Treatment in Autism spectrum disorders

Treatment in Autism spectrum disorders Dr K Razjouyan Associate Professor of ShahidBeheshty 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 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

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 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

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 self-injury, 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 25adolescents 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 recommendedto 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 • Sideeffects 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 clinician-rated measures of hyperactivity and inappropriate speech showed statistically significant improvement. • The authors reported that the medication was well tolerated

Treatment in Autism spectrum disorders