Schizophrenia

Question 1

What is schizophrenia?

Answer 1

• A severe psychiatric disorder characterised by distortion of thoughts, perception and mood.
• It is not just one illness. It is a spectrum with subtypes.

Question 2

How does schizophrenia progress?

Answer 2

• Schizophrenia begins as repeated episodes.

- The disease may progress into a chronic phase.

Question 3

How does positive schizophrenia compare to negative schizophrenia?

Answer 3

• Positive symptoms include abnormal thoughts and behaviours.
• Negative symptoms include absence of normal thoughts and behaviours.
• An individual can have both positive and negative symptoms.

Question 4

List 5 positive symptoms of schizophrenia.

Answer 4

1 - Delusions.

2 - Paranoia.

3 - Hallucinations.

4 - Disorganised speech.

5 - Catatonic behaviour.

Question 5

List 2 negative symptoms of schizophrenia.

Answer 5

1 - Reduced expression of emotion.

2 - Social withdrawal (avolition).

Question 6

List 4 possible factors that predispose towards schizophrenia.

Answer 6

1 - Genetics.

2 - Autoimmunity.

3 - Poor maternal nutrition.

4 - Developmental abnormalities caused by above points.

5 - Slow viral infections.

Question 7

What is the dopamine hypothesis of schizophrenia?

Answer 7

The dopamine hypothesis of schizophrenia suggests that dopaminergic hyperactivity underlies schizophrenia.

*Other neurotransmitters are likely to be affected too, hence some drugs in this lecture target other neurotransmitters such as 5-HT and glutamate.

Question 8

What is the effect of amphetamines at the synapse?

List 3 ways amphetamines achieve this.

Answer 8

• Amphetamines increase intracellular concentration of dopamine:

1 - Amphetamines act at VMATs at synaptic vesicles to reverse transport dopamine out of the vesicle for amphetamine in, increasing intracellular dopamine.

2 - Amphetamines act at dopamine transporters at the synaptic membrane to reverse transport dopamine into the synaptic cleft for amphetamines in.

3 - At high doses, amphetamines inhibit the action of monoamine oxidase.

Question 9

What is a toxic psychosis?

Answer 9

A reaction caused by amphetamine abuse that is similar in symptoms to that of positive schizophrenia. It manifests as:

1 - Paranoid delusions.

2 - Hallucinations.

3 - Compulsive behaviours.

Question 10

Give an example of a drug class, other than amphetamines, that can cause symptoms similar to that of positive schizophrenia.

List 2 examples of drugs within this class.

Answer 10

• Dopamine D2 receptor agonists can produce symptoms similar to that of positive schizophrenia.

1 - Apomorphine.

2 - Bromocriptine.

*L-DOPA will do the same thing, too.

Question 11

What was the first antipsychotic drug?

To which group of related drugs does it belong?

How does it work?

Answer 11

• Chlorpromazine was the first antipsychotic drug.
• It is a typical / first generation neuroleptic.
• It was developed as an antihistamine, however the drug was able to cross the blood-brain barrier (hence old antihistamines caused drowsiness), causing slight sedation and attenuation of positive symptoms of schizophrenia.
• It was able to attenuate symptoms of schizophrenia as it is a ‘dirty drug’ which blocks a variety of receptors, including D1 and D2 receptors.

Question 12

What is a neuroleptic?

Answer 12

An antischizophrenic drug.

*Also known as antipsychotics and major tranquilisers.

Question 13

List the 3 main classes of neuroleptics.

Answer 13

1 - Phenothiazines.

2 - Butyrophenones.

3 - Thioxanthenes.

Question 14

List 2 phenothiazines.

Answer 14

1 - Chlorpromazine.

2 - Fluphenazine.

Question 15

List 2 butyrophenones.

Answer 15

1 - Haloperidol.

2 - Droperidol.

Question 16

List 2 thioxanthenes.

Answer 16

1 - Flupenthixol.

2 - Clopenthixol.

Question 17

List 5 receptors blocked by phenothiazines (good examples of ‘dirty drugs’).

Through which receptor is antipsychotic activity mediated?

Answer 17

1 - Dopamine receptors (D1 and D2).

2 - Muscarinic receptors.

3 - H1 receptors.

4 - Alpha receptors.

5 - 5-HT receptors.

• Antipsychotic activity is mediated through dopamine receptor block.

Question 18

What is the difference between typical / first generation neuroleptics and atypical / second generation neuroleptics?

Answer 18

Atypical / second generation neuroleptics have a higher dopamine receptor selectivity than typical / first generation neuroleptics.

Question 19

List 3 advantages of atypical / second generation neuroleptics.

Answer 19

Atypical / second generation neuroleptics have:

1 - Fewer extrapyramidal motor side effects (remember extrapyramidal systems function to modulate voluntary movement).

2 - More effective against negative symptoms whilst still being effective against positive symptoms.

3 - More effective against treatment-resistant schizophrenia (TRS).

Question 20

List 3 atypical / second generation neuroleptic drug classes.

Answer 20

1 - Selective dopamine receptor antagonists (for D2 and D3 receptors).

2 - Multi-acting receptor-targeted agents (MARTAs).

3 - Serotonin-dopamine antagonists.

4 - Novel types.

*MARTAs are relatively dirty drugs compared to the other 3 drug classes.

Question 21

List 2 selective dopamine receptor antagonists.

Answer 21

1 - Sulpiride.

2 - Amisulpride.

Question 22

List 2 multi-acting receptor-targeted agents (MARTAs).

Answer 22

1 - Clozapine (this one’s meant to be really good). It’s classified as atypical / second generation because it doesn’t cause tardive dyskinesia - a motor symptom explained in a later card.

2 - Olanzapine.

Question 23

List 3 serotonin-dopamine antagonists.

Answer 23

1 - Risperidone.

2 - Zotepine.

3 - Sertindole.

Question 24

Give an example of a novel atypical / second generation neuroleptic drug that doesn’t fall into the other 3 drug classes.

Answer 24

Quetiapine.

Question 25

Describe the dopamine pathways of the brain.

Answer 25

1 - Dopamine is initially released from the substantia nigra and ventral tegmental area in the midbrain. 2 - The ventral tegmental area sends axons into 2 pathways: - The mesocortical pathway, which projects into the frontal lobe. - The mesolimbic pathway, which projects into the limbic system. 3 - The substantia nigra sends axons into the nigrostriatal pathway, which projects into the striatum. *The nigrostriatal pathway is involved in Parkinson's disease - not schizophrenia.

Question 26

Which dopamine pathway is responsible for the positive symptoms of schizophrenia? How is this pathway affected to produce positive symptoms?

Answer 26

Hyperactivity of the mesolimbic pathway is responsible for the positive symptoms of schizophrenia.

Question 27

Which dopamine pathway is responsible for the negative symptoms of schizophrenia? How is this pathway affected to produce negative symptoms?

Answer 27

Hypoactivity of the mesocortical pathway is responsible for the negative symptoms of schizophrenia.

Question 28

What might explain the concurrence of both positive and negative symptoms in an individual with schizophrenia?

Answer 28

The mesolimbic and mesocortical pathways are able to positively feedback, such that hyperactivity in the mesolimbic pathway causes hypoactivity of the mesocortical pathway.

Question 29

List 3 side effects of neuroleptic drugs.

Answer 29

1 - Antiemetic. 2 - Increased prolactin release. 3 - Extrapyramidal motor symptoms (remember extrapyramidal systems function to modulate voluntary movement). 4 - Non-dopaminergic (due to blockade of other receptors).

Question 30

Why do neuroleptic drugs have an antiemetic effect?

Answer 30

Neuroleptic drugs have an antiemetic effect due to: 1 - Dopamine receptor block in the chemoreceptor trigger zone in the 4th ventricle. 2 - H1 receptor block.

Question 31

Why do neuroleptic drugs increase prolactin releaser?

Answer 31

- Release of prolactin is normally inhibited by dopamine, which binds to D2 receptors at the pituitary. - Since neuroleptics block this inhibition, more prolactin is released.

Question 32

List 3 symptoms of increased prolactin release.

Answer 32

1 - Breast swelling. 2 - Pain. 3 - Lactation.

Question 33

What is the name given to acute and chronic motor symptoms caused by neuroleptic drugs?

Answer 33

- Acute motor symptoms due to neuroleptics are dystonias. | - Chronic motor symptoms due to neuroleptics are tardive dyskinesias.

Question 34

Describe the clinical features of dystonias.

Answer 34

- Dystonias are involuntary movements, particularly of the face, tongue and neck. - They are typical of the motor symptoms seen in Parkinson's disease (resting tremor, muscle rigidity and decreased mobility). - They are developed relatively rapidly. - They are reversible if the drug is removed.

Question 35

Describe the clinical features of tardive dyskinesias.

Answer 35

- Tardive dyskinesias are severely disabling motor disturbances characterised by involuntary movements of the face, tongue and neck. - They are slow developing (tardive). - They are irreversible.

Question 36

List 5 non-dopaminergic side effects.

Answer 36

1 - Postural hypotension (due to alpha block antagonising the baroreceptor reflex). 2 - Sedation (due to H1 block). Antimuscarinic effects: 3 - Dry mouth. 4 - Constipation. 5 - Visual disturbances (due to changes in accommodation).

Question 37

List 2 problems with the dopamine hypothesis of schizophrenia.

Answer 37

1 - Neuroleptics take weeks to work despite causing relatively quick changes to dopamine activity in the brain. It is therefore likely that there are secondary effects. 2 - The hypothesis doesn't fully explain the effect of dopamine antagonism to treat negative symptoms (Jame hypothesis - improves mesocortical hypoactivity because it decreases mesolimbic hyperactivity so the positive feedback loop is diminished but this is partially cancelled out by antagonising dopamine activity in general so hypoactivity is reestablished). 3 - Dysfunction of dopaminergic systems may not be the primary cause of schizophrenia.