Transcript CME LLC - Oren Mason MD

When Two Meds Are Better
Than One:
Combination Medication
Management for ADHD
Oren Mason, MD
Director, ATTENTION MD
Assistant Professor of Family Medicine
Michigan State U College of Human Medicine
Grand Rapids, Michigan
Disclosures—Oren Mason MD
• Speaker’s Bureau: Eli Lilly
• Consultant: Eli Lilly
• Royalties: Lulu Publishing
Learning Objectives
• Summarize the current literature supporting
combination therapy.
• Recognized clinical cases in which monotherapy is
suboptimal.
• Utilize combination therapy to improve efficacy,
duration and tolerability of ADHD therapy
• Monitor patient response and safety when utilizing
novel combination therapies.
• Utilize rational combination for treating ADHD
comorbid with depression, anxiety and mood disorder.
ADHD, attention-deficit/hyperactivity disorder
Disclosure
• Numerous examples of off-label usage of
medications are presented.
• The information in the presentation may not be
construed as specific recommendations for the
treatment of individual patients.
• Clinical caution must be exercised with both onlabel and off-label prescription of medications.
ADHD Medication Limitations
Side Effects
Partial Efficacy
Incomplete Duration of Effect
Cost
Medication Limitations
Side Effects
Efficacy
• Insomnia
• Agitation, dysphoria
• Anxiety
• Loss of appetite, weight
• Loss of personality, social “flatness”
• Headache
• Abdominal pain
Duration
Cost
Medication Limitations
Side Effects
Efficacy
Duration
Cost
• Nathan is an active 11 yr old with combinedtype ADHD and ODD.
• 54 mg OROS-MPH (0.9 mg/kg/d)
• Some symptoms improved:
• Hyperactivity
• Aggression
• Some are still problems
• Inattention in school
• Impulsivity with playmates
• Oppositionality with parents
• 72 mg OROS-MPH (1.2 mg/kg/d)
• ADHD and ODD symptoms much better
• Pulse 132 bpm
• Falls asleep 11 pm - midnight
Medication Limitations
Partial Efficacy
Side Effects
Duration
Cost
• Sarah is a shy 10 year old with
inattentive ADHD and dyslexia.
• Atomoxetine 40 mg (1.4 mg/kg/d)
• improved organization
• completes morning routine and
homework without support
• reading proficiency and social
function have improved.
• School conference
• reading specialist is pleased with her
improved reading scores
• but teacher sees distractibility in the
classroom causing problems.
Medication Limitations
Inadequate Duration
Side Effects
Efficacy
Cost
• Adriana is a 32 year old sales manager
and mother with ADHD-C.
• 30 mg AMPH XR at 6:30 am
• Drastically improved efficiency
• Good progress at work
• Gets home every night on time
• Effects wear off around 5-6 pm.
• Irritable, poor frustration tolerance
• Yells at children
• Home disorganized
• Evening “extender doses” cause
unacceptable insomnia.
Medication Limitations
Unacceptable Cost
Side Effects
Efficacy
Duration
• Josh is a 20 year old college junior with
ADHD as well as a 290 pound
defensive tackle on the football team.
• 144 mg OROS-MPH.
• (1.1 mg/kg/d)
• Good response – 65% symptom score
reduction
• Studies and time management are going
well
• Medication cost not affordable
• His insurance covers only 72 mg/d
• Josh pays $40 copay monthly AND
• $350 monthly for uncovered amount
FDA-Approved ADHD medications
Medication
Trade Name
Children &
Adolescents
Adults
Maintenance
Therapy
Mixed amphetamine salts
Adderall, GEQ
yes
-
-
Mixed amphetamine salts ER
Adderall XR, GEQ
yes
yes
-
OROS-methylphenidate
Concerta, GEQ
yes
yes
-
Transdermal methylphenidate
Daytrana
yes
-
-
Dextroamphetamine
Dexedrine, GEQ
yes
-
-
Dexmethylphenidate
Focalin
yes
-
-
Dexmethylphenidate ER
Focalin XR
yes
yes
-
Guanfacine ER
Intuniv
yes
-
-
Clonidine ER
Kapvay
yes
-
-
Methylphenidate ER (biphasic 30/70)
Metadate
yes
-
-
Methylphenidate
Methylin, Ritalin, GEQ
yes
-
-
Methylphendiate ER (biphasic 50/50)
Ritalin LA
yes
yes
-
Methylphenidate ER liquid
Quillivant XR
yes
yes
-
Atomoxetine
Strattera
yes
yes
yes
Lisdexamfetamine
Vyvanse
yes
yes
yes
Potential Benefits of
Combination Therapy
Dopamine pathways
Norepinephrine pathways
Concerns In Combination
Therapy Use
•
•
•
•
Cost
Compliance
Medico-legal implications
Pharmacokinetic interactions
– Absorption, distribution
– Elimination pathways
• Tolerability
– Side effects
– Adverse reactions
• Off-label use
Boxed Warnings
 Methylphenidate
 Dependence
 Amphetamine
 Abuse, dependence
 Misuse can cause sudden death, serious cardiovascular adverse
reactions
 Atomoxetine
 Suicidal ideation in children and adolescents
 SSRI antidepressants
 Suicidal ideation and behavior
Contraindications
 All agents




Hypersensitivity
Within 2 weeks of MAOI use
Glaucoma (narrow-angle)
Advanced/symptomatic cardiovascular disease
 Amphetamine
 Agitated states, history drug abuse
 Methylphenidate
 Marked anxiety, tics
 Atomoxetine
 pheochromocytoma
Warnings and Precautions
 All agents
 Structural cardiac abnormalities
 Increased blood pressure, pulse
 Psychotic, manic symptoms, worsened underlying psychiatric
conditions
 Stimulants
 Growth suppression
 Seizures
 Atomoxetine
 Urinary outflow restriction, priapism
 Concomitant CYP2D6 inhibitor use
Practicing Clinical Caution
• Vital signs are, in fact, vital
– Blood pressure, pulse, weight
– Auscultate pulse
– Height through age 21
•
•
•
•
Tolerability history at each visit
Generally avoid simultaneous medication initiation
Patient information handouts
Cardiology consult for suspicion of structural heart disease
or dysrhythmia
Perrin JM, et al. Pediatrics 2008;122;451
History of
combination therapy
Case Reports
Published Studies
Case Reports
Combination Therapy
Combination Therapy
Case Report
• 8-year-old male, 50 mg MPH-IR divided tid-qid
• Marked initial response
• Tolerance developed at 6 months, dose effects ~ 2 hours
• Further increases intolerable
• ATMX 1.2 mg/kg/d added
• MPH-IR slowly down-titrated to 10 mg/d
• ADHD-RS again measured 10
• Appetite and sleep issues no longer evident
• Efforts to further reduce MPH dose resulted in
significant return of baseline symptoms
IR, immediate release
Agarwal V, Sitholey P. J Can Acad Child Adolesc Psychiatry. 2008;17(3):160.
Combination Therapy
Case Report
• 11-year-old male treated with MPH 20 mg/d
• improved attention but mood and sleep worsened after
2 months
• MPH 10 mg/d
• resulted in return of inattention
• ATMX monotherapy 40 mg/d
• did not ameliorate inattention
• MPH 10 mg/d added to ATMX 40 mg/d:
• “ADHD symptomatology improved impressively”
Niederhofer H. Psychiatr Danub. 2009;21(3):330.
Published Studies
Combination Therapy
Studies of Combination Therapy
Date
Study
2000
Combination Meds
Attention
effect
Hyp/Imp
effect
Side
effects
Connor, Barkley MPH, clonidine
+++
+++
n/a
2002
Tourette Study
MPH, clonidine
++
++
--
2003
Hazel
Stimulant, clonidine
?
2007
Quintana
Stimulant, ATMX
-
-
-/
2009
Wilens
ATMX, OROS-MPH
+++++
+++++
-/
2009
Spencer
Stimulant, guanfacine XR
+++
+++
-/
2011
Kollins
Stimulant, clonidine XR
+++
+++
-/
2012
Wilens
Stimulant, guanfacine XR
+++
+++
-/
Conduct
++

1) Connor DF, Barkley RA, Davis HT. Clin Pediatr (Phila). 2000;39(1):15-25. 2) Neurology. 2002 Feb 26;58(4):527-36. 3) Hazell PL, Stuart JE.
J Am Acad Child Adolesc Psychiatry. 2003;42(8):886-894. 4) Quintana H. Clin Ther. 2007;29(6):1168-77. 5) Wilens TE et al. J Child Adolesc
Psychopharmacol. 2009;19(5):485-492 6) Spencer TJ. Child Adolesc Psychopharmacol. 2009;19(5):501-510 7) Kollins SH. Pediatrics.
2011;127(6):e1406-e1413. 8) Wilens TE et al. J Am Acad Child Adolesc Psychiatry. 2012;51(1):74-85.e2.
Wilens, 2009
Atomoxetine, OROS-MPH Combination
90
80
Symptom Reduction
70
60
50
40
30
20
10
0
MPH
Baseline
ATMX low
ATMX mod
ATMX hi
Combo
Wilens TE et al. J Child Adolesc
Psychopharmacol. 2009;19(5):485-492.
Wilens, 2009 (continued)
Safety and Tolerability
ATMX
ATMX + OROS-MPH
Fatigue (P<0.0005)
34
5
Gastrointestinal (P=0.64)
36
40
Headache (P=0.78)
24
22
Insomnia (P<0.0001)
14
52
Irritability (P=0.02)
16
32
Loss of appetite (P<0.001)
14
44
Rhinitis (P=0.78)
20
22
Other (P=0.03)
14
30
Hammerness P et al. J Child Adolesc
Psychopharmacol. 2009;19(5): 493–499.
Clinical Monitoring of
Combination Therapy
Safeguard Patients
Optimize Efficacy
Clinical Tools to Monitor
Combination Therapy
Vital Signs
Structured Symptom
Eval.
Clinical History
Clinical Tools
Monitor Safety and Tolerability
Normal Vital Signs
• Pulse
• Adult normal: 60 to 100
• Children ages 6 to 12: normal
70 to 120
• Blood Pressure
• Adult normal systolic: 110 to
135
• Adult normal diastolic: 65 to
85
• Children ages 6 to 12 normal
systolic: 100 to 120
• Children ages 6 to 12 normal
diastolic: 60 to 75
American Heart Association ECC Guidelines, 2000; Dieckmann R.
Pediatric Education for Prehospital Professionals. Sudbury, Mass,
Jones & Bartlett, American Academy of Pediatrics, 2000.
Clinical Tools
Monitor Safety and Efficacy
Clinical History--Safety
 Tolerability including intensity and time course
 Compliance
 Frequent updates of:




Social history
Substance use
Screen for anxious, depressed, manic symptoms
Sleep history
Clinical History--Efficacy
• Time course of symptom improvement
• Residual symptoms and impairments
• Progress in patient’s highest priority outcomes
Clinical Tools
Monitor Efficacy
Structured Symptom Evaluation
• Clinician Administered
– ADHD-RS
• Patient Self-Report
– Adult Self-Report Scale
– Conners-Wells’ Adolescent Self-Report Scales
• Observer Report
– NICHQ Vanderbilt Assessment Scale—Parent Informant
– Conners’ Parent Rating Scales
NICHQ, National Initiative for Children’s Healthcare
Quality
Clinical Tools
Monitor Efficacy
Vanderbilt Baseline
One Month Follow-Up
Clinical Tools
Monitor Efficacy
Structured Symptom Evaluation
• Case History
– 27-year-old female, school teacher with ADHD + anxiety
• Treated 10+ years: 15 mg MAS-IR tid + fluoxetine 20 mg
• Stopped fluoxetine 1 mo ago citing lack of efficacy
• Patient satisfaction high for MAS-IR effect
– 40 mg atomoxetine added with rapid subjective
improvement of anxiety*
*Off-label use
MAS-IR, mixed amphetamine salts immediate release
Clinical Tools
Monitor Efficacy
Structured Symptom Evaluation
ADHD Rating Scale
Baseline
MAS-IR 20 mg tid
Inattention
HyperactiveImpulsive
Total
14/27
16/27
30/54
1–month
MAS-IR 20 mg tid plus
ATMX 40 mg/d
9
7
16
4–month
MAS-IR 20 mg tid plus
ATMX 40 mg/d
6
5
11
8–month
MAS-IR 20 mg tid plus
ATMX 40 mg/d
5
3
8
Clinical Tools
Monitor Efficacy
Structured Symptom Evaluation:
progress AMPH + ATMX
30
ADHD-RS Score
25
20
15
10
5
0
AMPH
Combo 1-mo
Combo 4-m
Combo 8-mo
Inattention
Hyper/Imp
Clinical Tools
Monitor Efficacy
Structured Symptom Evaluation
• Case History (con’t)
– At 8-month follow-up, requested discontinuation of
atomoxetine: “I’m doing well. I don’t think I need both
medications.”
– She reviewed baseline and current self-assessments in
silence for about 2 minutes, then commented:
“I forgot what my life used to be like.”
Clinical Tools to Monitor
Combination Therapy
Structured Symptom Evaluation
• Benefits of serial measurements of ADHD symptoms
– Measure progress across long time spans
– Therapeutic trial comparison1
– Benchmark clinical relevance of medication effects2
Symptom score reduction Functional improvement
Measured change in
outcomes
<36%
None
0 SD
40-45%
Modest
0.25 to 1.0 SD
50-65%
Significant
> 1.0 SD
SD, standard deviation
1Newcorn J et al. Am J Psychiatry. 2008;165:721-730;
2Buitelaar JK et al. J Child Psychol Psychiatry. 2009;50(3):335-342.
Prioritized Goals Of
ADHD Medication Therapy
First, do no harm
Symptom Score Reduction > 50%
24-hour Symptom Reduction
No Impairing Symptoms
No Residual (Clinical) Symptoms
Functional Improvement
Examples Of
Combination Therapy
Case Histories
Managing Side Effects
Side Effects
Efficacy
Duration
Cost
• Guanfacine-ER 3 mg added,
OROS-MPH then decreased
to 54 mg/d.
• Nathan - 11 yr old
• ADHD-C and ODD.
• OROS-MPH 72 mg/d
• ADHD and ODD much better
• Pulse 132
• Insomnia until midnight
• ADHD and ODD symptoms
improved morning and
evening
• Able to fall asleep by 9 pm
• Pulse 96
• Alternatives
•
•
•
•
Atomoxetine 18-60 mg
Clonidine ER 0.2 – 0.4 mg
Clonidine 0.1 mg bid – tid
Guanfacine 2-4 mg
Optimizing Efficacy
Partial Efficacy
Side Effects
Duration
• D-MPH XR 5 mg added
Cost
• Improved focus per teacher
• Test scores improved
• Parent reports of attention
also improved
• No additional side effects
• Sarah - 10 year old
• inattentive ADHD
• dyslexia.
• Atomoxetine 40 mg
• 1.4 mg/kg/d
• effective except focus.
•
Alternatives:
•
•
•
•
•
MPH 5 mg bid
MPH-SR 10 mg
MAS ½ of 5 mg bid
MAS-XR 5 mg
LDX 20 mg ½ dose
Optimizing Duration
Inadequate Duration
Side Effects
Efficacy
Cost
• Atomoxetine 40 mg
added
• AMPH XR weaned to 15
mg
• Adriana, 32 year old
• ADHD-C
• 30 mg AMPH XR
• wears off by 6 pm
• Work performance still
excellent
• Evenings and family
time much calmer
• ADHD Coach helped her
organize kitchen and
home office
Improving Cost Burden
Unacceptable Cost
Side Effects
Efficacy
Duration
• Atomoxetine 80 mg added
• Concerta titrated to 72 mg
dose
• 80% symptom score
reduction
• Out-of-pocket cost now $80
per month
• Josh, 20 year old
• OROS-MPH 144 mg
• 65% symptom score
reduction
• High out-of-pocket cost
$390 per /month
Improving Cost Burden
Unacceptable Cost
Side Effects
Efficacy
Duration
• This case may not be typical.
• Many people will pay more, not less for combination
therapy.
Combination Therapy
Clinical Pearls
Initial Agent
• Start with “best fit” medication.
• Aim for monotherapy success.
• Limit initial agent to “highest
tolerable dose”.
Combination Therapy
Clinical Pearls
Combination Agent
• Initial target: ½ of usual dose
• Titrate slowly to that target dose
• Stimulant duration may be
improved when added to nonstimulant
• Unusually low dosages of second
agent are sometimes very effective
Managing ADHD with
Comorbid Conditions
Anxiety, OCD, Panic
Oppositional and Conduct Disorders
Substance Use Disorder
Depression, Bipolar
Comorbidity—ADHD + Anxiety
• ADHD plus Anxiety Disorders—GAD, Social Anxiety
• Method 1: Begin with atomoxetine
• Effective in both ADHD and anxiety
• Best chance for monotherapy
• Can add low-dose stimulant
• Method 2: Begin with stimulant (if anxiety not severe)
•
•
•
•
Anxiety commonly secondary to ADHD.
Prefer continuous-release forms—lis-d AMP, transdermal MPH
Titrate “low and slow”
Can add SSRI for residual anxiety
• Method 3: Begin with SNRI or SSRI
• Can add atomoxetine or stimulant carefully once anxiety diminishes
SSRI, selective serotonin reuptake inhibitors.
Geller D, etal. J Am Acad Child Adolesc Psychiatry. 2007 Sep;46(9):1119-27.
Young, Joel. (2007) ADHD Grown Up: A Guide to Adolescent and Adult ADHD. New York: W. W. Norton. p 231
Pfiffner L, Barkley R and DuPaul G, (2006). Treatment of ADHD in School Settings. In R Barkley (ed) Attention-Deficit Hyperactivity Disorder: A Handbook for
Diagnosis and Treatment. (pp. 547-589) New York, NY. Guilford Press.
Comorbidity—ADHD + Anxiety
• OCD, Panic, Severe Anxiety
• Control anxiety first
• Begin with SNRI—duloxetine, venlafaxine
• Anti-anxiety effect and ADHD symptom-reduction
• SSRIs and BZDs can give mixed effects
• May decrease motivation, executive function
• Add ADHD medication for residual ADHD symptoms
• Atomoxetine preferred
• ½ target dose if fluoxetine, paroxetine present
• Low-dose stimulant for atomoxetine non-responders
• Continuous-release preparations preferred: lis-d AMP,
transdermal MPH
BZD, benzodiazepine
Spencer, Thomas, (2006). Antidepressant and SNRI Treatment. In R Barkley (ed) Attention-Deficit
Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. (pp. 648-657) New York, NY. Guilford Press.
Comorbidity—ADHD + ODD, CD
• Oppositional Defiant and Conduct Disorders
• Oppositional and aggressive symptom response parallels ADHD
symptom response
• Psychosocial treatments AND medication are first-line
• Parent training highly effective
• Disciplinary consistency may prevent progression of ODD to CD
• Medications may be titrated more aggressively
• Methylphenidate daily doses 1-2 mg/kg/d
• Amphetamine daily doses 0.5-1.0 mg/kg/d
• Atomoxetine up to 1.8 mg/kg/d
• Combination therapy generally preferred
• Risperidone has best evidence base for aggressive behaviors
• Other mood stabilizers often useful
CD, conduct disorder.
Pappadopulos E, et al. J Can Acad Child Adolesc Psychiatry. 2006 Feb;15(1):27-39.
Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006 Jun;45(6):642-57.
Comorbidity—ADHD + SUD
• Substance Use Disorders
• Management plan
• ADHD control may augment therapy of substance use
• Decrease micro-management of mental states
• Atomoxetine preferred
• Decreases recidivism in alcohol abuse disorders
• Symptom relief extends into late evening social events
• Other non-stimulants useful
• Bupriopion, modafinil
• Guanfacine, clonidine
• Time-release stimulants preferred over IR forms
• Abuse is much less common with these forms
• IR stimulants relatively contraindicated
Wilens TE, et al. Drug Alcohol Depend. 2008 Jul 1;96(1-2):145-54.
Bright GM. Medscape J Med. 2008 May 7;10(5):111.
Comorbidity—ADHD + Depression
• Depression
• Active depression should be controlled first
• Bupropion and duloxetine often improve ADHD symptoms
• When depression stabilized, make haste to add ADHD
medications
• Stimulants can have adjuvant effect to antidepressants
• Atomoxetine titration should be slowed (1/2 target dose) if
added to SNRI, fluoxetine, or paroxetine
• Dysthymia and mood dysregulation
• may respond to ADHD medications alone without need
for antidepressant
Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry. 2006 Jun;45(6):642-57.
Comorbidity—ADHD + Bipolar
• Bipolar Disorder
• Mood stability is primary
• ADHD medications can be trialed if impairing symptoms
persist despite mood stabilizer therapy
•
•
•
•
•
Bupropion
Low-dose atomoxetine
Low-dose stimulants
Modafinil
TCAs
• Begin low and titrate ADHD medications cautiously
• Follow closely. All ADHD medications can induce
switches or rapid-cycling
TCA, tricyclic antidepressant.
Wilens TE, et al. Biol Psychiatry. 2003 Jul 1;54(1):9-16.
Chang K, et al. J Child Adolesc Psychopharmacol. 2009 Oct;19(5):547-51.
Conclusion
• Monotherapy for ADHD
– Historically preferred
– Effects may be sub-optimal or of limited duration
– Not always sufficient to lead to functional improvements
• Combination therapy for ADHD
–
–
–
–
–
–
Typically stimulant + non-stimulant
Affects more executive pathways
Very promising early studies
Acceptable safety and tolerability
Accessible safety monitoring
Improved symptom response leads to functional improvement
When Two Meds Are Better
Than One:
Combination Medication
Management for ADHD
Questions?
Managing Side Effects
Side Effects
Efficacy
Duration
Cost
• 9 yr old girl with ADHD-I, • Combination trials:
sub-threshold anxiety
• Atomoxetine 10-25 mg
symptoms
• Guanfacine 1-3 mg
• Guanfacine ER 1-3 mg
• OROS-MPH 27 mg/d
• Attention and grades
much better
• Anxiety is increasing
• Cannot fall asleep in her
own room
• Reads until 10 or 11 pm
• Clonidine 0.1 – 0.3 mg
• Clonidine ER 0.2 – 0.3 mg
• SSRI anti-depressant
Optimizing Efficacy
Partial Efficacy
Side Effects
Duration
Cost
• 34 yo businessman
• Combination trials:
• Atomoxetine 25-60 mg
• 50 mg lys-d-amfetamine
• 12-14 hour effect
• Tolerability good
• Attention and efficiency
improved
• Emotional dysregulation
remains a problem
• Guanfacine ER 2-3 mg
or guanfacine 1-2 mg
bid
• Bupropion 150-300 mg
Optimizing Efficacy
Partial Efficacy
Side Effects
Duration
Cost
• 6 yo hyperactive first• Combination trials:
grade boy
• Atomoxetine 10-18 mg
• Clonidine 0.05-0.1 mg tid
• 10 mg methylphenidate at
• Clonidine ER 0.1 to 0.3 mg
7:00 am, 10:30 am, 2 pm
• Clear improvements in
classroom setting
• Tolerability good
• Attention and efficiency
improved
• Still has outbursts in class
and initiates fights on
playground
per day
• Guanfacine ER 1-3 mg
• Guanfacine 0.5-1.0 mg
bid
Optimizing Duration
Inadequate Duration
• 20 year old college
student
• 40 mg MAS-XR
•
•
•
•
10-12 hour effect
Tolerability good
Pays attention in class
Needs to study in
evening, but too
distracted
• Friends have stolen
medications in past
Side Effects
Efficacy
Cost
• Combination trials:
•
•
•
•
•
•
Atomoxetine 10 - 80 mg
Clonidine 0.2 – 0.4 mg
Clonidine ER 0.1 – 0.3 mg
Guanfacine ER 1 - 4 mg
Guanfacine 1 - 4 mg
Buproprion 150 – 300 mg
Improving Cost Burden
Unacceptable Cost
• 40 year old factory
worker
• 40 mg MAS XR
• Attention good
• Less impulsive
• Driving much better
• Insurance pays 50%
• Patient pays $175 per
month
Side Effects
Efficacy
Duration
• Combination trials:
• Bupropion 150 – 300 mg
• ($20 per month)
• Clonidine 0.1-0.4 mg
• ($5 per month)
• Guanfacine 1-4 mg
• ($5 per month)
Note: any combination that
decreases MAS XR dose to
30 mg or less decreases his
stimulant cost by
$85 per month