Research in the neuropsychopharmacology of autism

1. Research in the neuropsychopharmacology of autism Evdokia Anagnostou, MD Assistant Professor Bloorview Kids Rehab University of Toronto

2. 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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4. What we know:

5. Summary of clinical trials in autism

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

7. Serotonin receptor

8. 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

9. Serotonin Reuptake inhibitors Modified from Schapiro et al 2007

10. 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

11. 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

12. 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

13. Clozapine (Clozaril) Olanzapine (Zyprexa) Risperidone (Risperdal) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Atypical Antipsychotics

14. Atypical Antipsychotics Modified from Posey et al 2007

15. Lithium Valproic acid (Depakote, Confulex, Epival, Depakene)) Carbamazepine (Tegretol, Garbagel) Lamotrigine (Lamictal) Gabapentin (Neurontin) Levetiracetam (Keppra) Mood Stabilizers & Anticonvulsants

16. Anticonvulsants

17. 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

18.  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

19. Evidence for medications targeting hyperactivity ABC hyperactivity subscale Modified from Scahill et al 2007

20. 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

21. Cholinergics • Mild improvements in language, hyperactivity, general functioning • SE: Agitation and nausea Modified Chez et al 2007

22. 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

23. What we have not done

24. 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)

25. 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

26. 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

27. 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.