1. Pharmacological Treatments for Individuals with Down Syndrome
Jeremy Turk
Academic Child & Adolescent Mental Health,
Institute of Psychiatry, University of London
&
Child & Adolescent Mental Health Neurodevelopmental Services,
South London & Maudsley Mental Health Foundation NHS Trust

2. Pharmacological Therapies:
Symptomatic
Psychiatric Disorder Specific
Aetiology Specific

3. Medication may be useful for:
Hyperactivity & attention deficit disorders
Aggression & violence
Anxiety
Self-injurious behaviour
Epilepsy & associated behavioural problems
Sleep disturbance
Mood disorder: unipolar, bipolar, cyclical
Obsessive-compulsive disorder
Social aloofness
Eating disorder
Early onset psychosis

4. Medication should never be the initial intervention
Medication should never be the initial intervention. Consider psychological, educational, family and social approaches first.

5. Thorough multi-disciplinary assessment must be undertaken.

6. Other interventions should have been tried.

7. If problems still persist, consider medication in addition to other approaches as a means to an end - not an end in itself.

8. Treat symptoms (e.g. self-injury, aggression, overactivity) not syndrome (e.g. fragile X syndrome).

9. Undertake a clinical trial of medication
Does it work or not?
Are there side-effects?

10. Consider the cost-benefit ratio
What is the likelihood of improvement?
How important is this?
What are the likelihoods of side-effects?
How serious might they be?

11. Beware of the increased risk of adverse effects in people with intellectual disability and other neurodevelopmental disabilities.

12. If medication does not work, stop it!

13. If medication does work:
give it for the minimum time possible
frequent monitoring and reviews regarding:
continuing need
possible adverse effects

14. Evidence-based pharmacological therapies
Psychostimulants, tricyclics & clonidine for hyperactivity & attentional deficits
“SSRI’s” for depression, anxiety & obsessive-compulsive features
Anticonvulsants for cyclical (& not so cyclical) mood & behaviour disorders (Turk 2012)
Melatonin for sleep induction problems (Turk 2003, 2010)
Clonidine for sleep maintenance problems (Ingrassia & Turk 2005)
Atypical antipsychotics for early onset psychosis

15. Medication: ADHD Methylphenidate, Dexamphetamine Clonidine Tricyclics*
Rapid, slow & pulsatile release preparations
Clonidine
Tricyclics*
SSRI’s*
Folic acid*
Atomoxetine
Atypical antipsychotics *
Anticonvulsants*
(* = unlicenced)

16. Hyperactivity & Attention Deficit Disorders
First line treatment = central nervous system stimulants
Methylphenidate, dexamphetamine, Adderal (in US)
Modified release preparations:
Ritalin SR
Concerta
Equasym XL
Medikinet XL
Elvance (lisdexamphetamine mesylate)

17. Stimulants: downsides
Lack of response (30%)
Paradoxical excitation
Overfocussing
Insomnia
Appetite, weight & growth suppression
Headaches, tummy aches, dizziness
↑ pulse & blood pressure
Tic disorders & nervous twitching
Anxiety, mood lability, psychosis

18. Downsides for those with intellectual disability
Difficulty swallowing
Or at least difficulty swallowing whole tablets without crunching them
Raised rates of adverse effects
Need for lower dosage
Need for more careful, frequent and intensive monitoring
Heightened individuality of clinical response
“start low – go slow”
Risk of commencing at too high a dosage

19. Other Options: α-2A noradrenergic receptor agonists
Clonidine, Guanfacine
Lack appetite and sleep disturbance
Good for tic disorders
But sedation & ↓ blood pressure
Tricyclic antidepressants
Imipramine, Amitriptyline
Good for anxiety, depression, enuresis, tics, insomnia
May need to do ECG
? Calming SSRIs – as above

20. Clonidine (Ingrassia & Turk, 2005)
α2A noradrenergic receptor agonist
Shown efficacy for anxiety, overactivity, impulsiveness, inattentiveness
Mildly sedating, mildly hypnotic
Good for tics & Tourette’s
Good for repeated night time waking
No effect on appetite
Can drop your blood pressure
μg daily in divided doses

21. Atomoxetine: Selective norepinephrine reuptake inhibitor
Evidence for benefits in children & young people of average intellignece
Less evidence for benifits in those with intellectual disability and/or ASD
Upset stomach, weight change, dizziness
Dry mouth, difficulty urinating, nausea, vomiting
Constipation, sexual problems, insomnia, fatigue
 heart rate & blood pressure
Hives, swelling
Hepatotoxicity, suicidal ideation & behaviour

22. Myths about stimulant medication & intellectual disability
Overactivity, inattentiveness & impulsiveness are to be expected in children with intellectual disability.
ADHD can not be diagnosed in children with intellectual disability.
Stimulants are contraindicated in children with intellectual disability and/or autistic disorders.
There is no evidence base for the use of stimulants in children with intellectual disability.
The risk of side effects is too great to justify their use.

23. Decision regarding which product to use should be based on:
Presence of co-occurring conditions e.g. tic disorders, Tourette’s, epilepsy, anxiety, insmonia
Different adverse effects of the drugs
Compliance issues e.g. midday treatment doses at school
Tablet v capsule v liquid
Drug diversion and/or misuse
Individual preference
Cost (if there is a choice)

24. Self-injurious behaviour #1:
Self-injury triggers release of endogenous opioids producing pleasurable sensations which are positively reinforcing.
→opioid antagonist: naltrexone
→pleasurable sensations extinguished →aversive consequence to self-injury →↓ frequency & intensity of behaviour

25. Self-injurious behaviour #2:
Self-injury is a form of tic disorder
Prescribe medication for tics
Butyrophenones – haloperidol
Dibutylphenylpiperidone – pimozide
Substituted benzamide – sulpiride
α-2A agonist – clonidine
Atypical antipsychotics: risperidone, aripiprazole

26. Self-injurious behaviour #3:
Self-injury is a form of obsessive-compulsive disorder
Prescribe anti-obsessive agents
clomipramine
fluoxetine
sertraline
paroxetine
citalopram

27. Melatonin (Turk, 2003) N-acetyl-5-methoxytryptamine Pineal indole
diurnal secretion variation
widely available as food supplement in North America
unlicensed in U.K. - only prescribable on named patient basis

28. Tryptophan Serotonin N-acetylserotonin Melatonin (N-acetyl-5-methoxytryptamine)

29. JAN ET AL 1994:
15 children, most with multiple neurological disabilities
improved sleep
“significant health, behavioural & social benefits”
BUT
responses not always complete
responses varied considerably depending on type of sleep disturbance
not double-blind

30. Melatonin is:
Highly beneficial, short-term, rapid-onset & safe treatment for intractable sleep disturbance
Therapeutic dose not predicted by:
severity of sleep disturbance
severity of intellectual disability
presence/absence of autism
Habituation common but not universal
Modified-release version (Circadin) probably no better than immediate-release – but cheaper!

31. Acebutolol: selective beta-1 adrenergic agonist
De Leersnyder et al (2003)
melatonin antagonist
nine children with Smith-Magenis syndrome
severe and intractable sleep difficulties
successful suppression of inappropriately high morning melatonin levels
improved behaviour and concentration, a reduction in delays in sleep onset, increased sleep duration and delayed waking

32. Down Syndrome: current understanding
intellectual disability
characteristic personality & temperament
relatively low rates of autistic spectrum disorders & attention deficit disorders in childhood
depression
Alzheimer disease

33. Targeted Medications mGlu5R GABAergics
Glutamate antagonists: e.g. mavoglurant
Lithium
Minocycline
Baclofen & Arbaclofen
Rapamycin – tuberous sclerosis
Statins – neurofibromatosis, Down Syndrome