Pediatric Psychopharmacology

July 25th 2012Pallav Pareek M.D. (Initial writings & contributions from the

various chief fellows over the years)

Pharmacokinetics: children are not little adults !!

• Pharmacokinetics: constitutes absorption, distribution, metabolism, and excretion

• Gastric absorption– Stomach contents are less acidic, so weakly acidic drugs

may be absorbed less efficiently

• Distribution– Most neuroleptics and antidepressants are lipophilic (less

body fat)

• Antipsychotics, TCA’s and Lithum eliminated more rapidly

• Metabolism– Increased hepatic metabolic capacity and more efficient

renal clearance

Before Starting Medications

• Physical exam: height, weight, vitals and abbreviated neurological exam

• Labs may be required:– CBC, CMP, UA/UDS, TSH– Urine HCG in females of reproductive age – Fasting lipids and glucose –May consider lead level, karyotype and/or specific

chromosomal analysis if MR is suspected

Treatment of ADHD : Atomoxetine

• Brand name Strattera ®• Available as 10,18,25,40,60

mg caps• FDA approved for ADHD in

children• Is a Sert, Ne, da reuptake

inhibitor• CYP2D6 substrate• Half life: 5 hours

Strattera ® Fun facts

• Eli Lilly first postulated this as a depression rx

• Failed clinical trial (trade secret): retried and submitted to FDA for ADHD

• Time to response : 1 » 6 weeks

• Use in patients with depressive symptoms

• Initial name tomoxetine , changed to atomoxetine as per FDA recommendations

Strattera word of caution

• Liver damamge• FDA warning for monitoring mood change• Can increase BP/HR on initiation, caution in known

heart disease• Induction of mania, suicidal thoughts/behaviors• Can precipitate seizures in combination with tramadol• Increased levels when co-administered with

paroxetine and fluoxetine (CYP2D6) • MAOIs contraindicated

α-2 adrenergic agonists

• First developed an antihypertensive agents

• Fisrt used in child psychiatry 70’s for tics, TS

• Dramatic increase last two decades• MOA » Initially thought to be

through presynaptic α2A receptors in LC firing and NE release. Now proposed postsynaptic action on PFC α2A receptors.

α2-adrenergic agonists contd:

• Clonidine:• Available as

0.1,0.2,0.3mg tabs and eqv dose patch system (1 week)

• Starting dose 3-5 μg/kg/day

• ↑ by 0.05 per 3 days• Max dose : 0.4

• Guanfacine:• Only available orally as

1,2,3,4 mg tabs• Roughly ten times less

potent• Start at 0.5 mgbid ↑ to

t/qid• ↑ 0.5mg/3d• Max: no studies for

dosages above 4mg/d

Adverse Effects

• Clonidine: Dry mouth, drowsiness, sedation, weakness, fatigue, hypotension, bradycardia

• GXR has similar but less pronounced s/e profile• Patch: dermatitis (hydrocortisone)• CV complicationsScenario 1: low BP, low pulse » ↓ ClonidineScenario 2: tachycardia, tachypnea, fever(+/-)

anxiety panic, acute mental status changes, reinstate dose and gradually taper

Stimulants

• MTA: Multimodal treatment study of children with ADHD

• 14 month study: 579 children• Pharmacological(P) vs.

behavioral(B) vs. combined(P+B) vs. controls

• P much superior than B, not much differnce P+B

Stimulants

• Two families of stimulants MPH preperations and Amphetamine preperations

• 1st use in children for ADHD as early as 1930’s• Well established role 1970’s• Global use of stimulants have ↑ 3 fold 1993-

2003 (Scheffler et. al 2007)• 80% of worldwide stimulant use is in US• 2003: 2.5 million children 4-17 in the US

receiving stimulants (CDC)

Stimulants contd:

• Methylphenidate and Amphetamine preparations are the two main families of stimulants

• MOA: not known, but proposed enhancement of NE and DA transmission

• Both MPH and AMPH are racemic mixtures of D or L enantiomers

• Only D enantiomer: D-MPH i.e. Focalin D-AMPH i.e. Dexedrine

• D&L enantiomer mixture: Ritalin or Adderall

Methylphenidate preparations

Amphetamine preparations

Should I order an EKG before starting

a stimulant

AACAP & APA verdict1

• American Academy of Child and Adolescent Psychiatry (AACAP) and the American Academy of Pediatrics (AAP) have concluded that sudden cardiac death (SCD) in persons taking medications for ADHD is a very rare event, occurring at rates no higher than in the general population of children and adolescents. Both of these groups also note the lack of any evidence that the routine use of ECG screening before beginning medication for ADHD treatment would prevent sudden death.

1: Cardiovascular Monitoring and Stimulant Drugs for Attention-Deficit/Hyperactivity Disorder (AAP May2008)

Stimulants: Adverse Effects

• Appetite suppression, growth delay– Reduction in growth velocity that reverses when stimulant is discontinued,

no effect on ultimate height

• Insomnia – Decreased sleep efficiency and REM sleep – Increase in stage 1 and 2 sleep

• Blood pressure and heart rate changes– Risk of sudden death

• End-of-dose withdrawal/rebound• Stimulant side effects generally worse in younger

populations, e.g. preschoolers

When should stimulants be avoided ?

• Cardiomyopathy• Serious structural or rhythm abnormalities• Add behavioral rx in kids with anxiety• Package inserts: contraindicate in seizure

disorder (no evidence base for this warning)• Uncontrolled epilepsy

Antidepressants

MAO Inhibitors• Last youth trials

have been more than a decade and a half ago

• Currently minimal enthusiasm amongst clinicians and researchers due to plethora of available options

• Cheese reaction →

Tricyclics

• FDA approval – Depression and Anxiety in ages 12 and up (Doxepin)– Also used to treat enuresis 6 (Imipramine)and OCD 10(Clomipramine)

• Considered “third-line” for ADHD• Used to treat chronic pain/headaches• Sudden death in 8 children—thought to be

cardiac related– Check baseline ECG

TCA’s continued

SSRI’s

• FDA approval for MDD, OCD– Fluoxetine approved for use in MDD in 8+– Escitalopram approved for use in MDD ages 12-17– Sertraline, Fluvoxamine approved for use in OCD– Preferred treatment for MDD in

children/adolescents• Less SE’s• Overdose less problematic• Once daily dosing in most

– Black-box warning

SSRI’s and Suicidality

• 2003: Great Britain’s department of health issued statement :Paxil in 18 yr and younger

• 2004: FDA: All SSRI’s Black-box warning 18 &↓ based on analysis of data indicating 4% ↑ suicidal thoughts on SSRI’s as compared to 2% PBO (Hammad et. al. 2006)

• TADS: Fluoxetine (F) vs. CBT(C) vs. Combination (Cb) vs. Controls (Pbo): 12 week trail » F-9.2%, C-4.5%, Cb-4.7%, Pbo-2.7%

Things to remember re: SSRI’s

• Suicidality: always discuss with parents and explain• Switch to Mania: discuss R/B analysis• Serotonin Syndrome: rigidity, myoclonus, hyper-

reflexia, autonomic instability, hyperthermia, agitation, delirium

• Discontinuation syndrome• Drug interactions: Pimozide & Atomoxetine (paxil

and prozac 2D6) ↑levels, Tramadol ↓ seizure threshold

Mood Stabilizers

Lithium

• Gold Standard• 1st used 40 yrs ago in children• Lithium carbonate is a naturally occuring salt.• FDA approved: mania 12 & older• MOA: Multiple complex mechanisms mostly

at second messenger level• Half life in children: ~18 hours• Recommended dose: 30 mg/kg/d• Levels: 0.8-1.2 meq/L

Recommended testing

• Baseline: BUN/creatinine, electrolytes, serum Calcium, TFT, CBC

• Repeat RFT: every 3 months till 6 mo• Repeat TFT: once in first 6 months• Repeat all labs, as needed/symptomatic,

repeat serum calcium/year.• Lithium levels: trough value without morning

dose, can do as early as 5th day.

Trivia !!

• Historically which soft-drink contained lithium as one of it’s ingredients

Valproic Acid• FDA approved

– Acute mania (up to 3 weeks) in patients over the age of 18– Migraine prophylaxis in patients over 16

• Dosing: Start at 15mg/kg/day• Testing: CBC, platelet, LFT at baseline, repeat every 6 mo• Cautions

– Severe or fatal hepatotoxicity, esp. for children under age 2– Teratogenic (neural tube defects)– PCOS, elevated serum testosterone in females under age 20 – Co-administration with clonazepam may induce absence seizures– Co-administration with guanfacine may increase VPA levels– Co-administration with lamotrigine may increase lamotrigine levels (PRITE)

Carbamazepine• FDA approved

– Any age for seizures– Tegretol XR approved for bipolar mania in adults

• Cautions– Follow CBC, LFTs, carbamazepine level– Bone marrow suppression– Sedating– Can be teratogenic (neural tube defects)– Strong potential for drug interactions

• Dosing– Children greater than 8 years: 15mg/kg/day divided TID with target

dose achieving level of 7-10 mcg/ml– Adolescents: 200 mg BID to start with treatment doses ranging from

600-1600 mg/daily divided BID and target level of 8-12 mcg/ml

Lamotrigine• FDA approved for

– Adjunct use for epilepsy in children > age 2– Bipolar in adults but not kids

• Cautions– Serious skin reactions in 1% of patients <16 are most likely to happen

within the first 8 weeks. • Fever, swollen LN’s, sores of mouth, eyes, lips or tongue all may

require D/C of med. • Dosing

– 25 mg/day x 2 weeks; double for 2 weeks; increase by 50 mg/day every 1-2 weeks

– Typical target for Bipolar Disorder 100-200 mg/day

Crux of the Story !!

• Other options include: oxcarbazepine, topiramate, gabapentin, pregabalin

• All research to date indicates: Evidence is strongest for lithium, somewhat strong for valproate, and weaker for others

• Lithium and VPA are also neuro-protective with more evidence for Lithium, also reduces suicidality (Chuang t. al. 2004)

Antipsychotics

• Typicals: Around longer; more experience in kids. – FDA approved for use in children– Studied in ADHD, MR, ASDs and movement

disorders– Concern for more extrapyramidal side effects and

tardive dyskinesia

Second generation Antipsychotics

FDA approvedPsychosis, mood stabilization in patients over 18

yrsPrimary Psychosis in kids is RARE

1-2/10,000 in ages <15 yrs; boys outnumber girls by approximately 2:1.

Childhood schizophrenia appears to be genetically related to the adult type of schizophrenia.

Used to treat aggression, irritability in multiple diagnosesHave been studied in MR, autistic populations, Bipolar Disorder

SGA’s

Desmopressin DDAVP• FDA approved

– Primary nocturnal eneuresis (ages 5-17)– Central DI

• Enuresis– 80% of cases are “primary”– Untreated, remission rate is 10-20% per year– Associated with ADHD, comorbid developmental delays and

encopresis– To dx: must be at least age 5, 2x/week for 3 consecutive months

• Dosing– 20 micrograms or 0.2 ml nasal spray divided between nostrils at HS,

can decrease to 0.1 ml if effective – 0.2 mg tab at HS– Max 0.6 mg at HS

Insomnia treatment• Benzos / Z drugs(acting

through the GABAergic transmitter) Best avoided

• Melatonin : pineal hormone→ • Remelteon (Rozerem) MT1 &

MT2 receptor agonist: available as 8mg tab →

• Mirtazapine• Trazodone

Thank You !!