Transcript ADHD - Atomoxetine, Clonidine, and Guanfacine

ATOMOXETINE, CLONIDINE
AND GUANFACINE FOR ADHD
Stephen Soltys MD
Professor and Chair
SIU Department of Psychiatry
Double click on speaker icon on
following slides
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)
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
ATOMOXETINE







Impacts both distractibility and hyperactivityimpulsivity 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
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
ATOMOXETINE

Dosing:
40-62 lbs 18mg X 4 days, then 25 mg
63-93 lbs 25 mg X 4 days, then 40 mg
94-126lbs 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
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
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
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
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
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
CLONIDINE AND
PSYCHOSTIMULANTS


Hazell and Stuart 2003 JAACAP DBPC
Patients were on .6-.7 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
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

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