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

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

Refractory ADHD Diagnosis Efficacy Adverse Effects Compliance Concomitant Medications Stressors ADHD Comorbidity

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

Atomoxetine Uses  Uncomplicated ADHD  Refractory ADHD  Comorbid ADHD Anxiety or depressive disorders Tic disorders Disruptive disorders Substance use disorders

Atomoxetine Dosing (Wilens’ Method): 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)

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

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 unpublished data) Improved ADHD RS (p=0.028) Improved CGI-Severity of ADHD (p=0.009) 85% of combined group considered much/very much improved Significant effect on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

Bipolar Disorder Pharmacologic Strategies and Tactics for Treating Bipolar Disorder

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

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 mg  Target range mg/d

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)

Newer Antiepileptic Drug (AEDs): Topiramate  Blocks voltage-gated sodium channels  Half-life: 21 hours (with inducers 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

Newer Antiepileptic Drug (AEDs): Oxcarbazepine  10-keto analogue of carbamazepine  Lower adverse effects than CBZ  Results of child/adolescent trial pending  Dosing  Start mg/d  Effective range mg/d

Atypical Efficacy Evidence Acute ManiaMaintenance AdultsPedsAdultsPeds Risperidone +++++ND Olanzapine ++++ ND Quetiapine ND Ziprasidone +++++ND Aripiprazole ND

Juvenile Depression

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

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

Effect Size for CGI-I (ITT)

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

Pharmacological Treatment of Anxiety Disorders

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

POTS Results Condition Remission Rate Effect Size CBT+Sertraline54%1.4 CBT39%0.97 Sertraline21%0.67 Placebo4%N/A

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.

Psychopharmacology of Autism and Related Disorders

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

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

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

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

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)