JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
Volume 20, Number 1, 2010
ª Mary Ann Liebert, Inc.
Pp. 79–80
DOI: 10.1089=cap.2009.0057
Effectiveness of Clozapine for the Treatment
of Aggression in an Adolescent with Autistic Disorder
Simon Lambrey, M.D., Ph.D.,1,2 Bruno Falissard, M.D., Ph.D.,3 Marion Martin-Barrero, M.S.,4 Cecile Bonnefoy,
M.D.,1 Gwendoline Quilici, M.D.,4 Antoine Rosier, M.D.,4 and Olivier Guillin, M.D., Ph.D.2,5
P ersons with autistic disorders frequently have aggressive
behavior including violent outbursts and self-harm for which
the recommended treatment is second generation antipsychotic
drugs (McDougle et al. 2008). While risperidone has been recently
approved by the Food and Drug Administration for this indication,
clozapine received very little attention and, in particular, has never
been compared to other antipsychotics, despite open-label reports
suggesting its potentially high anti-aggressive effect in autism
(Zuddas et al. 1996; Chen et al. 2001 ; Gobbi and Pulvirenti 2001).
Here, we report the open-label assessment of the anti-aggressive
effects of risperidone, haloperidol, and clozapine in an adolescent
with autism. Written consent was provided by the legal guardian for
treatment by clozapine.
A. is a 15-year-old girl with autism. She exhibits bizarre social
interactions and restricted patterns of behavior, beginning in early
childhood, with a developmental deficiency of spoken language
apparent after the age of 3. A DSM-IV diagnosis of autism was
postulated during the first years of life and subsequently confirmed
by standardized evaluations (Autism Diagnostic Interview – Re-
vised and Autism Diagnostic Observation Schedule).
At the age of 13, A. was hospitalized for severe behavior dis-
orders marked by recurrent and sudden outbursts of extreme ag-
gressiveness. At the time, spoken language was reduced to grunts
and screams. She was extremely difficult to engage on the inpatient
unit, even for highly trained caregivers, and psychiatric interviews
were not feasible. Due to the unpredictability and potential dan-
gerousness of her behavior, Ms. A. was initially excluded from all
proposed therapeutic activities.
In succession, risperidone (1.75–3 mg=day, 10 months), halo-
peridol (3–6 mg=day, 8 months) and clozapine (475 mg=day, 12
months) were tried to treat the aggressive behaviors of this patient.
Risperidone and haloperidol were ineffective, but clinical benefits
were evident after two weeks of treatment by clozapine at the
maintenance dose. On clozapine her aggressiveness decreased, and
her behavior improved dramatically in terms of social abilities
and communication. A. was able to engage with the treatment team,
and she was progressively included in the therapeutic activities of
the unit. The benefits observed on clozapine have persisted one year
later.
To more precisely compare the effect of each drug on aggres-
siveness, her medical file was systematically reviewed retrospec-
1
Unité Régionale d’Hospitalisation pour Enfants et Adolescents, Centre Hospitalier du Rouvray, Sotteville-lès-Rouen, France.
2
Neuropsychopharmacology of Depression Unit, Institute for Biomedical Research, University of Rouen, France.
3
INSERM U669, Maison de Solenn, Paris, France.
4
Centre de Ressources Autisme de Haute-Normandie, Centre Hospitalier du Rouvray, Sotteville-lès-Rouen, France.
5
Pôle Universitaire de Psychiatrie, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France.
79
tively, and each day was categorized as ‘with aggression’ when at
least one unquestionable physically aggressive act was present on
that day (i.e., destroying property, assaulting others, or self-harm).
A logistic regression using the R statistical software was performed
with 1) the antipsychotic drug, 2) the presence=absence of sedative,
3) and=or anticonvulsivant treatment being simultaneously entered
in the model as predictors of the occurrence of aggression on a
given day.
The results showed that clozapine differed significantly from
both risperidone (Z ¼ 3.35, p < 0.001) and haloperidol (Z ¼ 2.53,
p < 0.05), with no difference between risperidone and haloperidol
(Z ¼ 1.66, p ¼ 0.10). The presence of add-on sedative (clonazepam
or cyamemazine) or anticonvulsivant (carbamazepine, valpromide
or gabapentine) treatment did not make any significant difference
regarding the occurrence of aggression (Z ¼ 1.74, p ¼ 0.08 and
Z ¼ 0.37, p ¼ 0.71, respectively). Note that anticonvulsivants were
used here for the treatment of aggressiveness and not the treatment
of potential seizures.
Since the effect of clozapine may theoretically reflect a spon-
taneous improvement over time rather than a specific effect of the
molecule, we performed a stepwise logistic regression including
both treatment and time factors; the time effect was not significant.
The probability of non-aggression on a given day may also depend
on the absence of any aggression over the prior days. To test this
hypothesis, we conducted additional analyses, using two different
approaches. The first one relies on a cox model with robust esti-
mates of variance and a cluster effect corresponding to each week
of time (Beck et al. 1998). The second one relies on a logistic
autoregressive model in which the probability of aggression at day
n is regressed on the treatment received at day n as well as on the
occurrence of aggression at day n-1 (the same model was also used
to estimate the occurrence of aggression at day n with aggression at
day n-2) (Kedem and Fokianos 2002). These two statistical meth-
ods gave the same results, suggesting that clozapine was respon-
sible for the improved behavioral control in this patient.
Clozapine was well tolerated. There was no difficulty in ob-
taining blood draws in this patient, and the white blood cells count
remained unchanged. Neurological examination, metabolic fea-
tures, ECG, and weight remained unchanged. In particular, baseline
and end point body weight was 52.5 kg and 53 kg for risperidone,
53 kg and 54 kg for haloperidol and 54 kg and 55 kg for clozapine.
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To our knowledge, this is the first report comparing clozapine to
other antipsychotic drugs for the treatment of the aggressive be-
haviors associated with autism. Two limitations to this study should
be mentioned: 1) this is a description of a single case and 2) the
risperidone dose used in this case, as well as the recommended dose
for the treatment of aggressiveness in autism and other pervasive
development disorder (PDD), is not strictly equivalent to the dos-
age of clozapine used in this case. It is also worth noting that
clozapine is the atypical antipsychotic most likely to lower the
seizure threshold. Nevertheless, this case suggests that clozapine
could be effective in the treatment of aggressive behaviors when
other antipsychotic drugs have failed. Notably, an anti-aggressive
property has already been shown for clozapine in schizophrenia
(Volavka and Citrome 2008). Controlled randomized studies are
necessary to further explore this finding in autism and PDD.
Disclosures
Simon Lambrey, Bruno Falissard, Marion Martin-Barrero, Cé-
cile Bonnefoy, Gwendoline Quilici, Antoine Rosier, and Olivier
Guillin have no conflicts of interest or financial ties to disclose.
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Address correspondence to:
Simon Lambrey, Ph.D.
Unité Régionale d’Hospitalisation pour Enfants et Adolescents
Centre Hospitalier du Rouvray
4, rue Paul Eluard
76300 Sotteville-lès-Rouen
France
Email: simon.lambrey@gmail.com