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A placebo-controlled crossover study of oral clonidine in acute anorexia nervosa
P.pv~hirr/r.v
Rrstwrc~h.
20, 249-260
249
Elsevier
A Placebo-Controlled in Acute Anorexia Regina
C. Casper,
Crossover Nervosa
I?. Francis
Schlemmer,
Study
of Oral Clonidine
Jr., and Javaid
I. Javaid
Received February 14, 1986; revised version received June 27. 1986; accepted August 27, 1986. Abstract. The a,-adrenergic agonist clonidine has been reported to increase feeding in several species. This study evaluated the effects of clonidine (500-700 pug/day), administered per OS, to four treatment-resistant anorexia nervosa patients in a long-term placebo-controlled crossover trial. All patients increased their body weight significantly. Clonidine administration, however, did not influence the rate of weight gain, nor did clonidine affect hunger or satiety sensations. Similarly, 24-hour urinary 3-methoxy-4-hydroxyphenylglycol levels and levels of anxiety and depression were unchanged by clonidine. By contrast, clonidine showed significant hemodynamic effects; clonidine lowered systolic and diastolic blood pressure, reduced pulse rate, and produced sedation. Discontinuation of clonidine was associated with a small but significant weight ioss compared to a small weight increase during the initiation of clonidine treatment. The results suggest that clonidine may not be indicated in the treatment of anorexia nervosa. Key Words.
Anorexia
nervosa,
clonidine,
weight
gain.
Central noradrenergic systems have long been implicated in the regulation of feeding and eating (Grossman, 1973, and drugs that affect noradrenergic receptors have been used to elucidate the mechanisms controlling hunger and satiety (Leibowitz, 1978, 1984). Clonidine, a preferential a,-adrenergic presynaptic and probably postsynaptic receptor agonist (Svensson et al., 1975) is among the compounds that have been shown to influence feeding behavior in several animal species. First synthesized as a nasal decongestant, but then found to be effective as an antihypertensive drug (Seedat et al., 1970; Goldstein et al., 1985), clonidine has also been reported to stimulate eating in the rat (Broekkamp and Van Rossum, 1972; Atkinson et al., 1978; Mauron et al., 1980), in the dog (Le Douarec et al., 1972), in the rabbit (Katz et al., 1985), and in primates (Schlemmer et al., 1979, 1981). In primates, the effects on feeding were observed fortuitously during studies evaluating adrenergic agonist and antagonist drugs on solitary and social behavior of macaque monkeys. Prolonged repeated clonidine administration for I week in increasing
Regina C. Casper, M.D., is Director of the Eating Disorders Research & Treatment Program, Michael Reese Hospital, and Associate Professor of Psychiatry. Department of Psychiatry, The University of Chicago. R. Francis Schlemmer, Ph.D., is an Assistant Professor of Pharmacology, Department of Pharmacological Dynamics, College of Pharmacy, University of Illinois at Chicago. Javaid I. Javaid. Ph.D., is Associate Director of Research at the Illinois State Psychiatric Institute. (Reprint requests to Dr. R.C. Casper, Dept. of Psychiatry, Michael Reese Hospital and Medical Center. Lake Shore Dr. at 3lst St., Chicago, IL 60616, USA.) 016%1781/87/$03.50
@ 1987 Elsevier Science Publishers B.V
250 doses (0.01-0.1 mg/ kg) was associated with a significant increase in time spent eating, as well as time spent in other food-related categories such as “handling food” and an increase in high-pitched vocalizations, probably “food cries.” In a subsequent placebo-controlled study, repeated clonidine treatment resulted in a significant increase in body weight (from 5%) to 16%) in I week (Schlemmer et al., 1979). Administration of yohimbine, an q-receptor antagonist, blocked the clonidineinduced eating whereas prazosin, an c-r,-receptor antagonist, had no effect. These results suggest that the hyperphagia induced by clonidine is mediated through crl_adrenergic receptors (Schlemmer et al., 1981; Katz et al., 1985). Anorexia nervosa is a disorder in which resumption of eating is crucial for recovery. It is well established that anorexia nervosa patients are not anorexic (Garfinkel, 1974); i.e., they experience hunger, but are prevented from eating by an intense fear of losing control over eating and of becoming overweight. Studies on the action of clonidine upon locus ceruleus activity in monkeys (Redmond et al., 1977; Redmond and Huang, 1979) and in depressed patients (Svensson et al., 1975, 1978) have suggested anxiolytic properties. Pharmacologically this combination, a reduction in anxiety and an enhanced urge to eat, would make clonidine ideally suited for treating anorexia nervosa, especially the chronic condition, where weight gain is difficult to achieve. This reasoning led us to design a placebo-controlled study of clonidine in anorexia nervosa. The study was devised as a pilot study. because little was known about the hypotensive effects of clonidine in a population already hypotensive as a result of starvation. Since anorexia nervosa patients tend to regain weight without drug treatment in most specialized treatment programs (Casper et al., 1977), only patients who failed to improve during one or several previous hospitalizations elsewhere were chosen for inclusion in the study. Studies that have measured parameters of noradrenergic function in anorexia nervosa (Halmi et al., 1978; Gross et al., 1979; Abraham et al., 1981: Riederer et al., 1982; Luck et al.. 1983; Kaye et al., 1984) and in normals (Landsberg and Young, 1978) indicate that starvation itself can influence noradrenergic functional activity through reducing norepinephrine turnover. These reports suggest that the action of clonidine might differ at different stages of starvation. Therefore, clonidine was administered alternating with placebo in a crossover protocol.
Methods Subjects were four consecutively admitted female patients. who had failed to improve during hospitaliration elsewhere and who qualified for a diagnosis of anorexia nervosa according to the criteria of Feighner et al. (1972). All patients were nonsmokers and were drug free at the time of the study. One patient. the only patient to have a history of bulimic episodes. had previously received antidepressant medtcation that had been discontinued f.or more than a month before hospitalization. Patients ranged in age from 19 to 28 years, with a mean (+ SD) duration of illness of 5.8 k 2.3 years. Patients were hospitalired on a clinical research ward and randomly assigned by the pharmacist to either drug or placebo I week following admission. Each trial consisted of 4 weeks on placebo alternating with 4 weeks on clonidine. Clonidine was administered orally in three divided doses and gradually increased from a I50 gg: day to a maximum dose between 500 and 700 pg. day. The maximum dose reached was determined by individual tolerance for the drug’s hypotcn\t\,c effect. Patients were kept for 2
251 weeks at the maximum dose and then gradually tapered off to I week before starting placebo again. Blood pressure and pulse, supine and standing, were recorded twice daily, and the electrocardiogram was monitored weekly. Patients were admitted with the understanding that they would try to regain their normal weight. They were treated in psychotherapy four times per week and, when possible, family sessions were arranged each week. A liquid diet (Meritene) was offered in six divided meals. The caloric amount was gradually increased from 1800 calories to a maximum intake of over 3000 calories. After 2 weeks, patients had the option of switching to regular food. All patients were weighed daily and steadily gained weight. The drug protocol was discontinued once patients had reached a normal weight for age and height as calculated by the Metropolitan Life Insurance Tables, 1957. Two patients regained normal weight before completion of the third clonidine trial. Thus, altogether, four patients had three placebo and two drug trials. Two patients participated in a third clonidine trial. Three of the four pattents regained normal weight during the protocol. The fourth patient was still IV%, underweight at the end of the third drug trial. Body weights were obtained each morning in the fasting state with patients dressed in a gown after voiding. Twenty-four hour urine samples were collected twice weekly for measurement of 3-methoxy-4-hydroxyphenylglycol (M H PG) excretion. IJrincs wcrc refrigerated upon collection and preserved in bottles containing 0.5 mg/ ml metabisulfatc. Upon completion, urine volumes were measured and MHPG levels were detcrmincd according to the method of Dekirmenjian and Maas (1970). Behavioral ratings consisted of a IO-cm visual analog scale for depression ranging Irom “not at all depressed” to “very depressed.” For evaluating anxiety, patients completed the ‘l‘aylor Manifest Anxiety Scale (Taylor, 1953). This scale lists a considerable number of accessory, especially somatic, symptoms, which, if they occur in anorexia nervosa, are often starvation rather than anxiety related. Therefore, for evaluating anxiety level, items unrelated to physical symptoms
were selected.
The anxiety
48. and 50. Monello and Mayer’s (1967) before
dinner
feelings during
ordinary
“strong”
twice
weekly.
The
riding
Patients
completed
most
the
psychotherapy,
satiety
was given to patients
Patients
on 4point
rating
or sensation.
were also instructed
Patient
Parkinson-White
welt: asked with
scales
Each
to keep a diary
30 min
to describe thoughts
ranging
rating
from
their
of lood
“nom”
was completed
for recording
Analysis.
the effects
of clonidine.
(trial
completely drug
separately
postural
during
The
for trials
combination).
two fixed
to
by each
any unusual
Post
mixed
model
factors
ward
trials.
analysis
did not necessitate
drug
Yince
minute
she remained
of variance
for
subject the
indicated,
a Wolfclinically
was used to evaluate
lactor
otherwise
with
of the protocol.
as a random (each
on and
were treatment
condition
noticed
activities
in the design
hoc comparisons tinless
in
01 42 beats/
discontinuation
an unpleasant
especially
The side effects
bradycardia
were treated
and drug
were also performed.
Participation
each of two clonidine
A three-factor
clonidinc
to lightheadedness,
by clonidinc. severe
did not recommend
I, 2, or 3). Subjects
crossed
related
movements.
was unaffected
syndrome
even though all considered were
#3 developed
the intermst
Statistical and trial
complaints and
however,
asymptomatic,
f
Questionnaire
respectively.
urge to eat, and preoccupation
of a feeling
the protocol
frequent
elevators
discontinuation.
and
and during
here are based on items 2. 3, 5, 14,
or sensations.
All patients drug.
dinner,
mood,
to assess the intensity
patient effects
sensations,
hunger
reported
Hunger and Satiety
and 30 min following
and physical
assessments
(drug
in the design.
was measured
effect
of
medication
all values
vs. placebo) Subjects
under
on each
are expressed
were
each trial trial
as mean
SD.
Results Body Weight. Fig. consecutive
I presents
placebo-clonidine
on the top panel the changes trials. Each point represents
in kg body weight for the the irrtegrated mean 01
252
Fig. 1. Changes in body weight (kg), pulse, (bpm), and blood pressure (mmHg) during consecutive placebo-clonidine crossover trials in 4 anorexia nervosa patients
106
SYBTOLIC
BLOOD PRESSURE
TOLIC BLOOD PRE88URE
PLACESO-CLONIDINE CROSSOVER Note. Values are shown for mean body weights (kg) and satiety ratings (open quadrangles) (upperpanel) and 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) &g/24 hr +ZSEM) (lowerpanel) for each 6-day transition crossover from placebo to clonidine or clonidine to placebo Discontinuation of clonidine resulted In weight ioss as compared to the weight changes dunng im!iatlon of clonidlne admmistration (p < 0 03)
253
Fig. 2. Mean body weights, satiety ratings, and 24-hour urinary MHPG concentrations in 4 anorexia nervosa patients .2a
a ClOllidine 0-e Placebo
BODY WEIGHT
2.6
6 g
.2A
8
-2.2
F 2
-2.0
7 s
-1.3 -1.6 lat PEFnOC PLACEBO
3
181PERIOD CLONIDINE
3
2nd CLONIDINE
2nd PLACEBO PEmm
3
PERIOD
3
g F
3rd PLACEBO PERIOD
Values represent means f SEM; each time point represents the summarized values for 4 weeks. Doses of clonidine increased from 0.2 to 0.7 mgid.
daily recorded body weights for each trial period as well as the mean value for the four patients. Average body weight increased from 35.0 + 5.24 kg on admission to 45.7 + 5.65 kg (p < 0.001) over the entire 5- to 6-month study period. The mean changes in body weight during clonidine administration did not significantly differ from mean weight changes during placebo administration, i.e., patients gained similar amounts of weight during clonidine as during placebo periods. When we inspected the averaged weight gain curves, we noticed a weight drop during each transition from clonidine to placebo (last 3 days on clonidine and first 3 days on placebo). Comparisons of the mean body weight changes during the clonidine/placebo transitions (see Fig. 2) and the placebo/clonidine transitions (last 3 days on placebo and first 3 days on clonidine) showed significant differences, a fall in weight (-0. I6 + 0.2 kg) during clonidine/ placebo transition as opposed to a slight weight gain (0.58 f 0.19 kg; t = 2.61, p < 0.03) during the placebo/clonidine transition.
Hemodynamic Effects. During each trial of clonidine administration, systolic (F = 84.2, p < 0.0001) and diastolic (F = 67.6, p < 0.0001) blood pressures were significantly reduced relative to placebo administration (Fig. I). In contrast, during each placebo period, systolic and diastolic blood pressures significantly rose again, from a mean of 90.8 +- 8.7/64.4 + 9.4 mmHg at the first placebo trial, to
254
99.0 f
9.9/69.6
f
Ifr I I .2 mmHg blood
X.6 mmHgduring
(11 < 0.01)
pressure
was
the second placebo
at the last placebo
significantly
Pulse (F=
rate
(see
Fig.
4.X. /I < 0.01)
during
each
clonidine
of the
two
period
to a mean
significant
overall
indicating
clonidine
trials.
0.001)
and
in body
I
12.2/71.
and diastolic
weight
treatment
the pulse The
(r =
reduction
I X.2 beats/
trial
in pulse
0.91,
interaction
rate
significant.
minute
15.6 beats/minute
correlated
X
rate was differentially
to be statistically
a pulse of 76.9 f
pulse rate of X4.X f (~7 <
gain
significant
that
was not found
in pulse rate from
with
and to 100.7 +
rise in systolic
respectively).
showed
administration
increase was
I)
effects,
The
correlated
17 < 0.00 I, and r = 0.77, p < 0.004,
trial,
trial.
with
each
However,
from
the
the first placebo
at the third
positively
affected
during
placebo
weight
gain
period
(r =
0.62,
/’ < 0.00 I ).
Effects
on Sedation,
sedation
(F=
clonidine
trial.
during
days
placebo
Patients
when
sensations,
urge score
meals,
to eat, for
showed
indicating
considerable
reported
2) were
(2.2
meals
(satiety)
(2.X +
I .O).
Effects
t (2.7
f
over
(I, <
0.01)
were
observed,
were
noted
mean
3.2
IL
levels.
I. I) during
patients
MHPG.
2.3,
both
0.05).
Clonidine
that there
to patient
(F=
were significant
on
levels
14.81;
@ < 0.01)
following
administration
scale
period
significantly
to 4.61
-t 2.5 I
clonidine-related in the level slightly
not
effects
of depression
increased
consistently
0.004).
drug
effects
X
from trials
alter
trial
(F
on anxiety
in how clonidinc
nor was
and clonidine
placebo-clonidine
14.59, p < 0.001)
O.OOl),
hunger (hunger)
placebo
analog
Gastric
p <
meals
a
tenseness
0.01).
neither
placebo
overall did
differences
sensation, trial
clonidine
the
sequential 17 <
during
as gastric
to eat to be stronger
differences
administration 6.64.
=
each
to nap
and
(r, <
Overall,
the first
during
=
(F
No significant
Anxiety
(F
gastric
trial
and during
reported
ways.
pain,
scale) during urge
interindividual
patient-drug
and patient
for
period.
scale,
mentioned
LJrge to eat before
placebo
levels
not several
the first clonidine
patients.
z!z 2.96 during
placebo
on a 4-point
affected
a to
anxiety =
20.36,
were noted, anxiety
in
across time. Average
24-hour
the three
mg/24
hr, respectively).
309.6
a trend
(F = 9.74, p < 0.001). +
during f
6.73
the third
Significant
indicating
from
but significant
1.9 (11 <
17 < 0.05),
was
Depression
time
during
between
compelled
Only
clonidine
increased
scale during
felt
aches,
interactions
by clonidine.
There
eating.
during
second
(2. I + 0.X on a 4-point
0.6).
on Mood.
decreased
3.6
changed
in
rumbling,
patient-trial
variability
to be moderate
treatment
the
they
a tendency
to stop
reductions
significant
that
assessed
of emptiness,
significantly
on the hunger
diaries
were
willpower
during
Clonidine
as tiredness
clonidine,
satiety
significant
increase
sensations (Fig.
and
Satiety.
in their
taking
and
feelings
showed
a significant
satiety
were
Hunger
composite and
and
recorded
they
periods.
before
Hunger,
17.4 I, p < 0.0 I) measured
mg/24
placebo hr during
urinary periods MHPG clonidine
M HPG (700.2
levels were low initially f
443.5,
concentrations treatment
662.2 ranged
without
f
and changed
301 .X, and 665. I f
from
clonidine
773.X
+ 412.7
showing
little 343.9
to 643. I
a consistent
255 effect upon urinary MHPG. Mean MHPG values measured transition periods are plotted on the bottom panel of Fig. 2.
during
consecutive
Discussion In this study, four anorexia patients substantially increased, and three patients normalized, their body weight during the course of a placebo-clonidine crossover trial. However, clonidine treatment was not superior to placebo for promoting weight gain in four treatment-resistant anorexia nervosa patients. Hunger and satiety sensations were not consistently affected by clonidine, and clonidine did not alter levels of anxiety or depression. Several explanations for these findings are possible. The first explanation involves the dose of clonidine (I 2-17 pg/ kg), which might have been insufficient to trigger its appetite stimulant effects, since hyperphagic effects in macaque monkeys were observed at higher doses (30-100 pg/ kg) (Schlemmer et al., 1981). Similarly, the doses that increased food intake in rats were considerably larger (25-50 pug/kg) (Mauron et al., 1980; Leibowitz, 1984). Thus, the possibility cannot be ruled out that if larger amounts of clonidine had been given, the appetite stimulant and weightpromoting properties of clonidine would have become apparent in humans. The potential for dangerous side effects of clonidine at higher doses precludes the testing of this possibility. Clonidine’s bradycardic effects increase the risk for developing heart block. Severe hypotension could lead to fainting with the danger of fractures. One patient in our study developed a reversible Wolf-Parkinson-White syndrome on clonidine. The doses of clonidine that were administered over 4-week periods were well within the range of those administered therapeutically for Gilles de la Tourette syndrome (Cohen et al., 1980), and opiate withdrawal (Gold et al., 1978, 1980) as well as those given experimentally to psychiatric patients (Freedman et al., 1980; Jimerson et al., 1980; Knesevich, 1982). Another explanation would be that the pharmacological properties of clonidine are species-specific and that in humans clonidine has no appreciable appetitestimulating properties. Cohen et al. (1980) explicitly note lack of appetite changes after clonidine administration in patients with Gilles de la Tourette syndrome. Weight gain is listed as a rare side effect when clonidine is used in the treatment of hypertension. The notion of species-differential effects is supported by studies in the golden hamster (Brne et al., 1984) and rhesus monkey (Beluhan et al., 1983); in these species clonidine administration failed to induce hyperphagia or weight gain. The observation that clonidine did not intensify the urge to eat before and after meals was consistent with its failure to accelerate weight gain. Our study confirms that anorexia nervosa patients feel hungry (Garfinkel, 1974). Patients reported, on average, a moderate urge to eat; hence, there was room for clonidine to increase its intensity. Interestingly, there was a trend for the urge to eat to be stronger after meals. To our knowlege, no controlled studies evaluating the effects of clonidine on appetite have been published. As mentioned, Cohen et al. (1980) observed no effect on appetite, while Hoehn-Saric et al. (1981) report less appetite in patients with anxiety and panic disorders during the first week of clonidine treatment in doses comparable to those administered to our patients with anorexia nervosa.
256 Paradoxically, the side effects listed for clonidine from‘trials in hypertension include both anorexia and weight gain (Boehringer Ingelheim brochure on clonidine). Clonidine could conceivably lead to body weight changes through another mechanism-namely, through affecting energy utilization by down-regulating the sympathetic nervous system, involved in the regulation of body weight through control of brown adipose tissue. This route is unlikely, since calorically induced thermogenesis is believed to be mediated through P-adrenergic rather than aadrenergic receptors (Stock and Rothwell, 198 1; Girardier and Seydoux, 198 1). Discontinuation of clonidine was associated with an overall slight drop in body weight as opposed to a slight rise in weight during initiation of clonidine administration. Transient weight fluctuations during the first several days of clonidine treatment are not uncommon and have been described by Pettinger (1975) Davidow et al. (1967), and Hokfeldt et al. (1970). This weight gain seems to result from sodium retention and seems to reflect intrarenal adjustments to the lowered blood pressure. The transitory weight drop with termination of clonidine then probably indicates sodium and fluid loss instead of tissue weight loss. On the whole, anorexia nervosa patients tolerated prolonged clonidine administration surprisingly well, even its hypotensive effects, although postural changes regularly tended to induce lightheadedness and some dizziness. Whether this response is different from that of normals and perhaps reflects an adaptation to a functional deficit in noradrenergic transmission in anorexia nervosa would require further study and inclusion of a normal control group. There is some evidence that starvation is associated with noradrenergic functional changes measurable in neurotransmitter and metabolite levels. Several investigators (Halmi et al., 1978; Abraham et al., 1981; Gerner and Gwirtsman, 1981) have reported low urinary MHPG levels in the acute stage of anorexia nervosa, with an increase in MHPG concentrations occurring upon refeeding and weight gain. Luck et al. (1983) reported reduced plasma norepinephrine (NE) concentrations, yet increased platelet (x2adrenergic receptor density in emaciated anorexia nervosa patients. In contrast, Kaye et al. (198%~) reported normal NE plasma levels in malnourished anorexia nervosa patients. The administration of clonidine in a crossover design was an attempt to test putative changes in adrenergic receptor sensitivity at different body weight levels. Two measures, gastric sensations and pulse rate, which showed differential effects of clonidine between the two trials provide tentative support for changes in the sensitivity of the az-adrenergic receptor at different points of refeeding. Nevertheless, for the unequivocally affected variables, blood pressure and sedation, the effects of clonidine were of similar magnitude at each trial. A third possibility, the presence of a permanent functional adrenergic dysbalance in anorexia nervosa, has been proposed by Kaye et al. (1985h). Their findings of normal plasma NE in underweight anorexia nervosa patients and lower plasma and cerebrospinal fluid NE and MHPG concentrations in weight-recovered anorexia patients compared to those in healthy controls are at variance with data reported by Halmi et al. (1978). Abraham et al. (1981), Gerner and Gwirtsman (1981) and Luck et al. (1983). It should be noted that the majority of anorexia nervosa patients in the report by Kaye et al. (19856) would not be considered physiologically recovered,
257 since six patients had not resumed regular menstruation, thus leaving the question of a permanent NE dysregulation open. Twenty-four hour urinary MHPG levels were low initially, a finding reported by us (Halmi et al., 1978) and other groups previously (Abraham et al., 1981; Riederer et al., 1982). That MHPG levels remained depressed throughout the study is difficult to explain, unless one assumes that the central inhibitory effects of clonidine outlasted its administration. ‘The reports by Halmi et al. (1978), Abraham et al. (198 I), and Riederer et al. (1982) would have predicted increased urinary M H PG output with increasing body weight during placebo that would be depressed by clonidine administration. On the other hand, Biederman et al. (1984) reported lower urinary MHPG levels during baseline in anorexia nervosa patients with major depressive disorder. In the depressed group, urinary M H PC levels actually declined with treatment, as opposed to anorexia nervosa patients without depression who had MHPG levels similar to normal controls. Published reports indicate that the influence of short-term clonidine administration on peripheral NE and its metabolites, such as MHPG, is modest. Small decrements in plasma MHPG I to 3 hours after clonidine were described by Leckman et al. (1980), Charney et al. (1982), and Siever et al. (1984); and decreases in plasma NE were observed by Goldstein et al. (1985). Jimerson et al. (1980) reported for long-term administration no decline in 24-hour urinary MHPG from baseline levels when up to I .4 mg/day clonidine was given to psychiatric patients for several weeks. The effects of clonidine upon arterial blood pressure (Pettinger, 1975; Goldstein et al., 1985) have established cionidine as an antihypertensive agent. The blood pressure changes found in anorexia nervosa patients with each course of clonidine are comparable in magnitude to the depressor response observed in hypertensive and normal individuals (Leckman et al., 1980; Robertson et al., 1983; Goldstein et al., 1985). The hypotensive action of clonidine is largely centrally mediated, although there is evidence that the drug influences sympathetic outflow by a combination of central and peripheral effects (Wallin and Frisk-Holmberg, I98l). intact periphera! adrenergic receptors seem to be necessary for its hypotensive effects; for example, in patients with orthostatic hypotension associated with degeneration of sympathetic nerve endings, clonidine has no hypotensive effect and may even raise blood pressure (Robertson et al., 1983). The effects of clonidine upon blood pressure were reversible upon discontinuation of the drug. Furthermore, we saw a strong relationship between blood pressure gradually rising to normal levels and the rise in body weight, suggesting that weight gain is associated with a rise in sympathetic tone. In our study, clonidine produced sedative effects each time it was administered. The sedation did not interfere with daily activities but produced a tendency to nap. Most other studies have reported sedation or somnolence after pharmacological doses of clonidine (Gil-Ad et al., 1979; Cohen et al., 1980; Hossman et al., 1980; Leckman et al., 1980; Lanes et al., 1983) although some reports (Jimerson et al., 1980; Knesevich, 1982; Kave et al., 1985h) do not describe sedation with similar doses. The sedative effects, mediated most likely through activation of postsynaptic qreceptors (Nassif et al., 1983) are beneficial in the treatment of hypertension and may be of advantage for hyperactive anorexia nervosa patients.
258 The effects of clonidine on mood have not been so clearly determined. Anxiolytic effects have been found in patients with depression and anxiety disorders (Svensson et al., 1978; Hoehn-Saric et al., 1981), whereas Leckman et al. (1980) report no effects on mood or state anxiety in normals. Both depressant (Simpson, 1973) and antidepressant (Jimerson et al., 1980) effects of clonidine have been described. Our patients reported depressive feelings and anxiety throughout the study. but neither one was consistently affected by clonidine. Overall depressive feelings declined. probably as a result of the overall improvement in the physical and anorectic condition, whereas anxiety even slightly increased throughout the study period, probably in reaction to the weight gain. The observed action pattern of clonidine --its reproducible effects upon blood pressure largely controlled through sympathetic outflow. as opposed to its variable action upon physiologic states, such as hunger and satiety, and on psychologic parameters, such as depression or anxiety--suggests that noradrenergic mechanisms are not the sole contributors to the regulation of eating and mood states and that any drug that would be specific for the treatment of anorexia nervosa needs to have a broader pharmacological range. References Abraham, S.F., Beumont, P.J.V., and Cobbin. D.M. C’atecholamine metabolism and body weight in anorexia nervosa. Uri/i.sh Journul c!f’ P.y~~c,hiutr_~~.138, 244 ( 19X I ). Atkinson, J.. Kirchert7, E.J., and Peters-Haefeli, 1.. Effect of peripheral clonidine on ingestive behavior. fI~.r’.sio/o,q~~and Bdzavior. 21, 73 (197X). Heinle. W.J.. and Davis. J.M. Beluhan, l..J.. Schlemmer. R.F.. Jr.. Casper. R.C., hetween stumptail and rhesus macaques. Differential feeding responses to clonidine Fr&ration frowrdings. 42, I I60 ( 19X3). Biederman, .I., Herzog, D.B., Rivinus. ‘P.M.. Ferber, R.A.. Harper. G.P., Orsulak. P.J.. Harmat7. J.S.. and Schildkraut. J.J. IJrinary M HPG in anorexia nervosa patients with and without ;L concomitant major depressive disorder. Journul qf’ P.s.\,c,hiu/ric Rrwurc~ll. 18, I49
( 1984). Brne. T., Schlemmer, R.F.. and Kat/. N.I.. Failure of clonidine to increase feeding in the golden hamster. 7%~ f%urnmdogi.vt. 26, 223 ( 19X4). Broekkamp, C.. and Van Rossum, J.M. Clonidine-induced intrahypothalamic stimulation of eating in rats. ~.~_l,c,ho~/,hurn?u~,~~/~~,~iu.25, I62 ( 1972). Casper, R.C.. Davis. J.M., and Pandey. G.N. The effect of nutritional status and weight changes on hypothalamic function tests in anorexia nervosa. In: Vigersky. R.A.. ed. Anow.uiu Nerrwsu. Raven Press, New York, p. I.37 ( I977). Charney, D.S., Heninger, G.R.. Sternberg. I1.E.. Hafstad. K.M., Giddings. S., and I.andis. II. H. Adrencrgic receptor sensitivity in depression. Ar(./zi\v.s c?f’ Grmrul P.s.whiutr_l~. 39. 290 ( I982). C’ohen, D..I.. Detlor. .I.. Young, C;.. and Shavwitz. B.A. Clonidine ameliorates Gilles de la I‘ourette syndrome. Archiws c!f’ Gcnc,ru/ P.ytd~h/r_t~. 37, I350 ( 1980). Davidow, M.. Kakaviatos, N.. and Finnerty. F.H., .Ir. The anti-hypertensive effects of an imidaloline compound. ~‘/ir~ic~u/ f’~furr,luc,o/oe~, ant/ ‘Ihrrqwuric~s. 8, 8 IO ( I967). Ilekirmenjian, H., and Maas. J.W. An improved procedure of 3-methoxy-4hydroxyphenylethylene glycol determination by gas-liquid chromatography. Anu[~ricu/ Bioc,henlis/r,,,. 35, I I3 ( I970). Feighner, .I.P.. Robins. E.. Gule, S.B.. Woodruff, R.A.. Winokur, G., and Muno/. G. Diagnostic criteria for use in psychiatric research. ;Ir<~/zivc~sc!/’ General f,s~-c~hiu/r~~, 26, 57 ( I972).
259
Freedman, R., Bell, J., and Kirch, D. Clonidine therapy for coexisting tardive dyskinesia. American Journal of Psychiatry, 137,629 (1980). Garfinkel, P.E. Perception of hunger and satiety in anorexia nervosa. Medicine,
psychosis
and
Psychological
4, 309 ( 1974).
Gerner, R.H., and Gwirtsman, H.E. Abnormalities of dexamethasone suppression test and urinary M H PG in anorexia nervosa. American Journal of’ Ps.vchiarry, 138,650 ( I98 I). Gil-Ad., J., Topper, E., and Laron, Z. Oral clonidine as a growth hormone stimulation test. Lancet, 11,
of’ Clinical 49,805
Endocrinology
and Metabolism,
( 1979).
Grossman,
S.P. Role of the hypothalamus in the regulation of food and water intake. Review, 82, 200 ( 1975). Halmi, K.A., Dekirmenjian, H., Davis, J.M., Casper, R.C., and Goldberg, S.C. Catecholamine metabolism in anorexia nervosa. Archives of’ General Psychiatry. 35,458 ( 1978). Hoehn-Saric, R., Merchant, A.F., and Keyser, M.L. Effects of clonidine on anxiety disorders. Archives of’ General f.sychiatr_y. 38, I278 (198 I). Hokfelt, B., Hedeland, H., and Dymling, J.F. Studies on catecholamines, renin and aldosterone following catapresan (2-(2, 6-dichlor-phenylamine)-2 imidazoline hydrochloride) in hypertensive patients. European Journal c$ fharmacolog_v, 10, 289 (1970). Hossman, V., Maling, T.J.B., Hamilton, C.A.. Reid, J.L., and Dollerby, C.T. Sedative and cardiovascular effects of clonidine and nitrazepam. Journul of’ Clinical fharmacolog_~~ and Therapeutics. 28, I67 ( 1980). Jimerson. D.C., Post, R.M.. Stoddard, F.J., Gillin. J.C.. and Bunney, W.E.. Jr. Preliminary trial of the noradrenergic agonist clonidine in psychiatric patients. Biological P.s.vchiotrv. 15,45 (I 980). Katz., N.L., Schlemmer. R.F., Jr.. and Waller, D.P. Stereospecific reduction by narcotic antagonists of clonidine-induced food intake. Phormucolog~v, Biochemi.s/ry~ und Behavior, 22, Ps_vchological
649
( 1985).
Kaye. W.H., Ebert, M.H., Raleigh, M.. and Lake, C.R. Abnormalities in CNS monoamine metabolism in anorexia nervosa. Archive.s oJ’Generul /?sy~chiarry, 41, 350 (1984). Kaye, W.H., Gwirtsman, H.E.. Lake, C.R.. Siever, L.J.. Jimerson, D.C., Ebert, M.H., and Murphy, D.L. Disturbances of norepinephrine metabolism and alpha-2 adrenergic receptor activity in anorexia nervosa: Relationship to nutritonal state. P.s_l’c,hopharmac,olog,~, Bullefin. 21,419
(1985~).
Kaye, W.H.. Jimerson, D.C., I,ake, C.R., and Ebert, M.H. Altered norepinephrine metabolism following long-term weight recovery in patients with anorexia nervosa. /?s\~chiutr_,~ Research.
14, 333 ( 1985h).
Knesevich, J.W. Successful treatment of obsessive-compulsive disorder with clonidine hydrochloride. American Journul o/’ f.s,)~chiufry~. 139, 364 ( 1982). I.andsberg. I.., and Young, J.B. Fasting, feeding, and the regulation ofsympathetic activity. N~IM’England Journul c!f Medic~inc, 298, I295 ( 1978). I.anes, R., Herrera, A., Palacios. A., and Moncada, Ci. lIecreased secretion of cortisol and ACTH after oral clonidine administration in normal adults. Mc/uholi.sm, 32, 56X ( 1983).
260
Leckman. J.F., Maas, J.W., Redmond, D.E., Jr., and Heninger, G.R. Effects of oral clonidine on plasma 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in man: Preliminary report. L!/k Sciences. 26, 2179 (1980). Le Douarec. J.C., Schmitt, H.. and Lucet, B. Effects of cionidine and of alphasympathominetic agents on food intake: Antagonism by adrenolytics. Journal de Pharnracologie. 3, I87 ( 1982). Leibowitz, SF. Paraventricular nucleus: A primary site mediating adrenergic stimulation of feeding and drinking. fharmacolog_v, Biochemistry and Behavior, 8, 163 (1978). Leibowitl, S.F. Noradrenergic function in the medial hypothalamus: Potential relation to anorexia nervosa and bulimia. In: Pirke, K.M., and Ploog, D., eds. The Psychohiolog_v of Anore.riu Nervosa. Springer-Verlag, Berlin, p. 35 (1984). Luck, P., Mikhailidis, D.P., Dashwood, M.R., Barradas, M.A., Sever, P.S., Dandona, P., and Wakeling, A. Platelet hyperaggregability and increased alpha-adrenoceptor density in anorexia nervosa. Journal of’ Clinical Endocrinology and Metabolism, 57,9 I I (1983). Mauron, C., Wurtman, J.J., and Wurtman, R.J. Clonidine increases food and protein consumption in rats. Ld> Sciences. 27, 78 I ( 1980). Monello, L.F., and Mayer, J. Hunger and satiety sensations in men. women, boys and girls. American Journal of Clinic,al Nutrition, 20, 253 (1967). Nassif, S., Kemp, E., Cardo, B., and Velley, L. Neurochemical lesion of the locus coeruleus of the rat does not suppress the sedative effect of clonidine. European Journal of Pharmacology. 91, 69 ( 1983). Pettinger, W.A. Clonidine, a new antihypertensive drug. New England Journal of Medicine. 293, I I79 ( 1975). Redmond, D.E., Jr., and Huang, Y.H. New evidence for a locus coeruleus-norepinephrine connection with anxiety. L@ Sciemes. 25(26), 2 I49 ( 1979). Redmond, D.E., Jr., Huang, Y.H., Snyder, D.R., Maas, J.W., and Baulu, J. Hyperphagia and hyperdipsia after locus coeruleus lesions in the stump-tailed monkey. L@ Sciences. 20, 1619 (1977). Riederer, P., Toifl. K., and Krulik, P. Excretion of biogenic amine metabolites in anorexia nervosa. Clinica Chimica Acta. 123, 27 (1982). Robertson, D., Goldberg, M.R., Hollister, A.S., Wade, D., and Robertson, R.M. Clonidine raises blood pressure in severe idiopathic orthostatic hypotension. American Journal of Medicine, 74, I93 (I 983). Schlemmer, R.F., Jr., Casper, R.C.. Narasimhachari, N., and Davis, J.M. Clonidine induced hyperphagia and weight gain in monkeys. Ps.vc,hopharmac,ol~~~.v, 61, 233 (1979). Schlemmer, R.F., Jr., Elder, J.K., Casper, R.C., and Davis. J.M. Clonidine-induced hyperphagia in monkeys: Evidence for alpha-2noradrenergic receptor mediation. Psyc~hopharmac~olo~y, 73, 99 ( I98 I ). Seedat, Y.K., Vawda, E.I., Mitha. S., and Ramasar, R. A comparison of alpha-methyldopa (Aldomet) and ST I55 (Catapres) in the treatment of hypertension. South A,frican Medical Journal, 44,300 ( 1970). Siever, L.J., Uhde, T.W., Jimerson, D.C., Lake, C.R., Silberman, E.R., Post, R.M.. and Murphy, D.L. Differential inhibitory noradrenergic responses to clonidine in 25 depressed patients and 25 normal control subjects. American Journul or Psychiutry, 141, 733 (1984). Simpson, F.O. Hypertension and depression and their treatment. Australian and New Zealand Journal oj’ Psychiatry. 7, I33 ( 1973). Stock, M.J., and Rothwell, N.J. Sympathetic control of brown adipose tissue in the regulation of body weight. Biochemical Soviet.? Tronsuc~tions. 6, 525 ( 198 I). Svensson, T.H., Bunney, B.S., and Aghajantan, G.K. Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic antagonist clonidine. Bruin Resrurc~h. 92, 29 I (1975). Svensson, T., Persson, R., Wallin, L., and Walinder. .I. Anxiolytic action of clonidine. Nordisk Psykiatrist Tidsskrijt. 32,439 ( 1978). Taylor, J.A. A personality scale of manifest anxiety. Journal of Ahnormal and Sociul Psychology. 48, 285 (1953). Wallin, B.G., and Frisk-Holmberg, M. The antihypertensive mechanism of clonidine in man: Evidence against a generalized reduction of sympathetic activity. H_vpertmsion, 3, 340 (1981).
Rrstwrc~h.
20, 249-260
249
Elsevier
A Placebo-Controlled in Acute Anorexia Regina
C. Casper,
Crossover Nervosa
I?. Francis
Schlemmer,
Study
of Oral Clonidine
Jr., and Javaid
I. Javaid
Received February 14, 1986; revised version received June 27. 1986; accepted August 27, 1986. Abstract. The a,-adrenergic agonist clonidine has been reported to increase feeding in several species. This study evaluated the effects of clonidine (500-700 pug/day), administered per OS, to four treatment-resistant anorexia nervosa patients in a long-term placebo-controlled crossover trial. All patients increased their body weight significantly. Clonidine administration, however, did not influence the rate of weight gain, nor did clonidine affect hunger or satiety sensations. Similarly, 24-hour urinary 3-methoxy-4-hydroxyphenylglycol levels and levels of anxiety and depression were unchanged by clonidine. By contrast, clonidine showed significant hemodynamic effects; clonidine lowered systolic and diastolic blood pressure, reduced pulse rate, and produced sedation. Discontinuation of clonidine was associated with a small but significant weight ioss compared to a small weight increase during the initiation of clonidine treatment. The results suggest that clonidine may not be indicated in the treatment of anorexia nervosa. Key Words.
Anorexia
nervosa,
clonidine,
weight
gain.
Central noradrenergic systems have long been implicated in the regulation of feeding and eating (Grossman, 1973, and drugs that affect noradrenergic receptors have been used to elucidate the mechanisms controlling hunger and satiety (Leibowitz, 1978, 1984). Clonidine, a preferential a,-adrenergic presynaptic and probably postsynaptic receptor agonist (Svensson et al., 1975) is among the compounds that have been shown to influence feeding behavior in several animal species. First synthesized as a nasal decongestant, but then found to be effective as an antihypertensive drug (Seedat et al., 1970; Goldstein et al., 1985), clonidine has also been reported to stimulate eating in the rat (Broekkamp and Van Rossum, 1972; Atkinson et al., 1978; Mauron et al., 1980), in the dog (Le Douarec et al., 1972), in the rabbit (Katz et al., 1985), and in primates (Schlemmer et al., 1979, 1981). In primates, the effects on feeding were observed fortuitously during studies evaluating adrenergic agonist and antagonist drugs on solitary and social behavior of macaque monkeys. Prolonged repeated clonidine administration for I week in increasing
Regina C. Casper, M.D., is Director of the Eating Disorders Research & Treatment Program, Michael Reese Hospital, and Associate Professor of Psychiatry. Department of Psychiatry, The University of Chicago. R. Francis Schlemmer, Ph.D., is an Assistant Professor of Pharmacology, Department of Pharmacological Dynamics, College of Pharmacy, University of Illinois at Chicago. Javaid I. Javaid. Ph.D., is Associate Director of Research at the Illinois State Psychiatric Institute. (Reprint requests to Dr. R.C. Casper, Dept. of Psychiatry, Michael Reese Hospital and Medical Center. Lake Shore Dr. at 3lst St., Chicago, IL 60616, USA.) 016%1781/87/$03.50
@ 1987 Elsevier Science Publishers B.V
250 doses (0.01-0.1 mg/ kg) was associated with a significant increase in time spent eating, as well as time spent in other food-related categories such as “handling food” and an increase in high-pitched vocalizations, probably “food cries.” In a subsequent placebo-controlled study, repeated clonidine treatment resulted in a significant increase in body weight (from 5%) to 16%) in I week (Schlemmer et al., 1979). Administration of yohimbine, an q-receptor antagonist, blocked the clonidineinduced eating whereas prazosin, an c-r,-receptor antagonist, had no effect. These results suggest that the hyperphagia induced by clonidine is mediated through crl_adrenergic receptors (Schlemmer et al., 1981; Katz et al., 1985). Anorexia nervosa is a disorder in which resumption of eating is crucial for recovery. It is well established that anorexia nervosa patients are not anorexic (Garfinkel, 1974); i.e., they experience hunger, but are prevented from eating by an intense fear of losing control over eating and of becoming overweight. Studies on the action of clonidine upon locus ceruleus activity in monkeys (Redmond et al., 1977; Redmond and Huang, 1979) and in depressed patients (Svensson et al., 1975, 1978) have suggested anxiolytic properties. Pharmacologically this combination, a reduction in anxiety and an enhanced urge to eat, would make clonidine ideally suited for treating anorexia nervosa, especially the chronic condition, where weight gain is difficult to achieve. This reasoning led us to design a placebo-controlled study of clonidine in anorexia nervosa. The study was devised as a pilot study. because little was known about the hypotensive effects of clonidine in a population already hypotensive as a result of starvation. Since anorexia nervosa patients tend to regain weight without drug treatment in most specialized treatment programs (Casper et al., 1977), only patients who failed to improve during one or several previous hospitalizations elsewhere were chosen for inclusion in the study. Studies that have measured parameters of noradrenergic function in anorexia nervosa (Halmi et al., 1978; Gross et al., 1979; Abraham et al., 1981: Riederer et al., 1982; Luck et al.. 1983; Kaye et al., 1984) and in normals (Landsberg and Young, 1978) indicate that starvation itself can influence noradrenergic functional activity through reducing norepinephrine turnover. These reports suggest that the action of clonidine might differ at different stages of starvation. Therefore, clonidine was administered alternating with placebo in a crossover protocol.
Methods Subjects were four consecutively admitted female patients. who had failed to improve during hospitaliration elsewhere and who qualified for a diagnosis of anorexia nervosa according to the criteria of Feighner et al. (1972). All patients were nonsmokers and were drug free at the time of the study. One patient. the only patient to have a history of bulimic episodes. had previously received antidepressant medtcation that had been discontinued f.or more than a month before hospitalization. Patients ranged in age from 19 to 28 years, with a mean (+ SD) duration of illness of 5.8 k 2.3 years. Patients were hospitalired on a clinical research ward and randomly assigned by the pharmacist to either drug or placebo I week following admission. Each trial consisted of 4 weeks on placebo alternating with 4 weeks on clonidine. Clonidine was administered orally in three divided doses and gradually increased from a I50 gg: day to a maximum dose between 500 and 700 pg. day. The maximum dose reached was determined by individual tolerance for the drug’s hypotcn\t\,c effect. Patients were kept for 2
251 weeks at the maximum dose and then gradually tapered off to I week before starting placebo again. Blood pressure and pulse, supine and standing, were recorded twice daily, and the electrocardiogram was monitored weekly. Patients were admitted with the understanding that they would try to regain their normal weight. They were treated in psychotherapy four times per week and, when possible, family sessions were arranged each week. A liquid diet (Meritene) was offered in six divided meals. The caloric amount was gradually increased from 1800 calories to a maximum intake of over 3000 calories. After 2 weeks, patients had the option of switching to regular food. All patients were weighed daily and steadily gained weight. The drug protocol was discontinued once patients had reached a normal weight for age and height as calculated by the Metropolitan Life Insurance Tables, 1957. Two patients regained normal weight before completion of the third clonidine trial. Thus, altogether, four patients had three placebo and two drug trials. Two patients participated in a third clonidine trial. Three of the four pattents regained normal weight during the protocol. The fourth patient was still IV%, underweight at the end of the third drug trial. Body weights were obtained each morning in the fasting state with patients dressed in a gown after voiding. Twenty-four hour urine samples were collected twice weekly for measurement of 3-methoxy-4-hydroxyphenylglycol (M H PG) excretion. IJrincs wcrc refrigerated upon collection and preserved in bottles containing 0.5 mg/ ml metabisulfatc. Upon completion, urine volumes were measured and MHPG levels were detcrmincd according to the method of Dekirmenjian and Maas (1970). Behavioral ratings consisted of a IO-cm visual analog scale for depression ranging Irom “not at all depressed” to “very depressed.” For evaluating anxiety, patients completed the ‘l‘aylor Manifest Anxiety Scale (Taylor, 1953). This scale lists a considerable number of accessory, especially somatic, symptoms, which, if they occur in anorexia nervosa, are often starvation rather than anxiety related. Therefore, for evaluating anxiety level, items unrelated to physical symptoms
were selected.
The anxiety
48. and 50. Monello and Mayer’s (1967) before
dinner
feelings during
ordinary
“strong”
twice
weekly.
The
riding
Patients
completed
most
the
psychotherapy,
satiety
was given to patients
Patients
on 4point
rating
or sensation.
were also instructed
Patient
Parkinson-White
welt: asked with
scales
Each
to keep a diary
30 min
to describe thoughts
ranging
rating
from
their
of lood
“nom”
was completed
for recording
Analysis.
the effects
of clonidine.
(trial
completely drug
separately
postural
during
The
for trials
combination).
two fixed
to
by each
any unusual
Post
mixed
model
factors
ward
trials.
analysis
did not necessitate
drug
Yince
minute
she remained
of variance
for
subject the
indicated,
a Wolfclinically
was used to evaluate
lactor
otherwise
with
of the protocol.
as a random (each
on and
were treatment
condition
noticed
activities
in the design
hoc comparisons tinless
in
01 42 beats/
discontinuation
an unpleasant
especially
The side effects
bradycardia
were treated
and drug
were also performed.
Participation
each of two clonidine
A three-factor
clonidinc
to lightheadedness,
by clonidinc. severe
did not recommend
I, 2, or 3). Subjects
crossed
related
movements.
was unaffected
syndrome
even though all considered were
#3 developed
the intermst
Statistical and trial
complaints and
however,
asymptomatic,
f
Questionnaire
respectively.
urge to eat, and preoccupation
of a feeling
the protocol
frequent
elevators
discontinuation.
and
and during
here are based on items 2. 3, 5, 14,
or sensations.
All patients drug.
dinner,
mood,
to assess the intensity
patient effects
sensations,
hunger
reported
Hunger and Satiety
and 30 min following
and physical
assessments
(drug
in the design.
was measured
effect
of
medication
all values
vs. placebo) Subjects
under
on each
are expressed
were
each trial trial
as mean
SD.
Results Body Weight. Fig. consecutive
I presents
placebo-clonidine
on the top panel the changes trials. Each point represents
in kg body weight for the the irrtegrated mean 01
252
Fig. 1. Changes in body weight (kg), pulse, (bpm), and blood pressure (mmHg) during consecutive placebo-clonidine crossover trials in 4 anorexia nervosa patients
106
SYBTOLIC
BLOOD PRESSURE
TOLIC BLOOD PRE88URE
PLACESO-CLONIDINE CROSSOVER Note. Values are shown for mean body weights (kg) and satiety ratings (open quadrangles) (upperpanel) and 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) &g/24 hr +ZSEM) (lowerpanel) for each 6-day transition crossover from placebo to clonidine or clonidine to placebo Discontinuation of clonidine resulted In weight ioss as compared to the weight changes dunng im!iatlon of clonidlne admmistration (p < 0 03)
253
Fig. 2. Mean body weights, satiety ratings, and 24-hour urinary MHPG concentrations in 4 anorexia nervosa patients .2a
a ClOllidine 0-e Placebo
BODY WEIGHT
2.6
6 g
.2A
8
-2.2
F 2
-2.0
7 s
-1.3 -1.6 lat PEFnOC PLACEBO
3
181PERIOD CLONIDINE
3
2nd CLONIDINE
2nd PLACEBO PEmm
3
PERIOD
3
g F
3rd PLACEBO PERIOD
Values represent means f SEM; each time point represents the summarized values for 4 weeks. Doses of clonidine increased from 0.2 to 0.7 mgid.
daily recorded body weights for each trial period as well as the mean value for the four patients. Average body weight increased from 35.0 + 5.24 kg on admission to 45.7 + 5.65 kg (p < 0.001) over the entire 5- to 6-month study period. The mean changes in body weight during clonidine administration did not significantly differ from mean weight changes during placebo administration, i.e., patients gained similar amounts of weight during clonidine as during placebo periods. When we inspected the averaged weight gain curves, we noticed a weight drop during each transition from clonidine to placebo (last 3 days on clonidine and first 3 days on placebo). Comparisons of the mean body weight changes during the clonidine/placebo transitions (see Fig. 2) and the placebo/clonidine transitions (last 3 days on placebo and first 3 days on clonidine) showed significant differences, a fall in weight (-0. I6 + 0.2 kg) during clonidine/ placebo transition as opposed to a slight weight gain (0.58 f 0.19 kg; t = 2.61, p < 0.03) during the placebo/clonidine transition.
Hemodynamic Effects. During each trial of clonidine administration, systolic (F = 84.2, p < 0.0001) and diastolic (F = 67.6, p < 0.0001) blood pressures were significantly reduced relative to placebo administration (Fig. I). In contrast, during each placebo period, systolic and diastolic blood pressures significantly rose again, from a mean of 90.8 +- 8.7/64.4 + 9.4 mmHg at the first placebo trial, to
254
99.0 f
9.9/69.6
f
Ifr I I .2 mmHg blood
X.6 mmHgduring
(11 < 0.01)
pressure
was
the second placebo
at the last placebo
significantly
Pulse (F=
rate
(see
Fig.
4.X. /I < 0.01)
during
each
clonidine
of the
two
period
to a mean
significant
overall
indicating
clonidine
trials.
0.001)
and
in body
I
12.2/71.
and diastolic
weight
treatment
the pulse The
(r =
reduction
I X.2 beats/
trial
in pulse
0.91,
interaction
rate
significant.
minute
15.6 beats/minute
correlated
X
rate was differentially
to be statistically
a pulse of 76.9 f
pulse rate of X4.X f (~7 <
gain
significant
that
was not found
in pulse rate from
with
and to 100.7 +
rise in systolic
respectively).
showed
administration
increase was
I)
effects,
The
correlated
17 < 0.00 I, and r = 0.77, p < 0.004,
trial,
trial.
with
each
However,
from
the
the first placebo
at the third
positively
affected
during
placebo
weight
gain
period
(r =
0.62,
/’ < 0.00 I ).
Effects
on Sedation,
sedation
(F=
clonidine
trial.
during
days
placebo
Patients
when
sensations,
urge score
meals,
to eat, for
showed
indicating
considerable
reported
2) were
(2.2
meals
(satiety)
(2.X +
I .O).
Effects
t (2.7
f
over
(I, <
0.01)
were
observed,
were
noted
mean
3.2
IL
levels.
I. I) during
patients
MHPG.
2.3,
both
0.05).
Clonidine
that there
to patient
(F=
were significant
on
levels
14.81;
@ < 0.01)
following
administration
scale
period
significantly
to 4.61
-t 2.5 I
clonidine-related in the level slightly
not
effects
of depression
increased
consistently
0.004).
drug
effects
X
from trials
alter
trial
(F
on anxiety
in how clonidinc
nor was
and clonidine
placebo-clonidine
14.59, p < 0.001)
O.OOl),
hunger (hunger)
placebo
analog
Gastric
p <
meals
a
tenseness
0.01).
neither
placebo
overall did
differences
sensation, trial
clonidine
the
sequential 17 <
during
as gastric
to eat to be stronger
differences
administration 6.64.
=
each
to nap
and
(r, <
Overall,
the first
during
=
(F
No significant
Anxiety
(F
gastric
trial
and during
reported
ways.
pain,
scale) during urge
interindividual
patient-drug
and patient
for
period.
scale,
mentioned
LJrge to eat before
placebo
levels
not several
the first clonidine
patients.
z!z 2.96 during
placebo
on a 4-point
affected
a to
anxiety =
20.36,
were noted, anxiety
in
across time. Average
24-hour
the three
mg/24
hr, respectively).
309.6
a trend
(F = 9.74, p < 0.001). +
during f
6.73
the third
Significant
indicating
from
but significant
1.9 (11 <
17 < 0.05),
was
Depression
time
during
between
compelled
Only
clonidine
increased
scale during
felt
aches,
interactions
by clonidine.
There
eating.
during
second
(2. I + 0.X on a 4-point
0.6).
on Mood.
decreased
3.6
changed
in
rumbling,
patient-trial
variability
to be moderate
treatment
the
they
a tendency
to stop
reductions
significant
that
assessed
of emptiness,
significantly
on the hunger
diaries
were
willpower
during
Clonidine
as tiredness
clonidine,
satiety
significant
increase
sensations (Fig.
and
Satiety.
in their
taking
and
feelings
showed
a significant
satiety
were
Hunger
composite and
and
recorded
they
periods.
before
Hunger,
17.4 I, p < 0.0 I) measured
mg/24
placebo hr during
urinary periods MHPG clonidine
M HPG (700.2
levels were low initially f
443.5,
concentrations treatment
662.2 ranged
without
f
and changed
301 .X, and 665. I f
from
clonidine
773.X
+ 412.7
showing
little 343.9
to 643. I
a consistent
255 effect upon urinary MHPG. Mean MHPG values measured transition periods are plotted on the bottom panel of Fig. 2.
during
consecutive
Discussion In this study, four anorexia patients substantially increased, and three patients normalized, their body weight during the course of a placebo-clonidine crossover trial. However, clonidine treatment was not superior to placebo for promoting weight gain in four treatment-resistant anorexia nervosa patients. Hunger and satiety sensations were not consistently affected by clonidine, and clonidine did not alter levels of anxiety or depression. Several explanations for these findings are possible. The first explanation involves the dose of clonidine (I 2-17 pg/ kg), which might have been insufficient to trigger its appetite stimulant effects, since hyperphagic effects in macaque monkeys were observed at higher doses (30-100 pg/ kg) (Schlemmer et al., 1981). Similarly, the doses that increased food intake in rats were considerably larger (25-50 pug/kg) (Mauron et al., 1980; Leibowitz, 1984). Thus, the possibility cannot be ruled out that if larger amounts of clonidine had been given, the appetite stimulant and weightpromoting properties of clonidine would have become apparent in humans. The potential for dangerous side effects of clonidine at higher doses precludes the testing of this possibility. Clonidine’s bradycardic effects increase the risk for developing heart block. Severe hypotension could lead to fainting with the danger of fractures. One patient in our study developed a reversible Wolf-Parkinson-White syndrome on clonidine. The doses of clonidine that were administered over 4-week periods were well within the range of those administered therapeutically for Gilles de la Tourette syndrome (Cohen et al., 1980), and opiate withdrawal (Gold et al., 1978, 1980) as well as those given experimentally to psychiatric patients (Freedman et al., 1980; Jimerson et al., 1980; Knesevich, 1982). Another explanation would be that the pharmacological properties of clonidine are species-specific and that in humans clonidine has no appreciable appetitestimulating properties. Cohen et al. (1980) explicitly note lack of appetite changes after clonidine administration in patients with Gilles de la Tourette syndrome. Weight gain is listed as a rare side effect when clonidine is used in the treatment of hypertension. The notion of species-differential effects is supported by studies in the golden hamster (Brne et al., 1984) and rhesus monkey (Beluhan et al., 1983); in these species clonidine administration failed to induce hyperphagia or weight gain. The observation that clonidine did not intensify the urge to eat before and after meals was consistent with its failure to accelerate weight gain. Our study confirms that anorexia nervosa patients feel hungry (Garfinkel, 1974). Patients reported, on average, a moderate urge to eat; hence, there was room for clonidine to increase its intensity. Interestingly, there was a trend for the urge to eat to be stronger after meals. To our knowlege, no controlled studies evaluating the effects of clonidine on appetite have been published. As mentioned, Cohen et al. (1980) observed no effect on appetite, while Hoehn-Saric et al. (1981) report less appetite in patients with anxiety and panic disorders during the first week of clonidine treatment in doses comparable to those administered to our patients with anorexia nervosa.
256 Paradoxically, the side effects listed for clonidine from‘trials in hypertension include both anorexia and weight gain (Boehringer Ingelheim brochure on clonidine). Clonidine could conceivably lead to body weight changes through another mechanism-namely, through affecting energy utilization by down-regulating the sympathetic nervous system, involved in the regulation of body weight through control of brown adipose tissue. This route is unlikely, since calorically induced thermogenesis is believed to be mediated through P-adrenergic rather than aadrenergic receptors (Stock and Rothwell, 198 1; Girardier and Seydoux, 198 1). Discontinuation of clonidine was associated with an overall slight drop in body weight as opposed to a slight rise in weight during initiation of clonidine administration. Transient weight fluctuations during the first several days of clonidine treatment are not uncommon and have been described by Pettinger (1975) Davidow et al. (1967), and Hokfeldt et al. (1970). This weight gain seems to result from sodium retention and seems to reflect intrarenal adjustments to the lowered blood pressure. The transitory weight drop with termination of clonidine then probably indicates sodium and fluid loss instead of tissue weight loss. On the whole, anorexia nervosa patients tolerated prolonged clonidine administration surprisingly well, even its hypotensive effects, although postural changes regularly tended to induce lightheadedness and some dizziness. Whether this response is different from that of normals and perhaps reflects an adaptation to a functional deficit in noradrenergic transmission in anorexia nervosa would require further study and inclusion of a normal control group. There is some evidence that starvation is associated with noradrenergic functional changes measurable in neurotransmitter and metabolite levels. Several investigators (Halmi et al., 1978; Abraham et al., 1981; Gerner and Gwirtsman, 1981) have reported low urinary MHPG levels in the acute stage of anorexia nervosa, with an increase in MHPG concentrations occurring upon refeeding and weight gain. Luck et al. (1983) reported reduced plasma norepinephrine (NE) concentrations, yet increased platelet (x2adrenergic receptor density in emaciated anorexia nervosa patients. In contrast, Kaye et al. (198%~) reported normal NE plasma levels in malnourished anorexia nervosa patients. The administration of clonidine in a crossover design was an attempt to test putative changes in adrenergic receptor sensitivity at different body weight levels. Two measures, gastric sensations and pulse rate, which showed differential effects of clonidine between the two trials provide tentative support for changes in the sensitivity of the az-adrenergic receptor at different points of refeeding. Nevertheless, for the unequivocally affected variables, blood pressure and sedation, the effects of clonidine were of similar magnitude at each trial. A third possibility, the presence of a permanent functional adrenergic dysbalance in anorexia nervosa, has been proposed by Kaye et al. (1985h). Their findings of normal plasma NE in underweight anorexia nervosa patients and lower plasma and cerebrospinal fluid NE and MHPG concentrations in weight-recovered anorexia patients compared to those in healthy controls are at variance with data reported by Halmi et al. (1978). Abraham et al. (1981), Gerner and Gwirtsman (1981) and Luck et al. (1983). It should be noted that the majority of anorexia nervosa patients in the report by Kaye et al. (19856) would not be considered physiologically recovered,
257 since six patients had not resumed regular menstruation, thus leaving the question of a permanent NE dysregulation open. Twenty-four hour urinary MHPG levels were low initially, a finding reported by us (Halmi et al., 1978) and other groups previously (Abraham et al., 1981; Riederer et al., 1982). That MHPG levels remained depressed throughout the study is difficult to explain, unless one assumes that the central inhibitory effects of clonidine outlasted its administration. ‘The reports by Halmi et al. (1978), Abraham et al. (198 I), and Riederer et al. (1982) would have predicted increased urinary M H PG output with increasing body weight during placebo that would be depressed by clonidine administration. On the other hand, Biederman et al. (1984) reported lower urinary MHPG levels during baseline in anorexia nervosa patients with major depressive disorder. In the depressed group, urinary M H PC levels actually declined with treatment, as opposed to anorexia nervosa patients without depression who had MHPG levels similar to normal controls. Published reports indicate that the influence of short-term clonidine administration on peripheral NE and its metabolites, such as MHPG, is modest. Small decrements in plasma MHPG I to 3 hours after clonidine were described by Leckman et al. (1980), Charney et al. (1982), and Siever et al. (1984); and decreases in plasma NE were observed by Goldstein et al. (1985). Jimerson et al. (1980) reported for long-term administration no decline in 24-hour urinary MHPG from baseline levels when up to I .4 mg/day clonidine was given to psychiatric patients for several weeks. The effects of clonidine upon arterial blood pressure (Pettinger, 1975; Goldstein et al., 1985) have established cionidine as an antihypertensive agent. The blood pressure changes found in anorexia nervosa patients with each course of clonidine are comparable in magnitude to the depressor response observed in hypertensive and normal individuals (Leckman et al., 1980; Robertson et al., 1983; Goldstein et al., 1985). The hypotensive action of clonidine is largely centrally mediated, although there is evidence that the drug influences sympathetic outflow by a combination of central and peripheral effects (Wallin and Frisk-Holmberg, I98l). intact periphera! adrenergic receptors seem to be necessary for its hypotensive effects; for example, in patients with orthostatic hypotension associated with degeneration of sympathetic nerve endings, clonidine has no hypotensive effect and may even raise blood pressure (Robertson et al., 1983). The effects of clonidine upon blood pressure were reversible upon discontinuation of the drug. Furthermore, we saw a strong relationship between blood pressure gradually rising to normal levels and the rise in body weight, suggesting that weight gain is associated with a rise in sympathetic tone. In our study, clonidine produced sedative effects each time it was administered. The sedation did not interfere with daily activities but produced a tendency to nap. Most other studies have reported sedation or somnolence after pharmacological doses of clonidine (Gil-Ad et al., 1979; Cohen et al., 1980; Hossman et al., 1980; Leckman et al., 1980; Lanes et al., 1983) although some reports (Jimerson et al., 1980; Knesevich, 1982; Kave et al., 1985h) do not describe sedation with similar doses. The sedative effects, mediated most likely through activation of postsynaptic qreceptors (Nassif et al., 1983) are beneficial in the treatment of hypertension and may be of advantage for hyperactive anorexia nervosa patients.
258 The effects of clonidine on mood have not been so clearly determined. Anxiolytic effects have been found in patients with depression and anxiety disorders (Svensson et al., 1978; Hoehn-Saric et al., 1981), whereas Leckman et al. (1980) report no effects on mood or state anxiety in normals. Both depressant (Simpson, 1973) and antidepressant (Jimerson et al., 1980) effects of clonidine have been described. Our patients reported depressive feelings and anxiety throughout the study. but neither one was consistently affected by clonidine. Overall depressive feelings declined. probably as a result of the overall improvement in the physical and anorectic condition, whereas anxiety even slightly increased throughout the study period, probably in reaction to the weight gain. The observed action pattern of clonidine --its reproducible effects upon blood pressure largely controlled through sympathetic outflow. as opposed to its variable action upon physiologic states, such as hunger and satiety, and on psychologic parameters, such as depression or anxiety--suggests that noradrenergic mechanisms are not the sole contributors to the regulation of eating and mood states and that any drug that would be specific for the treatment of anorexia nervosa needs to have a broader pharmacological range. References Abraham, S.F., Beumont, P.J.V., and Cobbin. D.M. C’atecholamine metabolism and body weight in anorexia nervosa. Uri/i.sh Journul c!f’ P.y~~c,hiutr_~~.138, 244 ( 19X I ). Atkinson, J.. Kirchert7, E.J., and Peters-Haefeli, 1.. Effect of peripheral clonidine on ingestive behavior. fI~.r’.sio/o,q~~and Bdzavior. 21, 73 (197X). Heinle. W.J.. and Davis. J.M. Beluhan, l..J.. Schlemmer. R.F.. Jr.. Casper. R.C., hetween stumptail and rhesus macaques. Differential feeding responses to clonidine Fr&ration frowrdings. 42, I I60 ( 19X3). Biederman, .I., Herzog, D.B., Rivinus. ‘P.M.. Ferber, R.A.. Harper. G.P., Orsulak. P.J.. Harmat7. J.S.. and Schildkraut. J.J. IJrinary M HPG in anorexia nervosa patients with and without ;L concomitant major depressive disorder. Journul qf’ P.s.\,c,hiu/ric Rrwurc~ll. 18, I49
( 1984). Brne. T., Schlemmer, R.F.. and Kat/. N.I.. Failure of clonidine to increase feeding in the golden hamster. 7%~ f%urnmdogi.vt. 26, 223 ( 19X4). Broekkamp, C.. and Van Rossum, J.M. Clonidine-induced intrahypothalamic stimulation of eating in rats. ~.~_l,c,ho~/,hurn?u~,~~/~~,~iu.25, I62 ( 1972). Casper, R.C.. Davis. J.M., and Pandey. G.N. The effect of nutritional status and weight changes on hypothalamic function tests in anorexia nervosa. In: Vigersky. R.A.. ed. Anow.uiu Nerrwsu. Raven Press, New York, p. I.37 ( I977). Charney, D.S., Heninger, G.R.. Sternberg. I1.E.. Hafstad. K.M., Giddings. S., and I.andis. II. H. Adrencrgic receptor sensitivity in depression. Ar(./zi\v.s c?f’ Grmrul P.s.whiutr_l~. 39. 290 ( I982). C’ohen, D..I.. Detlor. .I.. Young, C;.. and Shavwitz. B.A. Clonidine ameliorates Gilles de la I‘ourette syndrome. Archiws c!f’ Gcnc,ru/ P.ytd~h/r_t~. 37, I350 ( 1980). Davidow, M.. Kakaviatos, N.. and Finnerty. F.H., .Ir. The anti-hypertensive effects of an imidaloline compound. ~‘/ir~ic~u/ f’~furr,luc,o/oe~, ant/ ‘Ihrrqwuric~s. 8, 8 IO ( I967). Ilekirmenjian, H., and Maas. J.W. An improved procedure of 3-methoxy-4hydroxyphenylethylene glycol determination by gas-liquid chromatography. Anu[~ricu/ Bioc,henlis/r,,,. 35, I I3 ( I970). Feighner, .I.P.. Robins. E.. Gule, S.B.. Woodruff, R.A.. Winokur, G., and Muno/. G. Diagnostic criteria for use in psychiatric research. ;Ir<~/zivc~sc!/’ General f,s~-c~hiu/r~~, 26, 57 ( I972).
259
Freedman, R., Bell, J., and Kirch, D. Clonidine therapy for coexisting tardive dyskinesia. American Journal of Psychiatry, 137,629 (1980). Garfinkel, P.E. Perception of hunger and satiety in anorexia nervosa. Medicine,
psychosis
and
Psychological
4, 309 ( 1974).
Gerner, R.H., and Gwirtsman, H.E. Abnormalities of dexamethasone suppression test and urinary M H PG in anorexia nervosa. American Journal of’ Ps.vchiarry, 138,650 ( I98 I). Gil-Ad., J., Topper, E., and Laron, Z. Oral clonidine as a growth hormone stimulation test. Lancet, 11,
of’ Clinical 49,805
Endocrinology
and Metabolism,
( 1979).
Grossman,
S.P. Role of the hypothalamus in the regulation of food and water intake. Review, 82, 200 ( 1975). Halmi, K.A., Dekirmenjian, H., Davis, J.M., Casper, R.C., and Goldberg, S.C. Catecholamine metabolism in anorexia nervosa. Archives of’ General Psychiatry. 35,458 ( 1978). Hoehn-Saric, R., Merchant, A.F., and Keyser, M.L. Effects of clonidine on anxiety disorders. Archives of’ General f.sychiatr_y. 38, I278 (198 I). Hokfelt, B., Hedeland, H., and Dymling, J.F. Studies on catecholamines, renin and aldosterone following catapresan (2-(2, 6-dichlor-phenylamine)-2 imidazoline hydrochloride) in hypertensive patients. European Journal c$ fharmacolog_v, 10, 289 (1970). Hossman, V., Maling, T.J.B., Hamilton, C.A.. Reid, J.L., and Dollerby, C.T. Sedative and cardiovascular effects of clonidine and nitrazepam. Journul of’ Clinical fharmacolog_~~ and Therapeutics. 28, I67 ( 1980). Jimerson. D.C., Post, R.M.. Stoddard, F.J., Gillin. J.C.. and Bunney, W.E.. Jr. Preliminary trial of the noradrenergic agonist clonidine in psychiatric patients. Biological P.s.vchiotrv. 15,45 (I 980). Katz., N.L., Schlemmer. R.F., Jr.. and Waller, D.P. Stereospecific reduction by narcotic antagonists of clonidine-induced food intake. Phormucolog~v, Biochemi.s/ry~ und Behavior, 22, Ps_vchological
649
( 1985).
Kaye. W.H., Ebert, M.H., Raleigh, M.. and Lake, C.R. Abnormalities in CNS monoamine metabolism in anorexia nervosa. Archive.s oJ’Generul /?sy~chiarry, 41, 350 (1984). Kaye, W.H., Gwirtsman, H.E.. Lake, C.R.. Siever, L.J.. Jimerson, D.C., Ebert, M.H., and Murphy, D.L. Disturbances of norepinephrine metabolism and alpha-2 adrenergic receptor activity in anorexia nervosa: Relationship to nutritonal state. P.s_l’c,hopharmac,olog,~, Bullefin. 21,419
(1985~).
Kaye, W.H.. Jimerson, D.C., I,ake, C.R., and Ebert, M.H. Altered norepinephrine metabolism following long-term weight recovery in patients with anorexia nervosa. /?s\~chiutr_,~ Research.
14, 333 ( 1985h).
Knesevich, J.W. Successful treatment of obsessive-compulsive disorder with clonidine hydrochloride. American Journul o/’ f.s,)~chiufry~. 139, 364 ( 1982). I.andsberg. I.., and Young, J.B. Fasting, feeding, and the regulation ofsympathetic activity. N~IM’England Journul c!f Medic~inc, 298, I295 ( 1978). I.anes, R., Herrera, A., Palacios. A., and Moncada, Ci. lIecreased secretion of cortisol and ACTH after oral clonidine administration in normal adults. Mc/uholi.sm, 32, 56X ( 1983).
260
Leckman. J.F., Maas, J.W., Redmond, D.E., Jr., and Heninger, G.R. Effects of oral clonidine on plasma 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in man: Preliminary report. L!/k Sciences. 26, 2179 (1980). Le Douarec. J.C., Schmitt, H.. and Lucet, B. Effects of cionidine and of alphasympathominetic agents on food intake: Antagonism by adrenolytics. Journal de Pharnracologie. 3, I87 ( 1982). Leibowitz, SF. Paraventricular nucleus: A primary site mediating adrenergic stimulation of feeding and drinking. fharmacolog_v, Biochemistry and Behavior, 8, 163 (1978). Leibowitl, S.F. Noradrenergic function in the medial hypothalamus: Potential relation to anorexia nervosa and bulimia. In: Pirke, K.M., and Ploog, D., eds. The Psychohiolog_v of Anore.riu Nervosa. Springer-Verlag, Berlin, p. 35 (1984). Luck, P., Mikhailidis, D.P., Dashwood, M.R., Barradas, M.A., Sever, P.S., Dandona, P., and Wakeling, A. Platelet hyperaggregability and increased alpha-adrenoceptor density in anorexia nervosa. Journal of’ Clinical Endocrinology and Metabolism, 57,9 I I (1983). Mauron, C., Wurtman, J.J., and Wurtman, R.J. Clonidine increases food and protein consumption in rats. Ld> Sciences. 27, 78 I ( 1980). Monello, L.F., and Mayer, J. Hunger and satiety sensations in men. women, boys and girls. American Journal of Clinic,al Nutrition, 20, 253 (1967). Nassif, S., Kemp, E., Cardo, B., and Velley, L. Neurochemical lesion of the locus coeruleus of the rat does not suppress the sedative effect of clonidine. European Journal of Pharmacology. 91, 69 ( 1983). Pettinger, W.A. Clonidine, a new antihypertensive drug. New England Journal of Medicine. 293, I I79 ( 1975). Redmond, D.E., Jr., and Huang, Y.H. New evidence for a locus coeruleus-norepinephrine connection with anxiety. L@ Sciemes. 25(26), 2 I49 ( 1979). Redmond, D.E., Jr., Huang, Y.H., Snyder, D.R., Maas, J.W., and Baulu, J. Hyperphagia and hyperdipsia after locus coeruleus lesions in the stump-tailed monkey. L@ Sciences. 20, 1619 (1977). Riederer, P., Toifl. K., and Krulik, P. Excretion of biogenic amine metabolites in anorexia nervosa. Clinica Chimica Acta. 123, 27 (1982). Robertson, D., Goldberg, M.R., Hollister, A.S., Wade, D., and Robertson, R.M. Clonidine raises blood pressure in severe idiopathic orthostatic hypotension. American Journal of Medicine, 74, I93 (I 983). Schlemmer, R.F., Jr., Casper, R.C.. Narasimhachari, N., and Davis, J.M. Clonidine induced hyperphagia and weight gain in monkeys. Ps.vc,hopharmac,ol~~~.v, 61, 233 (1979). Schlemmer, R.F., Jr., Elder, J.K., Casper, R.C., and Davis. J.M. Clonidine-induced hyperphagia in monkeys: Evidence for alpha-2noradrenergic receptor mediation. Psyc~hopharmac~olo~y, 73, 99 ( I98 I ). Seedat, Y.K., Vawda, E.I., Mitha. S., and Ramasar, R. A comparison of alpha-methyldopa (Aldomet) and ST I55 (Catapres) in the treatment of hypertension. South A,frican Medical Journal, 44,300 ( 1970). Siever, L.J., Uhde, T.W., Jimerson, D.C., Lake, C.R., Silberman, E.R., Post, R.M.. and Murphy, D.L. Differential inhibitory noradrenergic responses to clonidine in 25 depressed patients and 25 normal control subjects. American Journul or Psychiutry, 141, 733 (1984). Simpson, F.O. Hypertension and depression and their treatment. Australian and New Zealand Journal oj’ Psychiatry. 7, I33 ( 1973). Stock, M.J., and Rothwell, N.J. Sympathetic control of brown adipose tissue in the regulation of body weight. Biochemical Soviet.? Tronsuc~tions. 6, 525 ( 198 I). Svensson, T.H., Bunney, B.S., and Aghajantan, G.K. Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic antagonist clonidine. Bruin Resrurc~h. 92, 29 I (1975). Svensson, T., Persson, R., Wallin, L., and Walinder. .I. Anxiolytic action of clonidine. Nordisk Psykiatrist Tidsskrijt. 32,439 ( 1978). Taylor, J.A. A personality scale of manifest anxiety. Journal of Ahnormal and Sociul Psychology. 48, 285 (1953). Wallin, B.G., and Frisk-Holmberg, M. The antihypertensive mechanism of clonidine in man: Evidence against a generalized reduction of sympathetic activity. H_vpertmsion, 3, 340 (1981).