Research in the neuropsychopharmacology of autism

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Research in the neuropsychopharmacology of autism

• Evdokia Anagnostou, MD
• Assistant Professor
• Bloorview Kids Rehab
• University of Toronto

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Current approaches

• Medications to target symptom domains based on
  phenotypic overlap of such domains with other
  disorders, i.e.
• SSRI for repetitive behaviors (from OCD)
• Atypical antipsychotics for maladaptive behaviors
  (irritability and aggression across several other
  disorders)
• Stimulants, non-stimulants for inattention
  (overlap with ADHD)

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• What we know

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Summary of clinical trials in autism
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SRIs in Autism

• Clomipramine (Anafranil)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox, Faverin)
• Sertraline (Zoloft)
• Paroxetine (Paxil, Seroxat)
• Citalopram (Celexa, Cipramil, Actavis)
• Venlafaxine (Effexor)
• Escitalopram (Lexapro, Cipralex)

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Serotonin receptor
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Anafranil in Autism

• Serotonin reuptake inhibitor
• Also blocks DA/NE reuptake
• Open label and one placebo controlled trial
  (Gordon 1993)
• Effective in reducing
• autistic symptoms
• compulsive ritualistic behavior
• anger
• Side effects
• QT prolongation, urinary retention,sedation,
  insomnia, grand mal seizure

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Serotonin Reuptake inhibitors
Modified from Schapiro et al 2007
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Dopamine

• No convincing evidence for primary involvement of
  the dopamine system in autism.
• However
• Typical antipsychotics have been shown to be
  effective in this population

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Haloperidol (Haldol)

• effects dopamine function
• extensively studied in children with autistic
  disorder, using controlled studies
• improves
• orientation of attention, social relatedness,
  stereotypies, hyperactivity
• SE
• Withdrawal and medication induced dyskinesia,
  tardive dyskinesia, acute dystonic reactions,
  sedation

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Atypical neuroleptics

• Effect wider range of neurotransmitter systems
  (dopamine, serotonin, etc.)
• Improve overall functioning in other
  neuropsychiatric disorders
• Lower incidence of side effects
• Decreased severity of side effects

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Atypical Antipsychotics

• Clozapine (Clozaril)
• Olanzapine (Zyprexa)
• Risperidone (Risperdal)
• Quetiapine (Seroquel)
• Ziprasidone (Geodon)
• Aripiprazole (Abilify)

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Atypical Antipsychotics
Modified from Posey et al 2007
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Mood Stabilizers Anticonvulsants

• Lithium
• Valproic acid (Depakote, Confulex, Epival,
  Depakene))
• Carbamazepine (Tegretol, Garbagel)
• Lamotrigine (Lamictal)
• Gabapentin (Neurontin)
• Levetiracetam (Keppra)

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Anticonvulsants
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ADHD like symptoms and autism

• STIMULANTS
• Dextro-amphetamine (Dexedrin), Methylphenidate
  (Ritalin), amphetamine (Adderral)
• Multiple double-blind placebo-controlled trials
  of Methylphenidate
• Increased sensitivity to SE
• Improvements in hyperactivity and irritability
• RUPP, Quintana et al. 1995, Handen et al. 2000
• Atomoxetine
• One randomized trial, effect sizes similar to
  Ritalin

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• ? and ? blockers
• ? 2 NE Receptor antagonists anti-hypertensive
  agents (Jaselskis et al., 1992)
• Clonidine Open label and one placebo controlled
  studies
• Improvement in hyperactivity, irritability,
  stereotypies, global severity
• SE hypotension, bradycardia, sedation
• ? blockers
• Propranolol two open label studies
• improvements in aggression and irritability

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Evidence for medications targeting
hyperactivity ABC hyperactivity subscale
Modified from Scahill et al 2007
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Buspirone (Buspar)

• Serotonin agonist
• Shown to be effective for anxiety in adults
• Small open label study showed effectiveness in
  relieving anxiety, and calming children with
  autism

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Cholinergics

• Mild improvements in language, hyperactivity,
  general functioning
• SE Agitation and nausea

Modified Chez et al 2007
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Melatonin

• Produced in the pineal gland.
• Regulates sleep-wake cycle
• sets circadian clock
• induces sleep
• Open label study
• 42/50 responders
• SE mild, sedation, agitation upon awakening,
  fragmented sleep

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• What we have not done

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Future approaches

• Based on new info on neurobiology of disorder
• Developmental studies
• Studies to improve cognition, learning skills,
  motor skills and adaptive function
• Immunomodulation
• Glutamate/GABA modulation
• epilepsy
• Neuropeptide modulation
• Target executive function abnormalities
• Studies targeting specific classes of mutations
  (Shank 3, Neuroligins, etc)

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Future approaches

• Immunomodulation
• Steroids, IV IG, poor NNT for SE profile
• Other immunomodulators
• Glutamate/GABA modulation
• Memantine, Valproate, metabotropic glutamate
  receptor modulation
• epilepsy
• Neuropeptide modulation
• ?oxytocin
• Target executive function abnormalities
• NE modulation vs. cognitive remediation programs
• Studies targeting specific mutations ?design
  issues, RCTs? etc

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Future approaches

• COMPLEMENTARY AND ALTERNATIVE TREATMENTS
• Of interest Omega 3 fatty acids,
  methylation/demethylation agents, GABA enhancing
  compounds
• Delineate cases of mitochondrial dysfunction and
  treat appropriately

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Take home points

• Research Hold all agents/compounds to the same
  standard. Evidence based medicine is as good as
  the available data
• Clinical practice So far, medications are
  specific to symptoms, not diagnosis. They are
  there to facilitate psychoeducational
  interventions. They do not treat autism
  psychoeducational intervention treat autism.