CURRENT THERAPEUTIC RESEARCH@ VOL. 61, No. 6, JUNE 2000

Behavioral and Hormonal Effects of Low-Dose Pergolide in Children and Adolescents with

Gilles de la Tourette’s Syndrome

Donald L. Gilbert,’ Floyd R. Sallee, Lauren Sine,4 and Gopalan Sethuraman2

‘Division of Neurology, ‘Division of Psychiatry, and “Pediatric Pharmacology Research Unit, Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, and

*Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina

ABSTRACT

Objective: To assess the acute and subacute (24 weeks) toxicity of low-dose pergolide in children and adolescents with Gilles de la Tourette’s syndrome.

Background: Pergolide is a mixed dopamine-receptor agonist. At low doses, it may suppress tics in children with Tourette’s syn- drome. Potential adverse behavioral and hormonal effects of low- dose pergolide in children have not previously been reported.

Methods: Children with Tourette’s syndrome were studied after administration of pergolide for 1 day and for 24 weeks. Repeated measurements of serum prolactin and growth hormone levels were performed. Repeated psychologic assessments were performed us- ing the Visual Analogue Mood Scale subscales for happy, drowsy, energized, and tense. Repeated-measures analysis of variance was used for statistical analyses.

Results: Low-dose pergolide significantly suppressed serum prolactin levels, acutely and chronically. No changes in growth hor- mone or mood subscales were demonstrated.

Conclusions: Low-dose pergolide in children with Tourette’s syndrome suppresses prolactin but not growth hormone. Its use may not produce the mood-related adverse effects commonly associated with neuroleptic drugs.

Keg words: pergolide, children, adolescent, pharmacodynamic, prolactin, Gilles de la Tourette’s syndrome. (Curr Ther Res Clin Exp. 2000;61:378-387)

INTRODUCTION

Pergolide is an ergot derivative with mixed D,QjD, dopamine-receptor agonist activity.’ It has been used to treat adults with Parkinson’s disease2 and restless legs syndrome.3 Recently, 2 studies4a5 and 1 case series? have

Address correspondence to: Donald L. Gilbert, MD, Neurology, OSB5, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229.3039 (email: d.gilbert@chmcc.org). Accepted for publication April 13, 2000. Printed in the USA. Reproduction in whole or part is not permitted.

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D.L. GILBERT ET AL.

demonstrated efficacy of low-dose pergolide (150 to 300 pgld) for tic sup- pression in children with Gilles de la Tourette’s syndrome. In addition, pergolide appeared to be well tolerated.

In this study, our objective was to assess the acute and subacute (~4 weeks) toxicity of low-dose pergolide in children and adolescents with Tourette’s syndrome. We assessed common mood-related adverse effects of neuroleptic drugs, an established treatment for moderate to severe tics.7 We also assessed potential pituitary-related adverse effects previously re- ported in adults. Pergolide suppression of prolactin secretion in adults is dopamine receptor-mediated and forms the basis for medical treatment of pituitary prolactinomas.’ Suppression of pituitary release of growth hor- mone would thus be of concern in children.

The purpose of this study was to determine whether administration of low-dose pergolide is associated with adverse behavioral or hormonal events in children with Tourette’s syndrome. We also sought to determine whether such events were transient, chronic, or cumulative. For this rea- son, subjects were assessed at the time of first dose and after at least 4 weeks of treatment.

PATIENTS AND METHODS

Study Design and Patient Selection

The acute assessment involved 12 patients aged 8 to 17 years who were naive to pergolide. These patients received their first dose of per- golide or placebo, and acute behavioral and hormonal effects were assayed as described in the study protocol below. Five patients had previously received neuroleptic drugs (haloperidol, pimozide, risperidone, and ziprasidone).

The chronic assessment involved 16 patients aged 8 to 17 years. Ten of these were participants in the acute study; 6 additional patients treated chronically (1 to 9 months) with pergolide for tic suppression also were recruited. On the day of the chronic assessment, all patients received the dose they had been taking during the previous month, and behavioral and hormonal effects were assayed as described in the study protocol.

A medical history was obtained for each patient, and each received a standard medical and neurological examination, including assessment for abnormal involuntary movements. Diagnoses of Tourette’s syndrome, chronic motor disorder, or vocal tic disorder were made using Diagnostic and Statistical Manual, Fourth Edition9 criteria by the primary clinical investigator (FRS) using all available clinical information.

Pregnant or breast-feeding girls were excluded from the study. Chil- dren with other nontrivial medical illnesses or laboratory test abnormali- ties also were excluded.

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This protocol was approved by the institutional review board of the Medical University of South Carolina, where the study was conducted. Informed consent was obtained from parents and from adolescents aged 13 to 17 years.

Study Protocol-Acute Assessment

For the acute dose study, 12 patients nayve to pergolide were weaned off all other psychotropic medications for ~2 weeks. Previous medications included haloperidol, pimozide, risperidone, ziprasidone, clonidine, carba- mazepine, and clomipramine. Patients were admitted to the General Clini- cal Research Center (GCRC) at the Medical University of South Carolina, and an intravenous catheter was inserted for blood sampling. Patients were assigned to treatment groups by block randomization. Groups were placebo (n = 3) or pergolide 25 Fg (n = 4),50 pg (n = 3), or 100 kg (n = 2) in a single oral dose. Investigators and patients were blinded to the dose.

The Visual Analogue Mood Scale (VAMS)l’ and blood tests were performed 30 minutes before the oral dose of medication and were repeated at 30- to go-minute intervals for 6 hours. The following subscales were used in the VAMS: happy = cheerful, elated; drowsy = sleepy, tired; energized = fidgety, physically restless, unable to remain still, antsy; and tense = nervous, anxious, uptight, jittery. Patients were asked to place a mark on a line between 0 = not at all and 100 = extremely, and the re- sults were recorded in millimeters. Heart rate and blood pressure were checked when blood was drawn.

Adverse effects were elicited by spontaneous reporting at the time of VAMS.

Studg Protocol-Chronic Assessment

After discharge, 10 of 12 children chose to participate in the l-month chronic study. Of the 2 patients who did not participate in the second phase, 1 had received placebo in the acute study and chose not to return and 1 was lost to follow-up. Six patients already treated chronically (1 to 9 months) with pergolide also were recruited.

Patients were assigned to a dose group by block randomization. All patients were treated with an initial dose of pergolide 25 Fgld; in 2 to 3 days the dose was titrated to 50 Fgld TID. Four patients remained at this dose, and in 8 the dose was titrated upward by 50 Fgfd every 3 days to a final dose of 150 kg/d TID. In 4 patients the dose was titrated upward by 50 kg/d every 3 days to a final dose of 300 kg/d TID. All patients were treated for 1 month. Patients and investigators were blinded throughout to dosing.

All patients were admitted to the GCRC for the chronic assessment. Heart rate, blood pressure, and hormonal and behavioral effects were stud-

D.L. GILBERT ET AL.

ied 30 minutes before dosing and every 30 to 60 minutes thereafter for 6 hours, exactly as was done in the acute assessment.

After the chronic assessment, newly treated patients were given the option of continuing low-dose pergolide treatment for tic suppression.

Laboratory Methods

Serum prolactin levels were measured with a commercially available kit (Prolactin 1OOT Kit, Nichols Institute Diagnostics, San Juan Capis- trano, California), as were levels of human growth hormone (HGH 1OOT Kit, Nichols Institute Diagnostics).

Statistical Analysis

Prolactin and growth hormone levels and data from the VAMS were subjected to repeated-measures analysis of variance to assess the impact of time on outcomes related to dose. Variance was partitioned to assess the effects of dose group, time, and time x group interaction effect at -30, 30,60, 90, 120, 180, 240, and 360 minutes from the dose of pergolide or placebo. Type 1 errors for all analyses were controlled at 5%. A signifi- cant time x group interaction effect indicates a difference in response to the drug at a fixed time point. Time-response curves were plotted for all outcomes at each dose. More detailed pharmacokinetic analysis could not be performed in this low-dose study because the concentration of pergolide could not be reliably measured.

RESULTS

Eighteen subjects (17 males, 1 female; mean age, 12.2 years [range, 8-17 years]) were enrolled in the study.

Visual Analogue Mood Scales

There was wide between-patient variation in the reporting of VAMS subscales. In both the acute and chronic studies, the variance in VAMS measurements (happy, drowsy, energized, or tense) was accounted for by between-patient and within-patient variation, not by drug or dose effect (analysis of variance tables on file). The acute and chronic measurements of drowsiness are shown in Figures 1 and 2, respectively.

Prolactin and Growth Hormone

In the acute dose study, there was a significant decrease in serum prolactin levels after administration of low-dose pergolide. Of note, only 1 patient receiving pergolide 100 kg had blood suitable for analysis. Drug doses accounted for significant variance in serum prolactin levels (F = 7.92; df = 3, 7; P = 0.019). The time effect was also significant (F = 44.85; df = 6, 42; P = O.OOl), as was the time x dose effect

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F 80-

g 2 60-

s! .- 5

40-

6 20-

-30 30 60 90 120 180 240 360

t Pergolide 25 m -A- Pergolide 50 p-g -f Pergolide 100 pg 6 Placebo

Time (min) Figure 1. In the acute study, results of the Visual Analogue Mood Scale subscale for drowsy

(sleepy, tired) before and after the administration of placebo or pergolide 25 pg, 50 kg, or 100 kg. 0 = not at all; 100 = extremely.

(F = 6.83; df = 18, 42; P = 0.001). At 4 hours after dosing, serum prolac- tin levels were 5.6 + 5.7 ng/mL with placebo, 1.2 f 0.8 ng/mL with per- golide 25 kg, 1.1 + 0.8 ng/mL with 50 kg, and 0.4 ng/mL (sample n = 1) with 100 Fg (Figure 3, table).

100

80 F 5 3 60 -A- Pergolide 50 pi

it t Pergolide 150 JJJI

‘5 40 -O- Pergolide 300 kg

g h 20

0 -30 30 60 90 120 180 240 360

Time (min) Figure 2. In the chronic study, results of the Visual Analogue Mood Scale subscale for drowsy

(sleepy, tired) before and after oral administration of a chronic dose of pergolide. Sixteen patients had received ~1 months of 50 *g/d, I50 kg/d, or 300 pg/d TID. 0 = not at all; 100 = extremely.

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t Pergolide 25 pg + Pergolide 50 pg t Pergolide 100 pg A- Placebo

-2’ , I I I I I I I I -30 30 60 90 120 180 240 360

Time (min) Figure 3. In the acute study, serum prolactin levels in 12 patients before and after oral

administration of placebo or pergolide 25 kg, 50 pg, or 100 pg.

In the chronic dose study, all dose groups had serum prolactin levels <2 ng/mL; the levels remained suppressed after the administered dose (Figure 4). Fifty-three values measured were below the level of detection of the assay. Repeated-measures analysis of variance was not performed, because the power to detect a dose- or time-related difference would have been low due to the high number of missing (below-detection) values.

There were no significant acute or chronic low-dose pergolide effects on serum growth hormone levels.”

Spontaneously Reported Adverse Events

There were no serious adverse events. Two children at the first visit and 3 at the second experienced nausea. One patient had transient stom-

Table. Serum prolactin levels (mean * SD) in the acute study before and after oral admin- istration of the first dose of placebo, and pergolide 25 pg, 50 pg, and 100 pg.

Serum Prolactin Level (ng/mL)

Time’ (min) Placebo 25 p9

Pergolide Dose*

50 M 100 pg+

-2 4.6 9.7 + 5 9.4 5.0 14.4 4.9 f f 6.7 2.8 11.4k7.2 5.3 2 3.0 3.6 2.3

240 360

ii:! : ;:; 5.6 : 5.7 6.5 + 7.9

2.5 f 1.5

;1:28% 0.7 : 0.3

2.3 t 1.3 0.9 1.4 + 0.6 0.5 1.1 t 0.8 0.4 1.1 *0.5 0.3

* By analysis of variance, drug dose (P = 0.019), time (P = O.OOl), and time x dose (P = 0.001) were significant factors.

+ Only 1 patient randomized to 100 pg had blood that was suitable for analysis.

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s 14-

E a,

12-

5 lo- C ‘S 8- 4 ,o

fj-

n 4-

-A- Pergolide 50 pg t Pergolide 150 Fg -O- Pergolide 300 @IJ

-2’ 1 -30 30 60 90 120 180 240 360

Time (min) Figure 4. In the chronic study, serum prolactin levels before and after oral administration of

a chronic dose of pergolide. Sixteen patients had received ~1 months of 50 kg/d, 150 pg/d, or 300 *g/d TID.

ach pain. There was no hypotension or bradycardia. No children experi- enced headache or dizziness.

DISCUSSION

Gilles de la Tourette’s syndrome is a neuropsychiatric disorder with child- hood onset that is characterized by motor and phonic tics. The prevalence is estimated to be 5 to 10 per 10,000 children.12 Although studies7,13 have shown that the high-potency D, dopamine-receptor antagonists haloperi- do1 and pimozide are effective in suppressing tics, adverse effects such as sedation, restlessness (akathisia), extrapyramidal symptoms, and electro- cardiographic changes make these medications suboptimal in some pa- tients. l4 Long-term r’ asks of tardive dyskinesia are also of concern.15

Alternative medical treatments with fewer short- and long-term ad- verse effects should be studied. One area of recent interest is the use of dopamine agonists for tic suppression. 16,17 The mechanism of tic suppres- sion is unclear but may involve preferential binding to presynaptic D, receptors, thereby decreasing endogenous striatal dopamine.”

The effectiveness of a treatment encompasses both efficacy and ad- verse effects. This may be especially important in Tourette’s syndrome, in which comorbid behavioral problems are common, and, therefore, the be- havioral effects of medications may be especially troublesome. Hormonal effects are also important in the pediatric population. The present study is

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the first systematic study in children of these potential adverse events with the use of a dopamine agonist.

In this study of low-dose pergolide in children, the drug was well tolerated and significant effects on happiness, drowsiness, energy, and tension were not detected after acute or chronic administration. A limita- tion of this study is the possibility of type II error in the VAMS analysis due to the small number of patients plus the unexpectedly large between- patient and within-patient variation. This variability appeared to be sub- stantially greater than was seen in our previous study of clomipramine in depressed adolescents” and suggests that there may be issues of validity or reliability for the VAMS in children and adolescents with Tourette’s syndrome. Future pharmacodynamic studies using visual analogue scales in this population may require larger samples and other measures to assess more definitively any mood-altering adverse effects of low-dose pergolide.

Previous studies20,21 have shown that pergolide lowers serum prolac- tin levels in healthy adults without affecting other pituitary hormones. This study confirms and extends those findings to children and adolescents with Tourette’s syndrome. A single dose of pergolide 25 pg, one-100th of the daily dose used for Parkinson’s disease,2 suppresses serum prolactin levels. After 1 month of treatment, doses as low as 50 Fgld suppressed serum prolactin levels to ~2 ng/mL. This may have implications for female patients wishing to conceive or lactate. Further studies to determine whether levels normalize after discontinuation of pergolide therapy in chronically treated children will be important.

As previously shown in healthy adults,20 we were unable to demon- strate an effect of pergolide on serum growth hormone levels. Thus, in children as in adults, the pituitary actions of pergolide appear to be dopa- mine receptor-mediated and to affect only prolactin. It was important to confirm this finding in children, given the concerns about normal growth in this age group.

CONCLUSIONS

The present study suggests that low-dose pergolide, when used for tic suppression in children and adolescents, might not be associated with some of the more common adverse effects found with the neuroleptic treat- ment of Tourette’s syndrome, such as sedation, cognitive blunting, rest- lessness, and depression. These effects cannot be excluded on the basis of this study, however, and should be monitored closely in long-term studies of pergolide for tic suppression. There does not appear to be reason for concern about the effects on growth hormone with this treatment; how- ever, prolactin levels are suppressed.

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Acknowledgments

This research was supported by the National Institutes of Mental Health, Bethesda, Maryland (grant ROl MH46673) and the US Food and Drug Administration, Rockville, Maryland (grant FD-R-001111).

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