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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) ` Symptom Components in Autism Affective Instability Depakote ADHD Symptoms Social Deficits Effexor Stimulants Speech & Communication Deficits Mood stabilizers /anticonvulsants Atypical antipsychotics, Prozac Aggression/ Impulsivity Repetitive Behaviors & Restricted Interests EEG Abnormalities Mood stabilizers, atypicals SSRIs, Atypicals •What we know: Summary of clinical trials in autism Aggression / Irritability Repetitive behaviors Attention / hyperactivity Atypical neuroleptics +++ +++ +++ SSRIs, SNRIs - +++ - Stimulants - - +++ α and β blockers ++ - ++ Mood stabilizers +++ ++ - 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 Serotonin Reuptake inhibitors Medication Common Side Effects Evidence 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 + 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 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 Atypical Antipsychotics Clozapine (Clozaril) Olanzapine (Zyprexa) Risperidone (Risperdal) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Atypical Antipsychotics Drug Starting Dose Effective Dose Dosing Frequency Side-effect Consideration Monitoring Considerations Risperidone 0.25-0.5 0.5-6 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia Sedation Weight, BMI, Fasting glucose and lipid profile AIMS, Prolactin Olanzapine 2.5-5 5-40 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia1 Sedation Weight, BMI, Fasting glucose and lipid profile, AIMS Quetiapine 25-50 75-800 QDAY-TID Weight gain, EPS/TD Hyperprolactinemia1 Sedation Weight, BMI, Fasting glucose & lipid profile, AIMS Ziprasidone 20-40 20-160 QDAY-TID Weight neutral, EPS, QT prolongation Hyperprolactinemia Weight, BMI, Fasting glucose and lipid profile AIMS, ECG Aripiprazole 2.5-5 5-30 QDAY-BID Weight neutral EPS/TD Weight, BMI, Fasting glucose & lipids, AIMS Modified from Posey et al 2007 Mood Stabilizers & Anticonvulsants • Lithium • Valproic acid (Depakote, Confulex, Epival, Depakene)) • Carbamazepine (Tegretol, Garbagel) • Lamotrigine (Lamictal) • Gabapentin (Neurontin) • Levetiracetam (Keppra) Anticonvulsants Medication Side effects Recommended blood monitoring Evidence Valproate irritability, 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: 50-120 cg/ml +++ Lamotrigine dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, rash none +++ (negative) Levetiracetam Drowsiness, dizziness, weakness, headache, loss of coordination e.g., difficulty walking, muscle control, agitation, disinhibition none +++ (negative) Carbamazepine Drowsiness, 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 + Topiramate paresthesia, weight decrease, somnolence, anorexia, nausea, weakness, tiredness, drowsiness, dizziness, tingling sensations, dry mouth, constipation, and memory difficulties None + 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 • 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 Evidence for medications targeting hyperactivity ABC hyperactivity subscale N % change from baseline Evidence Ritalin 66 34% +++ Guanfacine 25 25% + Risperdal 180 46-55% +++ Haldol 36 27 % +++ Clomiparmine 36 11 % +++ Amantadine 30 22 % +++ Atomoxetine 16 30 % +++ 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 Author Year Agent N age Length of Study (weeks) Evidence Measurement Tools Chez, et al 2000 donepezil dose: 2.5-5mg 39 Pediatric 12 + CGI, POWVT, CARS Chez, et al 2003 donezepil dose: 2.5-5mg 43 Pediatric 12 +++ CGI, Gardner, POWVT, CARS Harden 2002 donezepil dose:5mg 8 Pediatric/ 12 + CGI & ABC Chez, et al 2004 rivastigmine., dose: 0.2-0.5mg BID 32 pediatric 12 + Hertzman 2003 galantamine dose: 4-12mg 3 adults Not fixed + GARS, CARS, PWOVT (E&R), Connors, CGI CGI 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.