Schizophrenia

Question 1

Risk factors

Answer 1

• maternal viral infections
• birth complications
• urbanicity
• early cannabis use
• older father
• childhood abuse
• stress
• Strong but incomplete hereditary tendency

Question 2

Clinical features

Answer 2

Schizophrenic symptoms may be categorised as positive or negative.
- Positive (type I) symptoms are abnormal thoughts and behaviours, and include:
 Hallucinations – usually audition
 Delusions – false beliefs
 Disorganised speech
 Grossly disordered and incoherent (catatonic) cognitive processes and behaviour

• Negative (type II/residual) symptoms = deficits of normal emotional or thought responses; they include:
   Impaired reality orientation – lack of insight
   Reduced emotional expression, poverty of speech
   Loss of drive and apathy
   Memory impairment
   Social withdrawal
   Other: olfactory impairment, pain insensitivity, neurological ‘soft’ signs
• It may be acute (mainly positive symptoms, florid) or chronic (often negative symptoms, with flare-ups)

Question 3

Describe macroscopic brain changes that schizophrenics typically have

Answer 3

 Larger ventricle-to-brain size ratio (ventricular enlargement) and smaller temporal lobe volume
than normal due to brain shrinkage – decreased brain volume and weight (-3%)

 Smaller

 Relatively smaller hippocampus and thalamus

 Larger basal ganglia – due to antipsychotic treatment

 Smaller grey matter volume and defective myelin sheaths (may cause/result from disease)

Question 4

Which neurotransmitters have been particuarly implicated in schizophrenia?

Answer 4

Dopamine and glutamate

Question 5

Describe the dopamine hypothesis

Answer 5

• schizophrenia associated with excess of dopamine
• based on the effects of various drugs → antipsychotic (neuroleptic) drugs such as chlorpromazine (initially developed as an antihistamine
  in the 1950s) can prevent schizophrenic symptoms by antagonising dopaminergic D 2 receptor

Question 6

What pathways are thought to be affected in the dopamine hypothesis?

Answer 6

The mesolimbic pathway, which projects from the ventral tegmental area (VTA) of the midbrain to
the nucleus accumbens

The mesocortical pathway, which projects from the VTA to the cerebral cortex (particularly the
prefrontal lobes)

It is thought that hyperexcitability of the mesolimbic pathway results in positive schizophrenic
symptoms, while reduced activity of mesocortical pathway causes negative and cognitive symptoms

Question 7

Discuss glutamate hypothesis

Answer 7

• the action of the drug phencyclidine (PCP), an NMDA receptor antagonist which produces
  schizophrenic-like symptoms, has led to the development of the glutamate hypothesis
• suggests disease is associated with HYPOFUNCTION OF NDMA RECEPTORS
• this may be due to the complex control that glutamatergic and GABAergic neurons exert on the mesocortical and mesolimbic dopamine pathways

Question 8

What macroscopic changes may the glutamate hypothesis explain?

Answer 8

Hippocampal atrophy

Question 9

How may hypofrontality be explaine?

Answer 9

Hypofrontality (a state of decreased cerebral blood flow to the
prefrontal cortex), prevalent in many of the tasks that require executive processing, is often
apparent in schizophrenia. This hypofrontality may be caused by altered dopaminergic signalling in
the limbic striatum and mediodorsal thalamus, as these regions form connections with part of the
prefrontal cortex called the corticolimbothalamic circuit, which contains GABAergic interneurons
expressing the NMDAR. This means that dopamine indirectly plays an important role in prefrontal
cortex functioning. Therefore, this hypofrontality caused by aberrant dopaminergic signalling, may
cause the decreased NMDAR activity associated with the negative and cognitive symptoms of
schizophrenia.

Question 10

What other NTs may be involved in schizophrenia?

Answer 10

5HT→ LSD porduces schizophrenia-like symptoms, many effective antipsychotics also block 5HTRs, %HT modulates dopamine pathways
NA

Question 11

Evidence of NMDA hypothesis?

Answer 11

Evidence for a role of NMDA receptor hypofunction comes from observations that drugs which attenuate NMDA receptor action such as ketamine induce both positive and negative symptomology of Schizophrenia and animal models of the disease and drugs which enhance NMDA receptor action do the opposite.

Question 12

Give examples of typical/ fir-gen anti-psychotics

Answer 12

Haloperidol

Chlorpromazine

Question 13

Give exmaples of atypical/second-gen anti-psychotics

Answer 13

Clozapine

Question 14

Which symptoms are typical antipsychotics used to treat?

Answer 14

the positive symptoms of schizophrenia,

however negative symptoms cannot be controlled in this way

Question 15

What do antipsychotics target? What is htier mechanism of action?

Answer 15

D2 receptors

They can act as antagonists or partial agonists

Question 16

Side effects of typical antipsychs

Answer 16

1. these drugs exert numerous and varied side effects, probably by acting on other receptors
   (eg. 5-HT 2A , H 1 and muscarinic) and also acting on D 2 receptors present in other areas of the brain and
   so disrupting brain dopaminergic pathways

E.g. nigrostriatal pathway → movement disorders
Tuberoinfundibular pathway from the hypothalamus→ pituitary may also be affected → endocrine disturbances → lactation

Other side effects:

• reduced pleasure
• anticholinergic effects (e.g. dry mouth etc)
• hypotension
• weight gain

Question 17

Describe atypical antipsychs

Answer 17

• may be better as some cases cant be controlled by typical
• may have fewer ‘extra-pyramidal side effects (may be since while typical
  antipsychotics show some selectivity for D 2 over D 4 and presynaptic D 1 receptors, second-generation
  antipsychotics are highly D 2 -selective so act less on D 1 receptors)
• Clozapine is toxic → lowered white cell count, cardiotoxicity