Transcript Advanced Psychopharmacology: AACAP Meeting Oct.18

Advanced Psychopharmacology:
AACAP Meeting Oct.18-23, 2005
Chanvit Pornnoppadol, M.D.
Institute 1: Timothy E. Wilens
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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
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Diagnosis
Efficacy
Adverse Effects
Compliance
Concomitant Medications
Stressors
ADHD Comorbidity
Refractory ADHD: Prominent Executive
Function Deficits
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Use of Norepi agent – Atomoxetine, TCA,
Bupropion (alone or combined with stimulant)
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Nicotinic/cholinergic agents
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Indirect: Donepezil, Galantamine – Ineffective
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Direct: Nicotinic agents/patch - Effective
Atomoxetine
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Uses
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Uncomplicated ADHD
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Refractory ADHD
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Comorbid ADHD
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Anxiety or depressive disorders
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Tic disorders
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Disruptive disorders
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Substance use disorders
Atomoxetine
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Dosing (Wilens’ Method):
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Start at 0.5 mg/kg/day for 2 weeks, then increase
to 1.2 mg/kg/d
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After 6 weeks if partial response, increase to 1.4
mg/kg/d (FDA approval) – 1.8 mg/kg/d (studied)
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Reduce dose to 0.5 mg/kg/d if using known
inhibitors of p448 (e.g. paroxetine, fluoxetine,
ketoconazole)
Atomoxetine
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Adverse effects:
- Somnolence, insomnia, nausea, headache,
appetite suppression, GI upset/dyspepsia, BP/pulse
(adults), sexual dysfunction (adults)
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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)
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Improved ADHD RS (p=0.028)
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Improved CGI-Severity of ADHD (p=0.009)
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85% of combined group considered
much/very much improved
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Significant effect on executive functioning
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High rates of side effects
Pharmacologic Strategies and
Tactics for Treating Bipolar
Disorder
Mood Stabilizers
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Traditional
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Lithium
Sodium Valproate
Carbamazepine
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New/Novel
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Gabapentin
Lamotrigine
Topiramate
Tiagabine
Oxcarbazepine
Levetiracetam
Zonisamide
Newer Antiepileptic Drug (AEDs):
Gabapentin
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Mimics GABA, low S/E
Adults: 2 controlled studies did not
demonstrate efficacy in acute mania
Cases of Disinhibition in children
Dosing
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Start 150-300 mg
Target range 900-2400 mg/d
Newer Antiepileptic Drug (AEDs):
Lamotrigine
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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 CGIC), 63% response (by CDRS-R)
Newer Antiepileptic Drug (AEDs):
Topiramate
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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
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10-keto analogue of carbamazepine
Lower adverse effects than CBZ
Results of child/adolescent trial pending
Dosing
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Start 150-300 mg/d
Effective range 900-1800 mg/d
Atypical Efficacy Evidence
Risperidone
Acute Mania
Adults
Peds
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+
Maintenance
Adults
Peds
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ND
Olanzapine
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ND
Quetiapine
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ND
Ziprasidone
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ND
Aripiprazole
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ND
Juvenile Depression
Treatment of Adolescent Depression Study
(TADS)
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Approximate 400 adolescents with MDD
11 sites, NIMH
Randomized to 12 weeks:
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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
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40
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10
0
CBT+Flx
Flx
CBT
Placebo
Effect Size for CGI-I (ITT)
0.9
0.8
0.7
0.6
0.5
0.4
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0.2
0.1
0
CBT+Flx
Flx
CBT
Suicidal Behavior
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General population:
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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
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35-50% of depressed teens make a suicide
attempt
Pharmacological Treatment
of Anxiety Disorders
Pediatric OCD Treatment Study (POTS)
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Multicenter NIMH-funded study of 112 youths
(7-16 yrs) with OCD
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Comparison of 12-wk CBT+Sertraline, CBT
alone, Sertraline alone and placebo
JAMA, 2004
POTS Results
Condition
Remission Rate
Effect Size
CBT+Sertraline
54%
1.4
CBT
39%
0.97
Sertraline
21%
0.67
Placebo
4%
N/A
School-Based CBT for Anxious Children
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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
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Best studied
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Efficacious in controlling aggression,
irritability, stereotypy, and hyperactivity
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Not efficacious in social impairment and
communication deficit
Other atypical antipsychotic trials in autism
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Clozapine: efficacious in 3 case reports
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Olanzapine: efficacious in 2 open-label
trials
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Quetiapine: mixed efficacy in 4
retrospective studies
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Ziprasidone: efficacious in 1 case series
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Aripiprazole: efficacious in 1 case series
Atomoxetine in PDDs with ADHD symptoms
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Prospective open-label study in 16 drug-free
children with PDDs + significant ADHD symptoms
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Dosing: 0.5 mg/kg/d x 1 wk, then 0.8 mg/kg/d x 1
wk, then 1.2 mg/kg/d
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Dose increased to 1.4 mg/kg/d at week 4 for
nonresponders
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Mean dose = 1.2 +/- 0.3 mg/kg/d
Atomoxetine in PDDs with ADHD symptoms
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12/16 (75%) much or very much improved on the
CGI
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2/16 (13%) much worse due to irritability
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Conclusions
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Encouraging results
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Possible alternative to stimulants and clonidine
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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)