNCTION
Although there is a rather extensive literature examining changes in endocrine function as a consequence/correlate of “stress,” with particular emphasis on the hypothalamic-pituitary-adrenal axis, until recently there has been relatively little attention paid to neuroendocrine function in anxiety disorders. This review will focus on the pituitary-adrenal and pituitary-thyroid axes, and on the secretion of growth hormone and prolactin. Although we are focusing on panic disorder, we will also include studies of endocrine function during exposure to feared situations in patients with simple phobias since there is evidence these patients experience fear similar in both intensity and temporal characteristics to a panic attack at this time. Finally, we will briefly discuss the possible implications of any abnormalities with regard to various neurotransmitter and receptor dysregulation hypotheses about panic disorder. Hypothalamic-Pituitac-Adrenal
(HPA) Ark
Although still quite preliminary. the greatest amount of data generated in panic disorder patients involved various measures of HPA function. Initial studies indicated that basal cortisol levels obtained in the morning, usually prior to infusion studies, were normal, whereas, subsequent investigators found elevated levels of cortisol in patients who were studied in the afternoon (Goldstein, Halbreich, Asnis, Endicott, & Alvir, 1987: Nesse, Cameron, Curtis, McCann, & Huber-Smith, 1984) and early evening (Roy-Byrne, Uhde, Post, et al., 1986). The late-afternooniearly-evening timing of these abnormalities is of some interest in view of a recent pilot study suggesting that the frequency of panic attacks is greatest in the early evening (Cameron, Lee, Kotun, & Murphy, 1986). However, since Halbreich, Asnis, Schindledecker, Zumoff, and Nathan (1985) have shown that the mean plasma cortisol levels between 1:00 and 4:00 p.m. are highly correlated with mean 24-hour plasma cortisol levels, these abnormalities may just reflect a time of day at which discrete sampling is a better reflection of overall HPA activity. Despite some evidence of cortisol hypersecretion, none of ten studies examining the dexamethasone suppression test in patients with panic disorder (Avery, et al., 1985; Bridges, Yeragani, Rainey, & Pohl, 1986; Coryell, Noyes, Clancy, Crowe, & Chaudrey, 1985; Curtis, Cameron, & Nesse, 1982; Goldstein et al., 1987; Lieberman et al., 1983; Peterson et
BIOLOGIC
FINDINGS
IN PANIC
DISORDER
19
al., 1985; Roy-Byrne, Bierer. PCUhde. 1985; Sheehan et al., 1983; Whiteford & Evans, 1984) found an incidence of cortisol nonsuppression approaching the average 45% figure seen in patients with major depression. Because the incidence found in some of these studies is higher than the accepted 5% figure for normals, and because two studies (Avery et al.. 1985; Coryell et al., 1985) that included a control group of outpatient depressives found comparable rates of nonsuppression in both patient groups, some investigators have suggested that it may still be “abnormal.” However, the three studies (Bridges et al., 1986: Goldstein et al., 1987; Roy-Byrne et al., 1985) including a normal control group tested under identical clinical and laboratory conditions failed to find that the incidence of nonsuppression in patients was significantly different than in controls. Although Goldstein et al. (1987) did find that post-dexamethasone cortisol levels were significantly higher in panic disorder patients than controls, both groups had low rates of suppression. This suggests that patients have, at the most, a subtle abnormality in feedback regulation. It should be noted that the combination of normal cortisol suppression following dexamethasone (normal feedback regulation) and basal cortisol hypersecretion, has been found in a subgroup of depressed patients (Halbreich et al., 1985). Unfortunately. there is currently no published data to determine whether patients in this subgroup share phenomenologic or treatment response characteristics with panic disorder patients. Additional evidence for HPA axis abnormality in panic disorder comes from a pilot study of ACTH and cortisol response to the hypothalamic peptide corticotropin releasing hormone (CRH) (Roy-Byrne, Uhde, Post et al., 1986). This study, performed in the early evening showed the elevated basal ACTH and cortisol levels mentioned earlier, with a pattern (the first of two basal ACTH levels was much greater than the second) suggesting an CICM,Zincrease in XCTH. More importantly. there was a decreased ACTH response to CRH and an inverse correlation between the basal cortisol level and ACTH response suggesting intact feedback with the pituitary responding normally to high cortisol levels by reducing its ACTH response to CRH. Finally. patients showed a markedly decreased ratio of ACTHicortisol secretion in response to CRH (more cortisol was being secreted per unit of secreted ACTH) suggesting an element of chronic hypercortisolemia (adrenal hypertrophy/hyperplasia as has been produced experimentally in animals by prolonged hyperstimulation of the adrenal cortex by ACTH (Symington, Dugvid. & Davidson. 1955)). These findings bring up the intriguing possibility that patients may episodically secrete CRH in response to “stress” and perhaps at times of panic. Regarding this latter possibility, it is interesting that the patient with the highest basal ACTH and lowest ACTH response to CRH, reported repeated attacks in the 30 minutes before and first 20 or so minutes after CRH administration. In addition, lactate has been shown to release CRH from cell culture (Gold et al., 1986) in vitro and CRH has been shown to increase locus ceruleus activity in animals (Valentino,
20
P.
P.
ROY-BYRNE.
T.
A.
MELLMAN.
ANDT.
W.
UHDE
Foote. & Aston-Jones, 1983). suggesting that CRH might play a role in mediating both the lactate-vulnerability and CY_? noradrenergic receptor dysregulation seen in patients with panic disorder. However, studies of panic disorder patients have failed to find consistent increases in cortisol or ACTH during lactate-induced panic attacks (Carr et al., 1986; Liebowitz et al., 1985) and during “situational” panic attacks (Woods, Charney, McPherson, Gradman. & Heninger, 1987). On the other hand, a small study of “spontaneous” panic attacks in four patients (Cameron, Lee, Curtis, & McCann, in press) and a larger study of panic-like states accompanying exposure to feared situations in patients with simple phobia (Nesse et al., 1985) have shown cortisol increases associated with panic attacks or panic-like states. However. these increases were not as consistent across individuals and often not as sustained or intense as the subjectively rated fear responses themselves. These findings are similar to those in the stress literature where normal subjects show great variability both within the same individual and between different individuals in the cortisol response to stress (Stokes. 1985). Although this evidence suggests that panic states themselves are not always accompanied by CRH increases. it is possible, as suggested by Woods et al. (1987), that initial attacks are indeed accompanied by elevation, but that later in the course of the illness (when most patients are studied) an adaptation takes place with down-regulation of the pituitary’s responsiveness to limbic-hypothalamic stimulation. This is consistent with animal evidence that the HPA axis is particularly likely, compared with other endocrine systems, to adapt to chronic stress by decreasing its responsivity (Armario. Lopez-Calderon, John, & Balasch, 1986) and with the reduced ACTH response to CRH seen in patients with panic disorder (Roy-Byrne, Uhde, Post et al.. 1986). Alternatively, if panic attacks are unlikely to be accompanied by greater activation of the HPA axis as compared with the times between attacks, increases in CRHiACTHicortisol may be more closely related to “anticipatory” anxiety. In fact, several investigators have suggested that higher or increasing levels of “background” anxiety in the basal state are sometimes related to the occurrence of both drug-induced and naturally occurring panic. This is consistent with findings that benzodiazepines reduce both HPA activity (Gram & Christensen, 1986) and anticipatory anxiety. Furthermore, the response-attenuating (i.e., anxiogenic) effects of centrally administered CRH in the Geller-Seifler conflict paradigm in rats and the ability of benzodiazepines to reverse this effect (Britton. Morgan, Rivier, Vale, & Koob, 1984) suggests that various behavioral aspects of anticipatory anxiety might be mediated by increased CRH secretions in other (i.e., extra-hypothalamic) areas of the CNS. Hypothalamic-Pitllitory-Thyroid
Although hyperthyroid attacks and generalized
Axis
states have been associated with both panic anxiety, (Katerndahl & Vande Creek, 1983:
BIOLOGIC
FINDINGS
IN PANIC DISORDER
‘I
Kathol & Delahunt, 1986) three studies failed to find evidence of abnormally increased thyroid hormone levels (i.e., hyperthyroidism) in panic disorder patients (Fishman, Sheehan, & Cat-r, 1985; Lesser, Rubin, Lydiard, Swinson, & Pecknold, in press; Pariser. Jones, Pinat, Young, & Fontana, 1979). However, one study (Adams, Wahby, Geller, & Mason, 1985), showed that panic disorder patients compared with a control group had significantly higher levels of free T3 and T4, although levels were still in the normal range. Furthermore, the study by Fishman et al. (1985) did TSH levels in show a high incidence of very low (i.e., “undetectable”) patients. These preliminary studies suggest the possibility of relative increases in thyroid function in panic disorder patients. Such a finding would be consistent with evidence that the increased adrenergic activity often seen in panic disorder patients (Charney & Heninger. 1986) may increase synthesis of thyroid hormone (Spaulding & North, 1975). Consistent with this possibility, three studies found reduced (“blunted”) TSH responses to TRH, in panic disorder patients. RoyByrne, Uhde, Rubinow, and Post (1986) found that patients had a significantly lower mean TSH response to TRH, with 5 of 15 patients (33%) having a maximal TSH response less than 7 ).rIU/ml (a rate of “blunting” comparable to many studies of depressed patients). Although basal TSH levels were also significantly lower in patients, the levels of both patients and controls were at the lower limits of assay sensitivity, compromising the validity of this finding. Although levels of T3 and T4 were within normal limits, there was a trend correlation (p < .lO) between T4 and the maximal TSH response suggesting that the blunted responses may be physiologically appropriate and that relative increases in free thyroid hormone, such as those found in the study by Adams et al. (1985), could be contributing to the reduced TSH responses. There were no clinicalendocrine correlations. Hamlin and Pottash (1986) also found reduced TSH responses to TRH with a 40% incidence of blunted responses (8 of 20 patients). In a separate study, Hamlin (1987) has shown that patients with prominent symptoms of dizziness and vertigo have much higher TSH responses than those without these symptoms. Finally, Schweizer. Winokur, and Rickels (1985) reported a 30% incidence of blunted TSH response and also noted a 10% incidence of augmented TSH response. Because increased hypophyseal dopamine can reduce the TSH response to TRH, Roy-Byrne, Uhde, Sack, Linnoila, & Post (1986) also measured basal plasma HVA levels in 15 patients just prior to TRH administration. Basal HVA levels were bimodally distributed in patients and those in the higher HVA mode were more anxious at the time of sampling and had significantly more panic attacks in the previous year and less time asymptomatic (free of panic attacks) overall. However, HVA was not correlated with TSH response. Although plasma HVA only reflects a small proportion of CNS dopamine, these findings are consistent with a recent study in which reduced TSH responses to TRH in depressed patients were unaffected by neuroleptic treatment (Loosen, Garbutt, & Tipermas. 1986) and suggest that tuberoinfindibular dopamine probably does not play a role in the reduced TSH responses seen in some
22
P. P. ROY-BYRNE,
T.
A.
MELLMAN,
ANDT.
W.
UHDE
psychiatric patients. Although some in vitro studies have suggested that increases in norepinephrine may cause TRH release, plasma MHPG, one commonly employed measure of central noradrenergic function was also measured at baseline in the Roy-Byrne, Uhde, Sack et al. (1986) study and was unrelated to TSH response. Although some studies suggest that hypercortisolemia can reduce the TSH response to TRH, Roy-Byrne and Uhde (unpublished observations) showed that TSH responses to TRH, and ACTH responses to CRH were unrelated in the eight patients who received both tests. Finally, despite some reports of TSH increases associated with “stress” in normals, TSH levels do not increase in simple phobics exposed to feared stimuli (Nesse, Curtis, & Brown, 1982) and were not elevated at baseline in one patient who had a panic attack just prior to TRH infusion (Roy-Byrne, Uhde, Rubinow et al.. 1986). The absence of any evidence of TSH stress responsivity as opposed to the variable increases in HPA activity in response to stress and the absence of any relation between TRH and CRH test results in the studies of Roy-Byrne, Uhde, Rubnow, et al. (1986) and Roy-Byrne, Uhde, Sack, et al. (1986), suggests that the abnormality in this system may be pathophysiologically distinct from the HPA axis abnormalities previously discussed. Growth Hormone Several studies have shown elevations in plasma growth hormone (GH) levels in response to a variety of “stressful” situations. Because GH secretion occurs episodically without clear-cut precipitants, as well as in response to specific stimuli (Rose, 1984), interpretation of the effects of stress on GH is complicated. Like cortisol and ACTH, GH increases at times may be greater during anticipation of an upcoming stress as opposed to at the time of stress (Rose, 1984). However, GH and cortisol responses are often dissociated, and some studies suggest that GH secretion may require a more intense stimulus compared with cortisol and may also be more likely to occur in subjects with certain coping styles (Kosten, Jacobs, Mason, Wahby, & Atkins, 1984). A number of investigators have identified basal growth hormone elevations in some panic disorder patients (Charney & Heninger, 1986; Uhde, Vittone, Siever, Kaye, & Post, 1986), although the relevance of this finding (based on only one or two samples) for pathologically anxious states is unclear. The above two studies have also found reduced GH receptor effect, and is consistent with other data implicating c+receptor dysregulation in this illness. Although some psychiatric patients have shown pathologic GH response to TRH, panic disorder patients have not (Roy-Byrne & Uhde, unpublished observations). Although GH is not increased in lactate-induced panic states (Carr et al., 1986), and was increased during spontaneous panic attacks in only one of four patients tested (Cameron et al., in press), it was the only hormone showing an increase in simple phobics exposed to feared situations (Woods et al., 1987).
BIOLOGIC
FINDINGS
IN PANIC DISORDER
23
an increase in simple phobics exposed to feared situations (Woods et al., 1987). Prolactin Numerous studies in normal subjects have documented prolactin increases in response to physical stressors such as surgery and exercise (Rose, 1984). A smaller body of literature shows increases in response to psychological stressors which can be dissociated from both cortisol and GH responses and, like GH, may also require a provocative stimulus of greater magnitude than required for cortisol. Although one study has shown a 40% incidence of increased PL responses to TRH at baseline (Schweizer, Winokur, & Rickels, 1985) in panic disorder patients, another study showed that patients have reduced prolactin responses to TRH (Roy-Byrne et al., 1985). Furthermore, prolactin levels do not increase in simple phobics exposed to feared stimuli (Nesse, Curtis, Brown, & Rubin, 1980) in panic disorder patients undergoing a cold presser test (Grunhaus, Gloger, Birmacher, Palmer, & Ben-David, 19831, or in panic disorder patients during lactate-induced panic (Carr et al., 1986). However, Cameron et al. (in press) found prolactin increases, compared with changes in other hormones, to be most consistently related to spontaneous panic attacks. Furthermore, the degree of elevation was highly correlated with the severity of the panic attack. SLEEP PHYSIOLOGY
AND SLEEP DEPRIVATION
Disturbed sleep patterns are frequent complaints in both primary anxiety and depressive states. Certain sleep EEG variables have been shown to have relative specificity for depression, although these features have also been reported in other conditions possibly related to the affective spectrum. Thus, assessment of these variables in panic disorder and other anxiety states could provide clues toward overlapping or non-overlapping mechanisms for these disorders. Furthermore, the psychobiological disturbances of psychiatric disorders, including anxiety states, are seldom restricted to waking and the state of sleep provides a means for studying these conditions with reduced conscious and environmental influence. Finally, assessment of the actual effects of sleep deprivation on mood and behavior in panic disorder patients, compared with depressed patients and controls, can clarify anecdotal reports of clinical deterioration in anxious patients following reduced, distrubed, or broken sleep, as well as determine whether panic disorder patients might manifest the paradoxical elevation of mood in response to sleep deprivation seen in some depressed patients. EEG Sleep Physiology Numerous studies have shown that reduced REM latency and increased early REM activity are relatively specific for depression, while
z-1
P. P. ROY-BYRNE.
T. A. MELLMAN.
AND-C.
W. UHDE
decreased delta sleep and decreased sleep continuity appear to occur in other psychiatric conditions besides depression. Only recently have several studies investigated these parameters in patient groups with anxiety disorders. Three studies have found that reduced REM latency and increased REM percent discriminated depressed outpatients from those with generalized anxiety (Reynolds. Shaw. Newton, Coble, & Kupfer, 1983) and from heterogeneous groups with both generalized anxiety and panic disorder (Akiskal et al., 1984; Sitaram, Dube, Jones, Pohl, & Gershon, 1984). In general, these studies have shown that anxious patients have equal (Reynolds et al., 1983) or greater (Akiskal et al., 1984) difficulty in initiating and maintaining sleep. Another small study demonstrated a substantial increase in movement time during the sleep recording, perhaps indicating hyperarousal despite the absence of environmental or conscious intluence (Uhde et al., 1984). Finally, unpublished data from the Unit on Anxiety and Affective Disorders at the National Institute of Mental Health (NIMH), involving I3 panic patients shows a large variability in REM latencies, reduced REM latencies tending to occur in patients with moderate concomitant depressive symptoms, and a trend for movement time to be lower on nights when panic attacks occurred during sleep. Of further interest with regard to panic disorder is the accumulating evidence that panic attacks can occur during sleep. Anecdotal reports have noted that nocturnal panic attacks often occur, awakening patients from sleep. In a recent survey from our unit at NIMH, 22 of 31 (71%) of non-hospitalized panic patients reported nocturnal panic attacks to have occurred at least once, and two of these patients reported sleep panic as a typical or frequent feature of their illness. Scattered reports suggest that these events are preceded by non-REM sleep. We have now recorded six nocturnal panic attacks occurring during all night sleep EEG recordings. To date all of the awakenings that were associated with panic symptoms were preceded by non-REM sleep that could be characterized as a transition from stage 2 to stage 3. In one subject where cardiac monitoring was available, a 20 beat per minute increase in heart rate occurred in the minute preceding the awakening. Time awake was brief for these events. Two preceded and four followed the first REM period and all events were relatively proximate to the first REM period. Of interest, there was a significant increase in REM latency associated with “panicking” nights compared to other “non-panicking” nights in the same patients. This delayed REM was also evidenced when comparing between groups of patients with and without nocturnal panic attacks and controls. Panic attacks occurring from sleep may provide a useful model for elucidating mechanisms of panic. These findings would support the observation that some panic attacks can occur spontaneously and suggest that they might be physiologically triggered. The association with nonREM sleep and autonomic activation preceding awakening renders it difficult to invoke cognitive factors as primary to these sleep-related events. It is also of interest that despite overlap in the phenomenology and bi-
BIOLOGIC
FINDINGS
IN PANIC
DISORDER
‘5 -_
ology of anxiety and depression, anxiety disorders including panic generally do not feature reduced REM latencies and that nocturnal panic appears to be associated with prolongation of the first non-RElM period. Finally, the fact that increased movement time is most prominent on nonpanic attack nights suggests it might be, paradoxically, a protective mechanism that somehow counteracts, rather than promotes, panic attacks. Response
to One-Night’s
Sleep Deprivation
Because of anecdotal reports that some panic disorder patients experience an exacerbation of their symptoms with lack of sleep, because some psychosensory symptoms in these patients resemble those seen in complex partial seizure disorder, and because it is well established that sleep deprivation can exacerbate EEG abnormalities. Roy-Byrne, Uhde, and Post (1986) investigated the effects of one night’s sleep deprivation on mood and behavior in panic disorder patients. In contrast to the improvement in symptoms of anxiety and depression shown by the majority of depressed patients, these patients did not improve and a subgroup (40%) experienced exacerbation of anxiety and panic attacks on the day following sleep deprivation. None of these 12 patients had abnormalities on EEG recordings with nasopharyngeal electrodes done the day following sleep deprivation, which would suggest evidence of temporal lobe seizure activity. This study suggests the possibility that sleep deprivation is either a non-specific stress that lowers the threshold for panic, or interacts more intimately with some underlying pathophysiologic abnormality. Recent findings that sleep deprivation may cause increases in TSH as well as peripheral thyroid hormones (Palmblad, Akerstedt, Froberg, Melander, SCVon Schenck, 1979) may provide an avenue for future investigations of possible underlying mechanisms. CONCLUSION
The neuroendocrine findings noted here in panic disorder patients show a large degree of overlap with those observed both in depressed patients and in naturally occurring and experimentally induced states of stress in humans and animals. The HPA axis may be activated more by the state of chronic anxiety seen in most panic disorder patients than by the panic attacks themselves (although the former often increase the likelihood of the latter), such that there is adaptation in the axis’ response to more acute perturbations (i.e., panic). The causes of reduced TSH and prolactin responses to TRH are unclear, although they may also represent adaptations to excess ongoing secretions of TRH, perhaps associated with chronic anxiety. Relative increases in T4 may play a role in the reduced TSH response. The relatively unique association of prolactin increases with spontaneous panic attacks is consistent with animal studies showing less adaptation in the response of this system to experi-
26
P. P. ROY-BYRNE,
T. A. MELLMAN,
ANDT.
W. UHDE
mental stress. Overall, these neuroendocrine findings are consistent with hypotheses implicating both noradrenergic and benzodiazepine abnormalities in the pathophysiology of anxious states, although they cannot be explained exclusively by them. In contrast to the neuroendocrine findings, the sleep findings provide more evidence of a biologic distinction between panic and major depressive disorders. The occurrence of specific sleep EEG changes preceding the occurrence of nocturnal panic attacks suggest that understanding individual variations in EEG sleep topography associated with specific clinical findings (i.e., nocturnal panic) may be more helpful in elucidating the pathophysiology of panic disorder. It remains to be demonstrated whether the sleep deprivation findings (i.e., clinical deterioration in panic disorder patients) are nonspecific, much like the overall sleep EEG findings documenting disturbances in sleep initiation and maintenance, or, like specific EEG findings occurring on the night of nocturnal panic, may be more initimately related to the underlying pathophysiology of the disorder.
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