©1996 by Eric Mick. All rights reserved
There has been considerable discussion regarding high levels of comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and Chronic Tic Disorder(CTD). Case reports and double-blind controlled studies have indicated this association may be confounded by the pharmacologic treatment of the ADHD. The most common indication for treatment in ADHD children is stimulants, and among those methylphenidate (MPH) has been the most popular (Spencer, 1996). This report will focus on the evidence for an association between administration of MPH and other stimulants and the onset of tic disorders.
ADHD is a psychiatric condition defined in DSM-III, DSM-III-R, and DSM-IV which onsets in childhood. Over the years, specific diagnostic symptoms have come and gone, but the core definitional criteria have included significant impairment in function in each of three basic domains: 1) increased impulsivity, 2) deceased attention, and 3) increased hyperactivity. It is a heterogeneous disorder estimated to affect at 3-5% of school age children (Anderson, 1987;Bird, 1988). Its impact on society is enormous in terms of financial cost, stress to families, disruption in schools, and its potential for psychopathologyand dysfunction (Mannuzza, 1989).
Follow-up studies of ADHD children (Biederman, 1992)have indicated that they are at increased risk for further psychiatric comorbidity including mood and anxiety disorders, psychoactive substance use disorders, and behavior disorders. ADHD is a chronic disorder of childhood which is estimated to continue to remain a problem into adulthood in as many as 30-50% of ADHD children (Gittelman, 1985; Weiss, 1985). The persistent adult form of ADHD leads to considerably more psychiatric comorbidity than in ADHD-free adults (Biederman, 1993), higher rates of ADHD in their offspring (Biederman, 1995a), and increased use of psychoactive substance use disorders continuing into adulthood (Biederman, 1995b).
Chronic Tic Disorder (CTD) is a neuropsychiatric condition commonly associated with social, occupational and academic dysfunction. CTDs are quite prevalent and are estimated to affect up to 5% of children (Fallon, 1992; Zahner, 1988). While the etiology of this disorder remains unknown, genetic and psychosocial risk factors have been proposed. (Leckman, 1993; Pauls, 1992). Although the relationship between CTD and Tourette's Syndrome remains uncertain, a recent study by Spencer, et al. (1995) suggested that both may be part of the same disease process, withTourette's syndrome a more severe form and CTD a less severe form of the same condition. Tourette's syndrome is defined by the concurrent presence of both vocal and motor tics. Previous work has confirmed that individuals with CTD not only have frequent comorbidity with ADHD and OCD but that they also have high levels of comorbidity with other disruptive behavior disorders, mood and anxiety disorders and commonly suffer from neuropsychological impairment (Comings, 1987a; Comings, 1987b; Comings, 1987c; Comings, 1987d; Comings, 1987e; Comings, 1987f; Pauls, 1993; Pauls, 1994; Spencer, 1995).
Spencer, et al (1996) recently reviewed the pharmacotherapy of ADHD. This review of more than 150 controlled studies of MPH in children, adolescents, and adults revealed that MPH had an average response of 70%. These studies demonstrated that there was slight variability in dose-response depending upon age group, but that universally there was no report of abuse or tolerance (Spencer, 1996). MPH therapy diminished prototypical ADHD behaviors such as hyperactivity, impulsivity and inattentiveness and enhanced social skills in school and within families (Barkley, 1979). It was hypothesized that the ability of stimulants, in general, to increase catecholmaines in the synaptic cleft account for their clinical effects (Zametkin, 1987).
ADHD is a significantly severe psychiatric disorder of childhood which is successfully managed by MPH therapy in the majority of cases. However, it has been postulated that this treatment may cause or exacerbate other disorders of equal concern - CTD and Tourette's syndrome. The remainder of this report will describe the history of the discovery of MPH-induced tics.
The earliest report of the association between MPH therapy and tics was in 1976 when ADHD was defined as Minimal Brain Dysfunction (MBD) (Denckla, 1976). In this series of 20 cases treated for MBD, methylphenidate was observed to precipitate tics in children with no previous history and to exacerbate tics in children in which they were already present. The time from exposure to the medication to the development of tics varied in this case series from less than one month (n=7), three months (n=4), six months (n=2), and one year (n=7). The location of the tics were relatively focused but multiple within a single child: eyelid or facial muscle tics in 14 patients; head, jaw, and neck tics in 14, and trunk and limb tics in only seven of the patients. Withdrawal of MPH resulted in a discontinuation of tics in 13 of the children (Denckla, 1976). Furthermore, in 6 children with a previous history of tics worsened by MPH therapy, all returned to the pre-treatment tic severity when taken off of the medication.
However, tics in one child stopped with withdrawal of medication, returned with a subsequent increase in medication, and failed to subside with later discontinuation of MPH. In another 4 subjects in whom tics subsided with medication discontinuation, there were no further episodes of tics with a retrial of the medication (Denckla, 1976).Yet another child spontaneously developed tics 2 years after MPH withdrawal in the absence of MPH. These situations indicate that there may be some cases of tics which develop coincidentally with an MPH trial and may not be etiologically linked to the medication. No attempt was made to determine if these anomalous cases were also those in which tics did not develop until some time after the trial of medication was started (Denckla, 1976). Since these children were in an age-window during which they were at risk for developing tics it is possible that some of the cases may not be directly linked to the medication.
Denckla, et al (1976), also report that these cases were derived from a very large clinic experience (1,520 children prescribed MPH, 45 with a previous history of tics). Six (13%) of the 45 patients with a pre-existing tic disorder developed worse tics while the remaining 14 patients free from tics prior to MPH therapy. This resulted in a cumulative incidence of only 1.3% of tics associated with MPH (Denckla, 1976).
Several years later a second report of 15 cases (Lowe, 1982) of Tourette's Syndrome following stimulant therapy were reported. From this series of 15 patients, four were presented in detail as "prototypical" cases of Tourette's induced by stimulant therapy. In the first a young boy with a positive family history for Tourette's syndrome and a positive history of intermittent motor tics was prescribed MPH. In the months following stimulant therapy, both vocal and motor tics became more severe and the diagnosis of Tourette's syndrome was made, eventually requiring haloperidol treatment. In the second prototypical case, a 10 year old boy was prescribed MPH for over two years before developing motor and vocal tics, also eventually requiring treatment. In this case, however, the treatment for the tic disorder caused serious cognitive blunting and was discontinued. The last two cases reported were similar in that the administration of MPH led to an improvement in hyperactivity, but also precipitated both vocal and motor tics. The tics were intermittent and were managed without complication with haloperidol (Lowe, 1982). From this case series, the authors concluded that a history of motor or vocal tics should be a contraindication for stimulant therapy and that a family history of motor tics or diagnosed Tourette's syndrome should arouse the suspicion of the psychopharmacologist before prescribing MPH (Lowe, 1982). The authors did not attempt to estimate the prevalence of tics associated with stimulant therapy in their clinic.
A retrospective analysis of the prevalence of stimulant therapy in a clinical population of Tourette's patients (Erenberg, 1985) was conducted. Of the 200 patients being treated for vocal and motor tics, 24% (n=48) had ever been treated with stimulants (predominantly MPH). Of these, only 4 were taking the medication at the point of onset of the tic disorder while the remaining 44 had not taken stimulants for six months prior to tic onset. Therefore, only 2% of the Tourette's patients in this clinic were potentially attributable to stimulant therapy (Erenberg, 1985). Similar to Denckla, et al (1976), however, 8 (20%) of the 39 patients that received stimulant therapy after diagnosis of a tic disorder experienced an increase in severity. From these results, the authors concluded that there was a small risk of Tourette's in children treated with stimulants, but that the benefits of stimulant therapy for hyperactivity warranted their careful prescription in children at risk (Erenberg, 1985).
In 1986 three more cases were reported in the literature (Casat, 1986; Gualtieri, 1986) which were very similar to the others. In these case reports, motor and vocal tics were evident shortly after methylphenidate administration, but were effectively treated with other medications. Casat et al (1986) observed an inpatient case in which hourly observations were made of the frequency of tics. In this case tics developed after 8 weeks of MPH and thioridazine treatment. MPH was discontinued but an associated increase in hyperactivity and decrease in attention were immediately apparent. One week later MPH was again prescribed with no change in tics. Subsequent removal of the thioridazine resulted in a drastic increase in tics (from 35 to 85 per minute). With the administration of clonidine tics were reduced, but persisted until treated with haloperidol. The authors concluded that while evidence was slowly accumulating, there was still a lack of adequate knowledge about drug-induced motor tics in children.
Another study of children treated in a psychiatric day hospital indicated a high prevalence of tics associated with MPH and dextroamphetamine treatment (Borcherding, 1990). Of the 45 patients included in a three-week trial of these stimulants, 60% experienced orofacial tics, other tics, sterotypies or tremor. The orofacial tics were the most common and were transient (lasting less than 48 hours). These transient tics were only observed at low doses of MPH,while there was no dose relationship for the other stimulants (Borcherding, 1990).
The most recent study to examine this relationship aimed to determine the incidence of tics or dyskinesias in children treated with stimulant medications for ADHD (Lipkin, 1994). A chart review of 122 children with ADHD prescribed stimulant medications estimated the retrospective incidence of tics associated with stimulant therapy. Of the children prescribed MPH 9 (9%) developed tics, and of the children on dextroamphetamine 3 (6%) developed tics. There was no relationship with dose or age, nor were there any differences between the types of stimulant prescribed. (Lipkin, 1994).
Lipkin et al (1994) cited the difficulty in comparing the results from this small body of literature due to methodological differences between the studies. Populations of patients identified by changing diagnostic criteria have made it difficult to compare the effects of stimulant over the 20 years since the first report of an association (Denckla, 1976). The identification of tics and related tic disorders have also varied by method of assessment from highly specific observations in an inpatient system to vague notes from medical records. Finally, most children treated with stimulants are within the age range during which tics develop spontaneously. This in combination with the long duration between MPH and tic onsets make it difficult to determine a causal relationship in some cases.
To date, there is no consensus that MPH, or stimulants in general, are significant causes of tics in children. The first report indicated that a small minority of children with no previous history of tics (1.3%) developed tics after stimulant therapy, and that only 13% of children with the pre-existing condition were at risk of an increase in severity (Denckla, 1976). While subsequent case reports were useful in describing the various temporal relationships that have been observed, they were not able to estimate risk because they had no denominator with which to work. Analysis of 200 children being treated for both motor and vocal tics, revealed that only 4 were prescribed stimulants before developing tics and that in those prescribed stimulants after the onset of tics 20% were worsened (Erenberg, 1985).
The most recent report estimates the highest prevalence of tics (9%) in children with no previous history (Lipkin, 1994) and may be an indication of future problems. Methylphenidate production increased dramatically in the early 1990's from 1,784 kg in 1990 to 5,110 kg in 1993 while the number of outpatient visits for ADHD treatments have increased from 1.6 million in 1990 to 4.2 million in 1993. Since MPH is considered the first line of treatment for children with ADHD, it is likely that considerable numbers of children are likely to exhibit stimulant-induced tics if the current treatment trends continue - even at the most conservative estimates of stimulant-induced tic incidence.
Further research needs to be conducted in order shed a more informative light on this subject. Ideally, prospective studies could be conducted to observe the incidence of tics associated with MPH therapy, but ethical concerns should prohibit such a study. Large scale observational research is likely to be the most fruitful.
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