NEURO: Schizophrenia

Question 1

What is schizophrenia?

Answer 1

major psychosis disorder characterised by:

· Mental state that is out of touch with reality.
· Abnormalities of perception, thought & ideas
· Profound alterations in behaviour (bizarre and distorting alienation)

Question 2

Why is schizophrenia the most important major psychosis disorder?

Answer 2

• Early in onset
• Prevalent
• Disabling and chronic

Question 3

Phases of schizophrenia

Answer 3

1) Prodome
>Late teens/the early twenties: often mistaken for depression or anxiety
>Can be triggered by stress

2) Active/Acute Phase
>Onset of positive symptoms (e.g. hallucinations, delusions)
>Differentiation of what is and isn’t real becomes difficult

3) Remission
>Treatment→return to “normality”

4) Relapse
>Go back to the active/acute phase

Question 4

What are the three classes into which schizophrenia symptoms can be grouped?

Answer 4

POSITIVE (an increase in abnormal behaviours):

• Hallucinations (e.g. visual, auditory)
• Delusions
• Disorganised thought/speech
• Movement disorders

NEGATIVE (an absence of normal behaviours):

• Social withdrawal
• Anhedonia (inability to feel pleasure at pleasurable activities)
• Lack of motivation
• Poverty of speech
• Emotional flatness

COGNITIVE (problems with thought processes):

• Impaired working memory
• Impaired attention
• Impaired comprehension

Two or more of these symptoms must persist for at
least 6 months to be classed as schizophrenia.

Question 5

Features of hallucinations

Answer 5

perceptions of experience without stimulus

Patients hear:

• voices talking about them (3rd person)
• voices talking to them
• voices giving a running commentary
• voices echoing their thoughts (thought echo)

Patients may engage in a dialogue with the voices or obey their commands.

Question 6

Features of delusions

Answer 6

a fixed unshakeable belief not consistent with cultural/social norms

Often paranoid or persecutory:
>e.g. under control of an external influence
>passivity of thoughts and actions

Question 7

Schizophreniform

Answer 7

disorder characterised by positive symptoms (hallucinations, delusions) for at least a month but less than 6 months

Question 8

What could be the causes of schizophrenia?

Answer 8

There are genetic factors:

• SCZ isn’t directly inherited, but can ‘run in families’
• ‘Candidate’ risk genes: gene deletions, gene mutations

There are environmental factors:

• Pregnancy/birth complications
• Stress
• Drug use

It is due to both nature and nurture that schizophrenia develops.

Question 9

Studies on SCZ

Answer 9

> Monozygotic twin studies showed 50% chance of developing schizophrenia if one twin is diagnosed
Dizygotic twin studies showed ~14% chance of developing schizophrenia if one twin is diagnosed

Question 10

What are some of the candidate genes for schizophrenia?

Answer 10

Examples of some of these genes is:

• COMT
• DISC1
• GRM3

Possessing these abnormal genes does not mean you will definitely get schizophrenia – similarly, some people who have schizophrenia do not have these genetic abnormalities.

Question 11

How can pregnancy/birth complications cause schizophrenia?

Answer 11

A Finnish study reported a spike in schizophrenia for people who were foetuses during the 1957 influenza epidemic. Thus, pregnant women in the UK are advised to be vaccinated against seasonal flu.

Low birth weight, premature birth, and asphyxia during birth are all causes of early-life stress (stemming from birth complications).

Question 12

Give some examples of stress that can cause schizophrenia.

Answer 12

• MOVING COUNTRY: Swedish cohort 1 first-degree relative further increased risk
• LOSS OF JOB/HOME/RELATIONSHIP
• PHYSICAL/EMOTIONAL/SEXUAL ABUSE

The mechanism by which stress may trigger schizophrenia is unknown.

Question 13

How can drug abuse lead to schizophrenia?

Answer 13

Continued cannibas use during early life for ~15 years has been shown to increase the risk of schizophrenia development.

Other drugs that could are:

• amphetamine
• cocaine
• LSD

Question 14

What are the two main hypotheses for the pathophysiology of schizophrenia?

Answer 14

There is the:

• dopamine hypothesis
• glutamate hypothesis

There are many other hypotheses:

• Brain structure differences
• Hypofrontality
• Inhibitory interneuron dysfunction
• Kynurenic Acid
• Oxidative Stress
• Immune System Abnormalities

Question 15

Describe the dopamine hypothesis.

Answer 15

Schizophrenia is associated with abnormally high dopaminergic transmission.

However, there is no conclusive evidence that dopamine levels are increased in schizophrenia.
Are we treating the symptoms via a mechanism different to the cause?

Question 16

Describe the evidence for and against the dopamine hypothesis.

Answer 16

FOR:

• both amphetamine and cocaine block the reuptake of dopamine and foster the symptoms of schizophrenia
• amphetamine promotes the release of dopamine and fosters symptoms of schizophrenia

AGAINST:
- chlorpromazine, a drug that blocks symptoms of schizophrenia, occupies the dopamine site on the D2 receptor, preventing receptor activation by dopamine

Question 17

Describe the evidence for the glutamate hypothesis.

Answer 17

• the NMDA receptor number has been found to be reduced in post-mortem brains with schizophrenia
• NMDA receptor antagonists (such as ketamine, PCP) exacerbate (make worse) the psychosis
• NMDA receptor antagonists can induce psychosis

Question 18

What are the different types of treatment for schizophrenia?

Answer 18

• Pharmacological (current + future therapies?)
• Cognitive Behavioural Therapy (CBT)
• Electroconvulsive therapy (ECT)

Question 19

What are the types of antipsychotics taken for schizophrenia?

Answer 19

There are two types:
TYPICALS:
- Also known as ‘first generation’
- First developed in the 1950s
- Mainly antagonise D2 receptors

ATYPICALS:

• Also known as ‘second generation’
• First developed in the 1980s
• Mainly antagonise D2 and 5-HT2A receptors

Question 20

As a recap, describe the different dopamine pathways and what they are responsible for.

Answer 20

MESOCORTICAL PATHWAY: cognitive control and motivation and emotion

MESOLIMBIC PATHWAY: reward

NIGROSTRIATAL PATHWAY: movement

TUBEROHYPOPHYSEAL PATHWAY: prolactin release

Question 21

Describe typical antipsychotics.

Answer 21

The four key types of typical antipsychotics:

• Chlorpromazine
• Fluphenazine
• Haloperidol
• Flupentixol

The effect takes days to develop.
They are only effective in treating the positive symptoms. They can induce some severe side-effects.

Question 22

Describe atypical antipsychotics.

Answer 22

They are atypical as they produce fewer side effects, and are more effective at treating negative symptoms. It exerts D2 receptor antagonism to a lesser
extent than the typicals.

The four key atypical antipsychotics:

• Clozapine
• Olanzapine
• Risperidone
• Aripiprazole

5-HT2A agonists can cause hallucinations.

Question 23

What are some general side effects of antipsychotics?

Answer 23

• Extra-pyramidal side effects
• Increased prolactin secretion
• Weight gain
• Sedation
• Hypotension
• Anticholinergic effects

The typical antipsychotics tend to induce these side-effects to a greater extent than the atypicals.

Question 24

Describe pyramidal and extra-pyramidal tracts.

Answer 24

Pyramidal and extra-pyramidal tracts descend from the brain to the spinal cord. These tracts are involved in
controlling movement.

Pyramidal tracts pass through the pyramids of the medulla and directly innervate motor neurons. Extrapyramidal tracts pass alongside the medulla and act to modulate and regulate movement.

They are controlled by the nigrostriatal pathway in the basal ganglia.

Extra-pyramidal side effects can therefore resemble Parkinson’s.

Question 25

List some extra-pyramidal side effects.

Answer 25

RIGIDITY:

• A mask-like face
• Bradykinesia (slowness in movement and initiation of movement)

DYSTONIAS:
- Spasms of the face and neck muscles

AKATHISIA:
- Motor restlessness

TARDIVE DYSKINESIAS:

• Tic-like movements
• Worm-like movements
• Appear late in the disorder

Question 26

Describe the effects of prolactin secretion as a side effect.

Answer 26

Prolactin (hormone) promotes milk production. Normally, dopamine negatively regulates it’s secretion. In schizophrenia, there is no blockade of the tuberohypophyseal pathway (where a lot of the dopamine receptors are), so prolactin is secreted.

Symptoms:

• Breast swelling (yes, even in men)
• Milk secretion (yes, even in men)
• Period cessation

Question 27

Describe the effects of weight gain as a side effect.

Answer 27

This is an ‘off-target’ side effect.

Antipsychotics can antagonise histamine H1 receptors.

Central H1 receptor antagonism can cause:

• increased appetite via stimulating the production of AMP- activated protein kinase (AMPK)
• decreased lipolysis
• decreased thermogenesis

An overall effect of stimulating appetite and fat accumulation and reducing energy expenditure.

Question 28

How can sedation occur as a result of taking antipsychotics?

Answer 28

It can occur via two different mechanisms:

• D2 receptor antagonism
• central H1 receptor antagonism

Question 29

Describe the effects of hypotension as a side effect.

Answer 29

This is another ‘off-target’ effect.

The α1-adrenoceptor antagonism leads to hypotension as it results in vasodilation in the blood vessels.

Question 30

Describe the anticholinergic effects of antipsychotics.

Answer 30

Antagonism of muscarinic acetylcholine receptors causes:

• Salivary secretion
• Pupillary muscle
• Smooth muscle contraction
• Blockage of mAChRs at the neuromuscular junction

However, anticholinergics are thought to detrimentally impact cognition.

Question 31

What is the aim of ECT?

Answer 31

ECT is electroconvulsive treatment.

It’s essentially like hitting the brain’s restart button. It is only used in the most severe cases where the symptoms are debilitating.