Advanced Psychopharmacology: AACAP Meeting Oct.18-23, 2005

1. Advanced Psychopharmacology:AACAP Meeting Oct.18-23, 2005 Chanvit Pornnoppadol, M.D.

2. Institute 1:Timothy E. Wilens • Pharmacological Straegies in Treatment Refractory ADHD • Advanced Psychopharmacologic Interventions for Adolescent Substance Use Disorders • Pharmacologic Strategies and Tactics for Treating Bipolar Disorder • Juvenile Depression • Pharmacological Treatment of Anxiety Disorders • Tics and Tourette’s Disorder • Psychopharmacology of Autism and Related Disorders

3. Refractory ADHD • Diagnosis • Efficacy • Adverse Effects • Compliance • Concomitant Medications • Stressors • ADHD Comorbidity

4. Refractory ADHD: Prominent Executive Function Deficits • Use of Norepi agent – Atomoxetine, TCA, Bupropion (alone or combined with stimulant) • Nicotinic/cholinergic agents • Indirect: Donepezil, Galantamine – Ineffective • Direct: Nicotinic agents/patch - Effective

5. Atomoxetine • Uses • Uncomplicated ADHD • Refractory ADHD • Comorbid ADHD • Anxiety or depressive disorders • Tic disorders • Disruptive disorders • Substance use disorders

6. Atomoxetine • Dosing (Wilens’ Method): • Start at 0.5 mg/kg/day for 2 weeks, then increase to 1.2 mg/kg/d • After 6 weeks if partial response, increase to 1.4 mg/kg/d (FDA approval) – 1.8 mg/kg/d (studied) • Reduce dose to 0.5 mg/kg/d if using known inhibitors of p448 (e.g. paroxetine, fluoxetine, ketoconazole)

7. Atomoxetine • Adverse effects: - Somnolence, insomnia, nausea, headache, appetite suppression, GI upset/dyspepsia, BP/pulse (adults), sexual dysfunction (adults) • Drug interactions: - Other p448 inhibitors can inhibit Atomoxetine catabolism (paroxetine, fluoxetine) - No drug interactions with stimulants

8. MGH Study: Atomoxetine + OROS MPH in ADHD(Wilens et al. unpublished data) • Improved ADHD RS (p=0.028) • Improved CGI-Severity of ADHD (p=0.009) • 85% of combined group considered much/very much improved • Significant effect on executive functioning • High rates of side effects

9. Pharmacologic Strategies and Tactics for Treating Bipolar Disorder

10. Traditional Lithium Sodium Valproate Carbamazepine New/Novel Gabapentin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide Mood Stabilizers

11. Newer Antiepileptic Drug (AEDs): Gabapentin • Mimics GABA, low S/E • Adults: 2 controlled studies did not demonstrate efficacy in acute mania • Cases of Disinhibition in children • Dosing • Start 150-300 mg • Target range 900-2400 mg/d

12. Newer Antiepileptic Drug (AEDs): Lamotrigine • Adults: 2 controlled studies demonstrated efficacy for bipolar depression • Not FDA-indicated in children age < 16 years • Concern: serious rashes, Steven-Johnson’s syndrome, serum sickness • Small open label study in 20 adolescents with bipolar depression: 84% response (by CGI-C), 63% response (by CDRS-R)

13. Newer Antiepileptic Drug (AEDs): Topiramate • Blocks voltage-gated sodium channels • Half-life: 21 hours (with inducers 12-15 hours) • Controlled adolescent trial was negative. • 2 adult BPD controlled studies were also negative. • Start dose at 25 mg bid; increase to 200 mg bid

14. Newer Antiepileptic Drug (AEDs): Oxcarbazepine • 10-keto analogue of carbamazepine • Lower adverse effects than CBZ • Results of child/adolescent trial pending • Dosing • Start 150-300 mg/d • Effective range 900-1800 mg/d

15. Atypical Efficacy Evidence

16. Juvenile Depression

17. Treatment of Adolescent Depression Study (TADS) • Approximate 400 adolescents with MDD • 11 sites, NIMH • Randomized to 12 weeks: • Fluoxetine up to 40 mg • CBT • Fluoxetine plus CBT • Placebo TADS: JAMA 2004;292:807-20

18. TADS: CGI-I response at the end of 12-weeks of Px

19. Effect Size for CGI-I (ITT)

20. Suicidal Behavior • General population: • 17% of teens think about suicide in given year • 12% of girls and 5% of boys make a suicide attempt • Complete suicide: Girls = 2/100,000 Boys = 12/100,000 • 35-50% of depressed teens make a suicide attempt

21. Pharmacological Treatment ofAnxiety Disorders

22. Pediatric OCD Treatment Study (POTS) • Multicenter NIMH-funded study of 112 youths (7-16 yrs) with OCD • Comparison of 12-wk CBT+Sertraline, CBT alone, Sertraline alone and placebo JAMA, 2004

23. POTS Results

24. School-Based CBT for Anxious Children • Comparison of group CBT for children, group CBT + parent training, and no-treatment control • Both active CBT interventions were more effective than control in decrease anxiety level. • Adding parent training to child CBT resulted in additional benefits.

25. Psychopharmacology of Autism and Related Disorders

26. Risperidone • Best studied • Efficacious in controlling aggression, irritability, stereotypy, and hyperactivity • Not efficacious in social impairment and communication deficit

27. Other atypical antipsychotic trials in autism • Clozapine: efficacious in 3 case reports • Olanzapine: efficacious in 2 open-label trials • Quetiapine: mixed efficacy in 4 retrospective studies • Ziprasidone: efficacious in 1 case series • Aripiprazole: efficacious in 1 case series

28. Atomoxetine in PDDs with ADHD symptoms • Prospective open-label study in 16 drug-free children with PDDs + significant ADHD symptoms • Dosing: 0.5 mg/kg/d x 1 wk, then 0.8 mg/kg/d x 1 wk, then 1.2 mg/kg/d • Dose increased to 1.4 mg/kg/d at week 4 for nonresponders • Mean dose = 1.2 +/- 0.3 mg/kg/d

29. Atomoxetine in PDDs with ADHD symptoms • 12/16 (75%)much or very much improved on the CGI • 2/16 (13%)much worse due to irritability • Conclusions • Encouraging results • Possible alternative to stimulants and clonidine • Placebo-controlled studies needed

30. Core Symptom: Social Withdrawal • Donepezil (Aricept®) better than placebo in crossover study of 43 PDDS children • Ongoing single site trials of donepezil and galantamine (Reminyl®) • D-cycloserine (NMDA partial agonist) reduced ABC social withdrawal in small pilot study (N=10)