Psychotherapeutics in Psychotherapeutics in Child PsychiatryChild Psychiatry

THE BPPA - BAPA ANNUAL CONFERENCE 2011Saturday 18th November

Dr Gordon BatesHuntercombe Hospital

University of Birmingham

OverviewOverviewBasic PrinciplesRange of medicationsAntipsychoticsAntidepressantsADHD treatments:

◦Stimulants◦Atomoxetine◦Alpha agonists

Principles of Child Principles of Child PharmacokineticsPharmacokinetics

Children are not small adults

Area is less well researched

Rates of absorption in children are faster and peak levels are reached faster (esp. liquids)

Proportion of Water in Body through Proportion of Water in Body through Life Life

Volume of distribution results for the full database (22 substrates). *p < 0.1.

Ginsberg G et al. Toxicol. Sci. 2002;66:185-200

© 2002 Society of Toxicology

Clearance results for the full database (27 substrates). *p < 0.01; **p < 0.0001.

Ginsberg G et al. Toxicol. Sci. 2002;66:185-200

© 2002 Society of Toxicology

Principles of Child Pharmacokinetics II

Hepatic metabolism is almost double adult rate in middle childhood and approaches adult rates by 15 years

Fat stores in children act to slow elimination of liposoluble drugs (e.g. fluoxetine, pimozide)

Cytochrome P450 2d6 and 2c19 unaffected by age but remember racial effects

Is it bad enough?Is it pervasive?Have psychological strategies or

environmental modification been tried?Is it part of a wider treatment package?Do parents and adolescent give consent?Is it licensed/unlicenced or off indication?Is it an emergency?Risk/Benefit analysis

When to use Medication

Monotherapy is better than polypharmacy

Develop a range of familiar drugsStart low and go slowReview frequentlyConsider use of rating scalesMonitor for side effectsMonitor for drug/drug interactionsPharmacogenomics: the future?

How to use MedicationHow to use Medication

Range of TreatmentsAnxiolyticsSedatives and MelatoninAntipsychoticsAntidepressants: FluoxetineMood stabilisersADHD treatments

Mostly unlicensed for children

Prescribing to children:Prescribing to children:Licensed or unlicensed in UKLicensed or unlicensed in UK

Antipsychotic Child (<12) Adolescent (12-18)

Chlorpromazine Yes Yes

Haloperidol oral Yes Yes

Haloperidol IM No Yes

Pimozide No Yes

Trifluoperazine Yes (anxiety) Yes

Sulpiride No Yes (>14)

Zuclopenthixol IM No No

Amisulpiride No Yes(>15)

Clozapine No Yes(>16)

Olanzapine oral No No

Olanzapine IM No No

Risperidone oral No Yes(>15)

Risperidone IM No No

AAntipsychoticsHaloperidol and Chlorpromazine have licenseUnlicensed Olanzepine, Risperidone and

Aripiprazole most commonly used in UK practice

Wide range of usage: ◦ Psychosis◦ Bipolar◦ Tourette’s◦ Rapid tranquillisation◦ Mood swings in Borderline Personality Disorder◦ Irritability in ADHD and Autism

NICE recommendations

Predominantly aimed at adults and remaining within product licence:◦Atypical antipsychotics (TA 43 June

2002)◦Core Interventions in Schizophrenia

(CG 1 Dec 2002)◦Bipolar Disorder (CG38 July 2006)◦Violence & Acute behavioural

disturbance (CG25 Feb 2005)

Personal experience

Side effect profileFamily history of

responsePatient or carers

preference“local expert”

How to chooseHow to choose

Side Effects of Antipsychotics Side Effects of Antipsychotics (Bazire 2007)(Bazire 2007)

Drug AntiCh Cardiac EPSE Low BP Sedation Minor O/D

Wt gain Prolactin Proconvulsant

Aripiprazole - + - - - ? + - -Olanzapine + - - - ++ - +++ + +Quetiapine + + - + + + + + +Risperidone - - + + + ? + ++ -Zotapine ++ ++ + ++ ++ ? +++ +++ +++Clozapine +++ +++ - + +++ ? +++ - +++Amisulpiride - - + - - - + ++ ?+Chlorpromaz +++ ++ ++ +++ +++ ++ +++ +++ +++Haloperidol + ++ +++ + + + + +++ ?+

AntidepressantsDepression in childhood and adolescence

has similarities and differences to adulthood

Response to medication is differentTricyclics ineffective in Childhood

depressionSSRI controversy: suicidality and mood

lability in early treatmentCSM and NICE guidance:

◦ Psychological therapies first◦ If medication indicated only Fluoxetine first line

Father of Child Psychopharmacology

14 of 30 children showed a ”spectacular change in behavior… remarkably improved school performance”

SerendipityGiven after pneumo-

encephalographyChildren called them

their “arithmetic pills”(Am J Psych 1937)

Potential Mechanisms of ActionDopamine-Reuptake inhibition and direct release

MethylphenidateDexamphetamine

Dopamine-reuptake inhibitor

Modafanil

Noradrenaline-Agonists

L-amphetamine

Noradrenaline-reuptake inhibitor

Atomoxetine

Alpha 2 adrenergic - agonists

ClonidineGuanfacine

Stimulants

LicensedMethylphenidateDexamphetamineUnlicensedAmphetamine –

◦L-amphetamine ◦mixed salts (Adderall)

Modafanil

Features of Stimulant activity

Greatest effects on Attention and restlessness

Less useful for impulsive behavioursRapid actingShort half lifeClear dose effect relationshipWell established side effect profile

Dose Response of Methylphenidate on Attention in clinic and classroom(Rappoport et al 1987)

1520253035404550556065

placebo 5mg 10mg 15mg 20mg

% on task

% academicefficiencyADHD CompTeachers RSCPT

Efficacy of the stimulantsEfficacy of the stimulants

Responder rate (%) 75-90• Methylphenidate 75• Amphetamine 70

Normalisation rate (%) 50-60Symptom improvement (%)

•Behaviour scales 30-50

Effect size (SD)• Behaviour 0.9 high• Attention 0.7 medium• IQ/ Performance tests 0.3 low

Time of effect Comments

Methylphenidate

Equasym XL 6-8hrs School day coverMedikinet

Concerta® XL 8-12hrs Sleep and appetite

Daytrana ® 6-16hrs Transdermal

US only

Amphetamine compounds Adderall XR 6-8hrs Import only

Vyvanase 12-14hrs Prodrug, ltd abuse (lisdexamfetamine) Awaiting UK approval

Long Acting Stimulants

Stimulant

Transdermal Methylphenidate(Daytrana))

Doses: 10mg, 15mg, 20mg 30mg

Applied to hip each morning

Stays on after swimming or bathing

Irritation rareSuggested use for 9

hours but effects last 3 hours after removal

Heal and Pierce CNS drugs (2006)

Lisdexamfetamine(Vyvanase)(Vyvanase)

Metabolised in GI tract to Lysine and Dexamphetamine

Doses: 30mg, 50mg, 70mg

Little euphoric effect reducing abuse potential

Clin Ther 2007;29: 450-463

Side EffectsAnorexia, weight loss

Give with mealsUse supplementsDietary advice

Insomnia Give earlierUse shorter acting prepConsider melatonin/clonidine

Rebound Change to long acting prepAssess timing and overlap

Dysphoria Consider comorbidity and treatChange to long acting or alternative stimulant

Cardiovascular Risk

Sudden death rates in General Population:◦ 0.6-6/100,000 children per year◦ 1/1000 adults per year

Estimated sudden death rate on Stimulants:◦ 0.25/100,000 people per year based on Rx data◦ 0.5/100,000 people per year (assuming 50%

under-reporting) FDA reevaluation 24/3/2006:

◦ No additional risk in medically healthy children

Atomoxetine

Recent analyses suggest:• Children similar to adolescents for

outcome• Monitor height and weight esp in

younger children• Some response by week 2 but

continue to 6-10 weeks• Reduction in irritability precedes core

symptom improvements

Atomoxetine

NichesTreatment resistance, partial responseIntolerable side effectsImportance of all day coverPossible substance misuse or diversionComorbid anxiety disorderTic disorder

AtomoxetineSide Effects:- Somnolence, insomnia, nausea,

headache, reduced appetite, abdominal discomfort, raised BP and pulse, sexual dysfunction

Drug Interactions:- Care with some SSRIs (fluoxetine and

paroxetine)- No interaction with stimulants or

alcohol

Atomoxetine

Rare hepatitis reported- 1 confirmed case in 3.4 million prescriptions- 1 further suspected case in 3.4 million

prescriptionsImplications: Discuss rare event not routine

LFTs

Known increase in mood lability in 3%Possible slight increase in suicidal ideation- 0.037% Atomoxetine v 0% Placebo- One suicide attempt/1357 studied

Clonidine

Used for ADHD therapy and night sedationBetter for restlessness than attentionUseful but popularity waning due to side fxGood for tics and comorbid ADHD

◦ Doses 0.05 mg-0.2 mg tds◦ Evening rebound◦ Patch available but import only◦ Care with joint prescribing (ECG recommended)

Look out for sedation, hypotension, depression, constipation and dry mouth

Clonidine controversyClonidine and Methylphenidate

◦ 3 case reports of sudden death◦ FDA review decided no causal link◦ Other relevant factors in all cases

Clonidine4 case reports of cardiac arrythmias, one

with congenital malformation

Use with care if history or family history of collapse. ECG sensible for combination.

GuanfacinePossible alternative to ClonidineHalf life of 18 hours in adults1 open label study and one RCT show

efficacy:◦ Scahill et al JAACAP 2001◦ Spencer et al JAACAP 2009

Similar to clonidine but less sedating, more headaches and insomnia

? Better for attention than hyperactivity

Recent licence in US

ConclusionsConclusionsVariations in child pharmacokinetics

can lead to less predictable responsesRequirement of closer monitoring and

shared care with parentsMany adult approved drugs are given

off licence to childrenMedications have a restricted but

important part in holistic care planMedications are often given

symptomatically rather than for diagnosis