Drug Treatment in AutismDrug Treatment in Autism

Tom BerneyNorthgate & Prudhoe NHS Trust

Fleming Nuffield Child & Family Psychiatry UnitEuropean Services for People with Autism (ESPA)

Athens University visitAthens University visit

Source of treatmentSource of treatment empirical theoretical

Does treatment work?Does treatment work? fenfluramine & secretin Why do we believe / not believe?

Drug Treatment in AutismDrug Treatment in Autism

How we think of drugs - their actionHow we think of drugs - their action

Source of treatmentSource of treatment

EmpiricalEmpirical

TheoreticalTheoretical

The drug has worked for someone, somewhere

The person has an abnormality (biochemical / electrical) that the drug might correct

It is similar to another disorderfor which the drug has worked

Slap the TV to make it work SecretinSerotonergic drugs

The theoretical rationalewill follow

TheoreticalTheoretical

haloperidolchlorpromazine

It is similar to another disorderfor which the drug has worked

Autism = schizophrenia ∴ neuroleptics

risperidonethioridazine

The person has an abnormality that the drug might correct

Autism = opiate addiction ∴ naltrexone

Raised serotonin ∴ fenfluramine

Inflamed bowel ∴ sulfasalazine

epileptic EEG ∴ AEDs / surgery

Source of treatmentSource of treatment

Source of treatment empirical theoretical

Does treatment work?Does treatment work? fenfluramine & secretin Why do we believe / not believe?

Drug Treatment in AutismDrug Treatment in Autism

How we think of drugs - their action

fenfluramine

3 people with autism had high serotonin levels in CSF– their autism improved with fenfluramine

30% people with autism had high serotonin levels fenfluramine effective in multicentre trial

response only in one (the main) centre of the trial further trials did not find positive effect fenfluramine withdrawn from the market ∵ toxicity fenfluramine has multiple actions

• depletes serotonin by increasing its release• dopamine blocker (like haloperidol)• stimulant (like methylphenidate)

Does treatment work?Does treatment work?

secretin

secretin given to a 10 yr child with autismas a test of pancreatic function– autism improved

2 other children responded - publication widespread use with enthusiastic media reports

double-blind RCT trial • 44% children responded to secretin infusion• 40% children responded to saline placebo

subsequent controlled trials confirmed the power of the placebo

Does treatment work?Does treatment work?

Why do we believe in a treatment?Why do we believe in a treatment?

Difficulty in measuring the response

Instruments rate diagnosis > severity/change

Short-term: day to day variation

Long-term: developmental change

Powerful placebo response

Passionate support for treatment

Why do we not believe in a treatment?Why do we not believe in a treatment?

If a drug works – the response will be:

Inconsistent • in some people• for some symptoms

Transient – tolerance inevitable

To a very specific dosage• very sensitive / insensitive to the drug• a dosage window (Goldilocks effect)• a paradoxical effect

SIBAutism

0mg 25mg 50mg12.5mg mg

Why do we not believe in a treatment?Why do we not believe in a treatment?

Dose0 0.1 0.5 1.0 2.0 mg/Kg

naltrexone:effects are dose specific

Source of treatment empirical theoretical

Does treatment work? fenfluramine & secretin Why do we believe / not believe?

Drug Treatment in AutismDrug Treatment in Autism

How we think of drugs - their actionHow we think of drugs - their action

Drug actionDrug action

Drugs are named by their:

Chemical structure benzodiazepinesbutyrophenonestricyclics

Neurotransmitter action dopamineserotinin (SSRIs)acetylcholine

Impulse

5-HT1A

5-HT2A

5-HT7

MAO enzymes

Tryptophan

5-hydroxyTryptophan

Serotonin (5HT)Serotonin (5HT) (5-hydroxy tryptamine)

Drug actionDrug action

Impulse

MAO enzymes

MAOI

5-HT1A

5-HT2A

5-HT7

SSRIs

fenfluramine

trazodone

risperidone

clozapine

buspirone

pindolol

Tryptophan

5-hydroxyTryptophan

Serotonin (5HT)Serotonin (5HT) (5-hydroxy tryptamine)

Drug actionDrug action

Block dopamine

Increase serotonin

Block neuropeptides

Block noradrenaline

SRIs 5-OH Tryptophan

D2 blockers (haloperidol)

α2adrenergic(clonidine)

propranololnadolol

ACh (nicotinic)(nicotine, galantamine)

Increase acetylcholine

naltexone

Drug actionDrug action

Drug actionDrug action

Chemical structure benzodiazepinesbutyrophenonestricyclics

Neurotransmitter action dopamineserotinin (SSRIs)acetylcholine

Clinical action antipsychoticsantiepilepticsantidepressants

Drugs are named by their:

Drug actionDrug action

balanced systems > an isolated systembalanced systems > an isolated system

acting on different areas of the brainacting on different areas of the brain

interaction between drugsinteraction between drugs

Clinical action is the sum of several effectsClinical action is the sum of several effects

Wide range of effects from single drugWide range of effects from single drug

primary effectprimary effect

side (adverse) effectsside (adverse) effects

Drug treatmentDrug treatment

Better researched

PurerBetter controlled

More aware of adverse effects

Better informed?