Cortisol response to clonidine in panic disorder: Comparison with depressed patients and normal controls

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Cortisol Response to Clonidine in Panic Disorder: Comparison with Depressed Patients and Normal Controls Murray B. Stein and Thomas W. Uhde

Abnormalities in regulation of noradrenergic function have been proposed as part of the pathology of depressive and panic anxiety disorders. However, abnormalities in hypothalami~-pituitary~drenu~ PAPAShis function have largely been limited to patients with depressive disorders. Using the cortisol response to clonidine, an alphaz-adrenergic receptor agonist, this study examined the relationship between the noradrenergic system and the HPA axis in IOpatients with major depression (4 unipolar, 6 bipolar), 10 patients with panic disorder, and IO normal controls. Baseline cortisol was si~ni~~antlyelevated in depressed as compared with panic patients, but not with controls. Depressed patients also tended to exhibit a greater absolute fall in plasma cortisol (5.2 k 4.0 pgldl) compared with panic patient.~ (1.7 k 2.4 pgldt) (p < 0.06, t-test). When expressed as a percentage of basetine, however, the cortisol response to clonidine did not differ signijicantiy between diagnostic groups (p > 0.10). Basal levels of cortisol were highly correlated with the degree of decrease in cortisol induced by clonidine in the group of 30 subjects (r = -O.&f, p < ~.~~~. The.~e~~ings are dis~us‘sed in the context of the utility of clonidine as a probe of the,functionai relatedness of the noradrenergic system and the HPA axis in these disorders.

Introduction Abnormalities in noradrenergic neurotransmission have been proposed as part of the pathology of depressive illness (Siever and Uhde 1984; Siever and Davis 1985) and panic disorder (Redmond and Huang 1979; Uhde et al. 1985; Charney et al. 1986). These findings may represent an area of neurochemical overlap in these two clinically related disorders. In contrast, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a well-recognized feature of depressive disorders (Carroll et al. 1981; Rubinow et al. 1984; Gold et al. 1986), but a less frequent finding in studies of panic disorder (Avery et al. 198.5; Coryell et al. 1985; Faludi et al. 1986). The majority of Dexamethasone Suppression Test studies in panic disorder have shown normal cortisol suppression after

From

the Unit on Anxiety and Affective

Disorders,

Biological

Psychiatry

Branch. National

institute of Mental

Health.

Bethesda.

MD. Address reprint requests to Dr. Thomas 9ooo Rockville

Pike.

Presented at the XVIII

Chapel Hill, Received

c

1988 Society

May

Bethesda,

Intentional

W. Uhde.

MD

Unit on Anxiety

and Affective

Dtsorders.

BPB. NIMH,

Bldg 10. Rm 3S239.

20892.

Congress

of theraternational

Society

of Psychoneuroendocfinology. June 28-July

3. 1987.

NC. 26.

of Biological

1987. revi\ed

Psychiatry

August

3. 1987.

(~-322~/88/~3.5(~

Panic Disorder: Cortisol Response to Clonidine

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dexamethasone administration (Curtis et al 1982; Lieberman et al. 1983; Sheehan et al. 1983; Roy-Byrne et al. 1985; Peterson et al. 1985; Bridges et al. 1986). In another measure of HPA axis function-the cortisol and ~n~o~~o~ophic hormone (ACTH) response to co~ico~opin-rel~sing hormone (C~~patients with panic disorder exhibited elements of acute and chronic hypercortisolism. They showed elevated baseline 8:00 PM cortisols, as well as blunted ACTH secretion in response to CRH, which is similar to depressed patients (Roy-Byrne et al. 1986a). Moreover, a study of 12 patients with panic disorder found no difference in 24-hr urinary free cortisol from that seen in 12 normal controls (Uhde et al. 1988). The relationship between altered noradrenergic function and h~rco~isolemia in depression is an area of recent study (Jimerson et al. 1983; Rosenbaum et al. 1983; Siever et al. 1984a; Price et al. 1986; Loo et al. 1986; Lu et al. 1986; Roy et al. 1986). Although the evidence is conflicting, it is possible that norepinephrine may regulate cortisol secretion by providing an inhibitory input to the HPA axis via actions at the postsynaptic alpha,adrenergic receptor (G~ong 1980; Lanes et al. 1983), although a direct stimulator effect of norepinephrine has also been reported via stimulation of beta-receptors on pituitary cells in culture (Reisine et al. 1983). Manipulation of the noradrenergic system with the relatively specific (Starke and Altmann 1978) alpha,-adrenergic receptor agonist clonidine hydrochloride provides a method for the study of the dynamic relationship between alphaznoradrenergic receptors and HPA axis function. In this study, clonidine hyd~~o~de was adminis~~ in~avenously to 10 patients with panic disorder and to 10 age- and sex-matched depressed patients and 10 age- and sex-matched normal controls. The plasma cortisol response to clonidine was measured in each of these groups to allow for comparison of noradrenergic effects on the HPA axis across diagnostic groups.

Methods Thirty subjects participated in this study after giving their informed consent. Depressed patients and normal controls were chosen by age- and sex-matching to the panic disorder patients. All three groups were studied concurrently using the same experimental design, with the intent being to allow com~son of all three groups. Ten patients with panic and phobic (agoraphobic subtype) disorders (4 men and 6 women; mean age 37.8 + 8.2 years), 10 depressed patients (4 men and 6 women; mean age 38.6 + 11.8 years), and 10 healthy controls (4 men and 6 women; mean age 36.0 +- 15.5 years) participated in the study. The mean ages of the three diagnostic groups did not differ significantly (ANOVA, F = 0.12, p > 0.10). All depressed (4 unipolar and 6 bipolar) and panicanxious patients satisfied the respective Research Diagnostic Criteria (RDC). All depressed patients were studied as inpatients, all normal controls were studied as outpatients, and 8 of 10 of the panic disorder patients were studied as inpatients. The controls were screened for the absence of psychiatric disorder on the basis of a structured psychiatric interview by an experienced psychiatrist. All patients and controls were free of medical illness, as indicated by a thorough medical evaluation, including chest x-ray, electrocardiogram (ECG), elec~~n~ph~o~~ (EEG), and laboratory hematologic and chemistry panels. No subject received any medication during the 3 weeks prior to the study. Seven subjects in each group were studied with both intravenous (iv) clonidine hydrochloride (2 p&kg) and saline placebo on different days, whereas three subjects in each group received only clonidine. A preliminary analysis showed that the between-

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groups comparison did not differ between placebo-corrected values and clonidine values only; subsequently, only results during the clonidine infusion are reported. All subjects fasted overnight before the study and were instructed to avoid excessive activity in the morning prior to the study. At 8:30 AM, an iv line was inserted into a forearm vein of the supine subjects. who then remained recumbent for the 3-hr duration of the study. A normal saline iv solution was given at a minimal rate to keep the iv line open for blood sampling. Blood samples for plasma cortisol concentrations were drawn 15 min before and immediately prior to the infusion, which took place at approximately 9:30 AM. Blood samples for cortisol determination were also drawn 15, 30, 45, and 60 min following the infusion. These samples were collected in heparinized tubes, kept on ice, centrifuged at 2,400 rpm for 10 min within 1 hr of collection, and the plasma frozen at - 80°C. Cortisol concentrations were measured by radioimmunoassay with an intraassay coefficient of variation of 4.2% and interassay coefficient of variation of 5.8%.

Data Analysis The effects of clonidine on plasma cortisol levels were initially compared across all three diagnostic groups using an Analysis of Variance with repeated measures (ANOVARs). This provided an analysis of the overall between-groups differences, as well as an assessment of differential effects over time (i.e., preclonidine versus postclonidine). Subsequently, where the ANOVARs revealed significant effects (p < 0.05) or trends (p < 0. lo), the following analyses were used to determine specific differences between groups and/or times. The baseline cortisol levels were compared across all three groups by an ANOVA. Changes in cortisol from baseline in response to clonidine were analyzed within each diagnostic group using a paired t-test. The absolute cortisol decrease in response to clonidine, calculated as the difference between the mean value for four samples drawn in the hour after the infusion of clonidine and the average cortisol baseline concentration (the mean of two values prior to the infusion), and the percentage of fall in cortisol concentration (expressed as percentage of baseline cortisol concentration) were also compared across all three groups by an ANOVA. For ANOVAs in which a significant difference (p < 0.05) or a trend (p < 0.10) was seen, Student’s t-tests were used to determine specific between-groups differences. Pearson correlation coefficients were determined between the neuroendocrine variables described for baseline levels and for changes in response to clonidine. Negative values represent a decrease in a measure from baseline. All data reported represent the findings in 10 subjects per diagnostic group and are reported as mean z SD.

Results The ANOVARs revealed a significant main effect of infusion) [Fc,.27) = 25.16, p < O.OOOOS], a trend group (i.e., panic versus depressed versus control) trend toward a significant time X group interaction There was a trend for the three diagnostic groups prior to infusion (panic 6.1 t 4.7 Fg/dl; depressed

time (i.e., pre- versus postclonidine toward a significant main effect of [FC2,2,) = 2.53, p < 0.101, and a [FC2,27j = 2.58, p < 0.101. to differ in baseline cortisol values 12.6 2 6.2 bgldl; controls 9.4 -+-

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7.0 p,g/dl; F = 2.95, p < 0.07). The significant difference was between the depressed and panic groups @ < 0.02). The mean fall in plasma cortisol after clonidine was 1.7 -t 2.4 pgldl in the panic disorder patients {p < 0.06), 5.2 ~fr4.9 pgldl in the depressed patients (p < O.Ol), and 2.8 rt 2.8 p_g/dl in the normal controls (p < 0.02). There was a trend for the three groups to differ in the fall in plasma cortisol in response to clonidine (F = 2.58, p < O.lO), with the trend seen between the depressed and panic groups (p < 0.06) (Figure 1). However, when the fall in plasma cortisol was expressed as a percentage change from baseline, there was no significant difference among the three groups (panic 26.2% 2 38.4%; depressed 38.8% -f 17.7%; controls 31.9% + 19.0%; F = 0.553, p > 0.10) (Figure 2). No significant correlation was seen between age and baseline cortisol in any of the three groups (p > 0.10). The preclonidine plasma cortisol level was significantly negatively correlated with the degree of clonidine-induced change in cortisol level in the depressed patients (r = -0.87, df = 8, p < 0.005), in the controls (r = -0.75, df = 8, p < 0.02), and in the panic patients (r = -0.77, df = 8, p < 0.001). The composite correlation for the group of 30 subjects was r = - 0.81, df = 28, p < 0.0001, indicating that those with highest pretreatment values had the greatest decrease following clonidine (Figure 3). However, the preclonidine plasma cortisol level did not correlate significantly (p > 0.10) with the percentage of change in plasma cortisol level in any of the three groups (Figure 4).

Discussion This is the first study, to our knowledge, to compare the cortisol response to clonidine across subjects with panic disorder, major depression, and normal controls. Although the enhanced cortisol drop following clonidine might suggest a difference in noradrenergic modulation of the HPA axis in depression compared to panic disorder, we believe that

Figure 1. Changes in plasma cortisol (clgldl)levels from baseline following clonidine ad~~s~tion in normal controls (circles), patients with panic disorder (triangles), and depressed patients (squares). There was a trend for the panic patients and depressed patients to differ @ C 0.06, Student’s G test, two-tailed). 0

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NORMAL CONTROLS

PANIC PATIENTS

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the inhibitory effects of clonidine on cortisol secretion may be a less than satisfactory probe of this relationship. The apparent greater drop in cortisol in depressed compared with panic patients may simply be a function of higher basehne cortisol levels in the depressed group. We found that the drop in cortisol folIowing clonidine was highly correlated with the baseline cortisol level. However, when a percentage, rather than absolute, drop was measured, this correlation was not seen. Accordingly, the percentage drop in cortisol-a measure independent of baseline cortisol level-did not differ across diagnostic groups. Given the dependence on baseline cortisol levels, the absolute drop in cortisol in response to clonidine may provide little information about alphas-adrenoreceptor sensitivity. In contrast, the cortisol response to yohimbine, wherein depressed patients have been shown to have a greater rise in cortisol despite starting from a higher baseline level

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Figure 3. Relationship between baseline plasma cortisol (pgldl) levels and change in plasma cortisol (p.g/dl) levels from baseline following clonidine administration in normal controls (circles), patients with panic disorder (triangles), and depressed patients (squares). The Pearson corm&ion shown represents the 30 subjects in the entire sample.

BIOL PSYC?IlATRY 1988:24:322-330

Panic Disorder: Cortisol Response to Clonidine

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Figure 4. Lack of relationship between baseline plasma cortisol (pg/dl) levels and change in pIasma co&sol (expressed as a percentage of baseline) in normal controls (circles), patients with panic disorder (triangles), and depressed patients (squares). The Pearson correlation shown represents

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-1ooL may be a more sensitive measure of alpha2-adrenergic receptor function. Although neur~ndoc~ne responses to clonidine and yohimbine cannot always be understood in terms of alpha-adrenergic receptor sensitivity (Chamey and Heninger 1986), our findings suggest that stimulatory, rather than inhibitory, neuroendocrine responses to alpha2-adrenergic agents may provide a better marker of the functional relatedness between catecholaminergic and neuroendocrine systems. Of interest, a brief review of neuroendocrine disturbances reported in panic disorder have all been based on tests that significantly stimulate a neur~nd~~ne response in normals, For example, panic disorder has been associated with a blunted growth hormone (GH) response to clonidine (Uhde et al. 1986), blunted ACTH and cortisol response to CRH (Roy-Byrne et al. 1986a), and a blunted thyroid-stimulating hormone (TSH) response to TRH compared to normal controls (Roy-Byrne et al. 1986b). Although we failed to find an exaggerated cortisol decrease after clonidine in this study, our previous findings of a blunted GH increase to clonidine (Uhde et al. 1986) and the exaggerated cortisol increase to yohimbine referred to by Charney and Heninger (1986) both indicate that noradrenergic-neuroendocrine interactions may be altered in panic disorder. Although paradigms that stimulate a neuroendocrine response in normals may not always prove to be preferable in the study of catecholaminergic-neuroendocrine function, it is of interest that parallel observations have been made with behavioral models of anxiety in humans. For example, “stimulating” chemical models of panic [i.e., yohimbine (Chamey et al. 1984), lactate (Liebowitz et al. 1984), CO2 inhalation (Woods et al. 1986), and caffeine (Chamey et al. 1985; Boulenger et al. 1986)] have generally been more productive in elucidating biological correlates and mechanisms of anxiety than have “inhibitory” strategies that employ anxiolytic substances. In both instances, alterations in baseline levels of anxiety and endocrine function among groups add possible confounding variables to the interpretation of the data. In conclusion, stimulation of alphaz-noradrenergic receptors decreases plasma cortisol in depressed and panic patients, as well as normal volunteers. It remains to be determined whether or not this effect on cortisol is a function of pre- or postsynaptic alpha*-receptors, although preclinical evidence supports the latter mechanism (Ganong 1980). However, as clonidine also reduces plasma MHPG and norepineph~ne in humans (Siever et al. (Price et al. 1986),

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1988:24:3X! 330

1984b3, a presynaptic alpha?-mediated event, the net effect of clonidine on plasma cortisol may involve a composite of pre- and postsynaptic influences. In contrast to the consistent evidence of decreased alphal-noradrenergic responsivity in depression, as revealed by a blunted growth hormone (GH) response to clonidine (Matussek et al. 1980; Checkley et al. 1981; Charney et al. 1982; Siever and Uhde 1984), no evidence for such a defect was revealed in this study of suppression of cortisol, either in depressed patients or panic patients [who also show reduced GH response to clonidine (Charney et al. 1986; Uhde et al. 1986)]. The specificity of the alpha2-receptor’s inhibitory effect on cortisol secretion deserves further study. It remains to be determined whether or not endocrine responses via a putatively subsensitive receptor will unifo~ly show consistent decreased responsivity to agonists (e.g., clonidine) that have both stimufatory (e.g., GH) and inhibitory (e.g.. cortisol) effects. Conversely, the effects of an antagonist (e.g., yohimbine) at the same putatively subsensitive receptor also remain to be elucidated. In the context of previous findings, our results suggest that caution must be used in inte~reting biological responses in terms of receptor sensitivity. Potential baseline differences, as well as differential utility of agonists and antagonists, must be taken into account. The authors wish to thank Harriet Brightman for secretarial assistance. and Drs.

Robert M. Post and

Larry 1.

Siever for their thoughtful comments and suggestions.

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