L4 Schizophrenia

Question 1

What defines psychoses?

Answer 1

Defined by presence of:
*Delusions (fixed, false beliefs)
*Hallucinations (false sensory perceptions)
*Lack of insight

Question 2

What can psychoses be categorised into?

Answer 2

*Schizophrenia
*Bipolar disorder
*Delusional disorders (paranoid psychoses)
*Depressive psychosis
*Drug-induced psychoses (e.g. amphetamine, phencyclidine)
*‘Organic’ psychoses (e.g. neurosyphilis, partial complex epilepsy)

Question 3

What specific features are required for a schizophrenia diagnosis?

Answer 3

number, nature, and duration of psychotic symptoms
evidence for functional impairment
no evidence for an ‘organic’ or drug-induced psychosis

Question 4

With schizophrenia, what are the symptoms often divided into?

Answer 4

*Positive symptoms (delusions, hallucinations, thought disorder)
*Negative symptoms (loss of drive, poverty of speech, anhedonia) - often harder to recognise and patients don’t often seek help for them and are also often responsible for the long term impairment.
*Cognitive symptoms (not part of diagnosis, but important)

Overall: positive symptoms make the disorder to diagnose, negative and cognitive symptoms are what propagate it

Question 5

What are the 2 diagnostic systems for schizophrenia?

Answer 5

ICD-11 (World Health Organisation)
DSM-5 (American Psychiatric Association)

Question 6

What % of the population are affected by schizophrenia world wide?

Answer 6

Affects ~0.8% of the population, worldwide

Question 7

When is the age of onset?

Answer 7

Age of onset usually in early adulthood

Question 8

What is the sex ratio for schizophrenia?

Answer 8

Equal sex ratio, but men get it earlier and more severely

Question 9

What are the common outcomes for schizophrenia?

Answer 9

Course variable: ~20% recover; ~40% remit and relapse: 40% have chronic symptoms and impairment

Question 10

What is the effect of schizophrenia on mortality?

Answer 10

Increased mortality (x3) – suicide (~10%) and natural causes. Life expectancy reduced by 15-20 years

Question 11

What proportion of patients respond to treatment? What is the most effective?

Answer 11

~70% of patients respond reasonably to antipsychotic (neuroleptic) drugs (mainly talking about +ive symptoms)
Clozapine is more effective than other antipsychotics, but use is limited by side-effects and toxicity

Question 12

Are co-morbidities common with schizophrenia?

Answer 12

Co-morbidity common (esp. substance abuse)

Question 13

Describe the model of onset for schizophrenia

Answer 13

Question 14

What neurotransmitters are involved in schizophrenia?

Answer 14

Dopamine, Glutamate, Serotonin

Question 15

What is the dopamine hypothesis of schizophrenia?

Answer 15

The positive symptoms of schizophrenia are due to excess dopaminergic function
*too much dopamine
*increased sensitivity to dopamine
*increased density of receptors, etc

Question 16

What is the dopamine hypothesis of schizophrenia based on?

Answer 16

Based upon pharmacological inferences from dopamine-blocking and dopamine stimulating drugs
*Antipsychotics block DA receptors
*Drugs which enhance DA release (cocaine, amphetamines) produce psychosis

Question 17

What is the pharmacological model, proposed mechanism and therapeutics for Dopamine in schizophrenia?

Answer 17

*Pharmacological models - psychostimulants (cocaine/ amph)
*Proposed mechanism - D2 agonist
*Therapeutics - Antipsychotics (D2 antagonist)

Question 18

What evidence is there supporting insufficient dopamine function in PFC?

Answer 18

Sliftstein et al (2015)
Amphetamine challenge in patients with SCZ and controls. Patients showed reduced dopamine binding in the dorsolateral prefrontal cortex compared to controls. Reduced dopamine binding was associated with reduced activation of DLPFC during a working memory task (association with poor cognition)

Question 19

What are the lines of evidence for the involvement of glutamate in schizophrenia?

Answer 19

*NMDA receptor antagonists (e.g. ketamine, PCP) produce/worsen psychosis
*Enhancing NMDA receptor co-agonist function (e.g. via D-serine) may improve symptoms
*Glutamatergic mouse models ‘mimic’ schizophrenia
*Glutamatergic alterations in schizophrenic brain
*Schizophrenia genes preferentially affect glutamate synapses and NMDAR signalling
*Anti-NMDA receptor antibodies in some patients

Question 20

What is the relationship between dopamine and glutamate in schizophrenia?

Answer 20

Glutamate (cortex) is usually considered primary; dopamine (midbrain) is secondary
*Put another way, glutamate is trait, dopamine is state
*Other relationships are also possible
Eg. Largely independent ‘dopamine schizophrenia’ vs ‘glutamate schizophrenia

Question 21

What is the pharmacological model, proposed mechanism and therapeutics for Serotonin in schizophrenia?

Answer 21

*Pharmacological models - Psychedelics (LSD, Psilocybin)
*Proposed mechanism - 5-HT2A agonist
*Therapeutics - Antipsychotics (5HT2A blockers)

Question 22

What are other NTs potentially involved in the pathology of schizophrenia?

Answer 22

Question 23

What is the heritability of schizophrenia?

Answer 23

Heritability is high: 65-80%
From twin studies and population studies
But says nothing about how many genes, or how they work, or how penetrant they are

Question 24

Where does the remainder of risk (not genetic) come from?

Answer 24

Remainder of risk is mostly individual-specific environment (e.g. prenatal factors); a small amount is shared environment
And genetic and environmental risks interact

Question 25

What disorders share genetic risk with schizophrenia?

Answer 25

Bipolar disorder, also depression, autism

Question 26

What types of genetic mutations are seen in schizophrenia?

Answer 26

No causal mutations; no Mendelian forms

SNPs (single nucleotide polymorphisms). All have very small effect size (odds ratios <1.2), but cumulatively explain majority of heritability.

CNVs (copy number variants) – deletions and duplications of parts of a chromosome. Individually very rare, but big effect size when present. Explain ~ 5% of cases

Rare variants – importance unknown, but several genes identified

Question 27

How do genes affect schizophrenia risk?

Answer 27

Convergence on key pathways:
NMDAR signalling and synaptic plasticity
Calcium signalling
Histones and chromatin regulation
Immune function

Via effects on gene expression and splicing, especially in fetal brains (Gandal et al, Science 2018;362: eaat8127)

And affects some cell populations more than others (Skene et al, Nature Genetics 2018; 50: 825-833)
Pyramidal neurons
Medium spiny neurons

Question 28

Describe the neurodevelopmental model of schizophrenia.

Answer 28

*Schizophrenia results from abnormal brain development
*Attributed to Weinberger (1987) – though first proposed in 1892
*The disease process long precedes the onset of symptoms

Question 29

What are the different versions of the neurodevelopmental model for schizophrenia?

Answer 29

Different versions of the model
- second trimester (neuronal migration, synaptogenesis)
- adolescence (synaptic pruning, hormonal influences)
- both (aberrant plasticity)

Question 30

What are some environmental risk factors for schizophrenia?

Answer 30

Question 31

Describe a timeline of schizophrenia development

Answer 31

Question 32

What are atypical antipsychotics?

Answer 32

A drug which does not produce catalepsy (= EPS) in rats
despite an antipsychotic profile in behavioural tests.
Originally referred specifically to clozapine.

Subsequently used (often by pharma) to refer to each new antipsychotic, which was claimed to:
…be more effective
…be effective against negative symptoms
…work like clozapine

Much hype about how (and how much) atypicals are
better than the older (typical) antipsychotics: in fact differences are modest.

In any event, (a)typicality is a spectrum not a dichotomy

Question 33

What makes an antipsychotic atypical?

Answer 33

Many theories, including:

*5-HT2A receptor (5-HT2: D2) antagonism

*D4 or D3 receptor antagonism

*Time course and reversibility of D2 receptor occupancy (as bind less tightly, so less risk of developing extra-pyramidal side-effects)

Question 34

How do atypicals differ in duration of D2 receptor occupancy?

Answer 34