Schizophrenia

Question 1

What is schizophrenia?

Answer 1

Divided mind
Severe psychiatric disorder that causes distortion of thoughts and perception, and mood.
There is specific cognitive impairment.

Question 2

What are the clinical features of schizophrenia?

Answer 2

Onset in early adulthood
Equal incidence in males and females.
Repeated episodes - relapse.
Or chronic disease, progressive decline, that does not subside.

Question 3

What are Positive symptoms / type 1 of Schizophrenia?

Answer 3

The presence of abnormal thoughts and behaviours - allow diagnosis of schizophrenia .
Delusions, often paranoid.
Hallucinations - specifically auditory.
Disorganised speech.
Grossly disorganised or catatonic behaviour.
Thought disorder - inserted thoughts.

Question 4

What are Negative symptoms / type II of Schizophrenia?

Answer 4

The absence of normal responses/behaviours, harder to use for diagnosis.
Reduced expression of emotion.
Social withdrawal.
Cognitive impairment.

Question 5

What is the schizophrenia spectrum?

Answer 5

It is not just one illness, it is a spectrum with subtypes.
Paranoid schizophrenia
Catatonic schizophrenia

Question 6

What is the aetiology of schizophrenia?

Answer 6

Genetic predisposition with an environmental trigger.
Possible environmental factors:
Slow viral infection
Associated autoimmune process.
Poor maternal nutrition.
Developmental abnormality from in utero, but not expressed until the brain is matured.

Question 7

What is the dopamine hypothesis of schizophrenia?

Answer 7

The idea that dopaminergic hyperactivity underlies schizophrenia.
This was based on evidence that dopaminergic agents cause schizophrenic symptoms e.g. amphetamine, and D2 agonists.

Question 8

What is the effect of amphetamine?

Answer 8

Amphetamine is a dopamine releasing drug.
Abuse leads to toxic psychosis, which manifests paranoid delusions, visual or auditory hallucinations, and compulsive behaviours.
These are type I-like symptoms, in people who are not schizophrenic.
Amphetamine abuse exacerbates (worsens) type I symptoms in schizophrenics.

Question 9

What is the effect of D2 receptor agonists?

Answer 9

e.g. apomorphine, bromocriptine, activate D2 receptors to increase dopamine and dopamine signalling.
Cause type I-like symptoms, and exacerbate type I symptoms in Schizophrenics.
Too much L-DOPA also causes type I symptoms, but is reversed by lowering the dose.

Question 10

What is chlorpromazine?

Answer 10

The first antipsychotic, now a typical/first generation neuroleptic.
Developed first as an antihistamine, then used as antipsychotics, because it attenuates positive symptoms without excessive sedation.

Question 11

What are typical neuroleptics?

Answer 11

Phenothiazines class - chlorpromazine, fluphenazine.
Butyrophenones class - haloperidol, droperidol.
Thioxanthines class - flupenthixol, clopenthixol.

Question 12

What are typical neuroleptics?

Answer 12

Receptor antagonists of a variety of receptor sites:
Dopamine receptors
Acetylcholine receptors
Histamine receptors
Noradrenaline receptors
5-HT receptors.
The D2 receptor blockage controls positive symptoms, but they block many receptors so have lots of side effects.

Question 13

What is the neuroleptic efficacy and D2 receptor blockage relationship?

Answer 13

The D2 receptor binding affinity increases with dose of drug.
While correlation does not mean causation, this is good evidence to show that the drugs work by binding and blocking the D2 receptor.

Question 14

What are atypical (second generation) neuroleptics?

Answer 14

Higher dopamine receptor selectivity
Few motor side effects - extrapyramidal control trunk muscles, posture.
More effective against negative symptoms than typical drugs.
More effective against treatment-resistant schizophrenia (TRS).

Question 15

What are the classes of atypical neuroleptics?

Answer 15

Selective dopamine receptor antagonists - sulpiride, amisulpride.
Multi acting receptor targeted agents - clozapine, olanzapine.
Serotonin-dopamine antagonists - risperidone, zotepine, sertindole.

Question 16

When are atypical neuroleptics used?

Answer 16

Most of these drugs are used as first-line for newly diagnosed schizophrenics, they are effective enough and have the lowest side effects.
If first line drugs are ineffective - treatment resistant schizophrenia - clozapine is used.

Question 17

What is the comparison of neuroleptics?

Answer 17

Typical neuroleptics control positive symptoms well, but less effect on negative symptoms, and problematic side effects due to the variety of receptors blocked.
Atypical drugs, mainly clozapine, control both positive and negative symptoms, less side effects, and some efficacy in TRS.

Question 18

What are the dopamine pathways?

Answer 18

Mesocortical pathway
Mesolimbic pathway
Substantia nigra pathway - motor, so blockage causes motor symptoms.
Dopamine receptor antagonists will affect all these pathways, and cause different symptoms.

Question 19

What is the mesolimbic pathway?

Answer 19

Axons from VTA to limbic areas, controls emotion.
Schizophrenic positive symptoms are linked to overactivity/ hyperfunction of the mesolimbic pathway.
So dopamine receptor antagonists reduce positive symptoms.

Question 20

What is the mesocortical pathway?

Answer 20

Axons from VTA to the cortex, control thinking.
Schizophrenic negative symptoms are linked to underactivity/hypofunction of the mesocortical pathway.
Dopamine receptor antagonists further reduce dopamine signalling, so are not useful against negative symptoms.

Question 21

What is the Anti-emetic side effect of typical neuroleptics?

Answer 21

Reduces nausea and vomiting
This is a beneficial /neutral side effect
Due to blocking dopamine receptors in chemoreceptor trigger zone (CTZ).
And blocking histamine receptors.

Question 22

What is the prolactin side effect of typical neuroleptic drugs?

Answer 22

Prolactin hormone release from the pituitary gland is normally inhibited by dopamine on the D2 receptor.
Neuroleptics block the D2 receptor, so increase prolactin release.
This causes breast swelling, pain and lactation, in both men and women.
This reduces compliance of taking the drugs, especially combined with paranoia voices saying the drugs are poison.

Question 23

What are the motor side effects of typical neuroleptic drugs?

Answer 23

Block striatal dopamine receptors, so reduces the nigrostriatal pathway.
This rapidly develops dystonias.
Involuntary movements, as well as Parkinsonian symptoms - tremor, muscle rigidity, reduced mobility.
Reversible by stopping the drug.

Question 24

What is the tardive dyskinesia side effect of typical neuroleptics?

Answer 24

Disabling motor disturbance.
Involuntary movements of face, limbs, trunk.
Slow developing, after chronic treatment (years), that is irreversible.
Causes serious side effects.

Question 25

What are the non-dopaminergic side effects of typical neuroleptics?

Answer 25

Due to blockage of other receptor sites. Anti muscarinic effects - dry mouth, constipation, visual disturbances. Sedation by blocking histamine receptors Postural hypotension by blocking a-adrenoceptors.

Question 26

What are the side effects of atypical neuroleptics?

Answer 26

Fewer side effects due to greater selectivity. Lower incidence of motor disturbance Fewer side effects mean more likely the person will continue to take the drugs - compliance.

Question 27

What is the mechanism of neuroleptics?

Answer 27

Many block 5-HT2A with similar affinity to D2 receptors, e.g. MARTAs - clozapine, block D2, D4, 5-HT2A, and ACh muscarinic. Effective treatment of positive and negative symptoms.

Question 28

What is the limitation of clozapine?

Answer 28

Risk of serious side effects that can kill you - agranulocytosis, myocarditis. So other drugs are used as first line before clozapine.

Question 29

What are the limitations of the dopamine hypothesis?

Answer 29

Neuroleptics have fast neurochemical effect, but symptoms don’t improve after a few weeks. Less effective on negative symptoms. Shows that the symptoms and dysfunction of dopamine are secondary to something else.