The following reports are based on a symposium held in New York City at the annual meeting of the American Academy
of Child and Adolescent Psychiatry.

Attention-deficit/hyperactivity disorder (ADHD) and other types of psychopathology are quite common among patients with chronic tic disorders. However, treating the attention difficulties in such patients has been hindered by concern that stimulants may exacerbate the tics; indeed, the label for methylphenidate continues to include a black box contraindication for patients with tics or a family history of tics.

Fortunately, recent studies indicate that most children with this comorbid combination either do not experience an exacerbation of tics while using methylphenidate or find that the benefits of improved ADHD symptoms far outweigh any minor increases in tic frequency. At a symposium at the annual meeting of the American Academy of Child and Adolescent Psychiatry, a panel of experts discussed recent findings on this and other clinical issues in the management of ADHD and tics.

DOES METHYLPHENIDATE INDUCE TICS?

The session’s first speaker, Kenneth D. Gadow, PhD, a Professor of Psychiatry and Special Education at the State University of New York, Stony Brook, presented key findings from a lengthy series of studies conducted by his lab. The initial study involved 34 prepubertal children with comorbid ADHD and chronic multiple tic disorder who participated in an eight-week methylphenidate trial. Subjects received four different treatments—placebo and three doses of methylphenidate (0.1, 0.3, and 0.5 mg/kg twice daily)—under double-blind conditions for two weeks each. Subsequently, study participants entered a long-term follow-up study in which they underwent extensive evaluations at six-month intervals for two years and at yearly intervals thereafter.

Addressing first the central issue of the symposium, Dr. Gadow reviewed his data on whether methylphenidate increases tic frequency. The tentative answer, he said, is no. When he and his colleagues monitored tics through a one-way window installed in a simulated classroom and analyzed the number that occurred during each five-second interval, they observed tics in 22% of the intervals in children using the 0.1-mg/kg dose and 21% of the intervals in children using the two higher doses. These rates were not statistically different from the rates seen with placebo (18%) or at baseline (19%).

The reason Dr. Gadow described his answer as tentative is because when trained observers posing as student teachers monitored the children at school, subjects on the 0.1-mg/kg dose did show a statistically significant increase in the rate of motor tics. (In contrast, vocal tics decreased slightly.) However, the increase in motor tics was apparently undetectable by other observers: Of the 23 physician-, teacher-, and parent-rated scales used in the study, only two showed worsening of tics. Seventeen revealed no change in tics and four actually showed decreases.

Moreover, tics did not increase in severity during the course of long-term treatment. Group data from a two-year period indicated that once the minimal effective dose had been established, the change in tics over time was “absolutely trivial,” Dr. Gadow said. Similarly, a withdrawal study found no evidence that children who have been on methylphenidate for at least a year experience changes in tic frequency once the medication is stopped.

WHAT ABOUT ADHD SYMPTOMS?

Equally important, of course, is the question of efficacy. When Dr. Gadow compared response to methylphenidate in ADHD patients with tics and those without, the results were identical. This, he said, indicates that the comorbid children have true ADHD and that their attention problems are not simply a manifestation of Tourette’s syndrome diathesis.

Moreover, methylphenidate also suppressed aggressive behavior. The Stony Brook study is unique, according to Dr. Gadow, in that it is the only trial of psychotropic medication to examine treatment response in a lunchroom setting. “I don’t know if you’ve been in a public school lunchroom lately, but it’s Armageddon in there. And I’ve discovered that you can study all known childhood behaviors. The only one I haven’t seen was cannibalism—but I did see one episode of attempted cannibalism,” he quipped. In the lunchroom, both physical and verbal aggression declined with increasing doses of medication. Dr. Gadow noted, however, that despite these improvements, levels of abnormal behavior (eg, disturbing others, noncompliance) were still in the abnormal range for most ADHD patients compared with their classroom peers.

Fortunately, levels of appropriate social behavior were essentially unchanged, he said. “I’ve often been fascinated by this finding that the drug can excise, with almost surgical precision, aggressive behavior from the child’s behavioral repertoire without affecting rates of appropriate social behavior. To me, that is absolutely amazing,” said Dr. Gadow.

OTHER CLINICAL ISSUES

Physicians encounter several problems when adjusting the dose of methylphenidate for children who have ADHD and chronic multiple tic disorder, Dr. Gadow noted. One is fluctuations in tic severity, both in the short and long term. For example, an analysis of tic counts taken during diagnostic intake and again during the placebo phase revealed “an extraordinary degree of fluctuation in tics on a week-to-week basis.” These changes, he observed, complicate clinician efforts to decide whether a given medication and dose are effective.

A related issue concerns long-term trends in tic expression. Tic severity follows the same developmental pattern as ADHD-inattentive–type symptoms, increasing through the early school years, peaking around age 11, and then declining during adolescence. Interestingly, children receiving stimulants (but not anti-tic medications) do not appear to show this gradual increase in tics—a finding that raises the question of whether methylphenidate might have a prophylactic effect.

Finally, Dr. Gadow discussed the question of whether stimulant dose should be titrated based on parent, teacher, or physician ratings. As in most other studies, Dr. Gadow’s findings indicate that teacher ratings are more sensitive than parent ratings in determining response to treatment. For example, in the acute methylphenidate trial, teacher-rated scales detected improvements in ADHD symptoms with low doses of methylphenidate (0.1 mg/kg), whereas parents were unable to detect improvement even at moderate doses (0.3 mg/kg). Therefore, clinicians may not want to titrate medication dose based on parental reports, Dr. Gadow said.

Office evaluations are not the ideal setting to monitor tic frequency, either. “You can sit in front of a patient with chronic multiple tic disorder, whether it is an adult or a child, start asking them about their tics, and often you will see the tics increase in frequency right before your eyes,” noted Dr. Gadow. He offered two theories for this phenomenon. First, as the child becomes more attentive and compliant on methylphenidate, he or she may comply with the physician’s request to observe tics. “It is also conceivable that there is an interaction between the drug effect, anxiety, and the situation that the child finds himself in,” he said. Determining which explanation is true will have enormous clinical implications on how we evaluate children with the disorder, predicted Dr. Gadow. In the meantime, it seems reasonable to conclude that titration of doses should not be based on office observations.

A MISTAKEN CASE OF TIC EXACERBATION

It is easy to falsely conclude that a stimulant medication has triggered or worsened a patient’s tics, observed the symposium’s next speaker, Joyce Sprafkin, PhD. She presented a case in which a boy named Mark, whose ADHD symptoms had been successfully treated with methylphenidate for three months, suddenly developed motor tics. “We thought maybe we had done damage,” said Dr. Sprafkin, who is Associate Professor of Psychiatry and Psychology at the State University of New York at Stony Brook.

Mark had initially been referred for evaluation at age 10 due to his impulsive behavior and short attention span. His developmental history indicated that ADHD symptoms had been present since his preschool years, though at the time his parents had not wanted Mark to be medicated, instead pursuing behavior modification techniques that were only partially effective. Now, however, they agreed to a trial of methylphenidate. Happily, a regimen of 5 mg in the morning and 10 mg at noon resulted in such significant improvement that Mark’s teacher wrote an unsolicited letter to his parents citing the “remarkable improvement in Mark’s academic development, motivation, and attitude.”

But three months after the initiation of treatment, Mark developed motor tics. The most severe of these was an ocular tic in which the eyeball darted upward for one or two seconds at a time, approximately once a minute. His parents discontinued the methylphenidate and came in for a clinic appointment.

UNFOUNDED WORRIES

Initially, the clinicians worried that the medication had caused the tics. However, further investigation into the boy’s history revealed that since age 4 he had exhibited eye blinking, throat clearing, and coughing to such a degree that his parents had sought medical advice. These tics had been misdiagnosed by several physicians as allergy-related. Though his parents had denied at the initial evaluation that Mark had a history of tics, it was now apparent that Mark did, in fact, have Tourette’s syndrome. Furthermore, the clinicians learned that the severe eye-rolling tic had developed 18 hours before the onset of a viral illness that was accompanied by severe vomiting and diarrhea, suggesting that the tic was triggered by the infection rather than by methylphenidate.

Indeed, when the clinicians arranged for Mark to undergo a double-blind medication trial—two weeks on methylphenidate and two on placebo—observations revealed no differences in tic frequency. Academic performance, moreover, was superior while Mark was medicated. At last report, Mark, now a decade older, was still taking methylphenidate and was attending a community college; he has continued to exhibit several tics but has not had a recurrence of the severe eye-rolling tic.

“This case indicates how easy it is to draw false conclusions about stimulant drug therapy and tic induction or exacerbation,” Dr. Sprafkin said. It also illustrates the value of placebo and drug-free periods as a means of monitoring the efficacy and adverse effects of medication.

“Although anecdotal reports of drug-related changes in tic status serve an important role in alerting physicians to the potential dangers of pharmacotherapy, their role as recommendations for general clinical management is tenuous. Clinicians are urged to carefully evaluate seemingly apparent presentations of stimulant-induced tic exacerbation,” concluded Dr. Sprafkin.

ARE TIC EXACERBATIONS REVERSIBLE?

F. Xavier Castellanos, MD, of the Child Psychiatry Branch of the National Institute of Mental Health in Bethesda, Maryland, noted that the worst exacerbation of tics he ever saw in a double-blind treatment trial was in a boy who turned out to be on placebo and later did very well on methylphenidate for several years. Nonetheless, Dr. Castellanos offered a somewhat different view of the effects of stimulants. The long-standing dogma that stimulants cause tic disorders “is no longer really tenable,” he stated. “But I also challenge the [perspective] that there is no relationship between stimulants and tics.” The question, he said, “is not if there is a relationship, but what is the relationship?”

As an example, Dr. Castellanos cited an open-label study, which he coauthored, in which patients with severe ADHD and tics received very high doses of methylphenidate (15 to 45 mg bid). “What we found is that in just about every case, if you push the doses high enough, you’re going to make tics worse.” Indeed, nearly a third of the patients did not stay on high-dose stimulants long-term due to adverse effects. In most cases, tic exacerbations were substantially better within a few days of discontinuing therapy, although some children did not improve until a week or two later. Encouragingly, long-term follow-up revealed no evidence that the drug had “sensitized” the children to be vulnerable to tics.

On the other hand, more than two thirds of the children in the high-dose trial either did not have tic exacerbations or felt the additional tics were a reasonable tradeoff in exchange for improvements in ADHD symptoms. Other patients echo this sentiment. “They’ll say, ‘My tics are 10% worse, but I can handle that,’” Dr. Castellanos reported.

A FRACTAL PHENOMENON?

Although researchers have made great progress in understanding Tourette’s syndrome in recent years, Dr. Castellanos emphasized that we should not “forget how inadequate our attempts to capture this phenomenon are.” One example, he said, is a study in which patients with Tourette’s syndrome sat in a room by themselves without engaging in any activity, for up to three hours, while researchers recorded their tics by videotape. An analysis of the duration of tic intervals revealed a nonlinear, possibly fractal relationship in which medium-length tic intervals increased the likelihood of a similarly sized interval, whereas short tic intervals increased the probability of both short and long tic intervals. What these findings indicate, Dr. Castellanos said, is that the occurrence of tics “is a very complex phenomenon; when we approach it by taking a mean, by looking at standard deviations, by assuming that the given observation is really descriptive of the entire phenomenon, we’re doing the best that we can—but we’re not there.”

In general, it’s a good idea to start low and go slow when prescribing stimulants, Dr. Castellanos advised. But perhaps the most important message from his own studies, he concluded, is that “even when we make tics intolerably bad, it’s a transient effect. We didn’t know that back in the 1980s. We didn’t know if we would be putting these kids on a new plateau.”

WHAT IS THE ETIOLOGY OF ADHD AND TICS?

The symposium’s final speaker, Russell Schachar, MD, FRCP, agreed with Dr. Gadow that methylphenidate does not seem to produce exacerbations in tic severity for the vast majority of children with ADHD. Although his own controlled ADHD trial excluded children with Tourette’s syndrome or severe tics, patients with mild tics were just as likely to have exacerbations while on placebo as they were on methylphenidate. And in the medication group, tic improvements and tic exacerbations were equally common.

Still, crucial questions remain. “We don’t know the etiology of either part of this comorbidity,” noted Dr. Schachar, who is Associate Professor of Psychiatry at the University of Toronto. As a result, he said, clinicians do not know the underlying phenomena that they should be tracking as they monitor the patient’s history and treatment; nor is the co-occurrence of the two disorders understood. “It is very clear that tics may be comorbid with just about every psychiatric syndrome, so there may not be any unique comorbidity with ADHD,” he said.

It is also possible that the apparent comorbidity is spurious. For example, ADHD and tic disorder may appear to be comorbid, either because of overlapping criteria or because of a “halo effect.” “If you see somebody who’s moving around, and that is part of their tics, it somehow creates the appearance of restlessness,” Dr. Schachar said. “That kind of restlessness may be attributed to ADHD.”

On the other hand, the laboratory data cited by Dr. Gadow “suggest that it’s not altogether a false comorbidity,” Dr. Schachar noted. Furthermore, recent studies identifying cognitive and executive deficits in ADHD patients raise the prospect of markers that will help discriminate between ADHD and Tourette’s syndrome and perhaps aid in prevention and treatment. “I think there are some important distinctions between the disorders,” he said, “and that gives me hope for the future.”

—Kathryn Blair

Suggested Reading
1.Gadow KD, Nolan EE, Sprafkin J, Sverd J. School observations of children with attention-deficit hyperactivity disorder and comorbid tic disorder: Effects of methylphenidate treatment. J Dev Behav Pediatr. 1995:16;167-176.
2. Gadow KD, Sverd J, Sprafkin J, et al. Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Arch Gen Psych. 1999;56:330-336.

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