Transcript Psychopharmacology of ADHD

PSYCHOPHARMACOLOGY
OF ADHD
Stephen M. Soltys, MD
Professor of Psychiatry
Southern Illinois University
DIRECT OR INDIRECT
Clonidine – alpha-selective adrenergic
agonist with direct action
 Amphetamines – release of biogenic
amines from nerve terminal storage sites
 Methylphenidate – also blocks dopamine
transporter preventing reuptake

FDA APPROVAL

FDA approval is focused on regulating
the indications for which a company can
market its drug
 Is not based on a constant monitoring of
scientific literature
 Companies will only go for FDA
approval if they feel the financial return
will be significant
FDA APPROVAL

As a result the scientific literature may
have numerous citations about how a
drug may be safely used yet not have
FDA approval for advertizing
 The FDA does not intend “approval” to
mean that medications cannot be used for
other indications supported by the
medical science literature, only that
companies cannot advertize for these uses
PRINCIPALS OF
TREATMENT

Core symptoms of ADHD are
distractability, hyperactivity and
impulsivity
 These are the only symptoms that
respond to ADHD meds
 Treatment failure can result from
diagnosing ADHD when it is not there or
not recognizing other disorders along
with ADHD
DIFFERENTIAL DIAGNOSIS

DEPRESSION
 CONDUCT
DISORDER
 OPPOISIOTNALDEFIANT
DISORDER
 LEARNING
DISABILITIES

BIPOLAR
DISORDER (OVER
DIAGNOSED)
 ANXIETY
DISORDER
 TOURETTE’S
INFORMATION

Patient interview
 Parent information
 School or daycare
 Past tesing
 Standardized scales (CBCL, Conners,
Vanderbilt)
TESTING

In the absence of clear indications of medical,
neurological or environmental issues in the
history, tests such as MRI, CAT Scan, EEG,
thyroid levels, lead levels are not indicated
 APA cites lack of validity of tests involving
radioactive nucleotides in the diagnosis and
treatment of ADHD and thus significant safety
issues with radiation exposure
 Psychological testing not indicated in absence
of low IQ or learning disabilities
MEDICATIONS

Stimulants and atomoxetine are the first line of
treatment
 Behavioral intervention alone ineffective in
ADHD as first line treatment
 Medication not likely to impact behaviors
resulting from other co-morbid disorders or
conduct and oppositional-defiant disorder need
behavioral interventions
 Clonidine, guanfacine, buproprion, imipramine
are second-line or augmenting treatments
MEDICATIONS FOR HOW
LONG?
Summer and long holiday’s can be
utilized to assess if meds still needed
 All meds have side effects, key lowest
dose that has benefit without adverse
effects
 Monitor height and weight

STIMULANTS

Effects on central norepinephrine (NE)
and dopamine (DA)
 Amphetamines increase intersynaptic
concentration of DA via indirect
mechanisms
 Methylphenidate with a radioisotope
marker occupies the DA transporter the
striatal area of the brain
STIMULANTS

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Preparations of methylphenidate and amphetamines
have been the mainstay of treatment for ADHD
Regular preparations are quickly absorbed, low plasma
binding and quickly metabolized extracellularly and
hepatically: Onset of action 30 minutes, peak 1-3 hours,
duration 4-6 hours
Generics may have fast absorption and peak sooner
Class II Controlled non-narcotic substance
Problems with break-through symptoms between
doses, non-compliance with multiple doses
STIMULANT TOLERANCE

Little evidence for tolerance to ADHD
symptoms
 No evidence to suggest behavioral sensitization
to long-term stimulants as used in children
 Can occur if drug is intermittently
administered in high parenteral doses that are
then allowed to fall to zero
 Use as prescribed is low oral intake
STIMULANT EFFECTS

Can see a rebound in the activity level with stimulants
when they wear off
 Equal general efficacy for MPH, DEX, AMP
 70% respond when single stimulant is tried, placebo
response of ADHD ranges 3-30%
 Produce improvement in day to day functioning, retain
behavioral problems, no consistent long-term academic
achievement or improvement in social skills
 Positive response does not mean ADHD
STIMULANTS AND
COMORBIDITY

ADHD and anxiety: increased placebo
response rates, more side effects, less
cognitive improvement
 ADHD and Tourette’s: generally
worsening but a few reports of
improvement
 ADHD and DBH: Generally decreases
rate of behaviors
STIMULANTS
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Mixed amphetamine salts and dextroamphetamine: Maximum 40 mg/day
Methylphenidate similar dosing with maximum
of 60 mg/day
Dexmethylphenidate dosing up to 20 mg/day
Maximum dosing should be guided by size of
child (mg/kg/day) but not exceed published
maximums
Behavior /education benefit trade off may be
in the 0.3 to 0.8 mg/kg/day range depending on
the medication
STIMULANTS


Long acting preparations developed
Methylphenidate was developed with a capsule
that had a coating of regular methylphenidate.
 When the coating was dissolved, moisture
absorbed in one end of the capsule caused inert
material in capsule to expand at a steady rate,
causing release of methylphenidate over twelve
hours.
 Available in 18 mg, 27 mg, 36 mg,and 54 mg
tablets.
STIMULANTS

Methylphenidate marketed as Concerta
 18 mg = 10-15 mg/day regular or 20 mg
methylphenidate-SR
 36 mg = 20-30 mg/day regular or 40 mg
methylphenidate-SR
 54 mg = 30-45 mg/day regular or 60 mg
methylphenidate-SR
 Also available in 27 mg
OROS METHYLPHENIDATE
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Wilens et al JAACAP 2003 OL study
71% completed one year
Start 18mg (29%), 36mg (47%), 54mg (24%).
End 18mg (15%), 36 mg (40%), 54mg (45%)
No tolerance to beneficial effects
6.9% discontinued because of adverse effects.
Most common tics, decreased appetite,
insomnia,
NEW PREPERATIONS

Other long acting methylphenidate
preparations developed that have
variable sized coatings on granules
 Patch which bypasses GI absorption and
hepatic first pass inactivation
STIMULANTS

The long acting preparation of mixed
amphetamine salts comes in a capsule that
dissolves releasing rapid acting and delayed
release beads that delivers two pulses of
medication. Marketed as Adderall XR.
 Capsule can be opened and mixed with apple
sauce for those with trouble swallowing pills
 Available in 5 mg, 10 mg, 15 mg, 20 mg, 25 and
30 mg. Not recommended in children under 6.
STIMULANTS

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Decreased appetite is a major problem. Need to
monitor height, weight and follow growth
chart.
Spencer et al 1996 found untreated ADHD
children have slower growth rate advances
than normal children
If taken with food will decrease chance of
stomach upset.
Headache
Document presence or absence of tics
Dysphoria
LISDEXAMFETAMINE

20 mg to 70 mg capsules
 Inactive until converted to dextroamphetamine in gut
 Longer length of action because of
conversion process
 Ineffective if taken by other routes than
oral
STIMULANT ABUSE

May be abused orally, internasally,
parenterally
 2-3% of high school seniors annually use
recreationally with 13% using at sometime in
their lives
 16% of all ADHD patients are asked to sell
 March 2003 JAACAP article suggested a 7X
increase in MPH abuse
AMPHETAMINE TOXICITY

Irritability, hyper-vigilance, situational
reactivity, stereotyped behaviors,
euphoria, impaired judgment, motor
agitation
 Tachycardia, dilation of pupils, elevated
BP, perspiration, nausea/vomiting
 Severe: weakness, respiratory depression,
cardiac arrhythmias, confusion, coma
PEMOLINE


Class IV controlled substance,
Hepatic failure 2 to 17 times that in the general
population. Monitor hepatic enzymes q 2 weeks
after baseline for duration.
 Otherwise same potential side effects as
stimulants, watch for skin rash
 Half life 12 hours with steady state at 2-3 days
 Start at 37.5 mg/day, increase by 18.75/week
until therapeutic. Usual dose 56.25 to 75 mg
range, maximum 112.5 mg/day.
ATOMOXETINE

Approved for use in individuals 6 years
or older with Attention DeficitHyperactivity Disorder
 Norepinephrine Reuptake Inhibitor
 Significant increase of dopamine in
prefrontal cortex but not in nucleus
accubens (stimulant and euphoric
properties) or striatum (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
ATOMOXETINE
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Impacts both distractibility and hyperactivityimpulsivity with 24 hour length of action
Insomnia about same as placebo
Appetite can decrease with gastric upset.
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
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Used with MAO inhibitors is contraindicated
No inhibition or induction of cytochrome P450
enzymes
Decrease 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 metaanalysis 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, loss of 2.7 cm
ALPHA-ADRENOCEPTOR
AGONISTS

Prefrontal cortex is involved with
behavioral inhibition and working
memory
 Stimulation of these receptors may help
in ADHD control
 Clonidine and guanfacine have been used
as adjunctive treatments since late 1980’s
off-label, FDA advertizing approval only
this year for guanfacine
CLONIDINE

Over 200,000 prescriptions for clonidine are
written for ADHD per year, not an approved
indication. About 20% of ADHD children are
on clonidine
 Unknown mechanism of action in ADHD
 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
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 effect 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
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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
BUPROPRION

Anti-depresseant targeting dopamine
 Expanding literature showing benefit for
ADHD symptoms in adults, adolescents
and children
 Serious risk of seizures if dose is over 6
mg/kg/day
 Risk may be there at lower doses if
seizure history present
IMIPRAMINE DOSING
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Off label use
Baseline EKG
Start low: 1 – 2 mg/kg/day in divided doses
Increase once a week while monitoring
response
Watch for anticholinergic side effects
If going above 3 mg/kg/day repeat EKG one
week after each dosing change
IMIPRAMINE DOSING
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Cardiac limits to titration: PR interval greater than
0.21 sec, QT interval greater than 450 msec, QTc
prolongation greater than 60 msec, QTC widening
greater than 10% over baseline, Heart rate greater
than 130.
Maximum dose: 5 mg/kg/day
Check blood level one week after each dose change.
Therapeutic 150-250 ug/dl (Half life 10 to 17 hours)
Always recheck two weeks after patient on stable dose
with good therapeutic response
Treat patient, not blood level
LITHIUM INDICATIONS ESTABLISHED
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Bipolar I (Mania/Depression): Adult,
adolescent
Bipolar II (Hypomania/depression): Adult
Treat manic episodes, stabilize mania and ?
depression
Impulsive aggressivity: Adults
Supplement antidepressants: Adults.
adolescents
Not approved for use in youth 12 years and
under
LITHIUM - PROBABLE
INDICATIONS

Bipolar I in child,
mania treatment, ?
stabilization
 Cyclothymia
 Major depression,
recurrent depression
 Schizoaffective
disorder

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Cluster headaches
Neutropenia
Prevent cycling
Inappropriate
antidiuretic hormone
secretion
Recurrent genital
herpes
Lithium - Conjectural Uses
(Questionable)

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Rapid cycling
Child impulsive
aggression
Conduct disorder
Non-Bipolar I
disorders in children
Nonpsychotic
behavior disorders

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Impulsivity
Trichotillomania
Acute agitation
Panic Disorder
Obsessivecompulsive disorder
Kids of bipolar
parents with negative
behavior
Lithium - Mental Retardation
and Pervasive Developmental
Disorder

Popper notes that there are only case
reports on this population. Aggressivity
and agitation may be improved in these
individuals if they have evidence of
bipolar disorder. Otherwise lithium does
not help.
Lithium - Common Side
Effects

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
Anti-thyroid: fatigue, dry-rough hair, hair loss,
hoarseness, depression, cold sensitivity, edema
Weight gain: due to thyroid, fluid retention,
polydipsia, carbohydrate metabolism
Diabetes insipidus: 60% adults initial, 20%
maintenance, higher in kids (enuresis)
Tremor
GI upset, diarrhea, nausea
Lithium - Toxicity

Very common in children, in dehydrated
individuals, thiazide diuretics, low salt
 Side effects seen at levels 1.5-2.5 mEq/L,
above this is extremely serious
 In some may appear at 1 mEq/L
 The difference between therapeutic levels
and toxic is small. One needs to
constantly be looking for toxic symptoms
Lithium-Degrees of Toxicity

Mild: Tremor, drowsiness, diarrhea, vomiting,
diabetes insipidus
 Moderate: Mild confusion, slurred speech,
muscle twitching-weakness-rigidity, lethargy,
appetite loss, nystagmus, coarser tremor
 Severe: Ataxia, blurred vision, confusion,
hypothermia, hyperreflexia, seizures,
arrhythmia, hypotension, tinnitus, collapse,
coma, death
Lithium - Initial Medical
Monitoring

PE, HPI, VS, Weight, height. Enuresis
and bladder control, tremor
 Labs: CBC+diff, SMAC-20 (Ca and Ph,
Creat, BUN), UA, Thyroid panel, EKG if
<16 or >40 or CV disease
 Pregnancy test and assure birth control
 EEG and neurology approval with
seizure disorder
Lithium-Follow Up I

Li level q M and Th before AM dose until
therapeutic and stable.
 Li level monthly
 Q 3 months: Thyroid panel, UA (SG <
1.010 , protein), serum Creatinine (if
50%>Baseline call renal), body weight
and height