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

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:

Aggression / Irritability Repetitive behaviorsAttention / hyperactivity Atypical neuroleptics +++ SSRIs, SNRIs-+++- Stimulants--+++ α and β blockers++- Mood stabilizers Summary of clinical trials in autism

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

Serotonin receptor

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

MedicationCommon Side EffectsEvidence Citalopram, Escitalopram Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Child ++ Fluoxetine (SSRI) Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Child +++ Fluvoxamine (SSRI) Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Adult +++ Sertraline (SSRI) Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Adult ++ Child ++ Clomipramine (tricyclic antidepressant)Increased aggression, increased irritability, sedation, EKG changes, urinary retention. Adult +++ Child ++ Venlafaxine (SNRI)Hyperactivity, irritability, aggression, agitation. Adult + Child + Serotonin Reuptake inhibitors Modified from Schapiro et al 2007

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

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

Atypical neuroleptics FEffect wider range of neurotransmitter systems (dopamine, serotonin, etc.) FImprove overall functioning in other neuropsychiatric disorders FLower incidence of side effects FDecreased severity of side effects

Atypical Antipsychotics FClozapine (Clozaril) FOlanzapine (Zyprexa) FRisperidone (Risperdal) FQuetiapine (Seroquel) FZiprasidone (Geodon) FAripiprazole (Abilify)

DrugStarting Dose Effective DoseDosing Frequency Side-effect Consideration Monitoring Considerations Risperidone QDAY-TIDWeight gain, EPS/TD Hyperprolactinemia Sedation Weight, BMI, Fasting glucose and lipid profile AIMS, Prolactin Olanzapine QDAY-TIDWeight gain, EPS/TD Hyperprolactinemia 1 Sedation Weight, BMI, Fasting glucose and lipid profile, AIMS Quetiapine QDAY-TIDWeight gain, EPS/TD Hyperprolactinemia 1 Sedation Weight, BMI, Fasting glucose & lipid profile, AIMS Ziprasidone QDAY-TIDWeight neutral, EPS, QT prolongation Hyperprolactinemia Weight, BMI, Fasting glucose and lipid profile AIMS, ECG Aripiprazole QDAY-BIDWeight neutral EPS/TD Weight, BMI, Fasting glucose & lipids, AIMS Modified from Posey et al 2007 Atypical Antipsychotics

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

MedicationSide effectsRecommended blood monitoringEvidence Valproateirritability, restlessness, rush, headaches, Weight gain, ataxia, alopecia, GI disturbance, hyperammonemic encephalopathy, sedation, thrombocytopenia, PCOS, pancreatitis, liver failure, teratogenic effects CBC / platelets, LFT, VPA levels If there is a change in mental status, then ammonia testing is Indicated, Therapeutic blood levels: cg/ml +++ Lamotriginedizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, rash none+++ (negative) LevetiracetamDrowsiness, dizziness, weakness, headache,eadache loss of coordination e.g., difficulty walking, muscle control, agitation, disinhibition none+++ (negative) CarbamazepineDrowsiness, diplopia, headache, ataxia, nausea, vomiting, dizziness, abdominal pain, diarrhea constipation, loss of appetite, serious rash, Low Na, agranulocytosis, liver dysfunction CBC with platelets, LFTS, carbamazepine levels, Therapeutic blood levels: 5-12 mcg/ml + Topiramateparesthesia, weight decrease, somnolence, anorexia, nausea, weakness, tiredness, drowsiness, dizziness, tingling sensations, dry mouthdry mouth, constipation, and memory difficultiesconstipation None+ Anticonvulsants

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 Atomoxetine –One randomized trial, effect sizes similar to Ritalin

 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

N% change from baselineEvidence Ritalin6634%+++ Guanfacine2525%+ Risperdal %+++ Haldol3627 %+++ Clomiparmine3611 %+++ Amantadine3022 %+++ Atomoxetine1630 %+++ Modified from Scahill et al 2007 Evidence for medications targeting hyperactivity ABC hyperactivity subscale

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

Cholinergics –Mild improvements in language, hyperactivity, general functioning –SE: Agitation and nausea AuthorYearAgentNageLength of Study (weeks) EvidenceMeasurement Tools Chez, et al 2000donepezil dose: 2.5-5mg 39Pediatric12+CGI, POWVT, CARS Chez, et al 2003donezepil dose: 2.5-5mg 43Pediatric12+++CGI, Gardner, POWVT, CARS Harden 2002donezepil dose:5mg8Pediatric/12+CGI & ABC Chez, et al 2004rivastigmine., dose: mg BID 32pediatric12+GARS, CARS, PWOVT (E&R), Connors, CGI Hertzman 2003galantamine dose: 4-12mg 3adultsNot fixed +CGI Modified Chez et al 2007

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

What we have not done

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)

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

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

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.