132
10. Dolan RW, Chowdhury K: Diagnosis and treatment of intracranial
complications of paranasal sinus infections. J Oral Maxillofac Surg
1995;53:1080-1087.
11. Odabasi AO, Akgul A: Cavernous sinus thrombosis: A rare complica-
tion of sinusitis. Int J Pediatr Otorhinolaryngol
1997;39:77-83.
Venlafaxine in Children, Adolescents, and Young
Adults With Autism Spectrum Disorders: An Open
Retrospective Clinical Report
ABSTRACT
Autism is characterized by social deficits, communication and lan-
guage impairments, narrow restricted interests, repetitive behav-
iors, inattention, and
hyperactivity. While selective serotonin
reuptake inhibitors have demonstrated efficacy in treating core
symptoms of autism, norepinephrine reuptake inhibitors have
demonstrated efficacy in symptoms of attention-deficit hyperac-
tivity disorder (ADHD). An open, retrospective clinical study with
venlafaxine evaluated its effect on core symptoms of autism as well
as associated features of ADHD. Ten consecutive subjects meet-
ing Diagnostic and Statistical Manual of Mental Disorders, 4th
edition (DSM-IV), criteria for an autism spectrum disorder were
treated with venlafaxine, initiated at 12.5 mg per day and adjusted
on aflexible basis. Six of 10 completers were judged to be sustained
treatment responders, by scoring 1 (very much improved) or 2
(much improved) on the Clinical Global Impressions improve-
ment scale. Venlafaxine was effective in low
dosages (mean, 24.37
mg/day; range, 6.25 to 50 mg/day) and was well tolerated. Improve-
ment was noted in repetitive behaviors and restricted interests,
social deficits, communication and language function, inattention,
and hyperactivity. Controlled treatment trials with venlafaxine are
warranted in autism spectrum disorders. ( J Child Neurol
2000;15:132-135).
Autism is a neurodevelopmental disorder characterized by dis-
turbance in social interactions, language, and communication, and
by restricted interests and repetitive behaviors. Other commonly
associated features include symptoms of attention-deficit disorder,
such as inattention, motor hyperactivity, and impulsivity, which also
cause considerable distress and morbidity.
There is considerable indirect evidence for serotoninergic
dysfunction in autism spectrum disorders. 1,2,3 Further indirect evi-
dence for serotoninergic dysfunction in autism derives from the find-
ing that serotonin reuptake inhibitors (clomipramine) and selective
serotonin reuptake inhibitors (fluoxetine, fluvoxamine, and ser-
traline) are effective in autism. Clomipramine was found superior
to both placebo and desipramine in reducing autistic behaviors,
anger, and compulsive and ritualized behavior.4 Fluoxetine was
reported to reduce aggression and compulsive rituals and improve
eye contact.-5 Fluvoxamine, in a double-blind, placebo-controlled
study in adults with autism, resulted in significant improvement in
repetitive thoughts and behavior, maladaptive behavior and aggres-
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sion, and social relatedness and language usage.6 Sertraline, in
small doses, was shown to be effective in reducing transition anx-
iety in children with autism.’7
Other neurotransmitter and neuropeptide systems also play
a role in autism.8
Dopamine antagonists such as haloperidol and
risperidone have demonstrated efficacy in autism.9,10 Norepi-
nephrine reuptake inhibitors such as desipramine are not effective
in core autistic symptoms, but significantly reduce accompanying
symptoms of hyperactivity.4
Venlafaxine exhibits potent inhibition of both serotonin and
norepinephrine reuptake, and to a lesser extent, dopamine reup-
take.11 Existing preliminary data suggest that venlafaxine could be
effective in treating symptoms of obsessive-compulsive disor-
der,12,13 attention-deficit hyperactivity disorder (ADHD),14 and social
phobia,l5 symptom clusters that overlap with autism spectrum dis-
orders.
The selective serotonin reuptake inhibitors have been shown
to be effective in targeting core autistic symptoms, and norepi-
nephrine reuptake inhibitors might reduce associated features
such as hyperactivity. This study examines whether venlafaxine,
which has serotonin and norepinephrine reuptake inhibition effects
without histaminergic, muscarinic, or a-adrenergic activity, holds
promise in treating autism spectrum disorders.
Method
This open, retrospective study examined treatment response of venlafax-
ine in the first 10 children, adolescents, and young adults with autism spec-
trum disorders treated with venlafaxine, and data are presented in a
descriptive fashion. The first 10 patients (8 children or adolescents and 2
young adults) between the ages of 3 and 21 years who met Diagnostic and
Statistical Manual of Meretal Disorders, 4th edition (DSM-IV) criteria for
pervasive developmental disorders including autism, Asperger’s syndrome,
and pervasive developmental disorders not otherwise specified and who were
treated with venlafaxine, are included.
All
patients were assessed by a board-certified psychiatrist (E.H.)
with extensive experience in treating children, adolescents, and adults
with autism spectrum disorders, and recruited from the author’s office-based
practice. Current DSM-7V diagnoses were determined on the basis of patient
and parent interview and all other available clinical data, including neu-
ropsychologic testing, individualized educational plans, and teacher reports.
Exclusion criteria included the presence of a significant medical illness such
as hypertension or seizure disorder. Psychiatric exclusion criteria included
bipolar illness or psychotic disorders.
Improvement in the severity of autistic spectrum disorder symptoms
was assessed with the Clinical Global Impressions improvement scale, a clin-
ician-rated instrument that involves comparing the patient’s current con-
dition to that at baseline, to determine how much the patient has changed
with clinical treatment. Improvement scores were 1 (very much improved),
2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally
worse), 6 (much worse), and 7 (very much worse). Responders were those
who obtained a Clinical Global Impressions improvement score of 1 to 2
(very much to much improved).
Patients were started on an initial dose of 12.5 mg of venlafaxine
after breakfast to avoid potential side effects. Doses were adjusted on a flex-
ible basis to minimize side effects and maximize improvement. At each visit,
patients and their parents were asked about potential side effects that are
most common to venlafaxine. Data collected on all patients who enrolled
in this trial were included in the report.
Results
Nine male patients and one female patient were included in the
report; eight were children or adolescents and two were adults.
 133

Table 1. Patient Characteristics

PDD NOS pervasive developmental disorder

=
not otherwise specified; ADHD = attention-deficit hyperactivity disorder; OCD =
obsessive-compulsive disorder;TS =Tourette
syndrome; BDD body dysmorphic disorder.
=

The patients’ ages ranged from 3 to 21 years with a mean age of
10.46 years (SD ± 5.55). Four patients met DSM-IV criteria for
autism, five for Asperger’s syndrome, and one for pervasive devel-
opmental disorder not otherwise specified. Of the 10 patients in
the study, 5 had comorbid diagnoses, including ADHD, body dys-
morphic disorder, separation anxiety, obsessive-compulsive dis-
order, and Tourette syndrome. Seven patients had IQ testing
performed at baseline; results ranged between 65 and 115. Two
patients took concomitant medication during the study. One
Patients were started on 12.5 mg of venlafaxine once daily at
breakfast. Venlafaxine was gradually increased as determined by
clinical response and side effects. The final and highest doses for
each patient are reported in Table 2. The mean final dose was
24.37 mg ± 14.86 mg/day (minimum dose, 6.25 mg; maximum dose,
50 mg) and the mean highest dose was 29.37 mg ± 12.51 mg/day
(minimum, 12.50 mg; maximum, 50 mg). The mean length of treat-
ment was 4.77 ± 2.46 months (minimum of 1 month and a maxi-
mum of 10 months). Side effects of venlafaxine included behavioral

received clomipramine at 75 mg per day and diazepam at 2 mg as activation (hyperactivity, irritability, agitation, restlessness, and
needed, and the other took divalproex sodium at 250 mg per day aggression), inattention, polyuria, and nausea, and are reported in
and dextroamphetamine at 15 mg per day (Table 1). Several Table 2.
patients had been on medication prior to venlafaxine treatment, The mean Clinical Global Impressions improvement score

but all had been off medications for at least 1 week before receiv- was 2.15 ± 1.03. Six of 10 patients were rated as sustained respon-
ing venlafaxine (Table 1). ders, with fmal Clinical Global Impressions improvement scores

Table 2. Drug Response

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134
of &dquo;much improved&dquo; (2) to &dquo;very much improved&dquo; (1). The other
four patients were rated as nonresponders with scores equal to or
greater than 3 (minimally improved). The mean
venlafaxine dose in the responder group (25 mg ± 13.69) did not
differ from that of the nonresponders (23.43 mg ± 18.66), nor did
the mean highest dose (28.125 mg ± 11 versus 31.25
Venlafaxine treatment was noted to improve symptoms in all
three core dimensions in autism. Patients were observed to show
decreased repetitive behaviors (motor stereotypies) as well as
fewer obsessional symptoms. Regarding the social dimension,
improvements were seen in eye contact and socialization, as well
as in increased complexity of play. In the communication domain,
improvements were noted in contextual language usage and abnor-
mal vocalizations. There were also improvements in associated fea-
tures of autism. Five of six responders showed signs of improvement
in features of ADHD with venlafaxine, with better focus or atten-
tion, or both, in four patients and improved impulse control in two
patients. Two patients had elevation in mood (Table 2).
Discussion
This open, retrospective pilot study provides preliminary evidence
that venlafaxine, in low doses, could be of benefit in children,
adolescents, and young adults with autism and other pervasive
developmental disorders. From the data collected, it appears that
there is some improvement in all three core dimensions of autism
spectrum disorders (social deficits, impairment in communica-
tion and language, and restricted interests and repetitive behaviors),
as well as improvement of associated features such as symptoms
of ADHD. Serotonin reuptake inhibitors and selective serotonin
reuptake inhibitors have been reported to improve several features
of autism, including repetitive and stereotypic behaviors and social,
communication, and language functions. On the other hand, nor-
epinephrine reuptake inhibitors have been noted to improve symp-
toms of hyperactivity. Venlafaxine (with dual serotonin and
norepinephrine reuptake properties) appeared helpful for com-
pulsive and repetitive behaviors as well as associated features of
ADHD, including inattention, lack of focus, impulsivity, and hyper-
activity, and was well tolerated in the low doses used.
Previous studies in children with autism have demonstrated
behavioral
arousal, including aggression, irritability, temper
tantrums, self-injurious behavior, and insomnia with clomipramine,
a tricyclic antidepressant with dual serotonin and norepinephrine
effects, mostly at higher doses (75 to 125 mg per day), but not at
doses below 3 mg/kg per day. 16 Signs of behavioral activation were
seen in five patients, even at low doses ranging from 12.5 to 37.5
mg. These behavioral activation symptoms were transient
appeared on dosage reduction in three patients, but two patients
were unable to stay on venlafaxine because of persistent behav-
ioral activation. The literature suggests that children are sensitive
to behavioral activation side effects of serotonin reuptake
inhibitors. 16 While venlafaxine has a dose-dependent effect on rais-
ing blood pressure,17 this is clinically significant only at doses
above 300 mg/day18 and none of our patients exceeded 50 mg/day,
nor were any noted to have elevated blood pressure.
This report is limited by its relatively small sample size, the
inclusion of two patients on concomitant medication, and primar-
ily by its open, retrospective nature. Nevertheless, these positive pre-
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liminary findings in 6 of 10 patients with autism spectrum disorder
treated with venlafaxine suggest the need for replication with a
endpoint prospective, placebo-controlled trial using standard rating scales and
diagnostic instruments such as the Autism Diagnostic Interview-
Revised and Autism Diagnostic Observational Scale-General.
± 16.13). Venlafaxine, a serotonin and norepinephrine reuptake inhibitor,
could be a beneficial treatment for autism spectrum disorders,
including restricted and repetitive behaviors and social and language
dysfunction, as well as for associated symptoms of ADHD.
EricHollander, MD
AliciaKaplan, MD
Charles Cartwright, MD
Daniel Reichman
Department of Psychiatry
and the Seaver Autism Research Center
Mount Sinai School of Medicine
New York, New York
Received March 10, 1999. Received revised June 4, 1999. Accepted for pub-
lication June 11, 1999.
Address correspondence to Dr Eric Hollander, Department of Psychiatry,
Box 1230, Mount Sinai School of Medicine, One Gustave L. Levy P1, New
York, NY 10029. Tel: 212-241-3623; fax: 212-987-4031; e-mail: e_hollander
@smtplink.mssm.edu.
Acknowledgments
This work was supported in part by a grant from the Seaver Foundation.
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1. Piven J, Tsai GC, Nehme E, et al: Platelet serotonin: A possible marker
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2. Cook EH, Charak DA, Arida J, et al: Depressive and obsessive-com-
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3. McDougle CJ, Naylor ST, Cohen DJ, et al: Effects of tryptophan deple-
tion in drug-free adults with autistic disorder. Arch Gen Psychiatry
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4. Gordon CT, State RC, Nelson JE, et al: A double-blind comparison of
clomipramine, desipramine, and placebo in the treatment of autistic
disorder. Arch Gen Psychiatry 1993;50:441-447.
5. Cook EH, Rowlett R, Jaselskis C, Leventhal BL: Fluoxetine treatment
of children and adults with autistic disorder and mental retardation.
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trolled study of fluvoxamine in adults with autistic disorder. Arch Gen
Psychiatry 1996;53:1001-1008.
7. Steingard RJ, Zimmitsky B, Demaso DR, et al: Sertraline treatment of
transition-anxiety and agitation in children with autistic disorder. J
Child Adolesc Psychopharmacol 1997;7:9-15.
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ical, genetic, neuropsychological, and neurobiological perspectives.
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autism: Effects on learning and behavioral symptoms. Am J Psychi-
atry 1984;141:1195-1202.
10. McDougle CJ, Holmes JP, Carlson DC, et al: A double-blind, placebo-
controlled study of risperidone in adults with autistic disorder and other
pervasive developmental disorders. Arch Gen Psychiatry
1998;55:633-641.
11. Kelsey JE: Dose-response relationship with venlafaxine. J Clin Psy-
chopharmacol 1996;16(Suppl 3):215-225.
12. Grossman R, Hollander E: Treatment of obsessive-compulsive disor-
der with venlafaxine, letter. Am 1996;153:576-577.
J Psychiatry

13. Rauch SL, O’Sullivan RL, Jenike MA: Open treatment of obsessive-com-
pulsive disorder with venlafaxine: A series of ten cases, letter. J Clin
Psychopharmacol 1996;16:81-83.
14. Findling RL, Schwartz MA, Flannery DJ, et al: Venlafaxine in adults
with attention deficit/hyperactivity disorder. J Clin Psychiatry
1996;57:184-189.
15. Kelsey JE: Venlafaxine in social phobia. Psychopharmacol Bull
1995;31:767-771.
16. Sanchez LE, Campbell M, Small AM, et al: A pilot study of clomipramine
in young autistic children. J Am Acad Child Adolesc Psychiatry
1996;35:537-544.
17. Rudolph RL, Dervan AT: The safety and tolerability of venlafaxine
hydrochloride: Analysis of the clinical trials database. J Clin Psy-
chophamacol 1996;16(B)(Suppl 2):545-595.
18. Thase ME: Effects of venlafaxine on blood pressure: A meta-analysis
of original data from 3744 depressed patients. J Clin Psychiatry
1998;59:502-508.
Fatality From Hepatitis A
in a Child Taking Valproate
ABSTRACT
We report an 8-year-old boy with complex partial seizures due to
congenital stroke, treated with valproate for more than 3 years (the
last 2 years were on monotherapy) with no complications during
that period except for transient thrombocytopenia. His sister had
uncomplicated hepatitis A. One month later, the patient became
jaundiced, went into fulminant hepatic failure, and quickly became
encephalopathic despite discontinuation of valproate, aggressive
supportive therapy, and treatment with carnitine. He then died. He
had positive hepatitis A IgM; other causes for acute hepatitis were
ruled out. Liver pathology revealed distended hepatocytes with
cholestasis and microvesicular changes. We could find in the lit-
erature two other articles on four cases who developed liver fail-
ure with hepatitis A while on valproate. All those cases, however,
recovered. In our patient a usually benign disease became deadly,
probably because of the concomitant use of a hepatotoxic med-
ication. Immunizing, with hepatitis A vaccine, all children on val-
proate therapy who are living in, or traveling to, endemic areas
should be considered and is probably advisable. ( J Child Neurol
2000;15:135-136).
Sodium valproate is widely used as an anticonvulsant in children.
Physicians are usually cautious when using it in infants and tod-
dlers, especially those on polytherapy or if they are suspected or
proven to have inborn errors of metabolism, because of the higher
risk of hepatotoxicity. It is generally considered safe to use val-
proate in older children, especially as monotherapy. Hepatitis A
is a benign disease that is still endemic in Lebanon and many
other countries. Immunization with hepatitis A vaccine is not yet
recommended for general use because of the presumed lack of
cost-effectiveness. Studies about this issue are needed. In view of
the common use of valproate and of the endemicity of hepatitis
A in Lebanon, the occurrence of the latter in a child treated with
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135
valproate is to be expected. We report a case of liver failure in a
child with hepatitis A, who was on valproate therapy.
CASE REPORT
M.J. was an 8-year-old boy who presented in February 1996 because of jaun-
dice and coma. He had been followed in our clinic for the preceding 2
years because of epilepsy. He was bom at term with no reported problems,
but he was found at the age of 8 months to have a right hemiparesis and
mild developmental delay. He started to have right focal tonic-clonic seizures
as well as akinetic seizures at the age of 4 years and received various com-
binations of antiepileptics, including corticotropin, phenytoin, clonazepam,
and valproate. His examination showed right spastic hemiparesis. His work-
up revealed a left-hemisphere porencephalic cyst and ventricular dilatation.
His electroencephalogram (EEG) in 1993 showed almost continuous gen-
eralized 2-Hz spikes and slow waves and a repeat in 1995 showed very fre-
quent left frontotemporal sharp and slow waves. Since we started following
him in 1994, he had been on a 40 mg/kg/day dosage of valproate monother-
apy and had been free of seizures for almost a year before presentation. He
was noted to be thrombocytopenic on a routine blood count in November
1995 (74,000 platelets/¡.LL), but a repeat count in January 1996 revealed
135,000 platelets/¡.LL and he never had any significant bleeding.
One month before presentation, his 10-year-old sister developed jaun-
dice and had an uncomplicated illness for 10 days. Five days before pre-
sentation, M.J. became jaundiced with tea-colored urine and clay-colored
stools. Like his sister, he was treated conservatively by his pediatrician as
a case of viral hepatitis. On February 24, 1996, he had a drop in his level of
consciousness and he was brought to our emergency room. There, he was
found to be severely jaundiced, lethargic, and responded to painful stimuli
by withdrawal. He had normal pupillary reflexes, full eye movements by
oculocephalic maneuvers, a right hemiparesis with hyperreflexia, and a pos-
itive Babinski reflex on the right. A computed tomographic scan was
unchanged from before. An EEG showed generalized slowing and left tem-
poral sharp and slow waves. His laboratory studies revealed a valproate level
of 160 ¡.Lg/mL (therapeutic, 50-100 ¡.Lg/mL), ammonia of 343 ¡.Lmol/L (nor-
mal, 20-50 ~,mol/L), blood urea nitrogen 55 mg/dL, creatinine 1. 7 mg/dL, total
serum protein 72 g/L with 30 g/L albumin, bilirubin of 10 mg/dL with direct
bilirubin being 8 mg/dL. Aspartate aminotransferase was 6200 IU/L, y-glu-
tamyl transpeptidase 129 IU/L, prothrombin time 23.1 seconds with an
international normalized ratio of 2.01. Hepatitis profile was performed,
including hepatitis A, B, and C, and cytomegalovirus and infectious mono-
nucleosis were screened. All were negative except for a positive IgM for the
hepatitis A virus.
In hospital, the patient had a progressive decline in his liver enzymes
and a progressive increase in his bilirubin and prothrombin time. He was
started on camitine (75 mg/kg/day by nasogastric tube), lactulose, and
neomycin, which he received between February 24 and March 12.
Despite aggressive supportive and medical therapy, he deteriorated in
the next few days and developed heavy nasal bleeding that required blood
product transfusions and packing of the nose. He went into deeper coma and
finally on March 12, 1996, he died. A liver necropsy revealed distended hepa-
tocytes with cholestasis and microvesicular changes. Scattered individual
hepatocellular drop-out was seen, but there was no evidence of necrosis. Por-
tal tracts were infiltrated with mononuclear and a few polymorphonuclear
cells. There was no portal duct proliferation or parenchymal fibrosis.
DISCUSSION
This patient died of what is usually a benign disease. This possi-
bly could have been prevented had he received y-globulin when his
sister became ill, and had the valproate been discontinued before
or as soon as he became jaundiced. Five days later, when he pre-
sented to us, the disease was already far advanced. The vaccine for
hepatitis A is available, but is not used routinely in Lebanon as its
routine use is presumed not to be cost-effective: the disease is