Advanced Psychopharmacology:

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

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

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

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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:

- 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

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 unpublished data)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

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 150-300 mg Target range 900-2400 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 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

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

Atypical Efficacy Evidence

Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole

Acute Mania

Adults +++ Peds + +++ + +++ +++ +++ ++ + +

Maintenance

Adults + Peds ND +++ ND +++ + ++ ND ND 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

80 70 60 50 40 30 20 10 0 CBT+Flx Flx CBT Placebo

Effect Size for CGI-I (ITT)

0.4

0.3

0.2

0.1

0 0.9

0.8

0.7

0.6

0.5

CBT+Flx Flx CBT

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

CBT+Sertraline

Remission Rate

54% CBT Sertraline Placebo 39% 21% 4%

Effect Size

1.4

0.97

0.67

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

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Donepezil (Aricept ®) better than placebo in crossover study of 43 PDDS children

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Ongoing single site trials of donepezil and galantamine (Reminyl ®)

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D-cycloserine (NMDA partial agonist) reduced ABC social withdrawal in small pilot study (N=10)