Schizophrenia

Question 1

What is SP? (4)

Answer 1

-long duration -Delusions and hallucinations -Anhedonia, social withdrawral -Cognitive symptoms

Question 2

Prevalence of SP

Answer 2

1%

Question 3

How many patients don’t respond?

Answer 3

30%

Question 4

Carlsson (1963)

Answer 4

Antipsychotic drugs reduce dopaminergic signalling. Enhanced accumulation of the metabolites of dopamine in rat brains, measured by chromatography

Question 5

Seeman (1975)

Answer 5

PET studies using radiotracer for D2 receptor. Clinical efficacy of most antipsychotics directly correlates with their ability to bind D2 receptor.

Question 6

Abi-Dargham (1998)

Answer 6

In vivo radiotracer assay for D2. After challenge with amphetamine, dopamine transmission increased more in SP patients than in healthy controls

Question 7

Kapur

Answer 7

Argues that dopamines role in providing salience to stimuli in out environment could require individuals to explain experience of aberrant salience through development of delusional constructs

Question 8

Why not dopamine in striatum?

Answer 8

Typical antipsychotics have little effect on - symptoms

Question 9

Silfstein (2015)

Answer 9

In vivo imaging of dopamine release in PFC through PET scanning. Deficit in capacity for dopamine release in DL PFC in SP patients.

Question 10

Evidence for PFC dopamine

Answer 10

-Silfstein (2015) -Pycock (1980s) -Human frontal lesions

Question 11

Pycock (1980s)

Answer 11

link excess dopamine in striatum with low concs in PFC. Lesions in PFC dopaminergic neurons lead to increased dopamine and D2R density in the striatum.

Question 12

Glutamate genes related to SP

Answer 12

-Dysbindin (uptake of glutamate into synaptic vesicles) -Neuregulin 1 (recruitment of NMDA receptors to synapse)

Question 13

Pleiomorphic roles of Neuregulin 1

Answer 13

-Interneuron migration -Myelination

Question 14

Weinberger

Answer 14

Mechanistic understanding of glutamate. NMDA hypo-function in cortical interneurons, leading to hyperexcitability of pyramidal neurons, acting on dopaminergic neurons. Increase stimulation of striatum and decrease stimulation of the PFC.

Question 15

Mohn (1999)

Answer 15

Mice expressing 5% of normal levels of the NR1 subunit of the NMDAR show behavioural alterations - increased motor activity and stereotypy. Ameliorated through action of antipsychotics.

Question 16

Belforte (2010)

Answer 16

transgenic mice with NR1 subunit selectively eliminated in around half of cortical neurons early in postnatal development show behavioural defecits in mating, nest-building and novelty-induced hyperlocomotion.

Question 17

Why not model animals?

Answer 17

-Symptoms hard to demonstrate in models -No known molecular or cellular abnormalities that can demonstrate SP phenotype.

Question 18

What receptor does clozapine act at?

Answer 18

Inverse agonist on 5-HT2C receptors for serotonin.

Question 19

Simpson (2011)

Answer 19

transgenic mouse line with increased striatal specific D2R density as model. Reversible increase in 5-HT2C receptor expression. Low level of motivation overcome by antagonist to receptor, not achieved by D2R blockade.

Question 20

Environmental factors increasing SP

Answer 20

-maternal malnutrition -maternal infection -Obstetric complications

Question 21

Imaging studies in support of neurodevelopmental hypothesis show..

Answer 21

enlarged ventricles, loss of cortical volume. Present at onset of SP yet PM no evidence of ND

Question 22

Jakob (1986)

Answer 22

Abnormalities in laminar organisation of neurons in majority of 64 Sz patients, with no evidence of gliosis. Implies changes occur before late pregnancy.

Question 23

Straub (2002)

Answer 23

Genetic linkage analysis on high-density irish pedigrees showing dysbindin in SP.

Question 24

What is the etymology of ‘schizophrenia’

Answer 24

schizo - split phrenia - mind

Question 25

How does graph theory work?

Answer 25

Mathematical framework describing relationship between nodes and edges.

Question 26

What is the assumption of graph theory?

Answer 26

Assumes that brain network organisation is guided by tendency to maximise communication efficiency whilst minimising connection cost.

Question 27

Alexander-Bloch (2010)

Answer 27

Used graph theory to investigate the topology of networks derived from fMRI data on COS and healthy volunteers. Modularity of brain networks decreased in COS, reduced density of intra-molecular connections.

Question 28

Gage (2011)

Answer 28

Reprogrammed fibroblasts from SP patient into hiSPCs. Showed diminished neurite number and connectivity (transneuronal spread of rabies), also altered expression of NRG1. Loxapine increased connectivity, normalised expression of NRG1.

Question 29

What percent of prodrome pateints will devlop SP?

Answer 29

30%

Question 30

What is the name of the 108 study?

Answer 30

Schizophrenia working group of the psychiatric genomics consortium

Question 31

What did the 108 study find?

Answer 31

-DRD2 -GRM3 -Strong association between HLA locus and SP. Synaptogenesis. Histone gene cluster ( non specific GWAS)

Question 32

Singh (2016)

Answer 32

GWAS study showing LOF in SETD1A. Epigenetic dysregulation a mechanism in SP?

Question 33

How do GWAS and DNA sequencing approaches differ?

Answer 33

GWAS studies target common variants with small effect. DNA sequencing identifies rare sequence variants, with potentially large effects.

Question 34

Why are DNA sequencing approaches promising?

Answer 34

- genetic variants in general population unlikely - SP patients less likely to reproduce -Larger effect sizes, point in direction of more interpretable results

Question 35

Genovese (2016)

Answer 35

DNA sequencing study of SP. Fail to implicate any specific genes (underpowered). Ultra-rare variants predicted to disrupt protein-encoding genes were enriched in sets of genes plausibly expressed at the synapse

Question 36

Seeman (1975) graph

Answer 36