Psychiatry Research, 3053-6 I Elsevier

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The Relationship of Panic Disorder and Its Treatment Outcome to 24-Hour Urinary MHPG Levels

Michael Garvey, Russell Noyes, Jr., Brian Cook, and Gary Tollefson

Received February 27. 1989; revised version received June 12. 1989; accepted July 26. 1989.

Abstract. Levels of 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (M H PC) were not markedly elevated in a group of 35 panic disorder patients when compared to healthy controls (mean = 2,430 ,ug/day vs. 2, I30 pg/day). There was a weak association between elevated pretreatment levels of M H PG and a positive treatment response to alprazolam or diazepam. Alprazolam and diazepam may differ in their effects on MHPG.

Key Words. Panic disorder, 3-methoxy-4hydroxyphenylglycol, treatment response, alprazolam, diazepam.

Several investigators have suggested that anxiety, stress, and fear are associated with increased norepinephrine (NE) activity. Studies of animals reveal that stress and fear are associated with increased NE activity (Redmond et al., 1976; Gold and Redmond, 1977; Mason and Fibiger, 1979; Redmond, 1979; Redmond and Huang, 1979; Roth et al., 1982). Anxiety-provoking situations in humans who are not psychiatrically ill are also associated with increased NE activity (Rubin et al., 1970; Frankenhauser, 1971; Edmondson et al., 1972; Mathew et al., 1980; Buchsbaum et al., 1981; Davis et al., 1985; Elwood et al., 1986). There is a substantial body of evidence that the NE system is involved in anxiety disorders. A number of investigators have found plasma or urinary NE to be elevated in patients with anxiety disorders (Wyatt et al., 1971; Mathew et al., 1982; Ballenger et al., 1984; Nesse et al., 1985; Dajas et al., 1986), but others have found either no meaningful differences in NE between anxiety patients and controls, or nonsignificant differences (Cameron et al., 1984; Charney et al., 1984; Nesse et al., 1984; Gasic et al., 1985; Schneider et al., 1987; Villacres et al., 1987). There are problems with the use of NE itself as a measure of NE activity. Free NE represents a small fraction of NE production, most of it being metabolized to such compounds as vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (Schildkraut et al., 1978; Blombery et al., 1980; Maas and Leckman, 1983; Kopin, 1984).

Michael Garvey, M.D., is Associate Professor of Psychiatry, University of Iowa College of Medicine, and Chief of Psychiatry at VA Medical Center, Iowa City; Russell Noyes, Jr., M.D., is Professor of Psychiatry, University of Iowa College of Medicine; Brian Cook, D.O., is Assistant Professor of Psychiatry, University of Iowa College of Medicine, and VA Medical Center, Iowa City; and Gary Tollefson. M.D., Ph.D., is Associate Professor of Psychiatry, University of Minnesota, and Chairman, Department of Psychiatry, St. Paul Ramsey Medical Center, St. Paul, MN. (Reprint requests to Dr. M.J. Garvey, Department of Psychiatry, VA Medical Center, Iowa City. IA 52240, USA.)

Ol65-17X1/89/$03.50 0 1989 Elsevier Scientific Publishers Ireland Ltd

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In view of this problem, many recent investigators have elected to measure plasma free MHPG rather than NE. Plasma free MHPG correlates closely with central NE activity (Maas et al., 1976; Karoum et al., 1977; Jimerson et al., 1981). Using different strategies, several research groups have found an association between anxiety and increased plasma free MHPG. For example, a study of panic patients showed plasma free MHPG levels were higher following panic attacks than during days with no panic attacks (Ko et al., 1983). MHPG levels were significantly correlated with ratings of anxiety. Another group confirmed these findings. They reported that panic attacks following a phobic stimulus led to increases in plasma free MHPG (Woods et al., 1987). In a third study, patients with frequent panic attacks demonstrated a greater rise in plasma free MHPG in response to yohimbine, an a,-adrenergic antagonist, than did healthy subjects (Charney et al., 1984). Differences between panic patients and healthy controls were also found in an investigation using clonidine, an a,-receptor agonist. Panic patients had a greater reduction of plasma free MHPG than did controls (Charney and Heninger, 1986). One study of 10 panic patients found infusions of isoproterenol or lactate produced no changes in plasma free MHPG, irrespective of whether the patients panicked or not (Pohl et al., 1987).

While most studies of plasma free MHPG showed an overresponsiveness of NE neurons to certain stimuli, these and other studies have not shown an increase in baseline MHPG levels (Charney et al., 1984; Charney and Heninger, 1986; Pohl et al., 1987; Woods et al., 1987, 1988). One explanation for such findings is simply that in panic disorder the NE neurons are overresponsive to stimuli, but not putting out noticeably increased amounts of NE and its metabolites. Another explanation is that NE output is in fact increased, but not detected by the point-in-time levels generated from plasma measurements of NE metabolites. Metabolites such as MHPG fluctuate during the day (Hollister et al., 1978; Potter et al., 1983). Not only do these substances have circadian rhythms (Markianos and Beckmann, 1976; Sweeney et al., 1980; Wehr et al., 1980; Leckman et al., 1981; DeMet et al., 1982, 1985; Pflug et al., 1982; Leckman and Maas, 1983; Halbreich et al., 1987), but these circadian rhythms may be phase-shifted in psychiatric disorders (Wehr et al., 1980). Several of these problems are obviated by collecting an entire day’s output of urinary MHPG.

In one small study, 24-hour urinary MHPG levels in two panic disorder patients were lower than levels measured in 11 control subjects (Hamlin et al., 1983). Contrary to this study, our own preliminary examinations suggested that urinary MHPG was increased in patients with anxiety disorders. On the basis of these initial results, we hypothesized that patients with panic disorder would have increased levels of 24-hour urinary MHPG.

A second study goal was to explore whether there is any relationship between pretreatment urinary MHPG and treatment response. A third goal of this study was to explore what kinds of changes in urinary MHPG would be produced in panic disorder patients during treatment with benzodiazepines generally and, more specifically, whether there would be differential effects on MHPG by alprazolam or diazepam. While both medications appear to interact with the benzodiazepine receptor, there is circumstantial evidence that suggests alprazolam may have additional actions not shared by diazepam. For example, diazepam does not appear

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to be effective in the treatment of depression (Schatzberg and Cole, 1978) whereas the triazolobenzodiazepine, alprazolam, may be effective, at least in some kinds of depression (Fabre and McLendon, 1980; Feighner et al., 1983; Rush et al., 1985; Fawcett et al., 1987; Rickels et al., 1987; Mooney et al., 1988). Most antidepressants effect changes in the NE system, including reduction in the function of P-receptors (Charney et al., 1981) and changes of plasma and urinary MHPG (Javaid et al., 1983). It appears that diazepam does not reduce P-receptors (Sellinger-Bornette et al., 1980), but alprazolam does (Charney and Heninger, 1985). Single doses of diazepam did not change plasma MHPG levels in healthy subjects (Charney et al., 1983). Chronic diazepam produced a nonsignificant reduction of plasma MHPG (Nutt and Molyneux, 1987). In contrast to these findings with diazepam, 13 of 14 panic disorder patients treated with alprazolam showed a significant reduction of plasma MHPG (Charney and Heninger, 1985). In view of these previous studies, we hypothesized that alprazolam would produce greater reductions in urinary M H PC than would diazepam.

Methods

Consecutive patients between 18 and 65 years of age who met DSM-//I criteria (American Psychiatric Association, 1980) for panic disorder with agoraphobia were selected for the study. Patients were excluded if they met criteria for major depressive disorder (M DD) in the past and the MDD preceded the onset of panic disorder. Patients with MDD at the time of the index interview were also excluded. Patients were excluded if they met criteria for alcoholism during the previous 6 months, or if they ever met criteria for mania or a psychotic disorder. Patients on any psychotropic medication were gradually withdrawn from the medication. Following medication withdrawal, patients were medication free for 7 or more days.

Thirty consecutive patients meeting study criteria were randomly assigned to double-blind treatment with placebo, alprazolam, or diazepam. (Seven additional consecutive patients who participated in a pilot project provided baseline urines for M H PC but did not participate in the treatment trial.) Over a period of 3 weeks, dosages were gradually increased to a maximum of six capsules ~ that is, alprazolam, 6 mg, or diazepam, 60 mg. Lower dosages were accepted if the patient demonstrated a good clinical response or if bothersome side effects precluded repeated attempts to increase the dosage. Patients unable to finish 3 weeks of treatment were replaced. The Hamilton Rating Scale for Anxiety (HRSA) (Hamilton, 1959) was used to measure symptom severity at baseline and weekly thereafter.

Fifty healthy controls were solicited through a hospital information service. Subjects selected were between the ages of I8 and 65, were in good physical health, and had no past history of major psychiatric disorders. Subjects were excluded if they had a history of a major medical problem that led to seeking regular medical attention or routine use of medications (e.g., hypertension, diabetes). Controls were matched to patients by sex and age. The age match was f 5 years for all but three pairs.

All study patients consented to collecting two consecutive 24-hour urines immediately before the beginning of treatment and after 3 weeks of treatment. Patients and controls were given detailed verbal and written instructions about collection procedures. For the 2 days preceding the urine collections and for the 2 collection days, patients followed a VMA- exclusionary diet that was low in monoamines or substances that could stimulate the body’s production of monoamines (Potter et al., 1983). The 24-hour collections were judged complete if total urinary creatinine was > 1,000 mg for males and > 750 mg for females. Incomplete collections were not used in the data analysis. The M H PG assays were performed at the Psychiatric

Chemistry Laboratory, New England Deaconess-Harvard hospital, using a modification of the method of Dekirmenjian and Maas (1970).

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Group comparisons for MHPG levels were made using the Student I test. Nonparametric tests were used when values for a particular variable were not normally distributed. When patients were separated into categories, the x* statistic was used. Because MHPG levels are greater for men than for women (Potter et al., 1983) some analyses were performed separately for males and females.

Results

Thirty-two patients entered the study, and 30 of them completed 3 weeks of treatment. Nineteen patients successfully collected two baseline 24-hour urine samples (a mean was used for data analyses), and nine patients successfully collected one 24-hour urine sample. One patient was unable to collect either sample of urine, and three patients refused. The 28 patients completing one or both urine collections are the subject of this report. The mean age (& SD) for these 28 patients was 40 f 12. Sixty-one percent of the patients were women. The mean (* SD) baseline HRSA score was 19 + 5, and the median score was 20. Nine alprazolam patients collected a baseline MHPG urine and completed 3 weeks of treatment, as did eight diazepam patients. These 17 patients had a mean (t SD) ?$c improvement of their 3-week HRSA score of 55% (+ 22%) and a median Yc improvement of 53%. The mean (+ SD) dose of alprazolam at 3 weeks was 3.6 + 1.5 mg/day, and for diazepam it was 38 + 19 mg/day.

Seven additional panic disorder patients were participants in a pilot project that used the same selection criteria. They collected baseline urines for MHPG but did not participate in the treatment study. Their M H PC levels were included with those of the 28 treatment study patients for baseline comparisons with the healthy control subjects.

Forty-seven of 50 controls successfully completed urine collections. There were 35 matched pairs of controls and patients. The baseline MHPG level (mean + SD) for the panic disorder (PD) patients was 2430 f I I15 pg/day, and for the matched controls it was 2130 & 773 lug/day 0, < 0.08, paired t test).

To assess whether there was an association between baseline MHPG levels and treatment response, a correlation was performed comparing the baseline MHPG to the yc of improvement of the 3-week HRSA. There was a modest Pearson correlation between baseline MHPG and % improvement (r = 0.44, p < 0.08) for the I7 patients treated with alprazolam or diazepam.

Alprazolam produced decreases of urinary MHPG in six of eight patients (75Yc) after 3 weeks of treatment, whereas only three of seven (43%) patients treated with diazepam showed decreases of MHPG. The difference between the baseline and the 3-week MHPG levels in these two treatment groups was significant @ < 0.03,

Mann-Whitney U test). Of the 35 patients who successfully collected a baseline MHPG, 13 had taken a

psychotropic medication within 2 months of the urine collection, and 22 had not. Most patients using medications were either using infrequent PRN dosages or total daily doses of 5 mg of diazepam or its equivalent. Comparisons of baseline MHPG levels between patients who had discontinued medications and those who had not

57

taken any medications did not differ significantly for either females or males. Those patients who had discontinued medications actually had lower MHPG levels than did those patients who were not taking psychotropic medications during the 2 months before treatment began; females ( 1766 f 657 pg/ day vs. 2275 f 845 pg/ day); males (2548 f 1410 pg/day vs. 3019 f 1279 pg/day) (mean + SD). Neither set of comparisons was significant (Student t test, two-tailed).

Discussion

The fact that the difference in MHPG levels between PD patients and controls did not achieve a greater level of statistical significance than p < 0.08 suggests that PD patients, as a group, do not have markedly increased 24-hour urinary MHPG levels. So while the evidence for the involvement of the noradrenergic system in stress reactions in animals and healthy human volunteers is rather compelling (Rubin et al., 1970; Frankenhauser, 1971; Edmondson et al., 1972; Redmond et al., 1976; Gold and Redmond, 1977; Mason and Fibiger, 1979; Redmond, 1979; Redmond and Huang, 1979; Mathew et al., 1980; Buchsbaum et al., 1981; Roth et al., 1982; Davis et al., 1985; Elwood et al., 1986) it appears that many PD patients do not have increased NE turnover.

In this study only PD patients with agoraphobia were studied. Possibly examination of PD patients without agoraphobia would have produced different results. However, previous clinical comparisons of PD patients with and without agoraphobia have suggested that the two groups are fairly similar (Garvey and Tuason, 1984; Noyes et al., 1987).

An important question about baseline MHPG levels in this study is whether the elevations seen in some patients could be due to withdrawal of medications. The study protocol specified patients must be off psychotropic medications 1 week before treatment initiation. Discontinuation of various medications, including benzodia- zepines and tricyclic antidepressants, leads to increased output of MHPG for days or perhaps weeks (Charney et al., 1982; Petursson et al., 1983; Redmond et al., 1984; Grant et al., 1985; Nutt and Molyneux, 1987). Thirteen of our 35 study patients had taken psychotropic medications at some time during the 2 months preceding study participation. There was no significant difference in baseline MHPG values between the 13 patients who had previously used some psychotropic medication and the 22 who had not used any medication. Part of the explanation for not finding any difference in MHPG values between these two patient groups may be that the patients who used medications used them infrequently and at relatively low dosages.

There was a trend for higher levels of pretreatment urinary MHPG to be associated with a positive treatment response in our PD patients @ < 0.08). This trend would appear to be of more research than clinical interest.

Six of eight patients (75%) taking alprazolam had decreases of MHPG, whereas only three of seven patients (43%) taking diazepam had decreases of MHPG (p < 0.03). These results are generally in the same direction as those of previous studies for alprazolam but not for diazepam. Other investigators have reported decreases of MHPG in patients taking alprazolam (Javaid et al., 1983). The two

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reports of diazepam’s effect on MHPG suggest little change (Charney et al., 1983; Nutt and Molyneux, 1987). These findings certainly do not prove alprazolam and diazepam work differently in PD patients, but the findings do leave this possibility open and invite further research in this area.

In summary, a group of PD patients did not demonstrate markedly increased levels of 24-hour urinary MHPG as previously found in stress reactions of animals and healthy humans. There was a trend for PD patients with increased baseline MHPG levels to have a better treatment response to alprazolam or diazepam. Finally, the study results suggest the possibility that alprazolam and diazepam might affect NE turnover differently.

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