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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

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0.5

Exec F

unctio

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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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