Pediatric�Psychopharmacology�

UpdateLaura Shapiro PMHNP-BC, MS, M.Ed, NCSN

Pharmacology Basics⦿  Studies with children are limited⦿  Off label use is common⦿  Almost all meds lower Sz threshold

•  *exceptions● Benzo’s● Antiepileptic's

⦿  Children metabolize differently•  Size-MG/kg•  Growth may increase CYP450 metabolism/inhibition- may

require higher dosing than adults-very individualized● Moving Targets

CYP 450 Hepatic Metabolism⦿ System of enzymes in the liver which

metabolizes compounds such as medications⦿ Many psyche meds inhibit of induce the

enzymes in this system. ⦿ This effects drugs levels in the body

•  Especially when medications compete for the same enzyme system

•  Most Common Source of drug/drug Interactions ● *OCP’s

CYP 450 med interactions⦿ http://ars.els-cdn.com/content/image/1-s2.0-S1470204510701054-gr1.jpg

SSRI�Selective Serotonin Re-Uptake Inhibitors

Ist line of treatment for tx of depression/anxiety

⦿  TAD study 2006⦿  Depression⦿  Initially combination

therapy + medication modestly favorable

⦿  On repeat virtually no difference between combination therapy and medication alone

⦿  (pt’s in combined tx more likely to dc SSRI)

Frequently prescribed SSRI⦿  Approved⦿  Fluoxetine (Prozac)

•  MDD 8years•  OCD 7 years•  Commonly used off-label

younger/anxiety⦿  More of a response

compared to placebo⦿  Long half life

•  Ideal for erratic adolescent administration

⦿  Escitalprolam (Lexapro)•  MDD over age 12•  10mg=40mg Citalopram

⦿  Sertraline (Zoloft)•  OCD 6 years

⦿  Fluvoxamine(Luvox)•  OCD 7 years

SSRI cont’d Paxotene(Paxil )

•  More withdrawal side effects

•  More sexual side effects•  Sometimes used for

premature ejaculation•  Sometimes written for

adolescents

⦿  Citalopram (Celexa)•  Well tolerated•  Cardiac effects● women

Quick and Dirty Neuro Bio SSRI

SSRI Effectiveness⦿ 40-70% of depressed patients treated have a

modest-moderate positive response.⦿ Placebo response rate 30-60%⦿ Medication with CBT reduces relapse rate.

Side Effects of SSRICOMMON RARE

⦿  Often Dose Dependent⦿  Head Aches⦿  GI⦿  Serotonin receptors in gut⦿  Activation of undiagnosed

Bipolar•  Sleep Issues•  Activation•  Sometimes used diagnostically

⦿  Serotonergic Syndrome•  Hyperthermia•  Agitation•  Confusion

⦿  Increase in bleeding time⦿  Nosebleeds/bruising

SSRI and Suicidality⦿ Black box warning⦿ Patients under 25⦿ 11 times more likely to have a + response than

to feel ++ suicidality⦿ Still legally/ethically need to explain risks ⦿ When first initiating tx or increasing dose

•  ? Reduces inhibitions/increase in motivation

Student Management on SSRI⦿  No labs routinely drawn⦿  Withdrawal Effects-agitation, somatization⦿  Meds have long half life's-take on average 4 weeks

of a therapeutic dose for any + effect⦿  Ask about medications when you hear head/GI

complaints⦿  Headache and GI upset commonly pass after 2

weeks•  Med still not titrated to effectiveness at this point

SSNI-Selective Serotonin Noreperinepherine Re-Uptake Inhibitors

⦿ Often 2nd line in adolescents/Adults⦿ Primary symptom:

•  Anhedonia-low motivation⦿ Stahl⦿ Serotonin deficiency vs. Noradrenergic

deficiency

Types of SSNI-seen in child/adolescents⦿  Venlafaxine (Effexor)

• +effect on depressed adolescents

• No efficacy on children pre-puberty

In high doses also block Dopamine uptake

Headaches/nausea reduced in extended release version

Bupropion (Wellbutrin)*NDRI

•  Inconclusive data on efficacy

•  Wt. loss•  Lowers Sz threshold•  Not given in females with

hx of eating disorder-Bulimia

TTT

⦿ Mirtazapine-MDD in adolescents off label⦿ Sometimes used in children over 10⦿ Often used as an augmenting agent when there

is a partial response to another med⦿ Sedation ⦿ Weight gain is common

•  Blocks histamine receptors

Other Antidepressant meds seen in pedi psyche

⦿  Dysarel (Trazadone)⦿  SARI

•  Blocks the transporter⦿  Used for sleep in

<100mg⦿  Priapism serious SE/

more commonly seen in adolescent males

⦿  QT prolongation

⦿  Imipramine (Tofranil)⦿  TCA

•  Blocks 5HT/Norepi reuptake.

•  Increases Dopa transmission in frontal cortex

⦿  Enuresis-6 years⦿  MDD-off label 12years

Other Antidepressants⦿ Amitriptyline (Elavil)

•  Used with caution in adolescents over 12•  Migraines•  The PCP’s TCA•  Sedating

Anxiety⦿  Commonly seen in pediatrics⦿  Trick is determining normal development from

pathology⦿  Types:

•  Separation Anxiety•  Generalized Anxiety Disorder•  Social Phobia•  PTSD•  Agoraphobia//School Phobia•  OCD•  Panic

Anxiety: The Benzo’s⦿  AACAP position⦿  “benefit in adult trials but

not in children”⦿  “clinically they are used as

an adjunct short term tx to achieve rapid reduction in severe symptoms”

⦿  May permit the exposure phase of CBT-(the gold standard)

⦿  “Should be used cautiously”⦿  Contraindicated in

adolescents with substance abuse

The Benzo’s⦿  Alprazolam/Xanex⦿  $$$$$$

•  Rapid onset•  Short half life•  QID

⦿  Clonazepam/Klonopin•  Longer half life•  BID-TID

⦿  Lorazepam/Ativan•  Sedation•  May be used for sleep•  PTSD

⦿ The research:⦿ Simon (1992)

•  Avoidant disorder•  Perseveration•  Alprazolam=PLC

⦿ Graae (1994)•  Clonazepam (.5mg-2mg)•  Separation Anxiety•  Clonazepam=PLC

Bernstein (1990)•  School Refusal•  Alprazolam (.75-4mg) = PLC

Anxiety: Buspirone⦿  Buspirone/Buspar⦿  Enhance serotonin activity

and contribute to antidepressant actions

⦿  Pregnancy B/animal studies⦿  Main Side Effect

•  Dizziness•  Activation

⦿  Off label in kids⦿  Commonly prescribed due

to safety profile⦿  2-4weeks for therapeutic

effect.⦿  Competes with CYP450

3A4 •  When used with some

SSRI*Luvox* may require lower dose

•  Induced by Tegretol, dose may need to be raised

PTSD: Special Situations⦿  Catapress/Clonodine⦿  Used in children over 6⦿  Off label⦿  Sedating⦿  Monitor BP

•  Rebound HTN with rapid d/c

⦿ Aids in Sleep⦿ Decreases activationAlso used as adjunct with

mood stabilizers.

OCD⦿  Approved⦿  Fluvoxamine/Luvox

•  Ages 8-17•  Above 50mg divide dosing•  Steady State

⦿  Sertraline/Zoloft•  Age 6-12 initial 25mg/day•  >12 adult dosing

⦿  Clomipramine/Anafranil•  For children over 10•  Sudden death has occurred

in kids•  Careful dose titration•  3mg/kg/day

Antipsychotics⦿ 1st generation

•  Haloperidol/Haldol● Approved>age 3● Tourette's, agitation, psychosis● EPS-● Anticholinergic,●  Akithisia●  TD

⦿ Second line after atypical

Atypical Antipsychotics(AAAs)⦿  2nd Generation⦿  Less uncomfortable SE

than 1st generation

⦿  Commonly prescribed for psychosis in adults

⦿  More commonly prescribed for aggression in children than psychosis

Most Common AAA’s⦿ Clozapine/Clozaril⦿ Risperidone/Risperdal⦿ Olanzapine/Zyprexa⦿ Quetiapine/Seroquel⦿ Ziprasidone/Geodon⦿ Aripiprazole/Abilify⦿ Paliperidone/Invega⦿ Asenapine/SAPHRIS

FDA Approvals⦿  Adolescent Schizophrenia (ages 13-17)⦿  Youth Bipolar I mixed/manic state ⦿  (ages 10-17)

RisperidoneOlanzapineQuetiapineAripiprazole

⦿  Autistic Disorders (irritability)• Resperidone (5-16 years)• Aripiprazole (6-17 years)

AAA General Info⦿  Work by blocking the D2 receptors in the

postsynaptic neuron

⦿  Individual drugs vary by the way the bind to block the receptor

⦿  Prescribing steadily increasing with the pediatric population

⦿  Prescribed more frequently to males, to those in foster care, and those on Medicare•  Rogers Procedure

Rogers Procedure⦿  Child in DCF custody with existing or new antipsychotic prescription

⦿  Court appoints Rogers GAL and schedules Rogers hearing

⦿  GAL conducts an investigation, meets with child, psychiatrist and other stake holders.

⦿  GAL submits report to the court

⦿  MD writes affidavit regarding the tx, submits to court

⦿  Court reviews these reports and affidavit and hears statements or objections from child or parents.

⦿  Judge will approve or deny prescription

⦿  Judge will again review Rogers order at a later predetermined time.

Clozapine/Clozaril 1989 ⦿  “800 pound gorilla”⦿  Severe agranulocytosis⦿  National registry⦿  Pharmacy parameters

⦿  2 Board Certified Psychiatrists sign off for initial prescription

⦿  Off label use in youth with tx refractory schizophrenia •  have experienced severe EPS with other

agents

• Research● Greater efficacy than Haldol

for both positive and negative symptoms of schizophrenia

Risperidone/Risperdal⦿  Most studied

•  Youth with “disruptive behavior”•  Co-Morbid ADHD/sub average IQ•  Risperdal > PLC•  Some research states may worsen OCD symptoms-not

replicated yet•  Long Action Consta injections•  Studied in children for long term safety for several different

dx● Aggression/Autism● Increases prolactin● Mod wt gain● Mod EPS Akithsia

Olanzapine/Zyprexa⦿ Well studied⦿ Has shown some efficacy with youth bipolar 1⦿ Weight gainàLipids, Diabetes

•  Risk benefit ratio⦿  Injected forms not studied in children⦿ Pedi-need close monitoring⦿ Symbax not yet approved in pedi

•  Olanzapine/Fluoxetine combo-Bipolar

Quetiapine/Seroquel⦿ Research:⦿ Approved for:⦿ Schizophrenia ages 13-17 years⦿ Bipolar ages 10-17⦿ Many off label uses

•  When combined with Depakote improved adolescent mania greater than PLC•  Sedating/Mod wt gain•  Potential Benefit:●  Aggression●  Conduct disorder●  Tic Disorders●  (AACAP, 2010)

Ziprasidone/Geodon⦿ Off label⦿ The Research:⦿ Low dose may be effective in ages 7-17 with

tic disorder⦿ Low to modest efficacy in youth with bipolar 1⦿ Low weight gain/metabolic effects⦿ Higher incidence of QT prolongation

Aripiprazole/Abilify⦿ Uses:

•  Mania•  Aggression•  PDD/Autism•  Adolescent Schizophrenia•  In smaller doses used as an adjunct with SSRI for tx

resistant depression•  Can be activation/take in morning.•  Higher Akathisia● Oral disintegrating tablet, liquid, IM available

Newer MedsInvega (Paliperidone)-Active metabolite of Resperidone

Approved for 12 and older, initially thought to have less side effects but case reports have rapidly increased.

Fanapt (Illoperidone)-Latuda (Lurasidone)Adults with schizophrenia

Saphris (Asenapine)- Approved for bipolar in ages 10-17 & adults and schizophrenia in adults. Requires sublingual delivery.Bad tasting. Avoid food or drink 10 minutes after taking. Any meal with in 4 hours reduces bioavailability by 20%. Drug Interactions inhibits CYP2D6, causing increase in serum levels of drugs metabolized by this enzyme-SSRI’s like Paxil.

Metabolic Syndrome⦿ Weight Changes

•  Greater in young people than adults⦿ Diabetes

•  Black box warning⦿ Hyperlipidemia

•  Alteration is triglycerides correlates with weight gain

ADA Screening guidelines for patients on AAA

⦿  Personal & Family History•  Baseline and annually

⦿  Weight•  Baseline, 4 weeks, 8 weeks, 12 weeks

⦿  Waist Circumference•  Baseline, annually

⦿  Blood Pressure•  Baseline 12 weeks, annually

⦿  Fasting Blood Glucose•  Baseline, 12 weeks annually

⦿  Fasting Lipids (HDL,LDL,TG, Total Cholesterol)•  Baseline, 12 weeks

Cardiovascular SE⦿ The research:

•  Cardiac side effects more common in youth than adults per case report.

•  Ziprasidone● Baseline EKG?● QT interval prolongation● Torsade's de pointes

•  Orthostatic hypotension● Clozapine

•  Tachycardia

Agranulocytosis Neutropenia⦿ Clozapine

•  Risperidone•  Olanzapine•  Quetiapine

⦿ Risk greater in children⦿ Potentially Fatal

Hepatic Dysfunction⦿  In youth related to rapid weight gain

•  Steatohepatitis•  Rare

Prolactin⦿ Dopamine inhibits prolactin⦿  Inhibiting Dopamine disinhibits prolactin⦿ Risperidone

•  Amenorrhea•  Galactorrhea•  Gynecomastia

Neuroleptic Malignant Syndrome (NMS)

⦿ Very rare⦿ Very serious⦿ Autonomic instability

•  Elevated temp•  Rigidity•  Elevated CPK

⦿ Reported in all AAA’s

Other Rare SE⦿ Seizures

•  Clozapine⦿ Movement Disorders

•  EPS•  Withdrawal Dyskinesia's•  TD•  Low but occurs more often in youth

School Nurse Implications⦿ Assessment⦿ Ask the question!

Mood Stabilizers⦿ Lithium

•  Approved in kids > 12 years for Mania/ Mood swings⦿ Anti-epileptics

•  Thought to decrease glutamate and increase GABA● Lamotrigine/Lamictal● 2012 adolescent maintenance Bipolar 1● Valproic Acid/Depakote● Carbamazepine/Tegretol● Oxcarbazepine/Trileptal

Pediatric Bipolar⦿ Diagnostic Controversy

• Irritability• NOS diagnosisBiological PredispositionPolypharmacy very common

Lithium⦿  Approval based on adult lit.⦿  Thought to alter

neurotransmission via NA transport

⦿  Requires labs at least every 12 weeks•  Lith level•  Renal function•  TSH/T4•  Lytes- CA

⦿  Pregnancy test⦿  Narrow therapeutic window (.

6-1.2)

⦿  Weight gain⦿  Tremor⦿  Dehydration⦿  Polyuria⦿  Thirst

•  Heat•  sports

Lithium Toxicity⦿ Tremor⦿ Ataxia⦿ Diarrhea⦿ Vomiting

Lithium⦿ Changing the preparation can address GI SE.⦿ Rapid discontinuation associated with increase

suicide risk⦿ NSAIDS increase plasma Lithium levels⦿ Youth are more likely to experience SE than

adults•  Sports•  Hydration

Lamotrigine/Lamictal⦿  Anti-seizure⦿  Maintenance tx of BP1-bipolor depression⦿  100-200mg/day⦿  Brittle initiation/taper

•  Skin rash ? Higher incidence in kids•  If stopped for more than 5 days re-titrate•  DC first sign of rash

⦿  5 weeks to dose starting at 25mg day•  Problem with erratic administration•  Dose by half if using with VPA

⦿  No labs

Stevens Johnson⦿  Life threatening

necrotizing rash

⦿  More likely to occur if previous rash developed

⦿  Can result in amputation and death

Valproic Acid (VPA)⦿  Anti-Seizure⦿  Acute Mania⦿  Requires Labs⦿  Baseline

•  LFT•  Platelets

⦿  Levels

⦿  Not recommended in children under 10•  PCOS● Infertility

⦿  Increase efficacy when used with Seroquel for mania•  Weight gain

Carbamazepine/Tegretol⦿  Anti-seizure⦿  Acute mania- 13 years

older⦿  Requires Labs

•  LFT•  Renal•  TSH/T3/4•  Levels

⦿  Auto inducer/genetic predisposition

⦿  Inexpensive⦿  GI upset⦿  Bone marrow effects

•  Minimized by conservative dosing

Oxcarbazepine/Trileptal⦿ Very similar to previous med but better

tolerated.⦿ Second and third line⦿ Off label in kids⦿ Strong inducer of other meds, careful of drug

drug interactions.⦿ Consider monitoring NA levels q 12 weeks

Toprimate/Topamax⦿  Anti-epileptic⦿  Migraines⦿  Off Label- Bipolar⦿  Binge eating

⦿  Sometimes used 2-3rd line with adolescents over 13

⦿  SE •  GI upset•  Metabolic acidosis•  Kidney stones

ADHD⦿  Just a quick mention⦿  Focalin⦿  Tenex-Long Acting

Case Study 1⦿  J is a 14 year old 8th . He had an initial dx of ODD

at age 8. Parents sought treatment last year due to his “lack of energy”. He was given a dx of MDD, treated with CBT for 9 months with minimal positive effect. •  Prescribed 10mg of Celexa, after 3 weeks the dose was

increased to 20mg.•  Two days after dose increase became increasingly irritable

and had angry outbursts when re-directed.

What may be going on⦿ True diagnosis.

⦿ Medication Issue?

⦿ Potential School Implications.

Continuation⦿ On day 6 he begins cutting his arm with a fork,

later that evening his mother found him trying to tie a shoelace around his neck. When asked why or if he was suicidal he states “I wanted to see what would happen?”.

Ideas??⦿ What are some options regarding diagnosis and

next level of care?

References⦿ www.aacap.org⦿ Practice parameters⦿ Stahl (2012) The Prescriber’s Guide; Stahl’s

Essential Psychopharmacology