1. ATOMOXETINE, CLONIDINE AND GUANFACINE FOR ADHD
Stephen Soltys MD
Professor and Chair
SIU Department of Psychiatry
Double click on speaker icon on following slides

2. ATOMOXETINE Norepinephrine Reuptake Inhibitor
Increased noradrenergic activity results in enhancement of signals that brain decided are important
In prefrontal cortex 70% of dopamine released into synaptic cleft is taken up by adjacent noradrenergic neurons
Thus atomoxetine increases prefrontal dopamine which works to diminish unimportant signals (noise)
No noradrenergic activity in nucleus acumbens (no abuse potential) or striatum (no tics)

3. ATOMOXETINE
Rapidly absorbed with peak plasma concentrations in 1-2 hours
Half-life 5 hours with metabolism via the cytochrome P450 2D6 pathway
80% excreted through urine and rest via feces
Brain concentrations may differ from plasma as therapeutic effects persist after drug has cleared peripheral circulation

4. ATOMOXETINE
Impacts both distractibility and hyperactivity-impulsivity with 24 hour length of action
Insomnia about same as placebo
Appetite can decrease if gastric upset develops.
Occasional headache or dizziness
Heart rate increase of 6 bpm, BP increase 1.5 mmHG for systolic and diastolic
No effects on QTC interval, no requirements for ECG monitoring
Lab monitoring not required

5. ATOMOXETINE Used with MAO inhibitors is contraindicated
No inhibition or induction of cytochrome P450 enzymes
Decrease atomoxetine dosing when giving to patient on paroxetine, fluoxetine and quinidine: all potent P450 2D6 inhibitors
Co-administration with IV albuterol may cause increase in blood pressure and heart rate
Non-stimulant, non-controlled substance

6. ATOMOXETINE
Dosing: lbs 18mg X 4 days, then 25 mg lbs 25 mg X 4 days, then 40 mg lbs 40 mg X 4 days, then 60 mg 127+ lbs 40 mg X 4 days, the 80 mg
Starting dose is in range of 0.5 mg/kg/day, target dose is 1.2 mg/kg/day
Doses above target dose or 100 mg in adults have little benefit

7. ATOMOXETINE LONG-TERM
Kratochvl et al did meta-analysis of 13 studies treating children age 6-7 with atomoxetine for 24 months JAACAP 8/2006
25.7 % stopped because of lack of efficacy
4% stopped because of side effects
Weight went from 63 to 51 percentile with height from 54 to 43 percentile = failure to gain 2.7 cm

8. ALPHA-ADRENOCEPTOR AGONISTS
Prefrontal cortex is involved with behavioral inhibition and working memory
Stimulation of these receptors may enhance signals that are important.
Clonidine and guanfacine have been used as adjunctive treatments since late 1980’s off-label, FDA with FDA approval only in last 5 years

9. CLONIDINE
Over 200,000 prescriptions for clonidine are written for ADHD per year, (Intuniv preparation FDA approved but usually generics are used). About 20% of ADHD children are on clonidine
Dosing recommendations vary but Hunt (1987) recommended a limit of .005 mg/kg/day
Peak is 2 to 6 hours after administration, 12 hour half life, excreted in urine

10. CLONIDINE Alpha 2-adrenergic agonist
Hypotension, sedation, bradycardia
Activates alpha receptors in cardiovascular control center in CNS with suppressed sympathetic activity
Also binds central imidazoline receptors which accounts for sedation

11. CLONIDINE
2 OL and 2 DBPC studies showed improvement in ADHD children. Has been suggested that it may decrease the need for stimulants but not proven.
Four sudden deaths on stimulant-clonidine combination and 17 non-fatal cardiac events on clonidine alone.
If child has questionable cardiac status, may want baseline and follow-up EKGs

12. CLONIDINE AND PSYCHOSTIMULANTS
Hazell and Stuart 2003 JAACAP DBPC
Patients were on mg MPH /mg/kg/day or its equivalent in amphetamine salts
Clonidine up to .2 mg/day given
Significant impacts in the clonidine group beginning week 5 especially in CD vs ADHD symptoms
Main side effects transient dizziness and sedation but decreased the number of stimulant side effects

13. CLONIDINE
4 out of 5 PC studies of clonidine in Tourette’s or tic disorders fail to show any benefit
Few uncontrolled studies of efficacy in aggression but may be due to sedation.
Clonidine frequently used for sedation in ADHD

14. GUANFACINE
2/2009 DPC study on 210 children showed extended release guanfacine significantly more effective than placebo on ADHD scales
Side effects somnolence, headache, fatigue, sedation, dizziness, irritability, upper abdominal pain and nausea
Sedation side effects resolve after two weeks