Dr K Razjouyan Associate Professor of Shahid Beheshty University 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 AGENT S For compulsive and repetitive behavior Anxiety 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