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A Double-blind Comparison of Desipramine and Placebo in Children and Adolescents With Chronic Tic Disorder and Comorbid Attention-Deficit/Hyperactivity Disorder
Thomas Spencer, MD;
Joseph Biederman, MD;
Barbara Coffey, MD;
Daniel Geller, MD;
Margaret Crawford, MD;
Sarah Kate Bearman, BA;
Reem Tarazi, BA;
Stephen V. Faraone, PhD
Arch Gen Psychiatry. 2002;59:649-656.
ABSTRACT
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Background Currently, there is no consensus on the best therapeutic approach to
chronic tic disorders and comorbid attention-deficit/hyperactivity disorder
(ADHD). To address this issue, we evaluated the tolerability and efficacy
of the noradrenergic tricyclic antidepressant desipramine hydrochloride in
the treatment of children and adolescents with chronic tic disorders and comorbid
ADHD.
Methods Forty-one children and adolescents with chronic tic disorders, including
Tourette disorder and comorbid ADHD, were studied in a 6-week, double-blind,
placebo-controlled, parallel trial. Desipramine was titrated weekly up to
3.5 mg/kg per day. We rated ADHD and tic symptoms weekly and monitored adverse
effects, laboratory findings, and cardiovascular parameters.
Results Treatment with desipramine (mean total daily dose, 3.4 mg/kg per day)
was well tolerated without meaningful adverse effects. Desipramine significantly
reduced core symptoms of ADHD (ADHD Rating Scale; 42% decrease from baseline
relative to placebo, P<.001), with equal response
in inattentive symptoms and hyperactive/impulsive symptoms (P<.001 for both). The ADHD response rate was robust (71% vs 0%;
desipramine vs placebo, P<.001). Likewise, desipramine
significantly reduced tic symptoms (Yale Global Tic Severity Scale; 30% decrease
from baseline relative to placebo, P<.001), with
equal response in motor and phonic tic symptoms (P<.01
for both). The tic response rate was substantial (58% vs 5%; desipramine vs
placebo, P<.001). There were small but statistically
significant differences between desipramine and placebo in heart rate and
blood pressure.
Conclusions Treatment with desipramine was well tolerated and was associated with
robust clinically significant reductions in tic and ADHD symptoms in children
and adolescents with chronic tic disorders and ADHD diagnoses.
INTRODUCTION
CHILDREN WITH tic disorders very frequently have comorbidity with attention-deficit/hyperactivity
disorder (ADHD).1 For many youth with this
spectrum of disorders, ADHD represents the major source of morbidity and disability.
Because standard treatments for tics (ie, neuroleptics) are not optimal for
the treatment of ADHD, and most treatments for ADHD (ie, stimulants) do not
treat tics, lingering uncertainties remain as to the most appropriate therapeutic
approach for such youth.
Because the tricyclic antidepressant desipramine hydrochloride (DMI)
has been found in case reports and case series to improve both tics and ADHD
symptoms, it has been suggested as a possible therapeutic agent for the treatment
of children with tics and ADHD. For example, Hoge and Biederman2
reported that DMI was efficacious and well tolerated in the treatment of a
young patient with a tic disorder and ADHD. Riddle et al3
documented the response of ADHD symptoms in 5 (71%) of 7 boys with chronic
tic disorders, with no change in tic symptoms in 86% (6/7) and tic worsening
in 1 child. In a systematic medical record review of 30 children with tic
disorders and ADHD who were treated with DMI, our group reported that 80%
had meaningful response of both ADHD and tic symptoms and that this improvement
was sustained for more than a year.4
Singer et al5 have offered further support
for the efficacy of DMI in the treatment of youth with tics and ADHD in a
3-arm, double-blind, crossover study that found DMI to significantly improve
ADHD symptoms (but not tics), while clonidine hydrochloride was ineffective
in improving either ADHD or tic symptoms.5
The importance of independent confirmation of findings as well as methodologic
limitations of this study (crossover design, use of a fixed dose of DMI, a
limited number of assessment points) supports the need to reassess the usefulness
of DMI in the treatment of children with tic disorders and ADHD.
To this end, we conducted a double-blind, parallel-design, placebo-controlled
randomized clinical trial of DMI in the treatment of children and adolescents
with chronic tics and ADHD, with careful, systematic, and frequent assessments
of both ADHD and tic symptoms. We hypothesized that DMI would be effective
and safe in improving both tics and ADHD symptoms in these children.
SUBJECTS AND METHODS
SUBJECTS
Subjects were clinically referred, outpatient children and adolescents
between 5 and 17 years of age, with the DSM-IV diagnosis
of combined-type ADHD and chronic motor tic disorder, chronic vocal tic disorder,
or Tourette disorder (TD) as ascertained from clinical referrals to a pediatric
psychopharmacology unit. We excluded potential subjects if they had any clinically
significant chronic medical conditions or abnormal baseline laboratory values,
low IQ (IQ <75), clinically unstable psychiatric conditions (ie, suicidality),
current bipolar disorder, psychosis, drug or alcohol abuse or dependence,
or current use of other psychotropic drugs. We also excluded pregnant or nursing
females. Although patients with a personal history of cardiac disease or a
family history of nongeriatric cardiac disease were specifically excluded
by the protocol, no patient had to be excluded because of this limitation.
This study was approved by the institutional review board, and prior to inclusion
in the study, all subjects and their parents provided written informed consent
(assent for children) after the study protocol had been fully explained.
In addition to a psychiatric evaluation, subjects were assessed with
a structured diagnostic interview, the Schedule for Affective
Disorders and Schizophrenia for School-Age Children–Epidemiologic Version (K-SADS-E),6 completed with the mother.
The structured diagnostic interview was administered by trained raters with
established interrater reliability (mean  = 0.9). For the diagnosis
of tics, TD, and ADHD, perfect reliability was established both between trained
raters and between raters and senior clinicians ( = 1.0 for both).
To receive a diagnosis of ADHD, the subject must have met full DSM-IV, combined-type ADHD criteria.7
Similarly, DSM-IV criteria were used for the diagnoses
of chronic tic disorder, including TD. Patients with transient tics were excluded
from the study. Family history of psychiatric disorders was determined using
the family history method,8 with a positive
family history defined as the presence of the disorder in at least one first-
or second-degree relative. Socioeconomic status was measured by the Hollingshead
Four-Factor Index of Social Status,9 with low
values indicating high socioeconomic status.
PROCEDURES
Prior to randomization, patients underwent a standard clinical assessment
comprising a psychiatric evaluation, a structured diagnostic interview, medical
history, and laboratory assessments (liver fuction tests, complete blood cell
count, and electrocardiograms [EKGs]). No subject was taking psychoactive
medication within 1 month of the baseline assessment, and no additional psychoactive
medication was allowed in the trial. Patients received 6 weeks of active medication
or placebo. The pharmacy randomized patients to drug and placebo treatments.
Separate balanced randomization was performed on 4 groups: preadolescent boys,
preadolescent girls, adolescent boys, and adolescent girls. Randomization
was blinded to all study personnel other than the pharmacy staff. Randomization
codes were kept in sealed envelopes in the medical records. Medication (DMI
or placebo) was given in identical-appearing 25-mg capsules. Study medications
were administered in twice-daily dosing to minimize adverse effects. Compliance
was monitored by pill counts at each follow-up visit. Study medication was
titrated up to 3.5 mg/kg by week 3 unless adverse effects developed.
For safety monitoring, EKGs, heart rate, and blood pressure were taken
weekly. Serum DMI samples were drawn at the end of week 6 at 10 to 14 hours
after the last dose and analyzed by high-pressure liquid chromatography.10 Observed limits of detection for DMI was 20 ng/mL
(75 nmol/L) and the intra-assay and interassay coefficients of variation were
2.7% and 4.1%, respectively.
ASSESSMENTS
Academic achievement was assessed at baseline with the Wide Range Achievement
Test (reading and arithmetic).11 Cognitive
functioning at baseline was assessed with the vocabulary, block design, arithmetic,
digit span, and digit symbol subtests of the Wechsler Intelligence Scales–Revised.
We estimated Full-Scale Intelligence Quotient from the vocabulary and block
design subtests and computed the Freedom from Distractibility IQ from the
other subtests.12 We used the procedure recommended
by Reynolds13 to define learning disabilities.14
To assess change during treatment, rating scales were used to document
initial and outcome severity of ADHD symptoms, and to document type, severity,
and frequency of tic symptoms. In addition, rating scales were used to document
initial and subsequent severity levels of multiple comorbid symptom domains,
including depression, obsessive-compulsive disorder (OCD), and anxiety. As
used previously,15 overall severity in each
of these domains was assessed with the Clinical Global Impressions Scale (CGI).15 The CGI includes the Global Severity (1 = not ill,
to 7 = extremely ill) and Global Improvement (1 = very much improved, to 7
= very much worse) scales.
The following domain-specific rating scales were used. The ADHD Rating
Scale16 assesses each of the 18 individual
ADHD symptoms from the DSM-IV on a severity grid
(0 = not present; 3 = severe; overall minimum score = 0; maximum score = 54
in DSM-IV). The psychometric properties of the ADHD
Rating Scale have been established in children, and it has been shown to be
sensitive to drug effects in pediatric16 populations.
The Yale Global Tic Severity Scale (YGTSS)17
is completed by the assessing clinician and measures the severity of 5 qualities
(number, frequency, intensity, complexity, and interference) of motor and
phonic tic symptoms on 10-point ordinal scales, as well as an overall tic
impairment score (0-50). The YGTSS has been shown to be sensitive and reliable.17 The Children's Yale-Brown Obsessive Compulsive Scale
(CY-BOCS)18 is a widely used instrument that
assesses the severity of 5 measures of obsessions and compulsions on 10-point
ordinal scales.
The 27-item Children's Depression Inventory (CDI)19
and the 51-item Revised Children's Manifest Anxiety Scale (RCMAS)20 are widely employed self-report scales used to measure
childhood psychopathology. Overall assessment of psychosocial function was
measured with the Global Assessment of Functioning (GAF).21
Domain-specific CGIs, the ADHD Rating Scale, YGTSS, CY-BOCS, CDI, RCMAS, and
GAF were administered weekly. The presence of adverse experiences was elicited
by open-ended questions from youth and parents at each visit.
STATISTICAL ANALYSIS
Response was defined as a reduction ( 30%) in the appropriate rating
scale, plus a CGI score of 1 or 2 (much or very much improved, respectively).
To compare the proportion of subjects who improved with DMI vs placebo, we
used the Pearson  2. Since our design required repeated measures
on subjects, we also conducted analyses using random effects, cross-sectional
time-series models using the method of generalized estimating equations (GEE)
as described by Liang and Zeger22 and Zeger
et al.23 We specified a first-order autoregressive
working correlation matrix. We tested for group differences in continuous
variables using a random effects model that estimated main effects of drug
(DMI vs placebo), time (week of study), and the interaction between the two.
All statistical tests were performed using Stata.24
We set statistical significance at the 1% level to avoid type I errors. All P values are based on 2-tailed statistical tests. Data
are expressed as mean ± SD unless otherwise specified.
RESULTS
CHARACTERISTICS OF THE STUDY SAMPLE
The sample consisted of 7 girls and 34 boys (n = 24 preadolescent, n
= 17 adolescent). All subjects met full DSM-IV criteria
for combined-type ADHD. All subjects had a history of DSM-IV TD (n = 37/41) or non-TD chronic tic disorder (n = 4/41), and all
but 2 subjects currently had TD (n = 34) or non-TD chronic tic disorder (n
= 5). Analysis of tic disorder outcomes was restricted to the 39 subjects
with current TD or chronic tics.
As depicted in Table 1,
half (22/41) of the subjects had been previously treated with stimulants.
Of these, stimulants preceded the onset of tics in half (12/22). Further,
of children treated with stimulants, 64% (14/22) reported an exacerbation
of tics induced by the stimulant treatment. In addition to tic disorders and
ADHD, 88% of subjects (n = 36) had at least 1 other comorbid psychiatric disorder.
Baseline ratings of depression (CDI: child T = 55 ± 10; parent T =
56 ± 9.8) and anxiety (RCMAS T = 50 ± 11) were relatively low.
Using a T score greater than 65 as an indicator of moderate severity on ratings
of depression and anxiety, 15% of subjects (6/41) had scores of depression
or anxiety that were moderately severe or worse. Baseline ratings of OCD (CY-BOCS
= 3.3 ± 6.2) were also relatively low. Eighty-two percent of children
with ADHD had one or more first- or second-degree relatives with ADHD. Despite
average intelligence (average IQ = 96 ± 14), 44% of subjects had evidence
of a learning disability in either math or reading, and 57% of subjects required
tutoring in school.
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Table 1. Clinical and Demographic Characteristics of Sample*
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Twenty-one subjects were randomized to the DMI group, and 20 to placebo.
Dose was gradually titrated from week 1 to week 4 with little change between
week 4 and week 6. Average daily doses of DMI and placebo by the end of each
week were 1.4 ± 0.2 mg/kg and 1.5 ± 0.2 mg/kg for week 1, 2.3
± 0.4 mg/kg and 2.4 ± 0.3 mg/kg for week 2, 3.1 ± 0.5
mg/kg and 3.3 ± 0.3 mg/kg for week 3, 3.2 ± 0.4 mg/kg and 3.4
± 0.2 mg/kg for week 4, 3.3 ± 0.4 mg/kg and 3.4 ± 0.2
mg/kg for week 5, and 3.4 ± 0.3 mg/kg and 3.4 ± 0.2 mg/kg for
week 6, respectively. Total doses were 154 ± 63 mg/kg and 150 ±
48 mg/kg for DMI and placebo by week 6. Doses of DMI and placebo were not
statistically different at any week.
ADHD OUTCOME
Desipramine treatment significantly and robustly reduced the symptoms
of ADHD (week 6 vs week 0: 24 ± 12 vs 46 ± 5.9, respectively; t20 = 6.9; P<.001).
In contrast, placebo did not (week 6 vs week 0: 42 ± 7.3 vs 44 ±
6.3, respectively; t19 = 1.5; P = .14). As Figure 1 shows,
under treatment with DMI, ADHD symptom reduction was progressive throughout
the 6 weeks of treatment. Random effects analyses revealed that response to
DMI attained statistical significance by the second week of treatment (z = 3.2, P<.01), with further
improvement in ensuing weeks (all z scores >3.4;
all P values <.001). Overall, the drug x
time interaction was statistically significant for ADHD symptoms (z = 5.1, P<.001) without main effects of
drug (DMI or placebo) or time (weeks 0-6), indicating that the effects of
drug treatment on ADHD symptoms increased with the duration of treatment.
The mean difference between DMI and placebo response constitutes a 42% difference
from baseline (end point placebo - end point DMI/baseline DMI). Improvement
in ADHD symptoms was equally robust when examining drug x time interactions
of both inattentive symptoms (z = 4.9, P<.001) and hyperactive/impulsive symptoms (z = 5.0, P<.001).
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Figure 1. Controlled study of desipramine
(DMI) in children with tics and attention-deficit/hyperactivity disorder (ADHD);
ADHD symptom outcome. Desipramine n = 21; placebo n = 20. A, Combined ADHD
symptoms. B, Inattentive ADHD symptoms. C, Hyperactive/impulsive ADHD symptoms.
Single asterisk indicates P<.01; double asterisk, P<.001.
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TIC OUTCOME
Desipramine treatment significantly and robustly reduced tics as well
(YGTSS week 6 vs week 0: 43 ± 23 vs 63 ± 18, respectively; t18 = 5, P<.001).
In contrast, placebo had little effect on tics (YGTSS week 6 vs week 0: 61
± 15 vs 65 ± 15, respectively; t19 = 1.8, P<.08). Tic symptom reduction
was progressive throughout the 6 weeks of treatment (Figure 2). Random effects analyses revealed that response to DMI
attained statistical significance by the fifth week of treatment (z = 3.1, P<.01), with further improvement
in the sixth week (z = 3.6, P<.001).
Overall, the drug x time interaction was statistically significant for
tic symptoms (YGTSS: z = -3.5, P<.001) without significant main effects of drug (DMI or placebo)
or time (weeks 0-6), indicating that the effects of drug treatment on tic
symptoms increased with the duration of treatment. The difference between
DMI and placebo constitutes a 30% difference from baseline (end point placebo -
end point DMI/baseline DMI). Improvement in tic symptoms was demonstrated
in both motor tic symptoms (YGTSS interaction: z
= -2.8, P<.005) as well as phonic tic symptoms
(YGTSS drug x time interactions: z = -2.6, P<.01) (Table 2).
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Figure 2. Controlled study of desipramine
(DMI) in children with tics and attention-deficit/hyperactivity disorder (ADHD);
tic symptoms outcome. Desipramine n = 19; placebo n = 20. A, Global tic severity.
B, Total tic severity. C, Phonic tic severity. D, Motor tic severity. Single
asterisk indicates P<.01; double asterisk, P<.001.
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Table 2. Proportion of Responders*
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To further evaluate response, we analyzed end-of-treatment results using
a preestablished definition of response (much or very much improved on the
CGI, and a more than a 30% reduction in symptoms). Using this definition,
71% of patients (15/21) were ADHD responders while taking DMI, compared with
0% (0/20) taking placebo (21 = 22.5, P<.001); and 58% (11/19) of patients were tic responders while taking
DMI, compared with 5% (1/20) taking placebo (21
= 12.8, P<.001). For subjects taking DMI, there
was a significant association of response between the 2 domains (21 = 9.3, P<.01). All 11 (of
19) who were tic symptom responders were also ADHD symptom responders. In
addition, 3 of 19 were ADHD symptom responders but not tic symptom responders.
For analyses of outcome measures, we included potential predictors of
response as factors in random regression analyses. We found no meaningful
associations between improvement of ADHD or tic symptoms and socioeconomic
status, psychiatric comorbidity, or a positive family history of psychiatric
disorder. No changes were noted in measures of anxiety, OCD severity, and
depression between DMI and placebo. In contrast, psychosocial functioning
(GAF) improved dramatically in those taking DMI compared with the placebo
group (z = 4.7, P = .001).
The difference (in GAF) between the DMI and placebo groups at the end point
(58 ± 5 vs 52 ± 5, respectively) constitutes a 12% difference
from baseline (50 ± 4 vs 51 ± 4, repectively).
ADVERSE EFFECTS
Desipramine was well tolerated, and no serious adverse effects were
observed. All but 2 patients completed the study, and both were taking the
placebo. Although decreased appetite was the only statistically significant
adverse effect observed (DMI vs placebo: 24% vs 0%, respectively; 21 = 5.4, P<.02), it was not
associated with weight loss. Difficulty sleeping and headaches were the next
most common adverse effects. Evaluation of cardiovascular parameters revealed
mild but statistically significant increases in diastolic blood pressure for
DMI vs placebo response (70 mm Hg vs 65 mm Hg, t36 = 1.2, P = .03). Treatment with DMI was
also associated with an increase in pulse (97 vs 84 beats per minute, t37 = 3.0, P<.005)
(Table 3).
As expected, small and not statistically significant changes in EKG
conduction parameters were observed in DMI-treated patients. Differences between
DMI and placebo include indices of conduction (PR and QRS duration) and repolarization
(mean increase in PR [4.6%], QRS [3.1%], and repolarization [0.3%]; for all
values, P>.5). Electrocardiograms confirmed that
the heart rate was increased in subjects taking DMI compared with placebo
(90 ± 3 vs 78± 3, respectively; t38 = 2.7, P<.02). However, there were no
symptoms referable to the cardiovascular system and no case of a worrisome
pulse rate, conduction, or repolarization interval.
Analyses of drug doses and levels (week 6) were conducted to examine
the relationship of these variables to the response of ADHD and tic symptoms.
Desipramine levels varied widely, and DMI dose and level were not correlated
(not significant). While DMI doses and levels were somewhat greater in responders,
no comparison achieved statistical significance. Desipramine levels were 177
± 139 vs 145 ± 173 ng/mL in responders vs nonresponders, respectively.
In addition, adverse effects and EKG parameters were not correlated with DMI
levels at week 6.
COMMENT
In a randomized, double-blind, placebo-controlled, parallel-design trial
of the tricyclic antidepressant DMI in the treatment of children and adolescents
with chronic tic disorders and comorbid ADHD, treatment with DMI at an average
oral daily dose of 3.4 mg/kg per day was well tolerated and highly effective
in improving both tics and ADHD symptoms. These results support the usefulness
of DMI in the treatment of children and adolescents with chronic tics and
ADHD.
To our knowledge, our findings are the first to document a statistically
and clinically robust improvement of tic symptoms associated with DMI treatment
under double-blind conditions. The 30% mean difference between DMI and placebo
response on the YGTSS is lower than that found in some25
but not all26 neuroleptic studies, and are
similar to that reported in  2-noradrenergic studies.27-28 While the effect of stimulants on
tic exacerbation continues to be evaluated, our results suggest that DMI may
offer an effective alternative for the treatment of patients with chronic
tics and ADHD. Additionally, DMI offers some advantages over stimulants, including
a longer duration of action obviating the need to administer medication during
school hours, absence of abuse potential, and putative positive effects on
mood and anxiety, and sleep.
Our finding documenting a robust response to DMI on ADHD symptoms is
consistent with a substantial literature (9 studies, N = 239 subjects) consistently
reporting the beneficial effects of DMI in the treatment of ADHD in children,
adolescents, and adults.29 In the largest controlled
study of DMI in children, our group reported a robust response in 62 clinically
referred children with ADHD, most of whom had previously failed to respond
to psychostimulant treatment.30 Further support
for the efficacy of DMI in the treatment of youth with tics and ADHD comes
from a 3-arm, double-blind, crossover study by Singer et al5
that found DMI to significantly improve ADHD symptoms.5
It is of note that the magnitude of ADHD response in the current study (70%
of subjects) approximated that in the study by Biederman et al30
(68%) despite a lower average daily dose (3.4 mg/kg vs 5 mg/kg, respectively),
suggesting that the therapeutic benefits of DMI may not be contingent on relatively
high daily doses. Rates of response of ADHD symptoms to placebo vary depending
on methodology. However, our rates of 5% by the ADHD Rating Scale and 0% by
CGI are almost identical to those of a recent study by Scahill et al.27
Although DMI has a wide range of neurochemical effects on neurotransmitters,
it is assumed that DMI's activity on tics and ADHD stems from actions on noradrenaline
reuptake. While a body of literature supports links between noradrenergic
dysregulation and ADHD,31 the mechanism by
which DMI exerts its beneficial effects on tic regulation remains unknown.
Consistent with previous studies of DMI in children,32
DMI was very well tolerated with no major adverse effects, changes in cardiovascular
parameters, or EKG intervals. Also consistent with previous studies, there
were no significant differences in the risk of subjective or clinically observable
adverse effects at higher or lower serum drug levels.
As was the case in this study, a rather extensive literature consistently
identified mostly minor, asymptomatic increases in heart rate and EKG measures
of cardiac conduction times associated with DMI treatment.32
Despite these rather benign cardiovascular changes observed, lingering concerns
remain as to the safety of DMI in children, stemming from reports of sudden
death in children with ADHD who were treated with this medicine.33-35
Although the causal link between DMI and these deaths remains uncertain, and
a systematic effort to estimate the magnitude of DMI-associated risk of sudden
death in children suggested that it may not be larger than the baseline risk
of sudden death in this age group,36 safety
concerns remain. Until this issue is resolved, children should be screened
for a personal or family history of early-onset cardiac disease, including
the long QT syndrome or other causes of sudden unexplained death, and assessed
for cardiovascular safety following the American Heart Association's recommended
guidelines (1) before starting a child on a tricyclic antidepressant, (2)
during dose adjustments, and (3) periodically during maintenance.37 These include a sustained resting heart rate less
than 130 beats per minute, a PR interval less than 200 milliseconds, or a
repolarization less than 460 milliseconds; if cardiac symptoms such as palpitations,
syncope, or near syncope develop, dose adjustments or alternate treatments
need to be considered, along with pediatric cardiology consultation.37
In this study, 32% of the sample was found to have current moderate
depression. Rates of comorbid depression in ADHD have varied depending on
assessment methodology and ascertainment; however, rates reported here are
consistent with those found in both psychiatric and pediatric samples.38-39 Recently, a comprehensive meta-analysis
of epidemiologic studies concluded that the association of ADHD and depression
was real, and not due to methodologic artifact.40
The results of this study should be viewed in light of methodological
limitations. The K-SADS-E was designed to be administered by clinicians. However,
in our study, the K-SADS-E was administered by trained research assistants
with documented reliability and reviewed by the lead author (T.S.). In this
study, clinicians rated ADHD symptoms based on parent and child interviews.
In future studies, direct teacher and parent reports would allow comparison
to other ADHD studies. However, for diagnostic purposes, parent and teacher
reports have been found to closely agree.41
Future studies should use separate raters for efficacy measures and adverse
effects. There was a relatively short exposure to medication; no measures
of cognitive or academic function, school behavior, and peer interactions;
and only one measure of tic severity. In addition, there were no data on long-term
efficacy, DMI discontinuation, or relative efficacy. Larger and longer studies
with appropriate instrumentation assessing these domains will be needed to
address these important issues. This was too small of a sample to determine
the safety of this compound in children. While our sample should generalize
to other pediatric psychiatry clinics, it may not generalize to other settings.
Despite these limitations, this study documents under controlled conditions,
that DMI significantly improved ADHD and tic symptoms and was well tolerated.
These promising results provide support for further studies of DMI in the
treatment of ADHD and tic disorders throughout an extended period of treatment
and with a more detailed assessment of functioning and quality of life.
AUTHOR INFORMATION
Submitted for publication May 21, 2001; final revision received September
26, 2001; accepted October 1, 2001.
This study was supported in part by funding from the Tourette's Society
Association and grant R29 MH57511 from the National Institute of Mental Health,
Bethesda, Md (Dr Spencer).
Corresponding author and reprints: Thomas Spencer, MD, Pediatric
Psychopharmacology Unit (ACC-725), Massachusetts General Hospital, Fruit Street,
Boston, MA 02114.
From the Pediatric Psychopharmacology Unit, Psychiatry Service, Massachusetts
General Hospital, Boston (Drs Spencer, Biederman, Crawford, and Faraone, Ms
Bearman, and Ms Tarazi); the Department of Psychiatry, Harvard Medical School,
Boston (Drs Spencer, Biederman, Coffey, Geller, and Faraone); the Tourette's
Disorder Clinic (Dr Coffey) and the Obsessive Compulsive Disorders Clinic
(Dr Geller), McLean Hospital, Belmont, Mass; and the Harvard Institute of
Psychiatric Epidemiology and Genetics, Harvard Medical School, Boston (Dr
Faraone).
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