pediatric psychopharmacology: mood disorders...
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Pediatric Psychopharmacology:Mood Disorders
Julie Carbray PhD, APN, PMHCNS-BC
Institute for Juvenile Research University of Illinois at Chicago
Child Clinical Psychopharmacology Institute 2009
CPI 2009
Disclosure: Julie Carbray Ph.D., APNSource Advisory
BoardResearchContract
Speaker Consultant StockEquity>$10,000
Honorariumfor this talkor meeting
Astra Zeneca X
Concept: Wiring Problems Can Explain the Clinical Presentation
�Neurocognitive Studies in the Laboratory
�fMRI Studies Mapping the Circuitry
�DTI Studies of the White Matter Tracts
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Pavuluri and Sweeney, JCAAP, 2008
Five Functional Circuits in PBD
fMRI Testing Environment:In an MRI Scanner
IR Camera
Head Coil
Rear Projection Screen
Mirror
Projection LensButton Press Projector
Respiratory Belt
Penn Emotion Differentiation Task (EmoDiff)
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Domain: Social Cognition
• Affect Discrimination
• Penn Emotional Acuity Task
Impaired ability to accurately interpret extremely happy and sad emotions, but not the mild or neutral emotions, worse in younger children
Schenkel et al., in press JACAAP
MPFC
MPFC
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Affective Circuitry Study
Hypotheses that in PBD subjects, relative to HC: �Disconnect in face-response circuitry
�Higher cortical centers (DLPFC and VLPFC) are decreased in activation in response to emotional st imuli with excessive reactivity of the subcortical areas
�Negative emotions may Impact the brain function mor e than positive emotions
Pavuluri et al., Biol Psych, 2006
Facial Stimuli: Positive
Facial Stimuli: Neutral
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Facial Stimuli: Negative
PBD vs. HC: Amygdala Hyperactivationto Angry Faces
Pavuluri et al., BiolPsych, 2006
Emotion Processing Circuits: Face Responsive Circuit + Affective Circuit
BG
Th
ACC
PFC
Amyg Amyg
V1/V2
STSSTS
AFFECTIVE CIRCUITFACE RESPONSIVE VISUAL PROCESSING CIRCUIT
ANTERIOR CINGULATE CIRCUIT
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Amygdala Activation with Neutral Faces While Judging Hostility
Rich et al., 2006
Clinical Interpretation
�Face responsive visual circuit may not be processing emotions accurately
�Limbic and Paralimbic areas are increased in activation with affective stimuli
�Higher cortical centers showed decreased activation in response to affective stimuli
�Negative emotions showed greater activation of amygdala than the positive emotions
Cognitive Circuitry Function
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-2
-1.5
-1
-0.5
0
0.5
Exec F
unctio
n
Attention
Verbal Mem
Visual M
em
Visuo-Sp
ac Percep
Motor sk
ills
Workin
g Mem
HealthyControl
UnmedicatedPBD
MedicatedPBD
Performance in Six Neurocognitive Domains
Pavuluri et al., AMJ, 2006
-2
-1.5
-1
-0.5
0
0.5
Exec F
unctio
n
Attention
Verbal Mem
Visual M
em
Visuo-Sp
ac Percep
Motor sk
ills
Workin
g Mem
HealthyControl
PBD Only
Comb.PBD+ADHD
Performance in Six Neurocognitive Domains
Pavuluri et al., AMJ, 2006
Directly Relevant to SchoolFunction
The devil lies in the details.
Mathematics Disorder ADHD
Reading and WritingDisorders
PBD
Social Skills Deficits
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Interface Between Affective and Cognitive Circuitry
Clinical Interpretation
�PBD are sensitive to negative stimuli and react excessively in the Fronto-limbic circuitry compared to the HC
�Emotional and cognitive processing areas are more activated in tandem in HC relative to patients with PBD
Clinical Implications
�Adolescents with BD may not focus, plan or problem solve effectively when exposed to affectively ladden stimuli
�In contrast, normal individuals can experience affect AND think effectively when exposed to excessive emotional stimuli
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Clinical Interpretation
�Emotional expressions, especially the negative facial emotions at school or home are likely to impact affective and cognitive circuitry function
�Emotions in the environment are critical to Brain Function in this vulnerable population
DTI Fiber Tracts Affected in PBD
Yang et al., RSNA 2007
Translational From Animal Models to Improved Brain and Behavior Function in Real Life
Neuronal
Physiology
Human
Neurophysiology
Clinical
Neurocognition
Role
Function
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Pharmacotherapy: How do you plan?
�Pediatric Efficacy Trials
�Algorithm Study
�Pharmacological fMRI Studies
�Pharmacological Neurocognitive Studies
�Adult Efficacy Studies
Developing the language
Symptom
List
FIND
Invisible
Fist
Signature
Brain
Disorder
Principles• Prescription hygiene
• Mood stabilization
• Problem Solving: • Addressing break through symptoms (depression, psychosis, persistent
aggression)
• Treatment resistance
• Sleep difficulties
• Co-morbid conditions: ADHD, Anxiety disorder
• Adverse events
• MDPAAS
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Algorithm Part I: Mood Stabilization
*Any history of a drug that had negative or no effe ct was not prescribed
Medication* First Choice Sequence ofChoices
Mood stabilizer Lithium
Li/DVPX, CBZ
Lamotrigine
Oxcarbazepine
Topiramate
SecondGenerationAntipsychotic
Risperidone
Aripiprazole
Quetiapine
Ziprasidone
Olanzapine
Algorithm Part II: Problem SolvingBreak-through Symptoms
• Depression
Lamotrigine or Lithium
Lamotrigine + Lithium
Escitalopram small dose
• Psychosis
• SGA as monotherapy
• Add SGA if partial response to other mood stabilizer
• Choose in an order of choice or based on tolerability
Algorithm Part II: Break-through Symptoms
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Algorithm Part II: Break-through Symptoms
• Aggression and hyper-arousal
Maximize Mood stabilizer dose
Add SGA
Treat like treatment resistant case
Add guanfacine
Propranolol
Algorithm Part II: Treatment Resistance
•
• Alternative agent/s
•
• Combination therapy
•
• Triple therapy
•
• Clozapine???
Algorithm Part II:Sleep Difficulties
•
• Melatonin
• Tiagabine
• Trazodone - lowered in the list
• Quetiapine - consider it as mood stabilizer
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Algorithm Part II: Comorbid ADHD
• Concerta OR Focalin XR
•
• Adderall XR - lowered on the list
• Methylphenidate - other LA preps
• Dexamphetamine - LA preps
•
• Atomoxetine
Algorithm Part II: Comorbid Anxiety
• CBT
•
• SSRIs - very small doses; added
•
• Benzodiazepines
•
• Propranolol - for performance anxiety
Algorithm Part II: Adverse Events
• Weight gain: ziprasidone, aripiprazole, lamotrigine, avoid olanzapine
• EPS: Benztropine, change to quetiapine (and other SGA trials)
• GI symptoms: long acting or PM doses, or alternatives
• Sedation: PM doses or alternatives
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Algorithm Part II: Adverse Events
• Lithium related hypothyroidism: supplement thyroid preparations
• Prolactin rise with risperidone: reduce the dose or replace
• Rash with lamotrigine: don’t rechallenge
Treatment of Bipolar Disorder in Children and
Adolescents: Lithium and Anticonvulsant Dosing
•4-12 µg/mL plasma level•100 mg wkly as tolerated•100-200 mg•CBZ
•150-400 mg/d•↑↑↑↑ by 12.5 mg per week for 2 weeks and then by 25 mg weekly
•12.5 mg*
•(in child)
•LTG
•50-125 µg/mL plasma level•(↑↑↑↑ by 5-10 mg/kg/d weekly)•15 mg/kg in adolescents; 10 mg/kg/d
in children
•DVPX
•300-1200 mg/d; 0.6-1.2 mEq/L plasma level)
•150 mg BID (↑↑↑↑ by 150 mg q 3 days as clinically
indicated)
•300-1200 mg/day•Li
•Max. Rec. Dose (Blood Level)
•Starting Dose (Titration)
•Child dose/day‡•Drug
Pavuluri and Janicak, 2004
*Double dose with CBZ, halve dose with DVPX; Re-titration necessary if interruption ≥5 days
•1500 mg/d•↑↑↑↑ by 150-300 mg every 3 days or as tolerated
•600-1200 mg/day•TRP
Treatment of Bipolar Disorder in Children and
Adolescents: Lithium and Anticonvulsant Safety
•Stevens-Johnson syndrome, toxic epidermal necrolysis
•GI, ataxia, constipation, serious AEs include serious rash•LTG
•Aplastic anemia, agranulocytosis, hepatotoxicity,
drug-drug interactions
•GI, dizziness, sedation rash•CBZ
•Hepatic failure, pancreatitis, thrombocytopenia, behavioral deterioration
•GI, sedation, weight gain•DVPX
•Neurotoxicity, hypothyroidism, renal function, cardiac conduction abnormalities, leukocytosis
•Nausea, vomiting, diarrhea, headache, polyuria, polydypsia, weight gain, tremor, fatigue, acne; youths tend to have more frequent side effects
•Li •Warnings•Tolerability/ Safety•Drug
Pavuluri and Janicak, 2004
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Treatment of Bipolar Disorder in Children and Adolescents: Antipsychotic Dosing
•500 mg•25-50 mg/d•50-400 mg•QTP
•20 mg•2.5-5 mg/d•5-15 mg•ABF
•4 mg•0.25-0.5 mg/d•0.25 mg (0.25 mg)
•RIS
•Max. Rec. Dose (Blood Level)
•Starting Dose (Titration q 3d)
•Child dose/day‡•Drug
•120 mg•20 mg/d•20-80 mg•ZIP
•20 mg/d•2.5-5 mg•2.5 mg•OLZ
Pavuluri and Janicak, 2004
Treatment of Bipolar Disorder in Children and Adolescents: Antipsychotic Safety
•None•Nausea, vomiting, EPS•ABF
•Hyperprolactinemia, orthostatic hypotension, EPS
•Sedation, EPS•RIS
•Black box warning for suicide
•Orthostatic hypotension, sedation, weight gain
•QTP
•Warnings•Tolerability/ Safety•Drug
•None•Weight gain, sedation•OLZ
•QTc interval prolongation•EPS•ZIP
Pavuluri and Janicak, 2004
Pediatric Bipolar Summary
�Follow the principles�Translate the science to service�Keep updating the Medication Algorithm�Match the patient symptoms (primary, secondary,
comorbid) and response (efficacy for central symptoms, tolerability and safety)
�It is a sculpture�First 4-6 months are hard: not so hard after that!
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• Validating the parents
• Taking a family approach
• Endurance
• Maintaining the center of gravity
• Everything in moderation
• There is hope
Art of TreatmentCombining with collective wisdom and clinical
expertise
Through home, school, peers, health system, reading material,
resources and measures
Book published
www.psych.uic/pmdc
• What you see is what you get
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www.cabf.org
Acknowledgements/Collaborators
Pediatric TRACT LaboratoryJohn Sweeney, PhDAlessandra Passarotti, PhDMegan O’Connor, PhDErin Harral, BAStephanie Parnes BAAnne Palmer MAMelissa Moss, BAAnne Palmer, BAEllen Herbener, PhDKush Kapur (PhD)Kiran Kamineni, MS
MRI MethodologyJoe Zhou, PhDDulal Bhaumik, PhDKeith Thulborn, MD, PhDDeb Little, PhD
Clinical T Mohammed, MDJulie Carbray, PhDAmy West, PhDJodi Heidenreich, MLSW
Genomics and NeurochemistryGhanShyam Pandey PhDYogesh Dwivedi PhDJeff Bishop Pharm D
Thanks for the Support�NIH-NCRR�NIMH�DANA Foundation�NARSAD Foundation�AFSP�Marshall Reynolds Foundation�NICHD-NIMH�Blue Harbor Foundation�NIH MO1-RR-13987
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