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Clonidine and Gilles de la Tourette's syndrome Double-blind study using objective rating methods.

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Clonidine and Gilles
de la Tourette's Syndrome:
Double-Blind Study Using
Objective Rating Methodi
Christopher G. Goetz, MD,' Caroline M. Tanner, MD,"
Robert S. Wilson, PhD,? V. Susan Carroll, MS,"
Peter G. Como, PhD,S and Kathleen M. Shannon, MD"
Clonidine has been suggested to be effective in Gilles de
la Tourette's syndrome (GTS), but no double-blind
study has ever evaluated its effects using objective measures. Thirty patients with GTS completed a Gmonth
placebo-controlled crossover study of the effectiveness
of clonidine. Videotapes were obtained at each +week
visit and were evaluated randomly at the end of the
study for distribution, frequency, and severity of motor
and vocal tics. Quantifiable psychometric examinations
were performed as well. T h e use of clonidine did not
significantly ( p < 0.05) reduce motor tics, vocalizations,
or behavior. T h e effect of a low dose (0.0075 mg/kg/day)
was no different from that of a high dose (0.015 mglkgl
day); children's responses were no different from adults';
and those also receiving neuroleptic agents showed the
same lack of efficacy as seen in patients on no other
medication. Dosing schedule did not affect the objective
ratings; scores from clonidine given twice a day were
equivalent to those for three times a day.
Goetz CG, Tanner CM, Wilson RS, Carroll VS,
Como PG, Shannon KM: Clonidine and Gilles
de la Tourette's syndrome: double-blind study
using objective rating methods.
Ann Neurol21:307-310, 1987
Gilles de la Tourette's syndrome (GTS) is a chronic
neurological disorder of childhood onset characterized
by multiple motor tics and vocalizations E13}. Associated psychological features include attention deficit,
obsessive compulsive disorder 191, and nonspecific
behavioral abnormalities El6}. Treatment with neuroleptic agents has been successful in up to 90% of
cases El}, but dose-limiting side effects and the risk of
tardive dyskinesia have led to the search for alternative
therapies. Since Cohen and associates 143 first reported
the successful use of clonidine in patients with GTS in
From the "Department of Neurological Sciences and ?Department
of Psychology and Social Sciences, Rush University, RushPresbyterian-St. Luke's Medical Center, 1725 W Harrison St,
Chicago, IL 60612; and the #Departments of Neurology and Psychiatry, University of Rochester School of Medicine and Dentistry,
Rochester, NY 14642.
Received May 5, 1986, and in revised form Aug 5. Accepted for
publication Aug 6, 1986.
Address correspondence to Dr. Goen.
1979, published studies of over 190 patients have reported response rates of between 10 and 90%. Most
studies have focused o n global changes and have not
used objective measures to monitor clinical response.
We report what we believe to be the first large
placebo-controlled double-blind crossover study of
clonidine with objective monitoring of changes in
motor, vocal, and behavioral manifestations of GTS.
We studied 23 males and 7 females who met the diagnostic
criteria of DSM-111 for GTS C2). Their mean age was 19.2
years (range, 8 to 62); 6 were adults (21 years or older) and
24 were children. Patients were excluded who had a history
of hypotension, coronary or cerebrovascular insufficiency,
chronic renal failure, and exposure to clonidine. Nineteen
patients were taking no medication for the treatment of
GTS, and 11 were receiving stable doses of neuroleptic
agents (haloperidol, 6; fluphenazine, 4; trifluoperazine, 1).
At baseline, the patient group included, as assessed using the
scale in Table I: motor tics--8 severe, 17 moderate, and 5
mild; vocal tics-1 severe, 4 moderate, and 16 mild. All
patients gave informed consent.
Drug Administration
The randomized double-blind crossover design included two
12-week treatment phases, one with clonidine and the other
with a placebo, each preceded by a 1-week placebo period.
The initial clonidine dose was 0.00251mg/kg/day, and patients increased their dose over 6 weeks to either 0.0075 or
0.015 mglkglday, depending on efficacy and toxicity. The
stable dose of medication was maintained for 6 weeks. Medication was given in two divided doses during the first 3 of
these 6 weeks, and in three divided doses during the last 3
weeks. Drugs were tapered over 1 week prior to crossover
or termination of the study.
Patients were seen every 3 weeks for clinical evaluation and
assessment of vital signs and adverse effects. At baseline and
every visit thereafter, simultaneous video and audio recordings were made of full frontal body views (far) and head and
shoulders only (near) under the following conditions: patient
seated quietly with examiner in the room; patient reading
aloud with examiner in the room; patient seated quietly with
no examiner in the room.
The only segments rated were those recorded with no
examiner present, as they reflected minimal voluntary tic
suppression 115). At completion of the study, two 1-minute
videotape segments focusing near and far for each patient
and each visit were randomized and rated by two blinded
observers. Each videotape segment was scored for the distribution of motor tics and for the frequency and severity of
motor tics and vocalizations. For the distribution of motor
tics, involvement of each of the following eleven body areas
was noted: eyes, nose, mouth, neck, shoulders, arms, hands,
trunk, pelvis, legs, and feet. The frequency score consisted of
the number of discrete motor tics or vocalizations counted
Table I. Severity Rating Scales
1-minimal; could be normal
2-mild; limited to a single muscle group
3-moderate; limited to a single body part
4-severe; involving more than one body part
5-extreme; complex behaviors
1-minimal; could be normal
2-mild; single words or sounds, separated by at least 1
breath or 4 seconds
3-moderate; words or sounds repeated 2 or 3 times in
series or single obscenities separated by at least 1
breath or 4 seconds
4-severe; words or sounds repeated 4 or more times in
series or obscenities repeated 2 or 3 times in series
5-extreme; obscenities repeated 4 or more times in
during each segment. Severity was determined on a 0 to 5
scale for motor tics and vocalizations (see Table 1).
Interrater reliabilities, computed on 30 cases from one
evaluation period, were: body areas, r = 0.60 ( p < 0.02);
number of motor tics, Y = 0.89 ( p < 0.001); number of
vocal tics, Y = 0.97 ( p < 0.001); severity of motor tics, r =
0.76 ( p < 0.001); and severity of vocal tics, r = 0.87 ( p <
0.001). The temporal stability of these scales was evaluated
by comparing scores over three consecutive 3-week placebo
periods. The resulting 15 correlations ranged from 0.53 to
0.80, with the exception of the number of vocalizations
which ranged from 0.05 to 0.43. To evaluate the extent to
which the scale data were representative of tic symptoms
over a period longer than the filming, we rated patients on
three outpatient visits using the global scale of Shapiro and
colleagues E12); this scale is based on both observation and
interview and is concerned with severity, character, and degree of volitional control over symptoms. When the five
measures from our scale were correlated with the Shapiro
scale, 13 of 15 correlation coefficients were significant and of
moderate size (0.30 to 0.60). These combined analyses suggested that our tic rating scale was reliable, showed good
temporal stability despite the natural expected tendency of
tic symptoms to wax and wane, and gathered data representative of tic behavior considered from a more global standpoint.
A psychological test battery was administered at baseline
and every 6 weeks. In all patients, obsessional traits were
assessed by the Sandler and Hazari obsession scale [l 11 and
attentiveness by simple visual reaction time. For the latter
procedure, there were 10 practice and 40 test trials; mean
reaction time in milliseconds was the dependent measure.
For children, conduct and hyperactivity were assessed by
Conners’ Parent Symptom Questionnaire [GI and a modified
version of the Werry-Weiss-Peters Activity Rating Scale
308 Annals of Neurology
Vol 21 N o 3 March 1987
[lo}. Adults completed the Depression, Psychasthenia, and
Hypomania scales from the Minnesota Multiphasic Personality Inventory [7}.
Videotape rating scores and psychological battery results
from the clonidine phase were compared to scores from the
placebo phase using paired t tests.
Objectively, there was no significant ( p < 0.05) improvement in motor tic distribution, frequency, or severity when patients were taking clonidine (Table 2).
The frequency and severity of vocalizations were also
not significantly reduced. Psychological measures in
both children and adults were also unchanged. There
was no statistically significant difference in any measure between a b.i.d. versus a t.i.d. dosing schedule.
For the 17 patients who reached 0.015 mglkglday,
there was no significant difference in any measure
compared to results seen at a dosage of 0.0075 mg/
kglday. When the subgroups receiving Concomitant
neuroleptic agents or no other medications were analyzed separately, results with clonidine still did not differ from those with placebo. Likewise, adults and children showed the same lack of objective response to
Subjectively, 13 patients felt that they improved
globally during the clonidine phase; 11 patients felt
motor tics abated, 7 felt vocal tics were reduced, and 8
felt behavior or attentiveness improved. Nine patients
felt that they improved globally during the placebo
phase; 9 patients reported diminished frequency or
severity of motor tics, 6 reported reduced vocal tics,
and 8 patients felt behavior or attentiveness improved.
Sixteen patients elected to continue taking clonidine
following completion of the double-blind phase. These
included some patients who had shown neither subjective nor objective improvement while on clonidine,
but who did not want to take a neuroleptic agent.
Separate analysis of the videotapes and psychological
scores from the 16 patients who continued on openlabel clonidine failed to reveal statistically significant
changes in any measure.
Adverse effects of clonidine were common and included sedation (57%), dry mouth (37%), and restlessness (2 7 %). While several patients also complained
of sedation and dry mouth during the placebo phase,
this was never experienced to the same degree as that
on clonidine. N o clinically significant changes were observed in the supine or standing blood pressure or
pulse, or in any hematological or biochemical measure.
In an open trial of clonidine in 25 patients with GTS,
Cohen and associates 153 reported that there was
global improvement in 70% and suggested that behavioral symptoms were most responsive to clonidine.
Tabh 2. Means and Standard Deviations" for Tic and Psychological Scores
Motor tics
Body areas
5.6 (1.9)
46.3 (28.2)
3.1 (0.9)
5.3 (2.0)
41.8 (23.6)
3.0 (0.8)
4.3 (4.4)
1.2 (1.0)
5.6 (8.7)
1.0 (1.2)
Reaction time (msec)
Obsession sum
WWPARS (hyperactivity)
Hyperactivity index
239.1 (35.4)
17.3 (7.8)
17.2 (9.5)
1.4 (0.6)
1.1 (0.6)
233.6 (36.1)
18.0 (7.3)
18.6 (10.2)
1.3 (0.6)
1.1 (0.6)
64.0 (16.8)
67.5 (17.4)
66.0 (16.1)
64.3 (19.1)
67.3 (16.7)
65.8 (12.0)
"Standard deviations are given in parentheses.
NS = not significant; WWPARS = Werry-Weiss-Peters Activity Rating Scale; MMPI = Minnesota Multiphasic Personality Inventory.
Shapiro and colleagues { 143 retrospectively analyzed
data in 68 patients, and found that 17% had global
improvement. When assessment was limited to motor
and vocal symptoms, Shapiro and co-workers found
improvement in 9 of 36 patients in an open trial c123,
and Borison and associates found 7 of 12 patients improved in a double-blind crossover trial with haloperido1 131. Only kckman and colleagues {l2] separately
evaluated motor, vocal, and behavioral symptoms in a
single-blind placebo-controlled study in 13 patients.
They found that 28 to 33% of patients showed improvement, that vocal symptoms were more likely to
respond than motor tics, and that in a small group of
patients behavioral measures improved more than
motor and vocal manifestations.
The wide variance in findings in these studies and
the general lack of objective measurement prompted
this controlled evaluation. The protocol was specifically designed to evaluate five controversies related to
clonidine: (1) Is it effective at all? (2) Are there differential effects of low dose versus high dose? (3) Is dosing frequency important? (4) Do patients on neuroleptic agents respond to clonidine differently than
those otherwise untreated? ( 5 ) Do children respond
differently than adults? Because Borison and coworkers {3] suggested that low dose improves and
high dose may exacerbate GTS, we evaluated two different doses. Because Cohen et al { 5 ] and Leckman et
al 181 suggested that the half-life of clonidine in children is short and that frequent dosing may be more
beneficial, we compared efficacy when clonidine was
given twice daily and three times daily. Since more
frequent dosing would have required additional involvement of school nurses and teachers, we did not
study more frequent doses. We recruited patients in
order to have at least one third taking concurrent
neuroleptic agents, and thereby evaluated additive,
synergistic, and antagonistic effects of drug combinations. Recognizing the natural fluctuations in tic distribution and severity over weeks, we designed a prolonged study with frequent patient evaluations. In
addition to the scientific objectivity afforded by the
double-blind protocol, this method was particularly
important in GTS, because tics can be volitionally suppressed and characteristically fluctuate with emotional
changes and expectations.
Our negative findings for all these questions challenge the role of clonidine in the treatment of most
patients with GTS. Realizing that GTS likely represents a heterogeneous disorder, we attempted to analyze all available subgroups and did not even note
trends toward improvement with clonidine. It is still
possible, however, that another subgroup would show
a positive effect from clonidine.
In spite of the high prevalence of side effects during
the clonidine phase, the frequent number of patients
and families who subjectively reported improvement
during the placebo phase suggest that the study was an
effective double-blind protocol even without an active
placebo. The use of objective video data combined
with quantifiable behavioral measures for evaluating
drug efficacy has not been reported before in GTS.
Brief Communication: Goetz et al: Clonidine and Tourette's Syndrome
These methods are quick and practical; they did not
require extensive ancillary equipment or personnel
and were easily incorporated into a regular outpatient
Undoubtedly, our short filming samples could not
completely summarize variations in patients’ symptoms
over a full 3-week evaluation interval. The same limitations have plagued objective rating methods for other
fluctuating movement disorders such as Parkinson’s
disease, Huntington’s chorea, and tardive dyskinesia.
However, the positive correlation between our scale
and the Shapiro global measure of GTS severity demonstrates that our technique, despite its brevity, provides a representative sample of symptomatic behavior. We believe it is the first objective scale to
quantitate tic disorders phenomenologically and may
be useful in testing the efficacy of future putative
therapeutic agents for GTS.
Supported in part by a grant from Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT.
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