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ADHD, Asperger syndrome, and high-functioning autism

Article  in  Journal of the American Academy of Child & Adolescent Psychiatry · December 2005
DOI: 10.1097/01.chi.0000177322.57931.2a · Source: PubMed

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LETTERS TO THE EDITOR
ADHD, ASPERGER SYNDROME, AND
HIGH-FUNCTIONING AUTISM
To the Editor:
In the March 2005 issue, Fitzgerald and Kewley (2005)
debated the pitfalls of making a diagnosis of Asperger syn-
drome in children with attention-deficit/hyperactivity disor-
der (ADHD). Based on preliminary data of an ongoing
study, we would like to contribute to the discussion on
the phenotypic overlap of ADHD and higher-functioning
autism spectrum disorders (ASDs). According to current
diagnostic classifications, the diagnosis of ASD continues
to remain in the exclusionary criteria for ADHD (American
Psychiatric Association, 2000); however, ADHD-like symp-
toms are frequent among individuals with high-functioning
ASD (Frazier et al., 2001; Goldstein and Schwebach, 2004).
Increasingly, authors question the appropriateness of diag-
nostic exclusionary criteria, suggesting that inattentive,
hyperkinetic, and impulsive symptoms should be treated
in terms of a comorbid ADHD diagnosis in ASD.
We examined the impact of different degrees of ADHD-
like symptoms on the clinical phenotype of 104 children and
adolescents with Asperger syndrome and high-functioning
autism (3.4–20.2 years; 20 females; mean IQ 97 ± 13; range
70–134). Sixty-five percent of the subjects scored above the
clinical cutoff on the attention problems scale of the Child
Behavior Checklist (CBCL 4–18), and the median value
on this syndrome scale was T = 74. When subjects were di-
vided into high (ASD+) and lower (ASD) attention problem
groups using this median and statistics controlled for IQ, age,
and socioeconomic status, ASD+ subjects exhibited a signif-
icantly higher degree of general psychopathology than ASD
subjects, indicated by significantly higher scores on all CBCL
subscales (except withdrawal and somatic complaints). It is
interesting that ASD+ girls (n = 14) tended to exhibit more
‘‘thought problems’’ than did boys; this scale has been shown
to be highly correlated with autistic conditions (Bölte et al.,
1999). Our results underscore previous studies on the asso-
ciation of ADHD and ASD, showing higher rates of difficul-
ties in daily life activities in children with comorbid ADHD
and ASD than in children with ASD alone (Goldstein and
Schwebach, 2004).
As DSM-IV-TR and ICD-10 stand, for some children
neither the criteria for ADHD nor those for ASD alone
are sufficient to make a comprehensive diagnosis. Evidence
J. AM. ACAD. CH ILD ADO LESC. PSY CH IAT RY, 44:11, NO VEM BER 2 005
is growing that the current exclusionary diagnostic criteria
of making a comorbid diagnosis of ADHD and ASD should
perhaps be reconsidered to promote appropriate manage-
ment of both disorders and to increase the likelihood for ad-
ditional research on the relationship between inattention,
hyperactivity, and impulsivity and ASD.
Martin Holtmann, M.D.
Sven Bölte, Ph.D.
Fritz Poustka, M.D.
Department of Child and
Adolescent Psychiatry and Psychotherapy
Goethe-University of Frankfurt/Main
Frankfurt, Germany
Disclosure: Prof. Poustka is a member of the advisory boards of Eli Lilly,
Janssen Cilag, AstraZeneca, and Novartis. The other authors have no
financial relationships to disclose.
American Psychiatric Association (2000), Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). Washington,
DC: American Psychiatric Association
Bölte S, Dickhut H, Poustka F (1999), Patterns of parent-reported problems
indicative in autism. Psychopathology 32:94–98
Fitzgerald M, Kewley G (2005), Attention-deficit/hyperactivity disorder and
Asperger’s syndrome? J Am Acad Child Adolesc Psychiatry 44:210
Frazier JA, Biederman J, Bellorde CA, Garfield SB, Geller DA, Coffey BJ,
Faraone SV (2001), Should the diagnosis of attention-deficit/hyperactiv-
ity disorder be considered in children with pervasive developmental
disorder? J Atten Disord 4:203–211
Goldstein S, Schwebach AJ (2004), The comorbidity of pervasive develop-
mental disorder and attention deficit hyperactivity disorder: results of a
retrospective chart review. J Autism Dev Disord 34:329–339
DOI: 10.1097/01.chi.0000177322.57931.2a
NMS AFTER CLOZAPINE INITIATION
To the Editor:
We would like to comment on our experience in attempt-
ing to treat a 16-year-old boy with clozapine and the reaction
that ensued. S.D. is a young man who has a dual diagnosis of
schizophrenia and pervasive developmental disorder. From
the time of his diagnosis of schizophrenia approximately
2 years ago, he has had greater than 10 admissions to the hos-
pital lasting from several days to several months each time. He
has been tried on multiple neuroleptics including loxapine,
olanzapine, risperidone, perphenazine, quetiapine, and
1101
LETTERS TO THE EDITOR
fluphenazine, none of which abated his psychotic symptoms.
Significantly, loxapine was administered before he came un-
der our care and he suffered an acute dystonic reaction, after
which the loxapine was discontinued. S.D.’s baseline mental
status has progressively deteriorated during the course of his
illness and his schizophrenic symptoms have persisted
throughout all therapeutic attempts.
During S.D.’s most recent hospital admission, his medica-
tions were olanzapine 5 mg orally in the morning + 15 mg
orally at bedtime and oxcarbamazepine 300 mg orally in the
morning + 150 mg orally at bedtime. This regimen was
clearly not working, and he was deteriorating during the
3 months that he was hospitalized. S.D.’s psychotic symp-
toms had been refractory to all atypical, typical, and intra-
muscular medications tried thus far. It is known from the
literature that clozapine can help with psychotic symptoms
in many patients who do not respond to other neuroleptic
drugs (Ciapparelli et al., 2003; Naber and Hippius, 1990).
Therefore, S.D.’s family elected to try a trial of clozapine
in the hopes of achieving some symptomatic relief. Before
starting S.D. on clozapine, his oxcarbamazepine was decreased
to 150 mg and olanzapine was titrated to 10 mg daily. Also,
a full baseline neurological workup, including metabolics,
magnetic resonance imaging, and EEG, was grossly normal.
S.D. was given his first dose of clozapine 12.5 mg orally at
10:00 A.M. on a Friday along with 5 mg intramuscular olan-
zapine for agitation. In the early afternoon, he became quite
somnolent and slept for several hours. Around 6 P.M., the staff
noticed that S.D. looked flushed (particularly at the ears), va-
cant, and confused, and appeared to be less responsive than
normal. Cogwheeling of his arms was present and his vitals
were as follows: temperature 38.2°C, heart rate 120, respira-
tory rate 20, blood pressure 140/100. Blood work was not
done during the weekend; however, the creatine kinase
(CK) level measured 3 days later was elevated at 411.
The fact that after initiating clozapine, S.D. developed fe-
ver, autonomic changes, muscle rigidity, and an elevated CK
level raised concern for a neuroleptic malignant syndrome
(NMS) diagnosis. This case is an interesting one because
NMS caused by clozapine is considered to be rare and the
clinical picture developed at a low dose within 8 hours of ini-
tiation of treatment. Although we do believe that this reaction
was NMS, there may also be an alternate explanation for
S.D.’s symptoms. His symptoms of rigidity and mild hyper-
tension may have been an acute dystonic reaction to the
clozapine together with the anticholinergic effects from
the olanzapine. The elevated CK value may be attributed
to the intramuscular olanzapine that S.D. received on
Friday morning with his clozapine.
In the literature, there have been 21 cases of NMS caused
by clozapine reported, a similar number to cases of NMS
caused by risperidone (23) and olanzapine (19; Ananth
1102 J. AM . ACAD. CHILD ADOLESC. PSYCHIATR Y, 44:1 1, NOVEMB ER 2005
et al., 2004). For clozapine, the mean age of the patients
who had NMS was 40.2 years (SD = 17.1) and the mean
dose of clozapine was 318 mg daily (SD = 299; Ananth
et al., 2004). Eleven of the cases were taking increasing doses
of clozapine, and the other 10 were taking stable doses
(Ananth et al., 2004). The mean number of days to onset
of NMS was 218 days, the mean CK during NMS was
1,571, and the mean temperature was 38.7°C.
Another interesting point with this case is that the patient
had a previous adverse dystonic reaction to loxapine. Al-
though their pharmacodynamics are different, loxapine
and clozapine have similar molecular structures, loxapine
being of the dibenzoxazepine class of drugs and clozapine
a dibenzodiazepine. One might wonder whether there is a
connection between the adverse reactions that our patient
experienced with the two different drugs.
Mia Skarpathiotakis, M.Sc.
University of Toronto
Toronto
Neal Westreich, M.D., F.R.C.P.C.
Sunnybrook and Women’s College
Health Sciences Center
Toronto
Disclosure: The authors have no financial relationships to disclose.
Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T (2004),
Neuroleptic malignancy syndrome and atypical antipsychotic drugs.
J Clin Psychiatry 65:464–470
Ciapparelli A, Dell’Osso L, Bandettini di Poggio A, Carmassi C, Cecconi D,
Fenzi M, et al. (2003), Clozapine in treatment-resistant patients with
schizophrenia, schizoaffective disorder, or psychotic bipolar disorder:
a naturalistic 48-month follow-up study. J Clin Psychiatry 64:451–458
Naber D, Hippius H (1990), The European experience with use of clozapine.
Hosp Community Psychiatry 41:886–890
DOI: 10.1097/01.chi.0000177328.92333.2b
TREATMENT OF WITHDRAWAL DYSKINESIA
To the Editor:
Second-generation antipsychotic medications (SGAs) are
used increasingly in children and adolescents to treat a wide
variety of disorders. Although better tolerated and with a lower
rate of inducing movement disorders than neuroleptics (at
least in adults), the risk of tardive dyskinesia (TD), a poten-
tially disfiguring movement disorder, still exists. Most of the
dyskinesias reported in children and adolescents became ev-
ident only upon withdrawal of the antipsychotic medication.
Kumra and colleagues (1998) reported that withdrawal

dyskinesia developed in 28% of the patients taken off their
antipsychotic medication for a period of 14 to 28 days as
part of NIMH studies. This rate is consistent with the with-
drawal dyskinesia rate of 29.7% reported by Campbell and
colleagues (1997) in their large prospective study of children
with autism.
Children and adolescents with dyskinetic movements may
refuse to go to school or interact with other children because
of legitimate concerns about being ridiculed. Therefore, a tol-
erable and effective treatment for these movements may return
a patient to functioning before the complete resolution of
movements. Significant reductions of dyskinetic movements
after treatment with a mixture of branched-chain amino
acids (BCAA)—L-valine, L-isoleucine, and L-leucine, a med-
ical food marketed as Tarvil—were reported in a double-
blind, placebo-controlled study of adult males with tardive
dyskinesia (Richardson et al., 2003). Mild gastrointestinal
symptoms were the most common adverse event. We report
a case of medication-related dyskinesia in an adolescent to
alert child and adolescent psychiatrists to a novel treatment
for medication-related movement disorders using BCAAs.
The patient is a 17-year-old white male who has had three
hospitalizations since the age of 15 as a result of bipolar dis-
order type I. He initially responded to lithium monotherapy,
but after his second hospitalization, aripiprazole was added to
treat hallucinations. He was stable on lithium 900 mg/day
and aripiprazole 12.5 mg/day for more than 6 months. Ad-
verse effects included mild urinary hesitancy, slight sedation,
and occasional shoulder shrugging (rated as ‘‘minimal’’
movements of his neck and shoulders, on the Abnormal In-
voluntary Movements Scale [Rapoport et al., 1985]). During
a recent rehospitalization because of a suicide attempt, his
aripiprazole dose was gradually decreased during a 2-week
period and quetiapine was started. Three weeks after discon-
tinuing aripiprazole, he presented with noticeable abnormal
movements of his jaw, tongue, and hands as well as facial
twitches. On the Modified Simpson Dyskinesia Scale (Simpson
and Angus, 1970), he received ratings of ‘‘moderate’’ on
global lip movement and choreoathetoid movements of his
left upper extremity and ratings of ‘‘mild’’ on global facial
expression and lateral jaw movements. On the Abnormal In-
voluntary Movements Scale, he was found to have moderate
movements of his facial expression muscles, as well as mild
lip and jaw movements.
The patient began treatment with three packs per day of
a BCAA mixture (176 mg BCAA/kg) and was increased to
J. AM. ACAD. CH ILD ADO LESC. PSY CH IAT RY, 44:11, NO VEM BER 2 005
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LETTERS TO THE EDITOR
five packs per day (293 mg BCAA/kg). One week later, there
was noticeable improvement in the dyskinesias. When he sur-
reptitiously skipped several doses, the movements worsened.
Three weeks later, the movements were no longer evident and
he returned to school. He is tolerating the BCAA mixture
well except for some complaints of dyspepsia. He was treated
for 12 weeks, coinciding with the end of the school year. His
dyskinetic movements (facial tics, lip movements, and chor-
eoathetoid movements of the fingers rated as ‘‘questionable’’
on the Modified Simpson Dyskinesia Scale) worsened slightly
after discontinuing the BCAA mixture but were not signifi-
cant enough to warrant restarting BCAA. We believe that
treatment with the BCAA mixture allowed our patient to re-
sume his usual activities more rapidly and to adhere to his
medication regimen of lithium, divalproex, and quetiapine.
Vivian Kafantaris, M.D.
Judith Hirsch, M.D.
Ema Saito, M.D.
Natasha Bennett, M.A.
The Zucker Hillside Hospital
Glen Oaks, NY
Disclosure: The distributor of the BCAA mixture has donated a
3-month supply of their product for use by this patient. Tarvil is avail-
able at www.tarvil.com. Dr. Kafantaris has received research funding
from Lilly and Pfizer and research support in the form of study med-
ication donations from AstraZeneca, GlaxoSmithKline, Janssen, Lilly,
and Pfizer. The other authors have no financial relationships to disclose.
Campbell M, Armenteros JL, Malone RP, Adams PB, Eisenberg ZW,
Overall JE (1997), Neuroleptic-related dyskinesias in autistic children;
a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry
36:835–843
Kumra S, Jacobsen L, Lenane M, Smith A, Lee P, Malanga CJ, et al. (1998),
Case series: spectrum of neuroleptic-induced movement disorders and
extrapyramidal side effects in childhood-onset schizophrenia. J Am Acad
Child Adolesc Psychiatry 37:221–227
Rapoport J, Connors C, Reatig N (1985), Rating scales and assessment
instruments for use in pediatric psychopharmacology research. Psycho-
pharmacol Bull 21:713–111
Richardson MA, Bevans ML, Read LL, Read LL, Chao HM, Clelland JD,
et al. (2003), Efficacy of the branched-chain amino acids in the treatment
of tardive dyskinesia in men. Am J Psychiatry 160:(6):1117–1124
Simpson GM, Angus JWS (1970), A rating scale for extrapyramidal side
effects. Acta Psychiatr Scand 212(suppl 44):11–19
DOI: 10.1097/01.chi.0000177329.69462.5f
All statements expressed in this column are those of the authors and do not
reflect the opinions of the Journal or the American Academy of Child and
Adolescent Psychiatry. See the Instructions for Authors for information
about the preparation and submission of Letters to the Editor.
1103