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?