1. Dr Gordon Bates Huntercombe Hospital University of Birmingham
Psychotherapeutics in Child Psychiatry THE BPPA - BAPA ANNUAL CONFERENCE 2011 Saturday 18th November
Dr Gordon Bates
Huntercombe Hospital
University of Birmingham

2. Overview Basic Principles Range of medications Antipsychotics
Antidepressants
ADHD treatments:
Stimulants
Atomoxetine
Alpha agonists

3. Principles of Child Pharmacokinetics
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)

4. Proportion of Water in Body through Life

5. Volume of distribution results for the full database (22 substrates)
Volume of distribution results for the full database (22 substrates). *p < 0.1.
Volume of distribution results for the full database (22 substrates). *p < 0.1.
Ginsberg G et al. Toxicol. Sci. 2002;66:
© 2002 Society of Toxicology

6. Clearance results for the full database (27 substrates). p < 0. 01;
Clearance results for the full database (27 substrates). *p < 0.01; **p <
Clearance results for the full database (27 substrates). *p < 0.01; **p <
Ginsberg G et al. Toxicol. Sci. 2002;66:
© 2002 Society of Toxicology

7. 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

8. When to use Medication 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

9. How to use Medication Monotherapy is better than polypharmacy
Develop a range of familiar drugs
Start low and go slow
Review frequently
Consider use of rating scales
Monitor for side effects
Monitor for drug/drug interactions
Pharmacogenomics: the future?

10. Range of Treatments Anxiolytics Sedatives and Melatonin Antipsychotics
Antidepressants: Fluoxetine
Mood stabilisers
ADHD treatments
Mostly unlicensed for children

11. Prescribing to children: Licensed or unlicensed in UK
Antipsychotic
Child (<12)
Adolescent (12-18)
Chlorpromazine
Yes
Haloperidol oral
Haloperidol IM No
Pimozide
Trifluoperazine
Yes (anxiety)
Sulpiride
Yes (>14)
Zuclopenthixol IM
Amisulpiride
Yes(>15)
Clozapine
Yes(>16)
Olanzapine oral
Olanzapine IM
Risperidone oral
Risperidone IM

12. Antipsychotics Haloperidol and Chlorpromazine have license
Unlicensed 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

13. 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)

14. How to choose Personal experience Side effect profile
Family history of response
Patient or carers preference
“local expert”

15. Side Effects of Antipsychotics (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

16. Antidepressants
Depression in childhood and adolescence has similarities and differences to adulthood
Response to medication is different
Tricyclics ineffective in Childhood depression
SSRI controversy: suicidality and mood lability in early treatment
CSM and NICE guidance:
Psychological therapies first
If medication indicated only Fluoxetine first line

17. Father of Child Psychopharmacology
14 of 30 children showed a ”spectacular change in behavior… remarkably improved school performance”
Serendipity
Given after pneumo- encephalography
Children called them their “arithmetic pills”
(Am J Psych 1937)

18. Potential Mechanisms of Action
Dopamine-
Reuptake inhibition and direct release
Methylphenidate
Dexamphetamine
Dopamine-reuptake inhibitor
Modafanil
Noradrenaline-Agonists
L-amphetamine
Noradrenaline-reuptake inhibitor
Atomoxetine
Alpha 2 adrenergic - agonists
Clonidine
Guanfacine

19. Stimulants Licensed Methylphenidate Dexamphetamine Unlicensed
L-amphetamine
mixed salts (Adderall)
Modafanil

20. Features of Stimulant activity
Greatest effects on Attention and restlessness
Less useful for impulsive behaviours
Rapid acting
Short half life
Clear dose effect relationship
Well established side effect profile

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

22. Efficacy of the stimulants
Educational intent:
to illustrate the efficacy of stimulant treatment according to various parameters
SPEAKERS’ NOTES
So far, stimulants are the gold standard pharmaceutical treatment for ADHD. However, pharmaceutical management should not be expected to solve all the problems associated with ADHD symptoms.
Responder rate (%) 75-90
Methylphenidate 75
Amphetamine 70
Normalisation rate (%) 50-60
Symptom improvement (%)
Behaviour scales 30-50
Effect size (SD)
Behaviour high
Attention 0.7 medium
IQ/ Performance tests 0.3 low

23. Long Acting Stimulants
Time of effect
Comments
Methylphenidate
Equasym XL 6-8hrs School day cover
Medikinet
Concerta® XL 8-12hrs Sleep and appetite
Daytrana ® hrs Transdermal
US only
Amphetamine compounds
Adderall XR 6-8hrs Import only
Vyvanase 12-14hrs Prodrug, ltd abuse
(lisdexamfetamine) Awaiting UK approval
Medication management plays a central role in the management of most patients with ADHD.
Stimulants are recommended as first-line therapy for patients with ADHD.
This slide shows the advantages and disadvantages of various stimulants used to treat ADHD.

24. Transdermal Methylphenidate (Daytrana)
Doses: 10mg, 15mg, 20mg 30mg
Applied to hip each morning
Stays on after swimming or bathing
Irritation rare
Suggested use for 9 hours but effects last 3 hours after removal
Heal and Pierce CNS drugs (2006)

25. Lisdexamfetamine (Vyvanase)
Metabolised in GI tract to Lysine and Dexamphetamine
Doses: 30mg, 50mg, 70mg
Little euphoric effect reducing abuse potential
Clin Ther 2007;29:

26. Side Effects Anorexia, weight loss Give with meals Use supplements
Dietary advice
Insomnia
Give earlier
Use shorter acting prep
Consider melatonin/clonidine
Rebound
Change to long acting prep
Assess timing and overlap
Dysphoria
Consider comorbidity and treat
Change to long acting or alternative stimulant

27. 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

28. 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 weeks
Reduction in irritability precedes core symptom improvements

29. Atomoxetine Niches Treatment resistance, partial response
Intolerable side effects
Importance of all day cover
Possible substance misuse or diversion
Comorbid anxiety disorder
Tic disorder

30. Atomoxetine Side 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

31. Atomoxetine Rare hepatitis reported
1 confirmed case in 3.4 million prescriptions
1 further suspected case in 3.4 million prescriptions
Implications: 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

32. Clonidine Used for ADHD therapy and night sedation
Better for restlessness than attention
Useful but popularity waning due to side fx
Good 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

33. Clonidine controversy
Clonidine and Methylphenidate
3 case reports of sudden death
FDA review decided no causal link
Other relevant factors in all cases
Clonidine
4 case reports of cardiac arrythmias, one with congenital malformation
Use with care if history or family history of collapse. ECG sensible for combination.

34. Guanfacine Possible alternative to Clonidine
Half life of 18 hours in adults
1 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

35. Conclusions
Variations in child pharmacokinetics can lead to less predictable responses
Requirement of closer monitoring and shared care with parents
Many adult approved drugs are given off licence to children
Medications have a restricted but important part in holistic care plan
Medications are often given symptomatically rather than for diagnosis