Psychotic Disorders - Schizophrenia

Question 1

Name 3 psychotic disorders you know.

Answer 1

Schizophrenia
Bipolar disorder
Major depressive disorder

Question 2

What are the main symptoms of psychosis ?

Answer 2

Delusions, hallucinations and ‘lack of insight’

Question 3

How are SCZ symptoms classified ?

Name which symptoms according to their class.

Answer 3

Positive (Type 1) : 
- auditory hallucinations 
- delusions 
- thought disorder
- thought broadcasting. 
Negative (Type 2) :
- lack of drive
- social withdrawal
- motor disturbance (catatonia). 
Cognition impaired

Question 4

What is the prevalence of SCZ ?
When does it usually arise ?
What percentage of affected individuals attempt suicide ?

Answer 4

• 1% prevalence
• Onset: late teens / early 20s
• 40% attempt suicide

Question 5

What are the possible causes of SCZ ?

Answer 5

• “It’s genetic” (17% dizygotic twins, 48% monozygotics)
• “It’s viral”
• Developmental disorder?
• The pink spot theory (rubish)

Question 6

What are the main NTs involved in SCZ ?

Answer 6

DA - Amphetamine
5-HT - LSD
Glutamate - PCP

Question 7

What are the “D1-like” DA Rs ?

What about the “D2-like DA Rs ?

Answer 7

D1-like = D1 + D5
D2-like = D2, D3, D4

Question 8

What evidence led to the “Dopamine Hypothesis” of SCZ ?

Answer 8

• Amphetamine
Drugs release dopamine and produce symptoms identical to positive symptoms of
schizophrenia – blocked by antipsychotics
• D2-like DA R agonists
Drugs like apomorphine and bromocriptine (used in PD) produce positive symptoms of schizophrenia.
• Reserpine (antihypertensive drug that depletes DA from synaptic vesicles)
• D2-like DA R antagonists
Reduce positive symptoms of schizophrenia and amphetamine-induced behavioural changes.

Question 9

Is there direct biochemical evidence supporting the DA hypothesis of SCZ ?

Answer 9

No, or at least it is not as supportive. There is only indirect evidence of this hypothesis.

Question 10

Which DA pathways are affected in SCZ ?

How does this correlate w/ +ve and -ve symptoms.

Answer 10

The mesocortical pathway (VTA to PFC) in hypoactive (“hypofrontality”) –> -ve symptoms
The mesolimbic pathway (VTA to NAcc) is hyperactive –> +ve symptoms

Question 11

In a normal individual, what is the interaction between the mesocortical and mesolimbic pathways ?

Answer 11

It is though that, normally, the mesocortical pathway inhibits thee mesolimbic pathway.

Question 12

What do we mean by typical anti-psychotics ?

Answer 12

Anti-psychotics that cause “typical” side effects :

• postural hypotension
• sedation
• anti-muscarinic effects (dry mouth, blurred vision, contipation etc.)

Question 13

Give examples of typical anti-psychotics.

Answer 13

Phenothiazines
- Chlorpromazine (aliphatic) –> low D2affinity (1, H1 and mAch receptor antagonist)
- Thioridazine (piperidine) (strong mAch receptor antagonist)
- Trifluoperazine/Fluphenazine* (piperazine) –> higher affinity (*depot administration - esters of decanoate/ethanate)
Thioxanthines
- Flupenthixol
Butyrophenones
- Haloperidol –> highest D2 affinity

Question 14

Does a typical anti-psychotic binding affinity have any influence on its effect ?

Answer 14

Correlation of typical antipsycholtic binding affinity with clinical effect.

Question 15

What effects do typical antipsychotics have on the different DA pathway ?
Which of these are desriable Vs non-desirable ?

Answer 15

Mesocorticolimbic tracts –> Neuroleptics prevent hallucinations ==> good
Nigrostriatal system –> Neuroleptics induce movement disorders (EPS) ==> bad
Tuberoinfundibular system (hypothalamic) –> Neuroleptics cause hyperprolactinaemia ==> bad

Question 16

What are the side effects of neuroleptics ?

Answer 16

Extrapyramidal Symptoms (EPS)
- Parkinsonian-like (akinesia, rigidity, tremor)
- Dystonia (head/neck/trunk muscle spasm – oculogyric crisis, glossospasm, torticollis)
- Tardive dyskinesia (involuntary face/tongue/limb movement)
- Akathesia (involuntary motor restlessness)
Hyperprolactinaemia (gynaecomastia/galactorrhea/pseudopregancy)
Sedation (H1 receptor block)
Autonomic effects
- Orthostatic hyptension (1-adrenoceptor block)
- Dry mouth, mydriasis/blurred vision/glaucoma, xerophthalmia, constipation, urinary hesitancy (mAch receptor block)
Aplastic anaemia (chlorpromazine) [Neuroleptic malignant syndrome]

Question 17

How effective are typical antipsychotics at treating the +ve Vs -ve symptoms ?

Answer 17

DA receptor antagonists reduce positive symptoms
- nucleus accumbens
Typical neuroleptics do not reduce negative symptoms
- hypofrontality syndrome (prefrontal cortex)

Question 18

What are the advantages of a drug such as clozapine ?

Answer 18

• High efficacy than previous neuroleptics with just 30% D2 occupancy
• Fewer EPS
• Positive AND negative symptoms addressed
• Drug-resistant psychosis
• Less tardive dyskinesia

Question 19

Name dibenzazepine derivatives and benzisoxazole derivatives that are atypical neuroleptics.

Answer 19

DIBENZAZEPINE DERIVATIVES
- Clozapine
- Olanzapine
- Quetiapine
BENZISOXAZOLE DERIVATIVES
- Risperidone
- Paliperidone (primary active metabolite of risperidone)
- Ziprasidone

Question 20

What is the proportion of D2 Rs occupied by atypical neuroleptics ?

Answer 20

30%

Question 21

What is the proportion of D1 Vs D2 Vs 5HT-2A Rs occupied by :

• chlorpromazine
• haloperidol
• atypicals

Answer 21

Chlorpromazine :
- medium D1, D2 and 5HT-2A occupancy
Haloperidol :
- no D1, Large D2, small 5HT-2A occupancy
Atypicals :
- small D1, small D2, medium 5HT-2A occupancy

Question 22

What are the side effects of atypical neuroleptics ?

Answer 22

Hyperprolactinaemia (gynaecomastia/galactorrhea/pseudopregancy)
Autonomic effects 
Orthostatic hyptension (1-adrenoceptor block)
ECG prolongation (QT interval)
Metabolic Effects
Weight gain (esp olanzapine)
Hypercholesterolaemia
Type 2 diabetes
Sialorrhoea (dribbling) 
Agranulocytosis (1%)/ leukopenia

Question 23

How do 3rd generation antipsychotics work ?

Answer 23

D2 partial agonist (high affinity/low intrinsic activity)
5HT-1A partial agonist
5HT-2A weak antagonist

Question 24

Name a 3rd generation anti-psychotic.

Answer 24

Aripiprazole.

Question 25

What are the pros and cons of 3rd generation antipsychotics such as aripiprazole ?

Answer 25

Pros:
- Few EPS – no difference from placebo
- Little weight gain –Few CV (Q-T) abnormalities
- Apparently safe in overdose
Cons:
- Hyperprolactinaemia
- Hypercholesterolaemia
- Akathisia - emerging as a problem