Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and growth hormone responses to yohimbine in panic disorder patients and normal controls

Psychoneuroendocrinology,VoL 15, No. 3, pp. 217-224, 1990

0306-4530/90 $3.00 + 0.00 l~'g~'non Press pk

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PLASMA 3-METHOXY-4-HYDROXYPHENYLETHYLENE GLYCOL (MHPG) AND GROWTH HORMONE RESPONSES TO YOHIMBINE IN PANIC DISORDER PATIENTS AND NORMAL CONTROLS GEORGE N. M. GURGtaS and THOMASW. UHDE Section on Anxiety and Affective Disorders, Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, U.S.A. (ReceWed 6 August 1989; Infvml form 29 Mao 1990)

SUMMARY Eleven patients with a DSM-III diagnosis of panic disorder and seven normal controls received yohimbine (20 mg) or placebo orally in a double-blind paradigm on two separate days. Compared to normal control subjects, the panic disorder patients had similar behavioral responses to placebo but a greater anxiogenic response to yohimbine. Compared to placebo, yohimbine produced a significant increase in plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHI~) levels (/7< 0.02), with a trend toward greater MHPG rises in the panic disorder patients compared to the normal controls. In the patients, but not in the controls, there was a significant positive correlation between yohimbine-induced peak changes in MHPG and increased ratings of panic anxiety. Yohimbine had no effect on plasma growth hormone (GH) levels in either patients or controls. These results are discussed within the context of the noradrenergic theory of panic disorder.

INTRODUCTION INCREASEDnoradrenergic function has been hypothesized in the pathophysiology of anxiety states. The exploration of this hypothesis has resulted in an extensive body of data that has increased our understanding of various neuronal mechanisms underlying anxiety disorders (Redmond, 1987). The nucleus locus coeruleus (LC) is the largest collection of noradrenergic neurons in the brain and was the neuroanatomical focus of Redmond et al. (1976a; 1976b) in their investigation of noradrenergic regulation of anxiety states. In those studies, electrical stimulation of the LC produced fearful behaviors in stump-tailed monkeys, whereas LC destruction reduced fearful responses to naturally threatening stimuli. Those investigators also demonstrated that activation of the LC by either yo.himbine or piperoxan, both a2-adrenergic antagonists, resulted in parallel increases in LC firing, fearful behaviors, and brain MHPG levels. These aforementioned effects were blunted or reversed by clonidine, an a2-adrenergic agonist (Redmond, 1979). In humans, yohimbine induces anxiety (Holmberg & Gershon, 1961; Holmberg et al., 1962) and autonomic activation as reflected by increases in heart rate and blood pressure. Yohimbine also increases plasma MHPG, the principal metabolite of norepinephrine (Chamey et al., 1982; Uhde et al., 1984b). Moreover, in many (Ko et al., 1983; Ballenger et al., 1984; Uhde et al., 1984b) but not all (Woods et al., 1987) studies, plasma and CSF MHPG levels have been shown to correlate Correspondence to be addressed to: Dr. Thomas W. Uhde, Section on Anxiety and Affective Disorders, Biological Psychiatry Branch, National Institute of Mental Health, 9000 Rockville Pike, Building 10, Room 3S239, Bethesda MD 20892, USA. 217

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with state anxiety. C h a m e y et al. (1984) found that yohimbine produced significantly greater increases in self-rated measures of anxiety and autonomic responses (e.g. palpitation, hot and cold flashes, tremors, piloerection, systolic blood pressure) in panic disorder patients compared to normal controls. Yohimbine-induced increases in MHPG, however, were found to be significantly higher only in patients with a frequency o f panic attacks greater than 2.5 attacks per week. These findings suggest that noradrenergic overactivity may play a role in panic disorder; but they are far from conclusive. Another strategy in the investigation of panic disorder has involved the use of clonidine, an ~ agonist. By measuring the GH response to clonidine, several groups have attempted to investigate post-synaptic cz2-adrenoreceptor sensitivity at the hypothalamic level and have found that the GH response is blunted in depressed patients (Siever et al., 1982; Siever & Uhde, 1984), and in patients with panic (Charney & Heninger, 1986; Uhde et al., 1986) and generalized anxiety disorders (Curtis et al., 1989). The data are less consistent for other anxiety disorders. For example, obsessive-compulsive disorder was first reported to have a blunted GH response to clonidine (Siever et al., 1983), but two other studies have been unable to replicate this finding (Curtis et al., 1989; Liebowitz, personal communication). Tancer and Uhde (1989) initially found that social phobic patients have a normal G H response to clonidine, but a subsequent expanded sample of social phobics was found to have a blunted GH response to clonidine (unpublished data). Of interest, no study has investigated the effects o f yohimbine on GH secretion in panic disorder patients. One might predict either an elevated or blunted GH response to yohimbine. For example, since clonidine, an o¢2-adrenergic agonist, stimulates G H secretion in humans (for review, see Uhde et al., 1984a), one might predict that yohimbine, an o~-adrenergic antagonist, would block GH secretion. In contrast, under circumstances of a maximally activated noradrenergic system (i.e. down-regulation of presynaptic receptors and up-regulation of post-synaptic receptors) y o h i m b i n e m i g h t potentiate G H secretion. The p u r p o s e o f this investigation was to re-examine the action of yohimbine on MHPG and to present new data regarding the effects of yohimbine on GH levels in panic disorder patients and normal control subjects. SUBJECTS AND METHODS Eleven patients (seven women and four men) who met DSM-III criteria for agoraphobia with panic attacks and seven normal controls (six women and one man) gave verbal and written informed consent to participate in the study. Pre-menopausal female subjects were studied during the first 10 days of their menstrual cycles; one woman in the patient group was post-menopausal. The normal controls had no current DSM-III Axis I diagnoses. All subjects received complete physical and neurological examinations and laboratory tests; results were normal, and there was no evidence of concurrent medical illnesses. All subjects were drug-free for a minimum of two weeks prior to participation in the study. The study was conducted on the 3-West Clinical Research Unit or in the Ambulatory Care Research Facility (ACRF) at the National Institute of Mental Health. Except for clear fluids, all subjects were instructed to maintain a fasting diet beginning at 0001h of the day of the study. All subjects reported to a standard research-procedure room at approximately 08t5h, whereupon an intravenous line was inserted and kept open with a slow-drip normal saline solution. Adaptation to the research room, while the subject was maintained at bedrest, was required for a minimum of 1 hr after the insertion of the intravenous line. Under double-blind conditions yohimbine (20 rag) or placebo or both drugs were orally administered to subjects on one or two separate days. Rating scales to assess the behavioral effects of yohimbine and placebo were administered at -15 and 0 min (baseline ratings) and at hourly intervals for 5 hr after drug :administration. In this report, we present only the subjects' peak change in subjective ratings (peak minus mean baseline) on two 100-ram analog scales: "anxiety" and "panicky" feelings. A research nurse, who was blinded to the drug code, also evaluated the subjects for the development of panic attacks. To be designated as a panic attack the episode of anxiety had to meet DSM-III criteria for a panic attack and achieve maximum intensity within 1 min after an abrupt onset. An additional requirement for

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the patients was that their panic episode be identified as being "almost identical" or "identical" to their typical natural panic attacks. These criteria are quite rigid compared to the guidelines employed by other research teams. Blood samples were drawn at -15 and 0 rain (baseline measures) and at hourly intervals for 5 hr after drug administration. Blood samples were collected, placed on ice, and plasma was separated within 1 hr in a refrigerated centrifuge and stored at -70* C until assayed for GH with a double-antibody radioimmunoassay (having a sensitivity of 0.7 ng/ml and inter-assay and intra-assay coefficients of variation of 6.9% and 9.6%, respectively). Plasma MI-IPGlevels were determined by high performance liquid chromatography with electrochemical detection (HPLC-EC) and a modification of the method of by Scheinin et al. (1983). MHPG levels had a coefficient of variation of 7.5% and 8.8% for intra- and interassay precision, respectively. Comparison between patients and normal controls at baseline was done with a two-tailed t-tests for GH, MHPG, and behavioral measures on both the placebo and yohimbine days. Dichotomous behavioral and demographic data were analyzed by Z2 or Fisher's exact tests. A two-way ANOVA was used to examine group differences, time effects and group x time interactions in post-drug plasma GH and MHPG levels and behavioral ratings for both the placebo and yohimbine days. In separate analyses, baseline-corrected two-way ANOVA was performed in those patients (N=6) and normal controls (N=6) who had received both placebo and yohimbine to compare between the placebo and active drug conditions. When the raw data showed a wide variance, particularly GH, log-transformed values were used in the statistical analysis in order to normalize the data. RESULTS

Demographic Measures Six patients and six normal controls received placebo, while received 20 mg yohimbine. The mean age for the patients was 28.8+6.6 years for the normal controls (t=0.16, dr= 17, p = N S ) . difference in sex distribution between patients and normal controls

11 patients and seven controls 35.7+11.2 years compared to There also was no significant (~2= 1.07, df= 1, p = NS).

Behavioral Ratings As expected, the patients (PD) had significantly higher ratings of "anxiety" at baseline than the normals (N¢) on both the placebo (PD: 47.0 + 26.1 vS. NC: 4.3 + 5.4; t = -3.92, dr= 10, p < 0.01) and the yohimbine (PD: 42.8+27.5 vs. NC: 7.3+8.0; t=-4.03, dr--16, p<0.002) days. Likewise, the patients had significantly higher scores of "panicky" emotions at baseline on both the placebo (PD: 35.8+30.9 vs. NC: 5.0+6.1; t=-2.39, dr= 10, p<0.058) and the yohimbine (PD: 26.6+21.4 vs. NC: 9.4 + 8.6; t = -2.36, dr= 16, p < 0.03) days. There were no significant between group differences in peak response (peak minus baseline) to placebo on either the "anxiety" or "panicky" rating scales. Neither the patients nor the normal controls experienced panic attacks in response to placebo. In response to yohimbine, none of the normal control subjects had panic attacks. In contrast, six of 11 (55%) of the patients had panic attacks after yohimbine. This differential response between panic disorder patients and normal controls was significant at the .04 probability level by Fisher's exact test (two-tailed). The panic disorder patients also had a significantly greater peak change (A) in ratings of "anxiety" (PD: A 13.2+26.9 vs. NO: A-3.1 +9.5; t=-2.34, N = 18, p<0.03) and "panicky" (PO" A 13.2+26.9 vs. NC: A-3.1 +9.5; t=-2.34, N = 18, p < 0 . 0 3 ) emotions after yohimbine compared to the normal control subjects. MHPG Measures Comparison of baseline data showed no between-group differences on either the placebo (PD: 15.8+4.3 pmol/ml vs. NC: 21.2+8.5 pmol/ml; t= 1.38, d f - - l l , p--NS), or the yohimbine (PO: 17.3+4.7 pmol/ml vs. NO: 21.8+8.1 pmol/ml; t= 1.50, df=17, p - - N S ) days. On the placebo day, there was no main group difference in MHPG (F= 3.07, df= 1,10, p--NS), no significant change in MHPG values over time (F=0.67, df= 1,10, p = N S ) , and not a group × time interaction (F=0.02, df= 1,10, p = NS).

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In contrast, yohimbine induced a significant change in MHPG (F=3.94, df= 1,16, p=0.02) in both groups as reflected by an increase from a mean baseline value of 21.8+8.1 pmol/ml to 24.6+ 11.3 pmol/ml in the normal controls and an increase from 17.3+4.8 pmol/ml to 23.9_+6.9 pmol/ml in the panic disorder patients 2 hr after drug administration. Although there was no group x time interaction, the data in Fig. 1 indicate a clear trend toward greater MHPG increases in the panic disorder patients compared to the normal controls. Moreover, within-group comparison of the subset of panic disorder patients and normal controls who received both yohimbine and placebo indicates that the yohimbine-induced increase in plasma MHPG was significantly greater than that for placebo for the patients (F=6.76, df= 1,10, p < 0.02), whereas there was no significant yohimbine vs. placebo effect for the controls (F=0.43, df= 1,10, p =NS). Despite the apparent trend toward greater yohimbine-induced increments in MHPG in the patients as a group, there was no difference in peak MHPG between the small subgroup of patients (N = 6) who panicked after yohimbine compared to the nonpanicking patients (N =5).

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TIME (hours) FIG. 1: Change (pmol/ml) in p l a s m a MHPG levels after placebo and yohlmbine in panic disorder patients and controls. Values are means_+ S EM.

Plasma Growth Hormone Measures Fifty percent of the patients but none of the normal controls had baseline GH levels greater than 3 ng/ml on the placebo day, whereas 27.3% and 28.6% of the patients and controls, respectively, had elevated (>3 ng/ml) values at baseline on the yohimbine day. Consistent with these data, analysis of log-transformed values indicated that patients had significantly higher baseline GH levels [5.68+6.8 (SD) ng/ml] than the controls [0.67+0.4 (SD) ng/ml] (t=2.69, df= 11, p<0.03) on the placebo day but similar values [3.17+4.35 (SD) ng/ml] as the controls [2.52+ 3.43 (SD) ng/ml] (t=-0.325, df= 16, p= hiS) on the yohimbine test day. There was no difference in GH baselines between the panicking and the nonpanicking patients on either test day. On the placebo day, a two-way ANOVA showed no statistically significant group difference (F= 1.81, df= 1,10, p = NS), no time effect (F=0.48, df= 1,10, p = NS), and no group × time interaction (F= 1.57, df= 1,10, p = NS). This remained true for both baseline-corrected and log-transformed GH values.

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On the yohimbine day as well, there was no significant group difference (F=0.06, dr=l,15, p=NS), no time effect (F=0.94, dr= 1,15, p =NS), and no group x time interaction (F=0.43, dr= 1,15, p = NS). These findings also remained true for log-transformed GH values. For the subgroup of subjects who received both yohimbine and placebo (six patients and six controls), a baseline-corrected two-way ANOVA showed no difference in GH between the placebo and the yohimbine days (Fig. 2). There was no difference in GH levels at any time point or in peak GH response after either drug (i.e. yohimbine or placebo) for the panicking vs. the nonpanicking patients.

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TIME (hours~ lhG. 2: Change (ng/ml) in p l a s m a GH levels after placebo a n d yohimbine in panic disorder patients and controls. Values are m e a n s + SEM.

Relationship between Behavioral and Biological Indices For both the patients and the normal control subjects, there were no significant correlations between changes in ratings of "anxiety" or "panicky" emotions vs. baseline, peak, or peak changes in levels of MHPG or GH after placebo. After yohimbine, there also were no significant correlations in normal controls between changes in "anxiety" or "panicky" emotions vs. peak changes in either MHPG or GH. There also were no significant correlations between changes in these behavioral measures and changes in GH after yohimbine in the patient group. In contrast, the yohimbine-induced peak changes in MHPG and "panicky" feelings were significantly correlated in the panic disorder patients (p = 0.62, df= 11, p < 0.04), with a similar trend apparent in relation to changes in "anxiety" (p = 0.54, df= 1I, p<0.08). DISCUS SION

The current investigation demonstrated that yohimbine can induce significant increases in plasma MHPG levels. Although the two-way ANOVA failed to achieve a significant group x time interaction, inspection of the data (Fig. 1) plus the analysis of our placebo-controlled data also suggest a strong trend toward greater yohimbine-induced increases in MHPG in patients compared to controls. Given the assay parameters and mean and standard deviation of MHPG levels in our

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study, power analysis indicates that only approximately 40 subjects (20 subjects per group) would have been required to detect significant between-group differences in the MHPG response to yohimbine. Moreover, changes in MHPG after yohimbine were associated with increased ratings of anxiety in the patients. Therefore, our MHPG findings, while not impressive, are nonetheless consistent with the noradrenergic hypothesis of panic disorder (Redmond, 1979; Uhde et al., 1984b). Our results also are in partial agreement with Charney et al. (1984), who found that yohimbine did produce a greater increase in plasma MHPG levels, but only in those patients who experienced panic attacks at a frequency greater than 2.5 panic attacks per week. Taken together, these observations suggest that the degree of yohimbine-induced increases in plasma MHPG may be related to several factors including, but not limited to, severity of anxious symptoms or rate of spontaneous panic attacks (Chamey et al., 1984), baseline levels of MHPG, laboratory setting (Uhde & Tancer, 1988), expectancy bias (Magraff et al., 1986), and perception of control (Sanderson et al., 1989). In fact, baseline levels of MHPG in our study were nonsignificantly lower in the panic disorder patients vs. the normal controls prior to both placebo and yohimbine administration. These slightly lower levels of plasma MHPG, consistent with a single report of lower resting urinary MHPG (Hamlin et al., 1983), might explain the trend toward greater increases in MHPG after yohimbine in the panic disorder patients. If so, these combined observations might indicate exaggerated responses (i.e. increased MHPG levels) under some circumstances (e.g. yohimbine challenge); however, under basal conditions the lower levels of MHPG might reflect relative depletion or decreased turnover of norepinephrine stores due to prior periods of prolonged noradrenergic overactivity (e.g. "spontaneous" panic attacks and chronic anxiety). Current studies regarding the noradrenergic control of GH secretion suggest an t~2-adrenoreceptor stimulatory effect and a ~-adrenoreceptor inhibitory effect. Many groups have used the GH response to clonidine as an index of post-synaptic hypothalamic ct2-adrenoreceptor function. While this strategy is not without controversy (for reviews, see Uhde et al., 1984b, and Uhde et al., in press), the situation with yohimbine is considerably more complex. Yohimbine's net effect on GH will be the result of several factors: the degree of blockade of pre-synaptic cx2-adrenoreceptors, resulting in an increase in synaptic norepinephrine; the degree of blockade of postsynaptic cx2-receptors, resulting in a relative decrease in post-synaptic ~2-receptor function; yohimbine's effect on pituitary D2-autoreceptors as an antagonist (Gold et al., 1979; Meltzer et al., 1983); and the timing of administration of yohimbine and whether or not it coincides with spontaneous GH secretory bursts. In our study, a number of patients had baseline GH levels that were higher than 3 ng/ml. These baseline elevations could have been due to natural secretory bursts or, more likely, represented a stress response to the procedure (Sevalahti et al., 1976; Kurokawa et al., 1977; Nesse et al., 1984). Concerning the GH response to yohimbine, there was no difference between patients and controls, nor was there a main drug effect. This remained true for a within-group analysis comparing the placebo and yohimbine days. Our negative findings are consistent with those of Goldberg et al. (1986) and Tatar and Vigas (1984) who found that yohimbine had no effect on plasma GH levels in humans and suggest that the blockade of hypothalamic ct2-receptors with yohimbine does not have an effect on basal (i.e. nonsecretory) levels of GH. In contrast to basal conditions, however, yohimbine has been shown to suppress nocturnal surges of GH in rats (Amold& Fenstrom, 1980), and phentolamine blocks the stimulatory effects of insulin-induced hypoglycemia (Blackard & Heidingsfelder, 1968) in humans. Sleep and hypoglycemia are not quiescent (i.e. basal) conditions for GH; thus, while ct2-receptor antagonism by yohimbine might not have an effect on GH under basal conditions, one might be able to demonstrate an inhibitory effect in humans during hypoglycemia or other conditions of sympathetic activation. This concept is supported by the finding that idazoxan, a specific ct2-receptor antagonist, had no effect on

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growth releasing factor-induced G H secretion under basal conditions, whereas it augmented exercise-induced increases in p l a s m a catecholamines and G H levels (Struthers et al., 1986). In conclusion, our findings indicate that y o h i m b i n e is not an ideal p h a r m a c o l o g i c probe to study noradrenergic regulation o f G H secretion in panic disorder patients under quiescent or basal conditions. Despite these apparent limitations, it would be of interest to examine the effects of yohimbine on stress-induced (e.g. h y p o g l y c e m i a , exercise or phobic exposure) increases in GH secretion in such patients. In contrast to our G H findings, the trend t o w a r d a greater M H P G response, c o m b i n e d with the greater anxiogenic and panicogenic response, to yohimbine lends some additional support to the hypothesis of dysregulated noradrenergic systems in panic disorder. Acknowledgements: The authors gratefully acknowledge Brenda Bessette for help with the statistical analysis and Theresa DiBari and Janis Thurman for preparation of the manuscript. The authors also recognize the ongoing support of Robert M. Post, M.D.

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