Psychiarry Research, 54:135-142 Elsevier

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Plasma Interleukin-1 Beta Concentrations in Panic Disorder

Francesca Brambilla, Laura Bellodi, Giampaolo Perna, Angelo Bertani, Albert0 Panerai, and Paola Sacerdote

Received April 7, 1993; revised version received November 22, 1993: accepted January 3, 1994.

Abstract. Plasma interleukin-lb (IL-ID) concentrations were measured in 10 outpatients with panic disorder before and on days 30 and 32 of treatment with alprazolam (2-2.5 mg/day). IL-lb concentrations were found to be significantly higher in patients than in control subjects both before and during therapy. Thus, IL-ID levels may be a marker of panic disorder that is not related to the current level of symptomatology.

Key Words. Anxiety, alprazolam, psychoimmunology.

Interleukin-lp (IL-l&, a protein produced predominantly by stimulated macro-

phages and monocytes, is one of the key mediators of immunobiological responses to

physical stress. In addition to possessing specific immunomodulatory activity, the cytokine stimulates the secretion of neurotransmitters and hormones that are involved in the stress response, including noradrenalin (NA), the hypothalamo- pituitary-adrenal (HPA) hormones and growth hormone (Besedovsky et al., 1986; Dunn, 1988; Kabiersch et al., 1988; Barbanel et al., 1990; Motta et al., 1990; Shapier and Ovadia, 1990; Suda et al., 1990; Ohgo et al., 1991; Ju et al., 1991; Watanobe et al., 1991; Saperstein et al., 1992). IL-lfi is also produced by astrocytes, microglia and neurons in the periventricular, preoptic, hyppocampus and arcuate nuclei, where it may have direct neurotransmitter, neuromodulator, and growth factor activities through specific IL-ID receptors (Breder and Saper, 1989; Takao et al., 1990). When administered intracerebroventricularly, intraperitoneally, or intravenously to experi- mental animals in rather high doses, the cytokine induces changes in sleep architecture, food and water intake, taste aversion, and sensitivity to pain; it decreases exploratory behavior and motor activity; disrupts operant performance; decreases defensive withdrawal; and advances the onset of behavioral despair, all features that are part of the stress reaction (Krueger et al., 1984; McCarthy et al., 1986; Uheara et al., 1987; Nakamura et al., 1988; Plata-Salaman et al., 1988; Del Cerro and Borrell, 1990; Chelmicka-Schorr and Arnason, 1990; Dunn et al., 1991;

Francesca Brambilla, M.D., is Director of the Psychoneuroendocrine Center, Ospedale Psichiatrico Pini; Laura Bellodi, M.D., is Associate Professor; Giampaolo Perna, M.D., is Ph.D. trainee in psychiatry; Angelo Bettani is a medical student, Dipartimento di Scienze Neuropsichiche dell’universita di Milano, Istituto Scientifico S.Raffaele. Albert0 Panerai, M.D., is Professor, and Paola Sacerdote, Ph.D, is Assistant, Dipartimento di Farmacologia dell’universita’di Milano, Italy. (Reprint requests to Prof. F. Brambilla, Centro di Psiconeuroendocrinologia, Ospedale Psichiatrico Pini, Via Ippocrate 45, Milan0 20161, Italy.)

0165-1781/94/$07.00 Q 1994 Elsevier Science Ireland Ltd.

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Tazi et al., 1991). IL-l/I might thus be considered one of the links in the chain of reciprocal influences of the central nervous system, the neuroendocrine system, and the immune system.

Panic attacks might represent repeatedly recurring severe stress episodes, and it has been suggested that they are coupled with hyperactivity of central and peripheral NA and HPA systems (Redmond, 1986; Cameron and Nesse, 1988; Holsboer, 1988; Gorman et al., 1989; Brambilla et al., 1991). Data in the literature on the immune function in panic disorder are scanty and controversial. Total lymphocyte count and lymphocyte subsets (T, B, T-4, natural killer cells) do not seem to be significantly different in panic patients and control subjects, even though increased lymphocyte and T-4 counts have occasionally been observed (Andreoli et al., 1990; Ramesh et al., 1990; Schleifer et al., 1990). Lymphocyte proliferative responses to mitogens have been reported to be normal, decreased, or increased (Surman et al., 1986; Andreoli et al., 1990; Schleifer et al., 1990; Brambilla et al., 1992). Because of the reported occurrence in panic disorder of activation of the T-lymphocyte system, the major source of Il-lp, and in parallel of hyperactivity of the NA and HPA systems, which may be linked to hypersecretion of 11-l/3, we decided to measure the cytokine plasma concentrations in a group of panic patients during an interictal phase of the disease. 11-lfi concentrations were measured again in the same patients after 30 days of treatment with alprazolam, a benzodiazepine that positively influences the dis- order and in parallel decreases NA and HPA secretion (Charney et al., 1986; Williams et al., 1986). The aim of this preliminary study was to see whether IL-10 concentrations were abnormal in the course of the disorder, possibly representing the

link between NA and HPA pathological functions, whether they are correlated with the phases of the psychopathology, and whether they might possibly be a state or a trait marker for the disorder.

Methods

Ten outpatients (4 men, 6 women; mean age = 33.4, SD = 8.4, range = 20-48) with panic disorder and agoraphobia without a comorbid Axis I disorder entered the study. Duration of illness ranged from 1 to 16 years (mean = 5.7, SD = 5.8). In the 15 days before the study, the weekly frequency of panic attacks ranged from one to seven (mean = 1.9, SD = 1.9), with the last attack having occurred between 2 and 3 days before the investigation. The diagnosis of panic disorder was made with the Structured Clinical Interview for DSM-IZZ/ Upjohn version (Spitzer and Williams, 1983) and the presence of a lifetime history of depression was excluded by clinical evaluation. Before our study, five patients had never taken psychopharmacological drugs, four had taken benzodiazepines (lorazepam, chlordesmethyldiazepam, diazepam, fluorazepam), and one had taken amitriptyline. Patients were withdrawn from medication at least 15 days before our investigation. Ten physically healthy volunteers, recruited from the hospital staff, formed an age-matched control group (4 men, 6 women; mean age = 32 years, SD = 7, range = 20-45) Socioeconomic status of both patients and control subjects was not homogeneous, but was matched in the two groups. Control subjects were interviewed with the Diagnostic Interview Schedule-Revised (DZS-III-R; Robins et al., 1989) to exclude previous or present Axis I or II disorders. Exclusion criteria for both patients and control subjects included organic disorders, infections, allergopathies, inflammatory disorders, endo- crinopathies, obesity or recent weight loss, alcohol or drug abuse, and immune or auto- immune disorders. All the patients and control subjects gave informed consent.

EDTA-treated blood for IL-ID assay was drawn from patients and matched control

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subjects in close proximity, to avoid temporal changes in the assay. The test began at 8:30 a.m. after 12 hours of fasting and 1 hour of bed rest in recumbent position, at the day hospital of our Institute. Blood was drawn twice, at a 48-hour interval, and the values of the two assays were averaged. Then, patients received orally administered alprazolam for 32 days in a divided daily dose of 2.0-2.5 mg. On days 30 and 32, blood was drawn again with the procedure explained above.

IL-10 plasma concentrations were measured radioimmunologically with the commercial kits of Medgenix Diagnostics (Italy). All the assays were run by a trained technician, who used the same batch of reagents to minimize intra-assay variability. The immunoradiometric assay (IRMA) is based on a coated tube separation of IL-ID and on the oligoclonal system-R, in which several monoclonal antibodies directed against distinct epitopes of IL-l/3 have been used. Sensitivity of the method corresponds to 5 pg/ml, and there is no cross-reactivity with interferon-a, -p, and -y, interleukin 2, and tumor necrosis factor-a and -/3. The intra-assay coefficient of variation was 2.7?$, and the interassay coefficient of variation was 6.6%.

The patient’s psychopathological condition was investigated twice during the blood sampling for the measurement of IL-l/3 levels. Measures included the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960), the Hamilton Rating Scale for Anxiety (HRSA; Hamilton, 1959), the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1970), and the Panic Attack and Anticipatory Anxiety Scale (PAAS; Klerman, 1988) to measure frequency and severity of the attacks. The psychobiological tests were repeated on days 30 and 32 of alprazolam therapy.

The results of both psychological and IL-ID measurements were analyzed statistically by the Student’s t test for paired and unpaired data, by the Pearson’s coefficient of correlation, and by linear regression analysis. Findings are reported as means and standard deviations.

Results

The severity and frequency of panic attacks (as measured by the PAAS) were elevated in basal conditions and were significantly improved by the therapy (2 f 2 vs. 0.3 f 0.1; t = 2.6, df = 18, p = 0.01). The severe pretreatment level of anxiety improved significantly after therapy (HRSA = 68.5 f 27 vs. 26 f 19; t = 4, df= 18, p = 0.0008; STAI = 51 f 9 vs. 40 f 10; t = 2.2, df= 18, p = 0.03). Depression (as measured by the HRSD) was practically absent in basal conditions and was not changed by the therapy.

Plasma concentrations of IL-ID (Fig. 1) before therapy were significantly higher in patients than in control subjects (38.1 f 12.4 vs. 13.1 f 9.1 pg/ml; t = 5.1, df = 18, p = 0.0007). After alprazolam therapy, IL-l/I levels decreased but were still signifi- cantly higher than in the control subjects (28.8 f 11.2 vs. 13.1 f 9.1 pg/ml; t = 3.3, df= 18, p = 0.04). The mean values of IL-lp of patients before and after therapy were not significantly different (38.1 f 12.4 vs. 28.8 f 11.2). There were no differences in IL-I/3 concentrations of the patients between the samples drawn at 48-hour intervals before and after therapy. Concentration levels from the two samples were therefore averaged.

When the patients were divided into group I, with five subjects who had never taken psychopharmacological treatments before our study, and group II, with five patients who had taken benzodiazepines (4) or amitriptyline (I), basal IL-l/I levels of the two groups were both significantly higher than those of control subjects and not significantly different from each other (group I: 34.9 f 15.5 vs. 11.5 f 2.8 pg/ml; F= 11.0, df=8.3,p=O.O1; group II: 41.3 f 11.7 vs. 10.9 f 3.2pg/ml; F= 21.5, df = 8.3, p = 0.002).

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Fig. 1. Plasma concentrations of interleukin-18 of 10 oatients with panic disorder (P.D.) and 10 control subjects

.

.

f :’ . 0. . .

01

Cootrolr P.D. P.D. before theram rftcr tber8py

Alprazolam therapy induced no changes in the IL-l/l levels of group I (34.9 f 15.5 vs. 35.0 + 10.9 pg/ml), while in group II it significantly decreased the cytokine levels (41.3 + 11.7 vs. 22.6 ?c 11 pg/ml; F= 8.7, df = 8.2, p = 0.02), which were not significantly different from those of control subjects.

IL-ID values, either before or after therapy, were not correlated with age of the patients, age of onset, duration of illness, or gender. Before therapy, there were no correlations between IL-Ip concentrations and severity or frequency of panic attacks (PAAS), anxiety (HRSA, STAI), or depression (HRSD). After therapy, the improve- ments of the psychopathology were not correlated with absolute IL-ID levels or with percent decrease from pretherapy concentrations. When the patients were divided again into two groups, with and without psychopharmacological treatment before our study, IL-lb levels of both groups did not correlate with the clinical data, either before or after therapy. Only trait anxiety (STAI-1) showed a significant positive correlation in regression analysis with the cytokine levels in group II patients (r = 3.5, df= 3, p = 0.04).

Discussion

Our preliminary data, even though obtained in too small a group of subjects to allow definitive conclusions, suggest that basal IL-lfi plasma levels are higher in panic patients than in normal subjects. The consistency of the results in two successive samples obtained at 48-hour intervals, both before and after therapy, suggests that the alteration may be a constant phenomenon and not due to occasional secretory fluctuations of the cytokine. The increased levels of IL-lb do not seem to be linked to previous psychopharmacological therapies, since they also are present in previously untreated patients. Moreover, they are not related to duration or severity

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of the disorder, to severity of anxiety, or to the presence of depressive symptoma- tology; thus, the biological abnormality is not related to symptomatology, but it could be a substratum of the disorder, an expression of its pathogenesis.

Alprazolam treatment was followed in parallel by significant clinical improvement and by a trend toward a normalization of IL-lfi levels, which became significant only in the group of patients who had been treated with psychoactive drugs before our study. This hints at the possibility that only long-lasting therapy will result in normalization of the biological impairment, independently of the clinical symptoma- tology. In fact, the five subjects who had never had therapy before our study and had been receiving alprazolam for only 1 month showed good clinical results without significant decrease of IL-I/I levels. The temporal dissociation between symptoma- tological and biochemical changes again suggests that the derangement of IL-lb secretion might be a pathogenetic substratum of a disorder, of which panic attacks are only a surface expression.

The increased secretion of IL-l/3 might be responsible for the HPA axis hyperactivity and the central noradrenergic hyperfunction that have been observed in panic patients and that have been suggested to be involved in the pathogenesis of the disease (Redmond, 1986: Charney et al., 1984, 1986, 1989).

At present, it is difficult to advance hypotheses on the cause of the IL-l/I hypersecretion. Physical and emotional stress reactions resulting in NA hyper- secretion seem to depress immune function in general and the production of IL-Ifi in particular (Besedovsky et al., 1979; Kiecolt-Glaser et al., 1984; Berkenbosch et al., 1991; Dobbin et al., 1991; Felsner et al., 1992). However, in a specific human psy- chological stress model (students taking examinations), it has been observed in vitro that IL-ID production by stimulated monocytes is increased and y-interferon production by lymphocytes is decreased. These observations suggest that stress may have different effects on different cell populations, enhancing the response of monocytes and depressing that of lymphocytes (Dobbin et al., 1991). Since panic attacks may be considered stressful episodes, a similar phenomenon could occur in the secretion of IL-l/I of panic patients, in whom hypersecretion of corticotropin releasing hormone (Holsboer, 1988; Brambilla et al., 1991) and inhibition of T-lymphocyte proliferative response to stimulation with conconavalin-A, phytohemagglutinin, and pokeweed mitogen have been reported to occur (Andreoli et al., 1990; Ramesh et al., 1990; Schleifer et al., 1990; Brambilla et al., 1991). Increased levels of IL-I/3 in the supernatant of phytohemagglutinin-stimulated lymphocytes of depressed patients have also been reported, with a blunted response to the inhibiting effect of dexamethasone, a possible expression of glucocorticoid receptor down-regulation (Besedovsky et al., 1986; Maes et al., 1991). Subsensitivity of glucocorticoid receptors may also exist in panic disorder (Cameron and Nesse, 1988), and therefore the higher than normal levels of IL-l/I observed in our patients might derive from a blunting of the inhibitory effects of glucocorticoids on the immune system.

Finally, a derangement of the well-known inhibitory activity of NA on the immune system may also be envisaged (Besedovsky et al., 1979; Maes et al., 1991; Felsner et al., 1992). Down-regulation and reduced density of /3-adrenergic receptors

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have been reported for lymphocytes of panic patients, with reduced response of cyclic adenosine-3’,5’-monophosphate to isoproterenol stimulation, possibly linked to NA hypersecretion (Takamoto et al., 1991; Maddock et al., 1992). This would result in a blunting of the inhibitory effect of NA on the immune system, with ensuing increase of plasma IL-l/l concentrations. It is difficult to say if the decreased IL-l/l levels observed in some of our patients after 1 month of alprazolam treatment are expressions of clinical improvement of the disorder or a pharmacological effect of the drug. Low doses of alprazolam have direct immunostimulant effects, and high doses of the drug have no effects (Fride et al., 1990). It must be remembered, however, that benzodiazepines depress NA and HPA hormone secretion (Charney et al., 1986; Williams et al., 1986), and they may therefore have complex direct and indirect effects on immune functions. These are obviously all hypotheses that must be investigated in long-term placebo-controlled studies of large populations, with parallel measurements of NA and HPA function.

References

Andreoli, A.; Keller, S.E.; Taban, C.; Rabeus, M.; and Garrone, G. Immune function in major depressive disorder: Relation to panic disorder comorbidity. Biological Psychiatry,

27(Suppl. 9A):95A, 1990. Barbanel, G.; Ixart, G.; Szafarczyck, A.; Malaval, F.; and Assenmacher, 1. Intra-

hypothalamic infusion of interleukin-lb increases the release of corticotropin-releasing hormone (CRH-41) and adrenocorticotropic hormone (ACTH) in free-moving rats bearing a push-pull cannula in the median eminence. Brain Research, 516:31-36, 1990.

Berkenbosch, F.; Wolvers, D.A.W.; and Derijk, R. Neuroendocrine and immunological mechanisms in stress-induced immunomodulation. Journal of Steroid Biochemistry and Molecular Biology, 40~639-647, 1991.

Besedovsky, H.; Del Rey, A.; Sorkin, E.; Da Prada, M.; and Keller, H.H. Immuno- regulation mediated by the sympathetic nervous system. Cellular Immunology, 48:346-3X, 1979.

Besedovsky, H.; Del Rey, A.; Sorkin, E.; and Dinarello, C.A. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science, 233:652-654, 1986.

Brambilla, F.; Bellodi, L.; Perna, Cl.; Battaglia, M.; Sciuto, G.; Diaferia, G.; Petraglia F.; Panerai, A.; and Sacerdote, P. Psychoimmunoendocrine aspects of panic disorder. Neuropsychobiology, 26:12-22, 1992.

Brambilla, F.; Picotti, G.B.; Bondiolotti, G.P.; Catalano, M.; Lucca, A.; Della Maggiora, P.; Genazzani, A.R.; Petraglia, F.; and Smeraldi, E. Neurochemical-hormonal investigation of panic disorder: Effects of alprazolam therapy. In: Genazzani, A.R.; Nappi, G.; Petraglia, F.; and Martignoni, E., eds. Stress and Related Disorders: From Adaptation to Dysfunction. Carnforth, Lancaster, U.K.: Parthenon Publishing Group, 1991. pp. 175-18 1.

Breder, C.D., and Saper, C.B. Interleukin-lb-like immunoreactive innervation in the human central nervous system. Society OfNeuroscience Abstracts, 15:715, 1989.

Cameron, O.G., and Nesse, R.M. Systemic hormonal and physiological abnormalities in anxiety disorders. Psychoneuroendocrinology, 13:287-308, 1988.

Charney, D.S.; Breier, A.; Jatlow, P.I.; and Heninger, G.R. Behavioral, biochemical and blood pressure responses to alprazolam in healthy subjects: Interactions with yohimbine. Psychopharmacology, 88:133-140, 1986.

Charney, D.S.; Heninger, G.R.; and Breier, A. Noradrenergic function in panic disorder. Archives of General Psychiatry, 41:751-763, 1984.

Charney, D.S.; Woods, S.W.; and Heninger, G.R. Noradrenergic function in generalized anxiety disorder: Effects of yohimbine in healthy subjects and patients with generalized anxiety disorder. Psychiatry Research, 27: 173-l 82, 1989.

141

Chelmicka-Schorr, E., and Arnason, B.G.W. Nervous system-immune system interactions. In: Waksman, B.H., ed. Immunologic Mechanisms in Neurological and Psychiatric Disease. New York: Raven Press, 1990. pp. 67-90.

Del Cerro, S., and Bortell, J. Interleukin-1 affects the behavioral despair response in rats by an indirect mechanism which requires endogenous CRF. Brain Research, 528:162-164, 1990.

Dobbin, J.P.; Harth, M.; McCain, G.A.; Martin, R.A.; and Cousin, K. Cytokine production and lymphocyte transformation during stress. Brain, Behavior and Immunity, 5339-348, 1991.

Dunn, A.D. Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism paralleling the increased plasma corticosterone. Ltfe Sciences, 43:429-435, 1988.

Dunn, A.J.; Antoon, M.; and Chapman, Y. Reduction of exploratory behavior by intraperitoneal injection of interleukin-1 involves brain corticotropin-releasing factor. Brain Research, 26539-542, 1991.

Felsner, P.; Hofer, D.; Rinner, I.; Mangge, H.; Gruber, M.; Korsatko, W.; and Schauenstein, K. Continuous in vivo treatment with catecholamines suppresses in vitro reactivity of rat peripheral blood T-lympocytes via alpha-mediated mechanism. Journal of Neuroimmunology, 37~45-57, 1992.

Fride, E.; Skolnick, P.; and Arora, P.K. Immuno-enhancing effects of alprazolam in mice. Life Sciences, 47~2409-2420, 1990.

Gorman, J.M.; Liebowitz, M.R.; Fyer, A.J.; and Stein. J. A neuroanatomical hypothesis for panic disorder. American Journal of Psychiatry, 146:148-161, 1989.

Hamilton, M. The assessment of anxiety states by rating. British Journal of Medical Psychology, 32:50-55, 1959.

Hamilton, M. A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23:56-62, 1960.

Holsboer, F. Implications of altered limbic-hypothalamic-pituitary-adrenocortical (LHPA) function for neurobiology of depression. Acta Psychiatrica Scandinavica, Suppl. 41:72-l 11, 1988.

Ju, G.; Zhang, X.; Jin, B.Q.; and Huang, C.S. Activation of corticotropin-containing neurons in the paraventricular nucleus of the hypothalamus by interleukin-1 in the rat. Neuroscience Letters, 132: 15 1 - 154, 199 1.

Kabiersch, A.; Del Rey, A.; Honnegger, C.G.; and Besedowsky, H. Interleukin-1 induces changes in norepinephrine metabolism in the rat brain. Brain, Behavior and Immunity, 2:267- 274, 1988.

Kiecolt-Glaser, J.K.; Glaser, R.; Strain, E.; Stout, J.; Tarr, K.; Holliday, J.E.; and Speicher, C. Modulation of cellular immunity in medical students. Journal of Behavioral Medicine, 9:5-21, 1984.

Klerman, G.L. Overview of the Cross-National Collaborative Panic Study. Archives of General Psychiatry, 45~407-50 1, 1988.

Krueger, J.M.; Walter, J.; Dinarello, C.A.; Wolff, S.M.; and Chedid, L. Sleep-promoting effects of endogenous pyrogen (interleukin-1). American Journal of Physiology, 246:R994- R999, 1984.

Maddock, R.J.; Carter, C.S.; Magliozzi, J.R.; and Gietzen, D.W. Reduced lymphocyte beta-adrenoceptor function in panic disorder with agoraphobia and changes with treatment. Biological Psychiatry, 3l(Suppl. 5A):67A, 1992.

Maes, M.; Bosmans, E.S.E.; Vandervorst, C.; DeJonckheere, C.; and, Raus, J. Depression related disturbances in mitogen-induced lymphocyte responses and interleukin-lp and soluble interleukin-2 receptor production. Acta Psychiatrica Scandinavica, 84:379-386, 199 1.

McCarthy, D.O.; Kluger, M.J.; and Vanders, A.J. Effect of centrally administered interleukin-1 and endotoxin on food intake of fasted rats. Physiology and Behavior, 36:745- 749, 1986.

Motta, S.G.; Singh, J.; Newton, R.; and Sharp, B.M. The adrenocorticotropin response to interleukin-l/3 instilled into the rat median eminence depends on the local release of catecholamines. Endocrinology, 127:2175-2182, 1990.

142

Nakamura, H.; Nakanishi, K.; Kita, A.; and Kadokawa, T. Interleukin-1 induces analgesia in mice by a central action. European Journal of Pharmacology, 14949-54, 1988.

Ohgo, S.; Nakatsuru, K.; Ishikawa, E.; and Matsukura, S. Interleukin-1 (IL-l) stimulates the release of corticotropin-releasing factor (CRF) from superfused rat hypothalamo- neurohypophyseal complexes (HNC) independently of the histaminergic mechanism. Brain Research, 558:2 17-223, 199 1.

Plata-Salaman, C.R.; Omura, Y.; and Kai, Y. Tumor necrosis factor and interleukin-l/I: Suppression of food intake by direct action in the central nervous system. Brain Research, 448:106-l 14, 1988.

Ramesh, C.; Yeragani, V.K.; Balan, R.; and Pohl, R. Immunological function in panic disorder patients and controls. Biological Psychiatry, 27(Suppl. 9A):65A, 1990.

Redmond, D.E. The possible role of locus coeruleus noradrenergic activity in anxiety- panic. Clinical Neuropharmacology, 9140-42, 1986.

Robins, L.; Helzer, J.E.; Cottler, L.; and Goldring, E. NIMH Diagnostic Interview Schedule: Version III-R (DIS-III-R). St. Louis: Washington University School of Medicine, 1989.

Saperstein, A.; Brand, H.; Audhya. T.; Nabriski, D.; Hutchinson, B.; Rosenzweig, S.; and Hollander, CS. Interleukin-l/3 mediates stress-induced immunosuppression via corticotropin- releasing factor. Endocrinology, 130: 152-158, 1992.

Schleifer, S.; Keller, S.E.; Cott, B.; and Vecchione, J. Lymphocyte function in panic disorder. Biological Psychiatry, 27(Suppl. 9A):66A, 1990.

Shapier, D., and Ovadia, H. Selective facilitation of putative corticotropin releasing factor- secreting neurones by interleukin-1. Neuroscience Letters, 114:283-288, 1990.

Spielberger, C.D.; Gorsuch, R.L.; and Lushene, R.G. Zi’re State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press, 1970.

Spitzer, R.L., and Williams, J.B.W. Structured Clinical Interview for DSM-HI, Upjohn Version (SCID-UP). New York: New York State Psychiatric Institute, 1983.

Suda, T.; Tozawa, F.; Ushiyama, T.; Sumitomo, T.; Yamada, M.; and Demura, H. Interleukin-1 stimulates corticotropin releasing factor gene expression in rat hypothalamus. Endocrinology, 126:1223-1228, 1990.

Surman, O.S.; Williams, G.; Sheehan, D.V.; Strom, T.B.; Jones, K.J.; and Coleman, J. Immunological response to stress in agoraphobia and panic attacks. Biological Psychiatry, 2 1:768-774, 1986.

Takamoto, T.; Hori, Y.; Koga, Y.; and Toshima, H. Norepinephrine inhibits human natural killer cell activity in vitro. International Journal of Neuroscience, 58: 127-13 1, 199 1.

Takao, T.; Tracey, D.E.; Mitchell, W.M.; and De Souza, E.B. Interleukin-I receptors in mouse brain: Characterization and neuronal localization. Endocrinology, 127:3070-3078, 1990.

Tazi, A.; Crestani, F.; and Dantzer, R. Aversive effects of centrally injected interleukin-I. Neuroscience Research Communications, 7: 159- 165, 199 1.

Uheara, A.; Gottsschall, P.E.; Dahl, R.R.; and Arimura, A. Interleukin-I stimulates ACTH release by an indirect action which requires endogenous corticotropin-releasing factor. Endocrinology, 121:1580-1582, 1987.

Watanobe, H.; Sassaki, S.; and Takebe, K. Evidence that intravenous administration of interleukin-1 stimulates corticotropin-releasing hormone secretion in the median eminence of freely moving rats: Estimation by pull-push perfusion. Neuroscience Letters, 133:7-10, 1991.

Williams, R.B.; Schanberg, S.M.; Kuhn, C.M.; and Lane, J.D. Influence of alprazolam on neuroendocrine and cardiovascular responses to stress in type A men. Abstracts of the Annual Meeting of the American College of Neuropsychopharmacology, 1986. p. 203.