First-onset tics in
patients with attention-
disorder: impact of
Monika Robatzek, Department of Child and Adolescent
Psychiatry, University of Goettingen;
Guido KnappPhD, Department of Statistics, University of
Tobias BanaschewskiMD PhD;
Aribert RothenbergerMD, Department of Child and
Adolescent Psychiatry, University of Goettingen, Germany.
*Correspondence to first author atDepartment of Child and
Adolescent Psychiatry, University of Goettingen,
Von–Siebold–Strasse 5, 37075 Goettingen, Germany.
First-onset tics during stimulant treatment of attention-
deficit–hyperactivity disorder (ADHD) are clinically relevant
and remain a matter of scientific debate. Because there are
limited clinical trials analyzing the risk of first-onset tics in
stimulant-treated ADHD, a comprehensive evaluation is
required for evidence-based clinical recommendations. An
analysis of studies with high methodological quality (i.e.
double-blind placebo-controlled) on first-onset tics during
stimulant treatment of ADHD revealed that there seems to be
no elevated risk of first-onset tics in children undergoing this
treatment. Although a close temporal relationship might be
seen in a few patients, the role of treatment duration, dose of
stimulant, genetic vulnerability, and developmental aspects
need to be further explored to clarify possible
pathophysiological mechanisms of tic emergence under
stimulant treatment. The results of high quality studies, in
addition to specialized studies with methodological
limitations, suggest that stimulants are the criterion standard
for the safe and successful treatment of ADHD.
Attention-deficit–hyperactivity disorder (ADHD) is a world-
wide and highly prevalent psychiatric condition, affecting
5 to 7% of school age children and probably as many as 1% of
adults.1,2While the management of ADHD only is usually
uncomplicated, individuals with ADHD often experience
comorbid psychiatric conditions, which increase long-term
psychosocial impairment and hamper treatment.3About
20% of children with ADHD are affected by chronic tic disor-
ders, whereas about half of the cases with chronic tics or
Tourette syndrome also meet criteria for ADHD.4Usually,
ADHD starts around 2 to 3 years before first tic onset, while
in a smaller proportion of cases ADHD follows the tic onset.5
Generally, early ADHD can be seen as a risk factor for further
associated psychiatric problems like tic disorders.3
Although stimulants are basically safe and effective in treat-
ing ADHD, some concern exists that stimulants may increase
the risk of first-onset tics or worsening of pre-existing tics. Since
Lowe et al.6claimed that Tourette syndrome or tics in a child
are a contraindication to the use of stimulants for hyperactive
syndromes, manufacturers placed a warning on packaging that
stimulant medication is contraindicated in patients with motor
tics or with a family history of Tourette syndrome.7Other
authors claim that there is inadequate evidence that appropri-
ate dosage of stimulants can cause tics in previously asympto-
matic patients.8There is increasing evidence that patients with
tics receiving stimulants do not experience a worsening of tics,
and some have even shown improvement.9
This equivocality might be explained by shortcomings of
the few studies on first-onset tics during stimulant treatment,
such as small sample sizes and unclear disentangling of first-
onset tics from exacerbation of pre-existing tics.6,10–19Import-
ant confounders include waxing and waning of tics and a high
Developmental Medicine & Child Neurology 2006, 48: 616–621
frequency of transient tics at an age when stimulant medica-
tion is usually commenced.17,20From a clinical point of view,
the common transient tics (up to 20% in children21–24) are gen-
erally negligible compared with chronic tic disorders (about
3%25)with their much more disabling consequences and com-
mon association with further psychopathology such as ADHD
or obsessive-compulsive disorder.26There are few prospective
epidemiological studies of first-onset tics27and differentiation
between transient tics and chronic tic disorders is still an unre-
solved problem of cross-sectional studies, especially in those
focusing on stimulant-induced first-onset tics.
Some authors have claimed that it can be difficult to
distinguish early signs of tic disorders from hyperactive behav-
iour with attention problems. This can lead the clinician to
consider treatment with stimulants, which are thought to
unmask latent tic symptomatology.6,15,28A report by the
Tourette Syndrome Study Group29did not support an increas-
ed risk of activating pre-existing tics with stimulants.
Although a meta-analysis focusing on the efficacy and safety
of methylphenidate for the treatment of ADHD has for the first
time systematically investigated side effects in contrast to
other meta-analyses, no data concerning tics are reported.30
As it is of clinical importance to know if stimulants initiate tics
in some patients with ADHD, and because previous data are
limited, this study investigated first-onset tics in two ways: (1)
by screening all published data on stimulant treatment of
ADHD and first-onset tics to select a group of homogenous
studies of high quality; and (2) by reviewing findings focusing
on first-onset tics independent of their methodological quality
to identify limitations in this field of research.
Screening the literature for stimulant treatment in ADHD
revealed that the majority of detailed data concerning first-
onset tics have been published as chart reviews,15,17,28,31case
reports,6,10–13or prospective open-label studies.18,32Assess-
ment of tics (if reported at all in double-blind, placebo-con-
trolled trials) varied by informant (expert, parent, teacher),
observation period (1wk–4y), retrospective versus prospective
clinical ratings, and direct tic observation versus different rat-
ing scales (e.g. the Subjective Treatment Emergent Symptoms
Scale,33Pittsburgh Side Effects Rating Scale [SERS],34and the
Side Effects Behavior Monitoring Scale based on SERS35).
Quality and/or comparability of data were reduced by the
uncertain exclusion of pre-existing tics and unclear statements
concerning comorbid conditions, as well as missing data on
medication at tic-onset, duration of stimulant treatment before
tic-onset, and on individual and familial tic history.
Due to these methodological problems, the planned
approach of a meta-analysis was abandoned. However, a
group of homogenous studies of maximum quality were
selected from MEDLINE, PubMed, EMBASE, and PsycINFO.
These were double-blind placebo-controlled trials (parallel-
group as well as cross-over design) focusing on the stimulant
treatment of ADHD and published as full reports in peer-
reviewed journals in English.
Studies of patients with ADHD showing comorbid condi-
tions other than conduct disorder, oppositional defiant disor-
der, developmental delay, or anxiety were not included. All
clinical trials before 1995 were excluded, because they are
highly variable and generally have low methodological quality.
Some ambiguity remained, so inclusion or exclusion of a study
was determined using all information available by consensus
of two members of the research team.
For the outcome measure, percentages of first-onset tics
during administration of placebo versus stimulants were cal-
culated from the data of eight studies.
All information extracted from the studies which are compa-
rable in study quality and quality of data concerning first-onset
tics and stimulant treatment in children with ADHD is sum-
marized in Table I.
This descriptive analytic review evaluated the influence of stim-
ulantson first-onset tics in patients with ADHD which was based
on a small group of methodologically valid data sets from the
literature. The main finding was that there is no evidence for
an elevated risk of first-onset tics during stimulant medication
in children and adolescents with ADHD without pre-existing
tics. This is concordant with a retrospective chart review eval-
uating the risk of first-onset tics during treatment with stimu-
lants.17Data from five studies of different design (three
included in Table I) also revealed no elevated risk.36
Although studies with low methodological quality that did
not primarily focus on first-onset tics came to the same con-
clusion,9,30,37–39several studies provided different informa-
tion with frequencies between 3.9 and 60% of first-onset tics
during stimulant treatment.19,40–44However, these studies
have methodological shortcomings in terms of first-onset tic
evaluation which might contribute to their deviance from the
TEMPORAL RELATIONSHIP AND OBSERVATION PERIOD
The identification of close temporal relationships between
start of medication, first-onset tics, and disappearance after
drug withdrawal might bring more clarity. This seems to be
probable in analogy to the immediately expected clinical
effects of one dose of stimulants on core symptoms of ADHD as
well as to the close temporal relationship between stimulant
medication and tic exacerbation in a small minority of pat-
ients.9However, as retrospective evaluation of the time at onset
of tics remains a challenge and requires careful inquiry,45the
possibility that unidentified tics preceded first administration
of stimulants cannot be excluded in most published
reports.8,46,47Clinicians’ beliefs of the possible association
between stimulants and tics may bias more detailed data.17
Future studies require standardized recording of previous,
actual, and, if possible, prospective tic status for all participants.
There is some evidence for a decrease or disappearance of
apparently stimulant-induced tics when medication is with-
drawn,12,18independent of the delay of tic onset during stimu-
lant treatment.27In one sample, first-onset tics that appeared
to be stimulant-induced were transient only at low doses of
methylphenidate.19First-onset tics occasionally persisted,
even when stimulant medication was discontinued.14,15,18
Conversely, re-occurrence of apparently stimulant-induced
tics after a medication free period of a few months had not be-
en observed in some children.18However, some patients with
ADHD who had remission of first-onset tics after discontinua-
tion of stimulants experienced tics every time medication was
recommenced (e.g. case report of a woman 31 years of age
treated with dextroamphetamine; Taylor FB, personal com-
Because the reported delay between starting the stimulant
medication and tic onset varies from days to weeks, months,
or 1 year8,28and natural waxing and waning of tics is an
important confounder,17longer observation periods are
required to improve the validity of statements concerning the
long-term influence of stimulants on the rate of stimulant-
induced tics in ADHD. The course and type of tics emerging
might be of interest due to their clinical relevance (e.g. stim-
ulant-induced first-onset Tourette syndrome was absent18or
seen in few patients6,12,13,15).
It may be argued that longer observation periods increase
the likelihood of confounding, as first-onset tics follow the
onset of first ADHD symptoms 2 to 3 years later.5Thus, suffi-
cient consideration of older patients would be informative.
Unfortunately, few long-term (longer than 1y) follow-up, dou-
ble-blind placebo-controlled studies on stimulants in
ADHD have been conducted and none of them gave detailed
information about first-onset tics. The only longer-term fol-
low-up double-blind study which randomized children to
receive methylphenidate or placebo for at least 1 year, found
a similar risk of developing first-onset tics for both groups
Developmental Medicine & Child Neurology 2006, 48: 616–621
Table I: Rate of first-onset tics during stimulant treatment vs placebo in double-blind placebo-controlled studies of children and
adolescents with attention-deficit–hyperactivity disorder
Design n; mean age (SD), y; range, y; sexa
% of first-onset tics Reference
Pre-existing tics excluded
Cross-over 32; 4.8 (0.5); 4–6; 27 males, 5 females MPH: 0.5mg/kg
Cross-over 65; 8.56; 6–11; 58 males, 7 femalesMPH: 20mg (highest)0 Rapport
Cross-over 31; 9–12; 31 males d-MPH: 10mg (highest)
d,l-MPH: 20mg (highest)
Cross-over 36; 9.6; 7–12; 33 males, 3 femalestransder. MPH: 0.45mg/h
transder. MPH: 0.9mg/h
transder. MPH: 1.8mg/h
Pre-existing tics included but differentiated from non-pre-existing tics
Cross-over 26; 9.63 (1.47); 6.5–12; 20 males, 6 femalesMPH: 0.78mg/kg (mean)0
Evans et al.61
Parallel group MPH: 46; 8.4 (1.6); 37 males, 9 females
Plc: 45; 8.3 (1.5); 37 males, 8 females
45; 13.8 (1.2); 12–17d; 40 males, 5 females
MPH: 0.5mg/kg (mean)19.6
Cross-over MPH: 0.54mg/kg (mean) 10.3
OROS MPH: n=233
Palumbo et al.36summarized unpublished data of following three studies
Cross-over68; 9.1 (1.6); 6–12; 60 males, 8 females MPH: 0.9mg/kg (mean)
OROS MPH: 1.1mg/kg
Parallel groupMPH: 97; 9.1 (1.9); 84 males, 13 females
OROS MPH: 95; 8.8 (1.7); 74 males, 21 females
Plc: 90; 8.9 (1.8); 75 males, 15 females
MPH: 0.9mg/kg (mean)
OROS MPH: 1.1mg/kg
Parallel group32; 9.9; 7–12; 28 males, 4 females MPH: 0.9mg/kg (mean)(3) Swanson
n=16 MPH: 45mg (highest)
OROS MPH: 54mg
n=1 left study early
Participants had no comorbid condition except conduct disorder, oppositional defiant disorder, developmental delay, and mild anxiety.
aAll data not available for every study. bDrug dose in mg/kg/day of body weight if available, otherwise in mg/day (mg/hr); standard drug dose
if available, otherwise mean drug dose if available, otherwise highest dose. cMissing information obtained by author on inquiry. dAge range
from Smith et al.39reporting same sample. MPH, methylphenidate; Plc, placebo; transder., transdermal application; d-MPH, d-threo-
methylphenidate; d,l-MPH, d,l-threo-methylphenidate; OROS, osmotically-controlled release delivery system.
(methylphenidate 20% vs placebo 17%) and 40% of the tics
developed after 4 months or more of treatment.16During a 4-
year period of treatment with stimulants for children with
ADHD, a limited impact on the course of tics and no associa-
tion with first-onset tics were reported.48
DOSE AND KIND OF STIMULANT
No correlation was observed between the emergence of tics
and the stimulant dose in the two studies with the largest sam-
ples.16,17This is consistent with the reported lack of influence
of stimulant dosage on severity and course of pre-existing tics
in studies with excellent methodological quality.29There seems
to be no difference between short-acting (immediate release)
and longer-acting (extended release) formulations (Table I). In
a total of 1082 patients in a long-term open-label study with
osmotically-controlled release delivery system (OROS) methyl-
phenidate (9-month community use study), 1.3% of patients
aged 6 to 12 years, 0% of patients aged 13 to 17 years, and 0.7%
of adult patients with no personal history of tics developed
tics.36Neither the type of stimulant (methylphenidate, amphet-
amine, pemoline) nor the mode of application (oral, transder-
mal) seems to have an influence on the rate of tics that appear
to be induced by stimulants (Table I).6,17,19
AGE AT ONSET
Many patients with tic onset that was delayed after the begin-
ning of stimulant medication were within the age range where
tic disorders most often occur spontaneously. Most groups
with tic onset during stimulant medication were younger than
those without.17,49This supports the view that the relationship
between stimulant medication and first-onset tics might indi-
cate an early triggering of otherwise later spontaneous tic
onset.28Further explanation is required to determine why, in
two methodologically robust studies, adults with ADHD treat-
ed with stimulants as well as placebo showed rates of first-
onset tics similar to those of children and adolescents.50,51
The increased sensitivity of dopaminergic brain systems has
been widely implicated in the pathophysiology of tics.5Thus,
stimulants, which increase dopamine in the synaptic cleft,
are predicted to induce tics. However, these theories do not
take into account the complexity of neurotransmitter inter-
actions. Moreover, genetic vulnerability in combination with
unknown complex neuronal processes may explain why not
all patients with ADHD who receive stimulants respond with
first-onset or exacerbation of tics. Neither a genetic relation-
ship between tics and ADHD52,53nor an influence of family
history on the emergence of tics during stimulant treat-
ment41,54has been supported by family studies.
The evaluated high-quality data did not identify a definite
impact of dosage or duration of stimulant treatment on first-
onset tics. This supports the view that the potential impact of
stimulant treatment for ADHD on the development of tics
might be negligible, or at least of short duration, and that a
direct causal relationship might be seen only in a small minor-
ity of affected children.17This relationship could suggest an
early triggering of otherwise later spontaneous onset of tics,28
rather than causing tics that would never have emerged with-
out stimulant medication. The time-delay phenomenon and
its influence on the long-term course of tics requires further
investigation in prospective studies.
Although a small proportion of stimulant-induced tics has
been reported, it should be noted that tic disorders follow a
remitting course and have little, if any, impact on the out-
come of ADHD compared with other comorbid conditions,
such as obsessive-compulsive disorder or major affective dis-
orders.44,55Stimulants are usually an effective and safe treat-
ment for children with ADHD. The potential benefits out-
weigh the possible disadvantage of precipitating first-onset
tics, even in children with a family history of tics who are like-
ly to have a pre-existing disposition.
Accepted for publication 17th March 2006.
This study was supported by an unrestricted educational grant from
Janssen-Cilag GmbH (Germany).
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