Autism in Spectrum Disorder: Challenge of Comorbidity and Treatment Autism Society of the Philippines

Cornelio G. Banaag, Jr., M.D.

Autism
Autism first described by Kanner (1943) Term autistic intended to convey profound social isolation as hallmark Autism is a brain-based disorder, onset prenatal Involves abnormalities in:
Qualitative aspects of social development Qualitative aspects of communication development Repetitive, stereotyped patterns of behavior &

interests
Affects 4 males to 1 female

Children and Adolescents with Autism: Definitions

Pervasive Developmental Disorders (PDD)

Childhood Disintegrative Disorder (CDD)

Autism Spectrum Disorders* (ASD)

Rhett Disorder

Autistic Disorder

Aspergers Disorder

Pervasive Developmental Disorder not otherwise specified (PDD-NOS)

*ASD is not a DSM-IV TR definition but reflects the categorization in the general public. Tidmarsh L, et al. Can J Psychiatry. 2003;48:517-525.; DSM-IV TR. Washington, DC: American Psychiatric Association; 2000.

Children and Adolescents with Autism: Prevalence

Changing prevalence rates of autism Before 1985: 2 per 10,000 1998 Study: 40 per 10,000 2003 Study: 34 per 10,000 Was true prevalence being underestimated? Diagnostic criteria have expanded to include a spectrum of disorders Increased public awareness More medical and educational resources More training and information for healthcare professionals Possible rise in true prevalence? Environmental factors that trigger expression of Autism, remain unclear
Yeargin-Allsopp, et al. JAMA. 2003;289:49-55.

Children and Adolescents with Autism: Importance of an Early Diagnosis

Facilitates earlier educational planning Participation in intensive, early intervention programs during toddler and preschool years improves longterm outcome for many children May ease family problems Identifies the need for family support and education Initiates development of strategies to manage stress Ensures early delivery of appropriate medical care: For the child with autism Parents require genetic counseling about increased risk of ASD in subsequent children
Committee on Children With Disabilities. Pediatrics. 2001;107:E85. Filipek PA, et al. Neurology. 2000;55:468-79.

Children and Adolescents with Autism: The Treatment Team

Psychiatrist General or Developmental Pediatrician Pediatric Neurologist

Psychologist

Effective patient care may include a dynamic treatment team

Speech Pathologist

Parents Social Worker

The Autism Society. http://www.autism-society.org/site/PageServer? pagename=autismprofessionals. Accessed 04.28.04

Teachers

Comorbidity in ASD
Very common Increases with age Worsens the course of ASD Makes intervention/treatment more difficult

Comorbidity in ASD
Recognition may be difficult Traits of ASD may overlap with symptoms of other disorders Nature of ASD make traditional diagnostic procedures difficult

In children with Autism

As many as :
60% have poor attention/concentration 40% hyperactive 88% with unusual preoccupations/rituals 37% with obsessive thinking 89% with stereotyped language 74% with significant fears/anxiety 44% with depressed mood, irritability & agitation 11% with sleep problems 43% with self-injury 10% with tics Seizures in ~14% of autistics with peaks in Infancy &

Adolescence A significant # have feeding & nutritional issues Data from Gillberg, 2004

The Problems of Co-morbid Diagnosis

DSM-IV somewhat arbitrarily imposes

restrictions, e.g. Cant diagnose ADHD & autism Cant diagnose OCD & autism Can diagnose Tourettes & autism Definitely a problem since clinicians CLEARLY see e.g. ADHD & autism, etc.

Co-morbidities
Cognitive delay (ID/MR)(60% AD; 30% ASD)

(Fombonne, 2006) Seizure disorder (5% to 44%) (Tuchman & Rapin, 2002: Lancet Neurol) Depression ( with age) esp with higher functioning individuals Anxiety disorders (all types)

Sleep (up to 80% of children with ASDs have sleep

issues) Eating/nutritional issues

ADHD

Autism and Comorbid Psychiatric Disorders

70% had at least 1 comorbid disorder 41% had 2 or more comorbid disorders Anxiety disorders Depression ADHD Oppositional Defiant Disorder

Nutrition/Feeding Issues in ASD

Numerous case studies have reported dietary

selectivity among children with autism Repetitive behaviors and restricted interests, a core feature of autism, may play a role in dietary selectivity Children with ASDs often resist novel experiences, which may include tasting new foods. Many children with ASDs have sensory hypersensitivities and may reject foods due to an aversion to texture, temperature or other characteristics of the foods (e.g appearance).
Herndon AC et al, 2008

Sleep Disturbance in Autism

Sleep problems in children with autism prevalence estimates of 4483% for sleep

disorders in this population Poor appetite and poor growth were associated with decreased willingness to fall asleep

Williams PG, et al: J. Sleep Res., 13, 265268; 2004

Sleep Disturbance in Autism

Sleep problems are associated with other health conditions and quality of life Sleep deprivation appears to intensify the behavioral problems of autistic children, improved sleep may improve childrens behavior, alleviating maternal stress as a result Decrease in quality sleep could be a source of stress that affects not only the child, but also other family members (Richdale, et al., 2000)

Anxiety Disorders
A variety of anxiety disorders tend to cooccur with ASD Specific phobia: most common co-morbid anxiety disorder, with lifetime prevalence of 38-63%
Fear of certain places, situations, objects, or animals Fear of people in uniform Fear of loud noises

Obsessive-compulsive disorder (OCD) occurs in 1135% of individuals with ASD (up to 81% not full syndrome) Individuals with ASD exhibit rigid thinking and compulsions (flapping, spinning, repeating phrases) Distinct from OCD symptoms (checking, cleaning, counting) Social phobia/anxiety disorder- 7.4% lifetime prevalence More common in higher functioning ASD Desire social interaction but aware of social deficits

Mood Disorders
Depression: very common disorder seen individuals with ASD Rates has wide range of 4-58% Occurs more in high-functioning individuals during adolescence and young adult During adolescence: greater insight into differences from others Lower functioning children and adolescent ASD Manifestation of depression: more behavioral (irritability, temper tantrum, regressive behavior)

Depression in ASD
Complicated by difficulties in recognizing/expressing emotions Suggestive signs and symptoms Low/depressed mood Diminished interest in activities previously enjoyed Changes in appetite Changes in sleep: insomnia, hypersomnia Fatigue, loss of energy Feelings of worthlessness or guilt Diminished ability to think or concentrate Thoughts of death

Autism and ADHD

Is it ADHD or Autism or both? Overlap of symptoms between ADHD and Autism Close to 50% of Autism/ASD have ADHD symptoms (Hyperactivity inattention) About 20% of children with autism have comorbid ADHD 18% of children with ADHD have autistic traits Studies suggest both disorders share a common genetic risk factor

Autism and ADHD

Overlap of symptoms seen in younger children As children become older the similarities between the 2 conditions will separate out
Children with ASD become more withdrawn, hyperactivity wanes out, social skills difficulties emerge Children with ADHD unlikely to become calmer with age, will develop social and communication skills

Autism and ADHD

ADHD symptoms affect/worsen the daily function and quality of life of child with ASD Only 10% receive appropriate treatment to relieve ADHD symptoms

ADHD: Attention Deficit Hyperactivity Disorder

A disorder of self-regulation and executive functions (planning, organizing, appropriate inhibitions, working memory) Brain-based neurodevelopmental disorder invariably needing medication as part of management Marked by significant symptoms in 3 areas: Inattention, Hyperactivity, Impulsivity

Common ADHD Behavior (Inappropriate for age)

Often cant pay attention to details; careless mistake Difficulty sustaining attention Does not seen to listen, follow through Difficulty organizing Loses thing Forgetful

Common ADHD Behaviors

Fidgety, cant stay seated Often runs around, climb excessively As if driven by motor; always on the go Talks excessively Blurts out answers Has difficulty awaiting turn Often interrupts or intrudes

Epilepsy and Autism

Seizures, periods of altered consciousness Due to upset in brain chemistry Messages that travel between nerve cells/neurons become scrambled Neuron activity disturbed manifesting as seizures 5-40% comorbid with autism Infancy and early childhood Adolescence 75% of EEG of ASD show abnormal patterns Up to 40% have seizures

Epilepsy and Autism

Common types of Seizures in ASD
Infantile spasm Absence seizure Complex partial seizure Gran mal

Appropriate diagnosis: neurologist

Behavior Which May Indicate Comorbid Illness

Sudden change in behavior Loss of previously acquired skills Irritability, low mood Tantrums, oppositional behavior Sleep disturbance Change in appetite Increase in aggressive behavior Self-injurious behavior (biting, hits/slaps face, head banging) Facial grimacing, wincing Agitation: pacing, jumping up and down

Treatment Options: Non -Pharmacologic and Non-Pharmacologic Pharmacologic Interventions

Treatment Options
Initial interventions are largely nonpharmacologic No medicine has significant effect on core symptoms of autism Associated challenging behavior (temper tantrum, self-injury, agitation, hyperactivity psychiatric comorbidities): target symptoms for pharmacotherapy Medication makes the child receptive to nonpharmacologic approaches but should not replace them

Non-Pharmacologic Interventions
Structured classroom training + behavioral methods most effective treatment Studies indicate gains in language and cognition, decrease in maladaptive behavior achieved by consistent behavioral program Even with the best psychosocial programs available, many children/adolescents with Autism remain significantly impaired Pharmacotherapy becomes valuable adjunctive treatment to ameliorate associated behavioral symptoms

Controversies on the use of medications

Exact cause of Autism remains unknown Fear of tampering with young brain actively developing Before 1997, no FDA approved medications for behavioral and psychiatric disorders in children How do you measure efficacy of medications in children with Autism

Psychopharmacology in ASD

Dysregulation of DA receptors Dysregulation of 5 hydroxytryptamine (5HT) receptors Implicated mechanisms for ASD sypmtoms

Treatment of Insomnia
The primary approach is so-called sleep hygiene or behavioral approaches (establishing routines, allowing to fall asleep alone, etc) It is only when these fail that medical approaches are entertained. These include
Traditional Medicines, e.g. diphenhydramine, clonidine, mirtazapine, risperidone. Non-traditional approaches, e.g. Melatonin,

Melatonin in Autistics
Melatonin (MLT) & sleep:
Jan JE, O'Donnell ME (1996) reviewed 100 children with a variety of developmental disabilities including Autism,

Melatonin, which benefited slightly over 80% of their patients, appeared to be a safe, inexpensive, and a very effective treatment of sleep-wake cycle disorders

The Antidepressants
Tricyclic non-selective serotonin reuptake inhibitor e.g. Clomipramine In an excellent study by Gordon et al (1993)this drug was more effective than placebo in treating some symptoms e.g. anger/uncooperativeness, hyperactivity, & OCD symptoms But, side effects of irregular heart rhythm, lowering of seizure threshold , make it less desirable than the SSRIs

SSRIs in Autism
Selective Serotonin Re-uptake Inhibitors Effective in anxiety and depression FDA approved for children and adolescents
Fluoxetine Sertraline Fluvoxamine Escitalopram

Early intervention with selective serotonin reuptake inhibitors

SSRIs have been presented as a model pharmacologic treatment, because serotonin is known to enhance synapse refinement in the brains of autistic children In the developing cortex, serotonin is concerned with maturation of thalamic afferents, cortical dendrites, and axons, with alterations in the levels of serotonin potentially resulting in negative effects.
High levels of serotonin may reduce pruning of the dendritic branches Too little serotonin causing a smaller number of dendritic spines than usual, miniscule dendritic arbors and somatosensory barrels, and a decrease in synaptic density

SSRIs in Autism
Fluvoxamine has shown excellent results in adult autistics with few side effectsdecreased repetitive thoughts & behavior, & maladaptive behavior & aggression and improved communication In children, in contrast, the results were not as consistent, esp. in younger children Adverse effects included insomnia, motor hyperactivity, agitation, aggression & anxiety (esp. pre-pubertal)+

+McDougle et al, 2002

Sertralines effectiveness was assessed in children in an open-label trial

Nine children with autism between the ages of 6 and 12 were administered sertraline for the treatment of transition-associated anxiety and agitation. It was found that 89% of the subjects had a positive response. Results suggest the importance of future controlled investigation of sertraline in pediatric and adult ASD populations.

Steingard RJ et al: J Child Adolesc Psychopharmacol. 1997;7(1):915.

The Psycho-stimulants: Their Role

Significant hyperactivity can exist with autism & Asperger syndrome (10-20%) (Ghaziuddin,1998; Martin et al, 1999) These medications act by increasing the neurotransmitters norepinephrine & dopamine indirectly in the brain (CNS) For years they were not used in children with Autism as it was claimed that they increased negativism (including self-injurious behaviors), tics & stereotypies

The Psycho-stimulants: Their Role

In 1995, however, Quintana et al described in an excellent study, that there was a statistically significant reduction in hyperactivity without an increase in stereotypic behaviour, using methylphenidate In some children, adverse effects are seen, including irritability, paradoxical in hyperactivity, stereotypic behaviors, or agitation

Aman et al, 2000

The Psycho-stimulants: Their Role

In higher functioning children with ASDs response is better, more predictable & often low doses are effective In children with cognitive impairment (IQ <45; mental ages <4.5), success is less likely, & idiosyncratic (negative) responses more likely, including agitation & stereotypies!

2-Adrenergic-agonists
Clonidine & Guanfacine are best studied Regulates noradrenergic neurotransmission Good study with clonidine Improvement in hyperactivity, irritability, stereotypes, inappropriate speech & oppositional behavior (only 8 children used!) Was a double-blind, placebo-controlled, crossover study Adverse effects were: sedation,irritability & hypotension

Jaselskis et al, 1992

Guanfacine effective in ~22%: Posey

Conclusions
ASD is a complex neurodevelopmental disorder Part of its complexity is the frequent cooccurrence of medical and psychiatric conditions Comorbid conditions affect the daily functioning and quality of life of individuals with ASD, as well the familys Part of effective management includes the early recognition and treatment of comorbid conditions Medications can be an effective part of a comprehensive management of ASD

Conclusion
Pharmacotherapy should be used as adjunct to behavioral and educational therapeutic approaches No drug as yet can treat the core symptoms of autism Target maladaptive behaviors which cause significant impairment generally responsive to medical treatment Consider potential benefits against risk Monitor carefully for response and side effects

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Thank You for your attention!