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PHARMACOLOGY FOR ADHD & CO-OCCURING DISORDERS IN CHILDREN & ADOLESCENTS
Nurse Practitioners of Idaho
2013 Winter Conference
American Academy of Child and Adolescent Psychiatry
http://www.aacap.org/galleries/PracticeParameters/JAACAP_
ADHD_2007.pdf
Dulcan M. et al. JAACAP. 1997;36(suppl 10):85S-121S.
American Academy of Pediatrics. Pediatrics. 2001;108:1033-1044
Greenhill LL, et al. Medication Tx strategies in the MTA study.(1996) JAACAP 35; 1304-1313.
AACAP Update
Source of Guidelines
Treatment Considerations
Brain-based disorder
Dysfunction results of interplay between genetic factors/predisposing vulnerabilities, precipitating factors, presence or lack of available structure and resources of school environment and home environment
ADHD
Treatment Considerations
Degree of severity and pervasiveness of symptoms guides treatment
When disability is ignored child suffers academically and socially and can lead to under-achievement, demoralization, lack of confidence, poor self-esteem
ADHD
Believed to Enhance Dopamine and Norepinephrine in PFC, enhancing frontal lobe functions:
Planning
Delaying gratification
Controlling behavior
Focusing
Common side effects include: decreased appetite, increase in tics, anxiety, rebound irritability
Rare cardiac SE; if risk factors present, consult with cardiology
Psycho stimulants
The TREATMENT OF CHOICE. All three sets of guidelines recommend trying both AMPH and MPH first before going to 2nd and 3rd line agents 1,2
unless there is a reason recorded in the chart… Patient/parent request
Recent or unstable substance abuse
Uncontrolled glaucoma
Uncontrolled seizures
Untreated cardiovascular disease
•1 Dulcan M. et al. JAACAP. 1997;36(suppl. 10):85S-121S. 2 American Academy of Pediatrics. Pediatrics. 2001;108:1033-1044
Stimulants are
How do we choose? Methylphenidate
Ritalin Ritalin SR Metadate Methylin Metadate ER Methylin ER Concerta Metadate CD Ritalin LA Focalin Focalin XR Daytrana
Amphetamine
Dexedrine Dexedrine spansule Adderall Adderall XR Vyvanse
Plus… Intuniv (Guanfacine XR) Kapvay (Clonidne) Desoxyn (methamphetamine) Strattera (atomoxetine) Plus two more in FDA stage 3 trials
20 Name Brands
Ritalin LA Individual Plots
0
5
10
15
20
0 2 4 6 8 10
Time (hrs)
Con
c (n
g/m
L)
There Is High Individual Variability in Efficiency of Absorption from the GI Tract…
Optimize the 1st Line Agents
Stimulant medications are fine-tuned to the Target Symptoms of the individual patient on the basis of 4 factors:
1. Optimal molecule
2. Optimal delivery system 3. Optimal dose 4. Optimal timing of doses
Greenhill LL, et al. Medication treatment strategies in the MTA.(1996) JAACAP 35; 1304-1313.
CPG
Stimulants
Guide to Common Stimulants
Medication Peak Duration of Action Delivery System
Methylphenidates
Ritalin and Methylin 1-2 hrs 3-6 hrs Tablet and liquid
Concerta 1-2 hrs 9-12 hrs Osmotic capsule
Metadate CD and Ritalin LA
Biphasic peaks at 1 hr and 4-7 hrs
8 hrs Slow release capsule
Methylin ER and Metadate ER
4-7 hrs 8-10 hrs Slow release tablet
Daytrana 2 hrs 12 hrs Transdermal patch
Amphetamines
Adderall 30 min to 1 hr 4-6 hrs Tablet
Adderall XR 30 min to 1 hr 12 hrs Slow release tablet
Dexedrine Spansules 1 to 1.5 hrs 4-6 hrs Capsule
Focal in XR 30 min 12 hrs Capsule
Vyvanse 3.5 hrs 8-9 hrs Capsule
Source: CCPR, January 15, 2011, Vol 2, Issue 1, ADHD
Extended Release Delivery Systems
1. Convenience.
2. More consistent and stable benefits. The goal of treatment is stability of performance, mood, impulse control, engagement…
3. By definition, people with ADHD are forgetful, likely to lose things, disorganized, poorly structured, easily distracted from activities.
4. Smoothes out rebound kinetics; more tolerable.
5. Poor sense of time; 85% of adults/95% of late adolescents with ADHD do not own a watch. How can we expect meds to be taken on time?
6. Sensitivity to embarrassment and teasing. Only time release formulations allow for privacy and confidentiality.
6 Advantages
20
30
40
50
60
70
80
90
100
110
Stimulant Class Medications
Stimulant Dose
Perf
orm
ance
(as M
easure
d b
y T
OV
A
Sta
ndard
Score
)
Normative
Range
0
No side effects - Side effects
Dose Response
Titration Methodology
1. List patient’s target symptoms.
2. Adjust stimulant medications in the smallest dosage increments available.
3. Continue to increase dose as long as the patient continues to see improvement in target symptoms without side effects.
4. Stop increasing the dose when the patient finds lowest dose that produces optimal target symptom relief and no side effects.
Target Symptom
Adjust the timing… Determined by:
• Delivery system
• Individual physiology
• Individual issues (school, home,etc.)
Duration of action
nap
Re
lief
of
Imp
airm
en
ts
Time 0
Doses
Don’t Medications Always Work?
Wrong Diagnosis
More than One Diagnosis
Underestimated Environmental Influences
Treatment Resistance
Why?
Co morbidity prevalence of study participants at baseline in the NIMH MTA study. Adapted from Arch Gen Psychiatry (1999)
COMORBIDITY PREVALENCE
OPPOSITIONAL DEFIANT
Up to 50% of children with ADHD: persistent negativistic, hostile and defiant behavior
Genetic and neurochemical studies: significant heritability; classification as brain-based disorder
Improves with stimulant-treatment of ADHD
Family based behavioral interventions highly effective (Russell Barkley’s Defiant Child and Defiant Teen good resources for therapists)
DISORDER
ODD Pharmacology
Clonidine, Tenex (Intuniv), Straterra, Wellbutrin and Tricyclic Antidepressants all may reduce symptoms
Risperdal effective in managing core symptoms for more severe behaviors
TREATMENT
Conduct
DISORDER
Physical aggression and cruelty to people or animals, deliberate destruction of property, theft, other crimes, lack of remorse
High risk of ASPD in adulthood
Improves with stimulant therapy
Co-occurring conditions are more responsive to treatment
Risperdal and Valproic Acid: demonstrated efficacy for outbursts of aggression; not favorable for calculated aggression
Family-based behavioral interventions
Tic Disorders
15% of children with ADHD have tic disorders; 50% of kids with tics disorders have ADHD
< 1 % of children with ADHD have Tourette’s Disorder; 50-80% of children with Tourette’s have ADHD
Tics wax and wane and may improve or worsen with stimulants
Removing caffeine from diet can reduce by 50%
DISORDERS
Tics and Tourette’s Disorder
For Tourette’s, 66% respond favorably to Clonidine or Tenex within 2-4 weeks; TCAs (Desipramine) may also be useful; both are useful adjuncts to stimulant treatment in ADHD
Stimulant + Clonidine for ADHD and Tourette’s or Straterra + Desipramine
Use of atypical antipsychotics is 2nd line treatment and typical antipsychotics (Haldol and Orap) are considered 2nd to 3rd line treatment in Tourette’s
Pharmacology
Anxiety
Estimated 25-35% of children with ADHD have co-occurring anxiety disorders including Separation Anxiety, Generalized Anxiety, OCD, Panic, and Social Phobia
Optimal treatment of ADHD should be tried before anxiety pharmacology
Behavioral modification, relaxation techniques, exposure therapy can all be helpful
For OCD, Anafranil, Zoloft, and Luvox are FDA-approved; Prozac, Paxil or Celexa may be helpful
For other anxiety disorders, Straterra or TCAs (Nortriptyline at HS) added to stimulants can be helpful
For severe anxiety, SSRIs (Prozac, Lexapro, Paxil, Zoloft) plus low-dose atypical antipsychotic or Benzo (Klonopin, Xanax or Ativan) may be needed.
DISORDERS
Depression
Depression and dysthymia have been found to be 6-10x more common in children with ADHD; significant overlap of symptoms including decreased memory, impaired concentration, irritability, sleep disturbances, dysphoria, hopelessness and pessimism.
Dyslexithymia as been found in children and adults with ADHD
Mood Disorders
Depression
Treat ADHD and add medication if depression persists
Most 2nd line ADHD meds are antidepressants and stimulant doses need to be adjusted when they are added.
Atypicals such as Abilify are often useful
Behavioral treatment alone (mild to moderate depression) or in combined treatment is most effective.
Mood Disorders
Bipolar Mood Disorder (BMD)
Most difficult differential diagnosis: ADHD vs. BMD vs. combination of the two
Estimated 6-7% of ADHD population also have Bipolar Mood Disorder
Both Disorders share common features: bursts of energy and restlessness, talkativeness, racing thoughts, mood instability, impulsivity, impatience, impaired judgment, irritability, a chronic course, lifelong impairment, strong genetic clustering
Mood Disorders
ADHD vs. Bipolar
Physical restless during sleep: SUSTAINED
Prolonged sleep latency (1-4 hours)
Gory dreams: (-) A.M. arousal:
Quick/Charged Appetite & Weight: Steady
gain Cravings for Salt: (-) Triggers for temper
tantrums: Overstimulation
Physical restless during sleep: VARIABLE
Prolonged sleep latency (1-4 hours)
Gory dreams: (+)
A.M. arousal: Slow/Irritable
Appetite & Weight: Marked fluctuations
Cravings for Salt: (+)
Triggers for temper tantrums: Limit setting
*Popper, Charles, M.D.: Diagnosing Bipolar vs. ADHD
COMPARISON
ADHD vs. Bipolar
Frequent fights: Stumbles into them
Physical energy: Can be mimicked
Regression during anger: Lesser
Destructiveness: Accidental
Duration of temper tantrums: 20-30 minutes
Family history of mood disorders: (+)
Frequent fights: Looks for them
Physical energy: Adult can’t mimic
Regression during anger: Greater
Destructiveness: Intentional
Duration of temper tantrums: 2-4 hours
Family history of mood disorders: (+)
*Popper, Charles, M.D.: Diagnosing Bipolar vs. ADHD
COMPARISON
ADHD vs. Bipolar
Hostile and Rejecting attitude: (-)
Danger: Oblivious to it
Psychoses present (-)
Dysphoria present (-)
Good verbal & artistic skills: (-)
Attention Span: Decreased, variable
Learning disability: Motivational
problems
Hostile and Rejecting attitude: (+)
Danger: Enjoys it
Psychoses present(+)
Dysphoria present (+)
Good verbal & artistic skills: (+)
Attention Span: Decreased, constant
Learning disability: Language deficits
*Popper, Charles, M.D.: Diagnosing Bipolar vs. ADHD
COMPARISON
ADHD with Bipolar Mood Disorder
Impaired mood of Bipolar Disorder in children tends to be irritability (92%), mood states usually mixed (84%) and irritability is chronic instead of cycling.
Childhood-onset Bipolar Disorder usually associated with severe ODD
For children under 12 years there; up to 98% correlation with ADHD: hypothesize may be a marker for a specific subtype of ADHD.
Wozniak L, Bierderman J, Richards JA. Diagnostic and therapeutic dilemmas in the management of pediatric-onset Bipolar Disorder. J Clin Psychiatry 2001; 62 (suppl 14): 10-15.
COMPARISON
ADHD and BMD
Bipolar Disorder must be treated first with atypical antipsychotic and/or mood stabilizer
When depression is prominent a non-SSRI antidepressant may be added such as Wellbutrin or Effexor at low doses
ADHD symptoms respond to treatment only if mood symptoms are treated
ADHD RX includes stimulant + Clonidine (Kapvay) or Tenex (Intuniv), Straterra, or TCA
TREATMENT
Disturbance in ADHD
Sleep disorders are common in patients with ADHD of all ages — is it a symptom of ADHD or a side effect of treatment?
Incidence of pre-treatment sleep problems in children is about 20%; increases to >85% by age 21.
Three types of sleep problems in ADHD: initiation insomnia / “can’t turn off” multiple awakenings / restlessness difficulty awakening in the morning
Chronic Delayed Sleep Phase Syndrome
Corkum et al. JAACAP.1999;38:1285; Regestein and Pavlova. Gen Hosp Psychiatry. 1995;17:335. Dodson WW. Gender Issues in ADHD. Advantage Press 2002; ch 13.
SLEEP
Psychotropic Medications in Children’s Insomnia
Melatonin
Trazodone
Remeron
Clonidine
Antihistamines (Benadryl, Vistaril)
Low dose TCAs
SLEEP
Comparative Effectiveness in Children
AHRQ Review of Strength of Evidence for Comparative Effectiveness for approved and off-label use, August 2012 Strength of Evidence Scale
High Confidence that evidence reflects true effect; further research unlikely to effect estimate of effect
Moderate Confidence that evidence reflects true effect; further research may effect estimate of effect
Low Confidence that evidence reflects true effect; further research likely to change confidence in estimate of effect
FGAs and SGAs
Clinical Bottom Line Abilify, Zyprexa, Seroquel, Risperdal improve CGI, and along
with Geodon, manic symptoms (Moderate) but not depressive symptoms (Low)
Risperdal and Geodon improve tics of Tourette’s Disorder (Moderate)
Risperdal improves behavioral symptoms and CGI for ADD/Disruptive Disorders (Moderate)
Abilify & Risperdal improve behavioral (irritability), obsessive-compulsive, and autistic symptoms of PDD (Low)
(AHRQ)
FGAs versus SGAs
Zyprexa & Risperdal more effective than Haldol for reducing autistic symptoms of anger and hyperactivity in PDD (Low)
Haldol versus Zyprexa: Haldol associated with lower risk for AE on weight and BMI but greater risk of EPS (Low)
Risk of Prolactin elevation is 2.6x greater with Risperdal vs. Zyprexa (Moderate)
Children
Rate or MD of SGAs vs. Placebo
Dyslipidemia:
Abilify NNH= 4 (Low)
Zyprexa NNH = 6 (Low)
Seroquel MD -29.1mg/dl (Low)
Weight Gain
Abilify MD = 0.77 kg (Moderate)
Zyprexa MD – 4.60 kg (Moderate)
Seroquel MD = 1.78 kg (Moderate)
Risperdal MD = 1.79 kg
Adverse Effect
Rate or MD of SGAs vs. Placebo
EPS:
Abilify NNH = 6 (Moderate)
Risperdal NNH =15 (Moderate)
Geodon NH =9 (Moderate)
Prolactin Levels:
Abilify MD = -4.1 ng/ml (Moderate)
Zyprexa MD = 11.5 ng/ml (Moderate)
Risperdal MD = 22.63 ng/ml (Low)
Adverse Effects
Head-to Head Comparisons
Zyprexa vs. Seroquel: 3.5x greater risk of dyslipidemia with
Zyprexa (Low)
Zyprexa vs. Risperdal: Triglycerides are 3.5 to 31.1 mg/dL
higher with Zyprexa (Moderate); weight is 1.5 kg to 3.3 kg more (Moderate)
Zyprexa vs. Abilify: Zyprexa risk for dyslipidemia is 4x greater with weight gain 2.7 kg to 5.5 kg more on Zyprexa (Low)
Abilify vs. Seroquel: Triglycerides are 39.4 mg. dL lower and
weight 1.62 kg lower on Abilify (Low)
Adverse Effects
Antipsychotics & Indications for Children
Bipolar Disorder:
Chlorpromazine: ages 1-12 years (mania)
Abilify: ages 10-17 yrs (manic/mixed)
Zyprexa: ages 13-17 years (manic/mixed)
Seroquel: ages 10-17 years (manic)
Risperdal (10-17 years (manic/mixed)
Irritability associated with Autism:
Abilify: age 6-17 years
Risperdal: age 5-16 years
FDA Approved
Psychotropic Drugs: Pediatric
General rule is 25% to 50% of adult starting dosages to start.
Children metabolize more efficiently and may need more frequent dosing
Often, “less is more”: Some drugs have demonstrated efficacy at much lower doses (Prozac 5mg or 10mg/day; Lexapro 5 -10 mg/day)
DOSING
Pediatric MPH start at .5mg/kg up to 1.0 mg/kg
Adderall – start at 1/3 child’s weight in pounds
Fluoxetine (Prozac)5-60 mg QD
Sertaline (Zoloft)12.5-200 mg QD
Fluvoxamine (Luvox) 25-150 mg QD
Citalopram (Celexa)10- 60 mg QD
Escitalopram (Lexapro) 5-20mg QD
Paroxetine (Paxil)10-40mg
Diphhenhydramine HCL (Benadryl) 12.5-50 mg. 1-3x day
Hydroxyzine HCL (Atarax or Vistaril) 25-100mg. 1-2x day
Buspirone (Buspar) 7.5-30 mg BID
Trazodone (Desyrel) 25-50 mg 1-2x day or 50-200mg for sleep
Risperidal 0.25 - 6.0 mg daily depending on age
Abilify 2 – 30 mg daily depending on age
DOSING
Recommended Reading
Straight Talk about Psychiatric Medications for Kids
When Being a Good Parent or Teacher Is Not Enough
Medication Fact Sheets
by: Dean E. Konopasek
When to Ask for Help
Questions?
Recommended