Dr K RazjouyanDr K Razjouyan

Associate Professor of Shahid Beheshty Associate Professor of Shahid Beheshty University and Medical SciencesUniversity and Medical Sciences

Autism spectrum disorders (ASDs) are a

heterogeneous group of neurodevelopmental disorders

Deficits in social communication Deficits in language Repetitive behaviors and restricted interests

DSM IV TR Criteria

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)

DSM 5

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 autism

As more children with ASD transition into

adulthood, the need for comprehensive services for adults with autism will also increase

Facts about ASD

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

Comorbidities

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

Treatment

Anxiety ADHD symptoms Compulsions and interfering repetitive

behaviors Sleep disturbance Irritability In higher-functioning ASD, depression is also

common

Common targets of medication

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 side-effect 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

Stimulants

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

Atomoxetine (Strattera)

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: Clonidine

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

Alpha-2-adrenergic receptor agonists: 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

Guanfacine

Attenuate the maladaptive symptoms of

patients with PDDs, and potentially target core socialization deficits

Atypical antipsychotics

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 two-month 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

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

The most common adverse events with

risperidone

Risperidone received FDA approval on October

10, 2006 for the treatment of irritability associated with autistic disorder

Including symptoms of aggression, deliberate self-injury, temper tantrums, and quickly changing moods in children and adolescents aged five to 16 years

Risperidone

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

Aripiprazole (Abilify)

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

Abilizole

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

Olanzapine

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

Quetiapine

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

Ziprasidone

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

Paliperidone

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

Clozapine

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

Atypical antipsychotics

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.

Haloperidol

SEROTONERGIC AGENTS

For compulsive and repetitive behaviorAnxiety

depression

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

Clomipramine

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

Clomipiramine

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

SSRIs

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

Fluvoxamine

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

Fluoxetine

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

Citalopram

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

SSRIs

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

Buspirone

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

Mirtazapine

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.

Venlafaxine

Drugs affecting glutamate function

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

Lamotrigine

A noncompetitive NMDA antagonis No significant difference was found between

drug and placebo on parent ratings, although clinician-rated measures of hyperactivity and inappropriate speech showed statistically significant improvement.

The authors reported that the medication was well tolerated

Amantadine

An NMDA partial agonist A 2-week, single-blind placebo lead-in phase,

drug-free 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

D-Cycloserine

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 self-stimulatory behaviors

Side effects included increased irritability, hyperactivity, and “manic-type behaviors

Memantine

Mood stabilizers

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,

placebo-controlled trials of Divalproex sodium in relatively small samples

One study reported significant improvement in irritability whereas the other did not find between-group 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

Divalproex sodium

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

levetiracetam

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

Oxcarbazepine

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

Topiramate

Only a few case report

Lithium

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

Oxytocin