Lecture 59: Neurobiology of Psychosis

Question 1

What is a key characteristic of schizophrenia?

Answer 1

Schizophrenia is an illness with a high degree of HETEROGENEITY
Patients present differently
Neurobio of illness remains poorly understood/characterized

Question 2

What are the characteristics of the brain of schizophrenics?

Answer 2

Greater ventricular volume
Less gray matter
Progressive loss of gray matter at a faster rate

Question 3

What is the heritability of schizophrenia?

Answer 3

60%

If you have an identical twin with schizo, you have 50% chance risk of having it too

Question 4

What is schizophrenia viewed as?

Answer 4

A neurodevelopmental disorder reflecting gene-environment interaction

Question 5

What are the early factors that lead to Schizophrenia?

Answer 5

Deleterious events disrupt brain development
Pre-natal development (early)
Peri-postnatal brain development (late
Disruption may lead to miswiring within and across different brain regions, dysregulation of neurotransmitters
Vulnerability may be mediated by genes

Question 6

What are late factors that lead to schizophrenia?

Answer 6

Environmental factors like substance use (marijuana) and psychosocial stress

Question 7

What is an endophenotype?

Answer 7

Some shit that you can use to identify subgroup of patient population to look for genetic similarities

Question 8

When can environment factors fcuk with you?

Answer 8

Perinatal and during adult life
Example of former = influenza in mother
Example of latter = stress in life

Question 9

What are the genetics of schizophrenia?

Answer 9

Results have been disappointing
Candidate genes include 
	DISC1
	Dysbindin
	Neuregulin
	COMT
Only explain a very small number of people with schizophrenia

Question 10

What is prepulse inhibition? Significance to schizophrenia?

Answer 10

The ability to control startle response to sudden loud noise
Schizophrenic patients do not suppress startle response and lacks prepulse inhibition
Could be linked to less neuregulin

Question 11

What is the strongest risk factor of schizophrenia?

Answer 11

Place and season of birth
-people living in the country are less likely to have schizophrenia
14% of schizophrenia cases would NOT have occurred if influenza exposure during early to mid pregnancy had been preventd
Also stress may be a risk factor

Question 12

What is the size of nasal cavities of schizophrenia? Olfactory bulbs?

Answer 12

Patients have smaller nasal cavity
Smaller olfactory bulbs
Reflects abnormality of development during the first trimester

Question 13

What is DISC1?

Answer 13

Protein that is important in neuronal migration
In schizophrenic patients, DISC1 is defective so may lead to the miswiring of schizophrenia
-Neuregulin, COMT, all have implications in synapse

Question 14

What is the dopamine hypothesis of schizophrenia?

Answer 14

Theory that schizophrenia is due to an abnormally HIGH dopamine illness
D2 receptor bidning correlates with antipsychotic efficacy of medications
Psychostimulants (amphetamine, cocaine) mimic positive psychotic symptoms
Implicated in only the POSITIVE symptoms of schizophrenia
Evidence 1: Proof: drugs that increase dopamine lead to schizophrenia-like symptoms
-schizophrenia medications act on dopamine system

Evidence 2: studies show that on average, schizophrenic patients have higher dopamine but not everybody…

Question 15

What sucks about dopamine hypothesis?

Answer 15

Is only true for subset of patients with subset of symptoms

Question 16

What is glutamate hypothesis of schizophrenia?

Answer 16

NMDA glutamate receptor ANTAGONISTS (PCP, ketamine) mimic BOTH positive and negative symptoms of acute schizophrenic break
NMDA receptor blockade at level of cortical interneuron can lead to glutamatergic hyperactivity in associated with pyramidal cells
Increased glutamate activity in pyramidal cells (vs. in interneuron) can have a neurotoxic effect, also result in secondary hyperdopaminergia (so goes with dopamine hypothesis)
Evidence 1: Reduction of NMDA glutamate receptors in schizophrenic patients??
Evidence 2: NMDA knockout mice have both positive and negative symptoms?

Question 17

Cocaine and amphetamine mimic

Answer 17

Only the POSITIVE symptoms of schizophrenia

Question 18

PCP and ketamine mimic

Answer 18

Both the positive and the negative symptoms of schizophrenia

Question 19

What drug improves negative symptoms in schizophrenia?

Answer 19

Clozepine

-atypical antipsychotic

Question 20

What are the candidate endophenotypes for schizophrenia?

Answer 20

1. Olfactory dysfunction
2. Eye movement dysfunction
3. Neuro-psychological deficits
4. P50 sensory gating defect
5. Impaired prepulse inhibition
6. Attentional Impairment

Question 21

What is mismatch negativity? Significance?

Answer 21

The ability to note the CHANGE in sound in environment
Patients with schizophrenia show LESS mismatch negativity or less ability to detect change in environment
Linked to Glutamate dysfunction
MOA of mismatch negativity (MMN) involves inhibitory neuron at the NMDA receptor

Question 22

What is an example of how schizophrenic patients can’t perceive the external world well?

Answer 22

Schizophrenic patients do not perceive the fact that there is a change from a square to no square
LACK of gamma oscillations, which are necessary to see change from square to no square

Question 23

What is the pathogenesis of schizophrenia?

Answer 23

-strong component of genetic susceptibility
-probable environmental insult during gestation
-Onset in early adulthood during time of synaptic refinement
-Multiple non-specific structural and functional abnormalities
-deficits in cortical synaptic function (interneurons?) give rise to failures in perceptual integration, cognition, motivation
Resulting increase in subcortical DA function gives rise to episodic positive symptoms