Transcript Treatment of autism

Dr K Razjouyan
Associate Professor of Shahid Beheshty
University and Medical Sciences
DSM IV TR Criteria

 Autism spectrum disorders (ASDs) are a
heterogeneous group of neurodevelopmental
disorders
 Deficits in social communication
 Deficits in language
 Repetitive behaviors and restricted interests
DSM 5

 the three DSM-IV-TR domains become two in DSM-5
 Must meet criteria 1, 2, and 3:
 1. Clinically significant, persistent deficits in social
communication and interactions
 2. Restricted, repetitive patterns of behavior,
interests, and activities
 3. Symptoms must be present in early childhood (but
may not become fully manifest until social demands
exceed limited capacities)
Facts about autism

 In 2012, the CDC estimated the prevalence of ASD
as 1 in 88 children
 An estimated increase of 78% from 2002 to 2008
 A 2011–12 telephone survey by the center’s National
Center for Health Statistics suggested that 1 in 50
U.S. school-aged children is now diagnosed with
ASD
Facts about ASD

 As more children with ASD transition into
adulthood, the need for comprehensive services for
adults with autism will also increase
Comorbidities

 The individuals with autism, 35% had another
comorbid psychiatric disorder
 Comorbidities can substantially increases health care
expenditures
 They can impede progress in educational and
therapeutic settings
 Cause significant distress for patients and their
families
Treatment

 The treatment is complex and different
 There is no single, definitive treatment for ASD
 Early intensive behavioral interventions can reduce core
autistic symptoms and improve developmental outcomes
 No pharmacotherapeutics have yet shown a consistent
primary effect on the core social disability of autism
 Appropriate pharmacotherapy can enhance an autistic
person’s ability to benefit from educational and behavior
modification techniques
Treatment

 In a database analysis of children with ASD aged 2–
17 years, 27% of all participants took at least one
psychotropic medication, with greatest rates of use
(66%) in adolescents.
 80% of children diagnosed with a comorbid
psychiatric disorder were taking at least one
psychotropic medication
Treatment

 For most medications, limited data are available
 Currently, only two medications—Risperidone and
Aripiprazole—have U.S. Food and Drug
Administration (FDA) indication for use in autism
Common targets of
medication

 Anxiety
 ADHD symptoms
 Compulsions and interfering repetitive behaviors
 Sleep disturbance
 Irritability
 In higher-functioning ASD, depression is also
common
Stimulants

 Co-diagnosis is allowed in DSM-5
 Response rates tend to be lower
 Symptom improvement is often less robust
 Side effects are more frequently reported
 Significantly more children are unable to tolerate
commonly prescribed medications
Stimulants

 A large double-blind, placebo-controlled, crossover trial
conducted by (RUPP) autism network
 The effects of methylphenidate 0.125–0.5 mg/kg/day
were investigated in 72 children with ASD over one-week
periods
 Improvement in the ABC-hyperactivity subscale score
was reported, with a small to medium effect size
 49% percent of children were determined to be
responders by a combined measure of improvement in
hyperactivity and global severity, as determined by
(CGI-I)
Stimulants

 The response rate was lower than the 70%–80%
response observed in the Multisite Multimodal
Treatment of Children with ADHD study, and side
effects were more common
 A small placebo controlled, crossover trial of 14
preschool-aged children with developmental delay
or PDD reported a similar response rate and sideeffect profile
Stimulants

 Adverse effects, which were more common with the
higher dose, included social withdrawal and
irritability
 Irritability is a particular vulnerability with
psychostimulant use in ASD
 Given the rapid onset of effect and side effects, short
trials might be used to readily clarify potential
treatment response
Atomoxetine (Strattera)

 A retrospective study noted a 60% response rate as
determined by a rating of “much improved” or “very
much improved” on the CGI-I
 Specific improvements were noted in conduct,
hyperactivity, inattention, and learning
 One large placebo-controlled trial of atomoxetine
(dosed at 1.2 mg/kg/day) in 97 children with ASD
found improved ADHD symptoms
 Nausea, decreased appetite, and mid-cycle
awakenings
Alpha-2-adrenergic receptor
agonists: Clonidine

 An open-label trial with clonidine in 19 children with
ASD
 Noted improved sleep and, to a lesser extent, ADHD
symptoms, aggression, and mood instability
 Two small placebo-controlled studies reported positive
findings, with improved irritability, hyperactivity,
inappropriate speech, oppositionality, stereotypy, sensory
reactivity, and global illness severity
 In the smaller sample study, however, no benefit for
clonidine over placebo was identified based on clinician
ratings
Alpha-2-adrenergic receptor
agonists: Guanfacine

 A chart review of 80 youth with ASD treated with
guanfacine demonstrated effectiveness in 24% of
participants, with specific improvements in
hyperactivity, inattention, insomnia, and tics
 Asperger’s disorder or PDD not otherwise specified
and those without mental retardation showed a
higher response rate
Guanfacine

 A small placebo-controlled, crossover study of 11
children with developmental disorders (the majority
of whom had ASD diagnoses) demonstrated
improved hyperactivity
 48% determined to be responders by a 50% reduction
in hyperactivity symptoms
 Drowsiness and irritability, Daytime sedation and
mid-cycle awakenings
Atypical antipsychotics

 Attenuate the maladaptive symptoms of patients
with PDDs, and potentially target core socialization
deficits
Risperidone

 In 2002, the RUPP Autism Network published
results of a multisite, controlled trial of Risperidone
in ASD (n = 101; age range, 5–17 years)
 An eight-week active treatment phase followed by a
four month open-label continuation phase and twomonth discontinuation phase
 69% of the participants in the Risperidone group met
responder status
 Two-thirds of participants maintained this benefit at
six months in the open-label phase
Risperidone

 Improvement has also been observed in secondary
measures of restrictive, repetitive, and stereotyped
behaviors; adaptive functioning; hyperactivity; social
withdrawal; and communication
The most common adverse
events with Risperidone

 Somnolence
 Increase in appetite
 Fatigue
 Upper respiratory tract infection
 Increase in saliva
 Constipation
 Dry mouth
 Tremor
The most common adverse
events with risperidone

 Muscle stiffness
 Dizziness
 Involuntary movements
 Repetitive behavior
 Rapid heartbeat
 Confusion
 Increase in weight
 Possible hyperprolactinemia, which could result
gynecomastia or galactorrhea
Risperidone

 Risperidone received FDA approval on October 10,
2006 for the treatment of irritability associated with
autistic disorder
 Including symptoms of aggression, deliberate selfinjury, temper tantrums, and quickly changing
moods in children and adolescents aged five to 16
years
Aripiprazole (Abilify)

 In 2009, Aripiprazole became the second agent
approved by the FDA for managing irritability in
children 6–17 years old with autism
 A decision based on positive results from two
multisite, industry-sponsored, randomized, double
blind, placebo-controlled trials for the treatment of
irritability associated with autistic disorder
 Including symptoms of aggression towards others,
deliberate self-injurious behavior, temper tantrums,
and quickly changing moods
Abilizole

 In both studies, sedation and somnolence were the
most commonly reported adverse effects
 Aripiprazole was associated with significantly more
weight gain at eight weeks compared to placebo
 Treatment-emergent EPS occurred at rates of 14.9%–
23% in treatment groups compared to 8%–11.8% in
placebo groups.
 Vomiting was twice as common with active
treatment (13.7%)
Abilizole

 HDL levels declined in 30% of individuals
 Clinically significant elevations of total cholesterol,
low-density lipoproteins, triglycerides ,and serum
glucose were less common
 No abnormal ECG finding
Olanzapine

 Two small open-label trials of olanzapine reported
high response rates though results from an
additional two studies were less robust
 Weight gain was substantial across studies and
greater than observed with Risperidone and
Aripiprazole
 Mild, transient sedation was also common in all
studies
Quetiapine

 Open-label studies of Quetiapine have generally
found minimal efficacy and poor tolerability due to
excessive sedation, weight gain, and increased
aggression or agitation
 One study suggested Quetiapine may be helpful for
sleep disturbance and aggression
Ziprasidone

 In one open-label study, one case series, and two
case reports Ziprasidone has shown promise in the
treatment of irritability, aggression, hyperactivity,
and impulsivity in autism
 Initial sedation was common and in two patients
with comorbid bipolar disorder, symptoms were
rated as “much worse” with Ziprasidone
Paliperidone

 The extended-release active metabolite of
Risperidone, in patients with ASD is limited to one
open-label study and three case reports
 Results from a study of 25 adolescents with autism
and severe irritability are encouraging, with 84% of
participants showing significant improvement in
irritability
 Weight gain and increased serum prolactin were
common, and mild to moderate EPS were reported
in 4 individuals
Clozapine

 Small case reports
 Clozapine is not considered a first line agent for
severe irritability, given its potentially serious side
effects of agranulocytosis, seizures, and
cardiomyopathy
 The need for frequent blood draws
Atypical antipsychotics

 Atypical antipsychotics should probably be reserved
for children with comorbid irritability, aggression,
and/or self-injurious behavior
 Whose hyperactivity and impulsivity are severe
and/or extremely dangerous
 Fatigue, sedation, dizziness, drooling, and EPS can
occur with all antipsychotics
Atypical antipsychotics

 Tardive dyskinesia can potentially occur with
atypical antipsychotics, and monitoring for abnormal
movements should be performed periodically
 Neuroleptic malignant syndrome is a rare but
potentially serious side effect that can occur with
typical and atypical antipsychotics
 it is recommended to monitor baseline and subsequent
measures, including, but not limited to, the
following: height, weight, BMI
Haloperidol

 Haloperidol (doses 1–2 mg/day) to be efficacious in
young children (ages 2–8 years)
 For treatment of stereotypies, aggression,
withdrawal, hyperactivity, and irritability
 A positive treatment effect on learning
 Older children responded better than younger
children.
Haloperidol

 Sedation and acute dystonic reactions were the most
frequent short-term adverse effects
 Dyskinesias were also frequent occurring especially
upon medication withdrawal
 Its use is reserved for severe treatment-refractory
symptoms associated with autism.
SEROTONERGIC
AGENTS

For compulsive and repetitive behavior
Anxiety
depression
Clomipramine

 In open trials and case reports: Positive reports noted
improvements in repetitive behaviors, aggression,
social engagement, language, adventitious
movements, and adaptive behavior
 In the largest of the open studies (n = 35 adults), 13
participants experienced adverse effects, with 3
reporting seizures
 Two of the open-label trials in children reported
difficulties with agitation and aggression
Clomipiramine

 In two blinded controlled trials , each with 12
participants, reported improvement in overall
autistic symptoms and also in compulsive behaviors
and anger as compared to both placebo and
Desipramine
 One participant had a prolonged QTC interval (0.45
seconds), and another became tachycardic (resting
heart rate 160–170 beats per minute)
 These effects resolved after dose reduction
SSRIs

 Open trials in children and adults with ASD have
been mostly positive
 Notable improvements in obsessive-compulsive
symptoms, anxiety, depressive symptoms,
aggression, and overall symptom severity
 Difficulty with activation side effects and agitation
were frequent in some reports.
 Placebo-controlled trials of SSRIs in children have
been mostly discouraging
Fluvoxamine

 A 12-week double blind investigation of fluvoxamine
in 30 adults with ASD noted improvement in
repetitive thoughts and behaviors, aggression,
language function, and maladaptive behavior
 Side effects mostly limited to nausea and sedation
Fluoxetine

 A double-blind, placebo-controlled study has been
conducted for fluoxetine in children with ASD in 2005
 Low-dose liquid fluoxetine was superior to placebo in the
treatment of repetitive behaviors, and it was only slightly,
and not significantly, superior to placebo on global
improvement score
 Several other studies of fluoxetine have demonstrated
efficacy in treating ASD symptoms
 Case reports have documented decreases in symptoms
such as outbursts , rituals/OCD behaviors , depressive
symptoms , and trichotillomania
Citalopram

 Results from a 12-week National Institute of Mental
Health–funded, multicenter, placebo-controlled
study of citalopram (mean dose, 16.5 mg daily) in
149 children with ASD found no difference in
repetitive behaviors or global improvement
compared to placebo
 Activation side effects ,impulsivity, hyperactivity,
distractibility, stereotypy, and insomnia were
common
 2 children had seizure episodes
SSRIs

 Despite the positive placebo-controlled trials with
SSRI treatment in adults with ASD, findings in
children have been mostly negative
 Age-related differences in serotonin functioning
 Because of the limited alternatives and sometimes
severe repetitive and compulsive behaviors that
often impair functioning, a trial with an SSRI in
children and adolescents might be considered
Buspirone

 Buspirone is a partial serotonin receptor type 1A
agonist
 Improved anxiety, irritability, and hyperactivity in
ASD in a few case reports and one open-label study
with 22 participants
 Has a relatively mild side-effect profile in
comparison to SSRIs and neuroleptics
 It could be an option in who have tolerated SSRIs
poorly
Mirtazapine

 A serotonin reuptake inhibitor at low doses with
Noradrenergic effects (a2 antagonism) at higher
doses
 An open-label study of mirtazapine reported
significant overall improvement in 34.6% but no
improvement in core autistic features
 Show some promise in sexual behaviors in ASD
 It could be an option in who have tolerated SSRIs
poorly esp. in anxiety and sleep disorder
Venlafaxine

 Carminati and colleagues (2006) published three case
reports on the use of low-dose venlafaxine (18.75 mg
daily) in adolescents and young adults with ASD.
 Venlafaxine was prescribed to improve self-injurious
behavior and attention deficit/hyperactivity disorder
(ADHD)-like symptoms in ASD.
 Hollander and colleagues (2000) conducted a
retrospective clinical study of venlafaxine :Six of ten were
rated as responders, with improvement noted in
repetitive behaviors, restricted interests, social deficits,
communication, inattention, and hyperactivity
 Side effects included activation, nausea, and polyuria.
Drugs affecting
glutamate function

Lamotrigine

 The drug attenuates some forms of cortical
glutamate release
 Lamotrigine and placebo showed no difference in
effect as measured by the ABC, Vineland scales,
Childhood Autism Rating Scale (CARS), and
PreLinguistic Autism Diagnostic Observation Scale.
 Most common side effects: Insomnia ,hyperactivity,
rash
Amantadine

 A noncompetitive NMDA antagonis
 No significant difference was found between drug
and placebo on parent ratings, although clinicianrated measures of hyperactivity and inappropriate
speech showed statistically significant improvement.
 The authors reported that the medication was well
tolerated
D-Cycloserine

 An NMDA partial agonist
 A 2-week, single-blind placebo lead-in phase, drugfree subjects with autistic disorder were
administered three different doses of D-cycloserine
during each of three 2-week periods
 In this pilot study, D-cycloserine treatment resulted
in significant improvement in social withdrawal
Memantine

 Memantine is a moderate affinity antagonist of the
NMDA glutamate receptor
 In chez study (2012): Open-label add-on therapy was
offered to 151 patients
 Results showed significant improvements in
language function, social behavior, and selfstimulatory behaviors
 Side effects included increased irritability,
hyperactivity, and “manic-type behaviors
Mood stabilizers

Divalproex sodium

 In a pilot study of 14 children showed substantial
improvement in retrospectively assigned CGI- scores
 Areas of subjective improvement included autistic
symptoms, aggression, impulsivity, and mood
lability
Divalproex sodium

 Two subsequent randomized, double-blind, placebocontrolled trials of Divalproex sodium in relatively
small samples
 One study reported significant improvement in
irritability whereas the other did not find betweengroup differences for aggression and irritability
 Divalproex sodium was associated with improved
repetitive behaviors as measured by the Children’s
Yale-Brown Obsessive Compulsive Scale in a
randomized, placebo controlled trial of 13
individuals with autism
Divalproex sodium

 Though divalproex sodium is generally well
tolerated
 Side effects: behavioral activation, rash, sedation,
nausea and vomiting, and weight gain may be
limiting factors for some
 Monitoring valproate blood levels and administering
liver function tests periodically can also present a
challenge in children with ASD
levetiracetam

 In two small samples of children with autism
 It was associated with significant improvement in
measures of ADHD symptoms, emotional lability,
and aggression
 A double-blind, placebo-controlled trial in 20
children failed to support these earlier, positive
findings
Oxcarbazepine

 limited to a retrospective case series of 30 youth and
a case report of 3 patients
 In the case series, 14 patients (47%)were
retrospectively rated as “much improved” on the
CGI-I though 7 patients (23%) terminated treatment
due to significant adverse events, including
hyponatremia, seizures, allergy, and, most
commonly worsened irritability
Topiramate

 Topiramate has not been evaluated in controlled
trials
 A small case series (n = 5) and retrospective chart
review (n = 15) reported response rates for overall
improvement
 Side effects in a minority included mild sedation,
cognitive difficulties and rash
 Weight loss was inconsistent in conjunction with
atypical antipsychotic use
Lithium

 Only a few case report
Oxytocin

Oxytocin

 Involve in social behavior, including affiliation,
attachment, and social cognition
 In a randomized, placebo-controlled, within-subject
study, 15 adults with ASD received single
intravenous infusions of either OT or placebo,
followed by infusions of the other a week later
 Superior retention of affective speech comprehension
compared to those receiving placebo first
Oxytocin

 A subsequent controlled trial in 19 adults with ASD
found that OT 24 IU administered intra nasally twice
a day for six weeks led to significant improvements
in social cognition on the RMET task and in overall
quality of life
 With no significant change, compared to placebo, on
primary outcome measures of social ability and
repetitive behaviors
Oxytocin

 Hollander and colleagues administered a four-hour
intravenous infusion of synthetic OT (Pitocin) to 15 male
adults with ASD, with each participant receiving both
placebo and OT
 During the OT infusion 86.7% showed a decline in
repetitive behaviors from beginning to endpoint
 No serious adverse effects were reported in these studies
 Limitations of published reports include small sample
sizes, and exclusion of individuals with intellectual
disability