Treatment approaches in Gilles de la Tourette syndrome

Emin R~.wctrch Bullerin, Vol. 11, pp. 205-208, 1983. 0 Ankho International Inc. Printed in the U.S.A.

Treatment Approaches in Gilles de la Tourette Syndrome RICHARD L. BORISON,* LOLITA ANG,t WILLIAM J. HAMILTON,S BRUCE I. DIAMOND* AND JOHN M. DAVIS?

*Department of Psychiatry, Downtown V.A. Medical Center Medical College of Georgia, Augusta, GA 30910 tNlinois State Psychiatric Institute, 1600 West Taylor Street, Chicago, IL 60612 *Department of Neurology, Medical College of Georgia, Augusta, GA 30912

BORISON, R. L., L. ANG, W. J. HAMILTON, B. I. DIAMOND AND J. M. DAVIS. Treurment ccpprouchcs in Gil/es de lo Tourefte syndrome. BRAIN RES BULL ll(2) 205-208, 1983.-The neurological disorder Gilles de la Tourette syndrome is most often treated with the receptor blocker haloperidol, which also produces multiple side-effects, including the risk for tardive dyskinesia. In placebo control double-blind studies, two other neuroleptic drugs, fluphenazine and trifluogerazine, were found to be as efficaceous as haloperidol, but with fewer side-effects. In other studies, clonidine was shown to be equally efficaceous with haloperidol, but did not produce adverse central nervous system side-effects. To treat the extrapyramidal side-effects accompanying the treatment of Tourette syndrome with neuroleptic agents, amantadine and benztropine were compared in a crossover study. It was demonstrated that amantadine is a superior agent in treating the side-effects of haloperidol treatment in Tourette syndrome. The use of lithium was without significant action upon lessening the tics of Tourette syndrome. Amantadine

Clonidine

Gilles de la Tourette syndrome

GILL&3 de la Tourette’s Syndrome (GTS) is a neurological disorder characterized by multiple and migratory involuntary motor and vocal tics. Previously it has been assumed that GTS involves a hyperdopaminergic state in the corpus striatum, primarily affecting nigrostriatal dopaminergic transmission, as is manifest in Huntington’s chorea and tardive dyskinesia. For these reasons, the major pharmacotherapeutic intervention in GTS has been the use of neuroleptic drugs, with their potent extrapyramidal system dopamine blocking abilities. In particular, haloperidol, which is among the most potent neuroleptic agents in the production of extrapyramidal side-effects, has proven eflicaceous in the treatment of GTS 161. Although of proven efficacy, haloperidol and similar agents also produce many disabling short-term side-effects, including sedation, apathy, depression, dystonic reactions and pseudoparkinsonism. More ominous are the potential long-term adverse sideeffects of these drugs, namely tardive dyskinesia. It is for these reasons that in our GTS clinic we have carried out pharmacological trials aimed at finding therapeutic altematives to haloperidol, which may produce equivalent therapeutic efficacy with fewer side-effects.

Lithium

60% of patients first received the diagnosis of GTS at our clinic, with the remaining 40% having been previously diagnosed and treated elsewhere, but had been treatment failures. Patients in the clinic routinely have electroencephalographic and neuropsychological tests taken to aid in the diagnosis of GTS which is made by history and clinical impression, according to the criteria of Shapiro [5]. All patients participating in studies signed informed consents. The evaluation of tics was accomplished using a 15 item scale which measured individual tics as to their frequency and intensity. In this fashion it was possible to not only follow global changes in tics, but to also determine changes in individual tics. When appropriate, both the patient and family members rated tics, as well as the clinical determination made by the physician on every outpatient visit. RESULTS AND DISCUSSION

A. Comparison

of Haloperidol

with Clonidine

There has been recent evidence that the a-adrenergic agent clonidine may possess therapeutic efficacy in GTS [1,2]. To study the therapeutic effects of clonidine we selected a study group of fourteen males and eight females, ranging in age from 844 years (mean= 16 years), who had been symptomatic with GTS for an average of 8.5 years. Patients were blind to the medication that they received, and participated in trials comparing placebo and halopetidol to

METHOD

Patient

Halopexidol

Sample

In 1978 we established a GTS outpatient clinic in Chicago and a clinic in 1981 in Augusta, during which time we have had over 200 patients registered in our clinic. Approximately

205

cionidine in an ABACA design. Assessment of efficacy was made using a global assessment scale for tics. The minimum duration of treatment with each medication was nine weeks. A flexible dosage design was used, allowing for increasing the dosage of medication until either full suppression of the tics occurred or side-effects intervened. Dosages were increased by 0.25 mg increments in the case of haioperidol, and 0.025 mg increments for clonidine. The daily dosage range for clonidine was 0.25-0.9 mg, and that for haloperidol was 2.5-U mg. During the course of the study patients were seen weekly for the assessment of therapeutic actions as well as sideeffects. The major side-effects encountered with haloperidol administration were sedation (151221, lethargy f 121221, depression (5/22), akathisia (9/22), pseudoparkinsonism (6122) and dystonic reactions (3/22). The major side-effects associated with clonidine use included dry mouth (5/22), sedation (4122) dizziness and palpitations (2122) and insomnia (1122). When patients were receiving placebo the comptaints were of dry mouth (2122) and insomnia (2122). Hypotensive changes due to any of the three medications could not be demonstrated. When comparing baseline tic scores without treatment to treatment tic scores, we found that both haloperidol and clonidine produce sign~~ant therapeutic benefit, whereas placebo did not. Both haloperidol and clonidine produced a greater therapeutic effect that did placebo @<0.005 by ANOVA), however, there was no statistical difference when comparing clonidine to haloperidol. The onset of therapeutic benefit with haloperidol was usually abrupt, often first becoming noticeable at daily doses of 1.5 mg or greater. This was not true with clonidine which appeared to have a slower onset of the therapeutic action over a period of weeks which generally did not become apparent until doses of approximately 0.45 mg daily were obtained. Of the 22 patients, eight were classified as haloperidol non-responders, which we arbitrarily defined as 25% or less reduction of tics with the maximal tolerated dose of haloperidol. In six of these patients we found that clonidine was also unable to provide a therapeutic benefit greater than 25% In 12 of the patients, substantial and equivalent therapeutic benefit was obtained by treatment with either haloperidol 01 cIonidine. Our study group was too small to determine specific factors which may have differentiated responders from non-responders. In one case a haloperidol non-responder, a I4 year old white male, showed a dramatic improvement with clonidine (0.75 mg daily), These beneficial results with clonidine have lasted greater than one year. There are two other cases of patients who responded we11only to clonidine. In contrast, in one case a 24 year old white male, who responded well to haloperidol(l.75 mg daily), failed to respond adequately to clonidine (maximum daily dose 0.60 mg). This patient received only slight therapeutic benefit from clonidine and later complained of dizziness and palpitations. although no changes in blood pressure or the electrocardiogram could be demonstrated. Among the seven patients who had a favorable response to clonidine, in three cases we found that continued incremental increases of dose produced a worsening rather than a further improvement of the tics. We speculate. that this may be accounted for by clonidine’s antianxiety effect at higher dosages. In some patients a significant lessening of anxiety decreases their vigilance for the suppression of tics, allowing more tics to become manifest. Those patients who deteri-

orated at higher doses of clonidine did admit LU&a Cu~xietr concerning their tics, and that they paid les\ attention ttj their suppression. Alternatively, increases in the dose ot clonidine may shift the site of action of this drug from presynaptic to postsynaptic mechanisms 1I ITwhich may alxo potentially account for the clinical change\ we oh~crved. Overall our results show that a patient’\ response to haluperidot appears predictive of their response to ctonidine. which suggests that they may be working through similar mechanisms. This may be understood by speculating that clonidine’s central effect on presynaptic norepinephrine receptors may modulate dopamine release. By decreasing dopamine release, clonidine may fun~t~ol~~llly deprive the postsynaptic dopamine receptors from interactmg with dopamine, just as haloperidol does physically. An alternative hypothesis may be that clonidine’s effect on postsynaptic striatal dopamine function so as to produce a lessening ofthe apparent hyperdopaminergic state in the ctriatum m GTS patients. At the present, these explanationa :rre ~peculativc and await further testing.

If, as is commonly believed, GTS is the result of a hyperdopaminergic state, which would explain haloperidol’s therapeutic efftcacy, then other neuroleptic drugs with high indices of extrapyramidal side-effects should be as equally efftcaceous as haloperidol. The accumulated evidence to date in the literature does not support this supposition, but rather suggests a unique role for halo~~dol in the therapeutics of GTS. It should, however, be pointed out that previous comparative studies of neuroleptics in GTS were either open, poorly controlled, or made no allowance for the differing potencies of neuroleptic drugs. Therefore. we have now conducted studies to test whether haloperidol has unique effects as a neurolepti~ agent in specifically treating GTS. Ten patients participated in our study and consisted of nine males and one female, with an age range of 12-43 years (mean=20.5 years), who had been ill with GTS for an average of 10.2 years. The study was run using a blind placebo controlled design, with haioperidol being compared to fluphenazine and tri~uoperazine in an ABAC manner. A flexible dosage regimen was used with patients incrementally increasing their dose of haloperidol (0.25 mg increments) or fluphenazine and trifluoperazine (0.5 mg increments) until either full tic suppression occurred or the maximum dose with tolerable side-effects was achieved. The range of dosages was 5-20 mg for halope~dol, 8-24 mg for fluphenazine and 10-25 mg for trifluoperazine. When compared to placebo. all three drugs produced statistically significant @
TOURE’ITE’S SYNDROME age 24.5 years). We found substantial therapeutic benefits in seven of eight patients receiving fluphenazine, with only one patient complaining of adverse effects. In six patients, using an open design we combined haloperidol with either trifluoperazine or fluphenazine after achieving maximal therapeutic effects with haloperidol. We found that the drugs were additive only in their side-effects and not iu their therapeutic actions, thus proving no more advantageous than the administration of one drug alone. C. ~~th~arn Therapeati~s In an attempt to develop new and safer treatment modalities for GTS, our attention has been turned to the role of lithium carbonate (Li). There are anecdotal case studies of Li proving effective both in GTS 141,and in the related exttapyramidal system disorder tardive dyskinesia [3]. We have now investigated the efficacy of Li in ten patients. The ex~~rnent~ design for admi~stration of medication was single-blind placebo controlled, capsules of 300 mg Li. prior to beginning Li treatment, normal renal and thyroid function was ascertained in all subjects. A drug washout period for a ~n~urn of two weeks preceded Li treatment, and when not possible, dosages of adjunct drugs were kept stable during treatment. Doses of Li were increased weekly by 300 mg increments and were correlated with weekly serum Li con~nt~tion until a blood level of O&1.0 meq/l was achieved. Subjects were seen weekly for the determination of medication side-effects and for obtaining serum Li levels which were measured by atomic absorption spectrosCOPY. The ten subjects participating in the study ranged in age from 10 to 42 years, and had been symptomatic with GTS from 4 to 32 years. In three of the ten cases, patients were m~n~ined on stable dosages of halo~~dol and benztropine while receiving Li treatment. The serum levels of Li achieved ranged between 0.6 and 1.5 mEq/l. The comparison of baseline pretreatment motor and vocal tic scores with scores obtained during treatment when optimal Li serum levels were obtained, showed that only one subject’s tics significantly improved (p~O.05, Wilcoxin, matched-pairs signed-ranks test). In contrast, there was a significant worsening of the tics in four subjects, Using the Wilcoxin matched-pairs signed-ranks test, we compared interindividual treatment response, and found that treatment of patients with Li produced a non-significant effect on the clinical picture of GTS. D. Amantadine Side-Efleects

and Benztropine Treatment of Haloperidol

Although relatively low doses of haloperidol are administered to control the motor and vocal tics of GTS, these doses are still often capable of producing acute extrapyramidal side-effects, namely dystonic reactions, drug-indu~ parkinsonism, and akathisia. As the usual treatment of these acute extrapyramidal side-effects is with anticholinergic antiparkinsonian agents, it must be questioned as to whether the admi~stration of these agents will adversely affect the hyperdoparninergic-hypocholinergic balance in Tourette’s Syndrome, and thus exacerbate the tic-like movements characteristic of this disorder. In order to assess the role of anti~kinsoni~ ~ticholine~c agents in the therapeutics of Tourette’s syndrome, we have compared one of these agents, benztropine mesylate, with the non-anticholinergic

207

antiparkinsonian agent amantadine, in the treatment of haloperidol-induced extrapyramidal side-effects. The subjects in this study were six male and one female patient, between the ages of %23 years. All seven presented with a 4-12 year history of multiple involuntary motor and vocal tics, with these tics showing a periodic shifting in their locations, and a waxing and waning intensity. The electroencephalograms for all six patients showed no abnormalities, and neurological examinations were positive only for the rapid tic-like movements of the patients. In the study design, all patients wefe placed on haloperidol, beginning with dose of 0.25 mg, and increasing until adverse side-effects emerged, or optimal suppression of tics was achieved. Patients were seen once weekly by a physician in order to determine medication side-effects. When extrapymmidal side-effects were recognized, the patients were placed either on benztropine mesylate (l-7 mg daily) or amautadine (lOO300 mg daily) in a single-blind crossover fashion. The dose of these two drugs were titrated so as to achieve optimal control of extmpyramidal side-effects. Within the group of seven, four patients developed recurring dystonic reactions. Of the four, two involved recurrent oculogyric crises. Six of the seven patients developed akathisia, whereas four patients developed bradykinesia and cogwheel rigidity, and two of these four patients also developed sialorrhea. The use of either benztropine or amantadine reversed bradykinesia, cogwheel rigidity and sialorrhea in all patients. Although benztropine reversed acute dystonic reactions in patients, one patient each with recurrent nuchal dystonias and oculogyric crises proved refractory to treatment. Both of these patients were successfully treated with amantadine. Among the four patients who developed dysarthria, only one individual showed improvement after benztropine. The dysarthria was disabling to all four patients and impaired their classroom performance. In all of these cases amantadine greatly reduced the dysarthria and led to normal verbal classroom participation from these four patients. The most frequent and troublesome side-effect to haloperidol was akathisia. This side-effect was experienced by the patients as the most annoying. In two of the six cases of akathisia there was an improvement after benztropine administ~tion, however, five of the six patients responded adequately to amantadine. The one patient who failed to respond individually to these two drugs did respond to the combination of amantadine (300 mg) with benztropine (1 mg). In four of the seven patients, the addition of amantadine decreased the sedation produced by haloperidol, whereas benztropine successfully reduced sedation in only two patients. Moreover, those same four patients who responded with less sedation after the addition of amantadine also reported increased concentration and an improvement in their schoolwork was noted. In three of the patients a total improvement in vocal and motor tics led to a reduction in the total dosage of haloperidol administered, whereas no patient receiving benztropine had a reduction in haloperidol dosage. Extrapyramidal side-effects are a common complication found in treatment with neuroleptic agents. As younger individuals are the most susceptible to neuroleptic-induced extrapyramidal side-effects, these adverse reactions occur commonly in Tourette patients receiving haloperidol. The most usual treatment for these side-effects is with anticholinergic antiparkinsonian agents, however, this may fiuther exacerbate the proposed hyperdopaminergic state in the

20x

striatum of Tourette patients. We have now demonstrated that amantadine can be successfully substituted for an anticholinergic antiparkinsonian agent the patient’s response to haloperidol.

without

compromising

CONCLUSION

Our results indicate that Li is a treatment which will be of little benefit to most GTS patients, and that haloperidol may not be specific in its therapeutic action in GTS. Although previous studies indicate haloperidol’s therapeutic superiority, this may now seemingly be accounted for mistaking its

greater potency rather than its efficacy. Furthermore, II would appear that other neuroleptics huch a\ fluphenazine produce fewer disabling side-effects than does haloperidol. making for a preferred therapeutic choice. Moreover. ‘I non-neuroleptic, clonidine is as efficaceou\ as haloperidol without producing the same spectrum of adverse reactions. The clinical efficacy of clonidine in GTS must make us look beyond dopamine alone as the major neurotranbmitter \ystern which shows pathology in GTS. Further. the ability of a dopamine agonist, amantadine, to be useful in GTS again suggests a reworking of the biochemical pathophysiolopy of GTS is necessary.

REFERENCES Cohen, D. J., J. Detlor, G. Young and B. A. Shaywitz. Clonidine ameliorates Gilles de la Tourette syndrome. Arch Gen P.s~~hicrtr~ 37: 135&1357, 1980. Cohen, D. J.. J. G. Young, J. A. Nathanson and B. A. Shaywitz. Clonidine in Tourette’s syndrome. Lancer ii: 551-553, 1979. Dalen. P. Lithium therapy in Huntington’s chorea and tardive dyskinesia. Lancer i: 107-108, 1973.

4. Messiha, F. S., H. M. Erickson and J. E. Goggm. Lithium carbonate in Giiles de la Tourette’s disease Rc.5 C‘on~n~t C/ICWI Putho/ Phurmcrcol 15: 609-611, 1976. 5. Shapiro, A. K.. E. S. Shapiro, R. D. Bruun and R. D. Sweet. Gille.c de lu Tourette Syndrome. New York, Raven Press, 1978. 6. Shapiro. A. K.. E. S. Shapiro and H. Wayne. Treatment of Tourette’s syndrome. Arc/~ GC~IP.syc,hitrrrv 28: 92-97. 1973.