Schizophrenia: Neurobiology and Treatment

Question 1

Schizophrenia is a …: a collection of signs and symptoms of unknown …, predominantly defined by observed signs of …

Answer 1

Schizophrenia is a syndrome: a collection of signs and symptoms of unknown aetiology, predominantly defined by observed signs of psychosis.

Question 2

Aetiology of schizophrenia - what causes it?

• Genes and environment
• Genetic Risk:
  
  • 1% general population up to ~…% risk in monozygotic twin
• Partial … (interaction of genes and environment)
• Likely to be p… - multiple susceptibility genes
• Presence of these and environmental factors triggers schizophrenia

Answer 2

• Genes and environment
• Genetic Risk:
  
  • 1% general population up to ~50% risk in monozygotic twin
• Partial penetrance (interaction of genes and environment)
• Likely to be polygenic - multiple susceptibility genes
• Presence of these and environmental factors triggers schizophrenia

Question 3

Genetic Risk - Schizophrenia:

• …% general population up to ~…% risk in monozygotic twin

Answer 3

1% general population up to ~50% risk in monozygotic twin

Question 4

The genetics of schizophrenia

Answer 4

• “Genes do not encode hallucinations, delusions or thought disorganisation per se. Genes determine the structure of simple molecules in cells, usually proteins, and these proteins affect how cells process and respond to stimuli. A variation in the sequence of a gene… could lead to changes in the interactions that cell has with other cells, in the connections and cell assemblies that develop, and in how such assemblies and networks operate as functional systems”
• Daniel Weinberger, World Psychiatry, 2002

Question 5

Genes and Environment

• Onset of schizophrenia
  
  • males 20-28 years, females 26-32
• (Post synaptic pruning events during puberty - brain maturation)
• Genetic factors - … genes
• Environmental factors:
  
  • birth - … complications, … infection, … deficiency
  • adolescence - … life effects, … misuse -> 6x risk using cannabis

Answer 5

• Onset of schizophrenia
  
  • males 20-28 years, females 26-32
• (Post synaptic pruning events during puberty - brain maturation)
• Genetic factors - susceptibility genes
• Environmental factors:
  
  • birth - obstetric complications, prenatal infection, nutritional deficiency
  • adolescence - adverse life effects, substance misuse -> 6x risk using cannabis

Question 6

How much does cannabis increase risk of schizophrenia?

Answer 6

6x

Question 7

Onset for schizophrenia (males)?

Answer 7

20-28

Question 8

Onset for schizophrenia (females)?

Answer 8

26-32

Question 9

Neuropathology of Schizophrenia:

• Structural changes:
  
  • … enlargement
  • … brain volume (… gray matter) (temporal lobes, frontal lobes, subcortical structures)
  • Cytoarchitectural differences in … and hippocampus

Answer 9

• Structural changes:
  
  • Ventricular enlargement
  • Reduced brain volume (less gray matter) (temporal lobes, frontal lobes, subcortical structures)
  • Cytoarchitectural differences in cortex and hippocampus

Question 10

Neuropathology of Schizophrenia:

• Structural changes:
  
  • Ventricular …
  • Reduced brain volume (less … matter) (temporal lobes, frontal lobes, subcortical structures)
  • Cytoarchitectural differences in cortex and …

Answer 10

• Structural changes:
  
  • Ventricular enlargement
  • Reduced brain volume (less gray matter) (temporal lobes, frontal lobes, subcortical structures)
  • Cytoarchitectural differences in cortex and hippocampus

Question 11

Which have schizophrenia?

Answer 11

• ventricular enlargement and reduced brain volume

Question 12

Neuropathology - Schizophrenia

• … sulcus morphology associated with hallucinations:
  
  • J.R. Garrison et al. 2015, Nature communications
• … length of the sulcus had a correlation with hallucinates

Answer 12

• Paracingulate sulcus morphology associated with hallucinations:
  
  • J.R. Garrison et al. 2015, Nature communications
• Shorter length of the sulcus had a correlation with hallucinates

Question 13

Neurodevelopmental model of schizophrenia

• During adolescence grey matter is … (pink), which may speed up in …-… schizophrenia
  
  • (Grey matter … can be due to: 1. synaptic pruning and 2. increased myelination)

Answer 13

• During adolescence grey matter is lost (pink), which may speed up in early-onset schizophrenia
  
  • (Grey matter loss can be due to: 1. synaptic pruning and 2. increased myelination)

Question 14

Wisconsin Card Sorting Task

• You are told to … the sample, but not … to … it
• . Sensitive to executive dysfunction, set-shifting, cognitive flexibility etc.
• Those with Schizophrenia have little engagement of what cortex? whereas healthy volunteers?

Answer 14

• You are told to match the sample, but not how to match it (what the rule of matching is in the current trial). Sensitive to executive dysfunction, set-shifting, cognitive flexibility etc.
• Schizophrenia- little frontal cortex engagement, whereas healthy volunteers use frontal cortex

Question 15

Neurodevelopmental model of schizophrenia

• measure used: gray matter …
  
  • 12 patients vs. 12 controls MRI scanned repeatedly over 5 years
  • (aged ~14 years at first scan)
• . A consistent pattern of progressive gray matter … in those with schizophrenia, in parietal, frontal, and temporal cortices, is observed in independent groups of males and female patients.

Answer 15

• measure used: gray matter density
  
  • 12 patients vs. 12 controls MRI scanned repeatedly over 5 years
  • (aged ~14 years at first scan)
• . A consistent pattern of progressive gray matter loss in those with schizophrenia, in parietal, frontal, and temporal cortices, is observed in independent groups of males and female patients.

Question 16

Neurophysiology - Schizophrenia

• Functional changes:
  
  • … cortex activation during hallucinations (fMRI evidence)

Answer 16

• Functional changes:
  
  • Auditory cortex activation during hallucinations (fMRI evidence)

Question 17

Neurophysiology of Schizophrenia

• Functional changes:
  
  • Hypofrontality during periods of high … load
    
    • (e.g. Wisconsin Card Sorting Test - test of … flexibility)
  • Increases in activity in … seen in healthy volunteers absent in schizophrenics.

Answer 17

• Functional changes:
  
  • Hypofrontality during periods of high cognitive load
    
    • (e.g. Wisconsin Card Sorting Test - test of cognitive flexibility)
  • Increases in activity in dlPFC (dorsolateral prefrontal cortex ) seen in healthy volunteers absent in schizophrenics.

Question 19

Neurophysiology - Schizophrenia

• Functional changes:
  
  • Auditory cortex activation during … (fMRI evidence)
  • … frequency oscillations and synchrony emerge during the transition from adolescence to adulthood.
  • Differences in neural oscillations and synchrony between … and patients with …

Answer 19

• Functional changes:
  
  • Auditory cortex activation during hallucinations (fMRI evidence)
  • High frequency oscillations and synchrony emerge during the transition from adolescence to adulthood.
  • Differences in neural oscillations and synchrony between controls and patients with schizophrenia.

Question 20

Psychopharmacology - Schizophrenia

• Dopamine neurons
  
  • • cell bodies in the …
  • • project into the …
• Nigrostriatal system
• … system and … system = Mesocorticolimbic pathway (reward & reinforcement, provides stimulus salience)

Answer 20

• Dopamine neurons
  
  • • cell bodies in the midbrain
  • • project into the forebrain
• Nigrostriatal system
• Mesolimbic system and Mesocortical system = Mesocorticolimbic pathway (reward & reinforcement, provides stimulus salience)

Question 21

Psychopharmacology - Schizophrenia

• … neurons
  
  • • cell bodies in the midbrain
  • • project into the forebrain
• … system
• Mesolimbic system and Mesocortical system = Mesocorticolimbic pathway (reward & …, provides … salience)

Answer 21

• Dopamine neurons
  
  • • cell bodies in the midbrain
  • • project into the forebrain
• Nigrostriatal system
• Mesolimbic system and Mesocortical system = Mesocorticolimbic pathway (reward & reinforcement, provides stimulus salience)

Question 22

Psychopharmacology - Schizophrenia - Dopamine hypothesis – evidence

• 1) Typical Antipsychotic (neuroleptic) Drugs
  
  • … receptor antagonists
  • Prevent positive symptoms
  • First antipsychotic (discovered in 1950s): Chlorpromazine
  • H…: more potent than Chlorpromazine
  • ….-like side effects: - dopamine mechanism?
  • Antipsychotic dosage correlates with their potency as … receptor antagonists
• 2) DA agonists e.g. cocaine, amphetamine, L-DOPA can (in large doses) cause positive symptoms of schizophrenia (e.g. psychosis)
  
  • These drug-induced psychoses can be treated with the … antagonist antipsychotic drugs.

Answer 22

• 1) Typical Antipsychotic (neuroleptic) Drugs
  
  • D2 receptor antagonists
  • Prevent positive symptoms
  • First antipsychotic (discovered in 1950s): Chlorpromazine
  • Haloperidol: more potent than Chlorpromazine
  • Parkinsonian-like side effects: - dopamine mechanism?
  • Antipsychotic dosage correlates with their potency as D2 receptor antagonists
• 2) DA agonists e.g. cocaine, amphetamine, L-DOPA can (in large doses) cause positive symptoms of schizophrenia (e.g. psychosis)
  
  • These drug-induced psychoses can be treated with the D2 antagonist antipsychotic drugs.

Question 23

Psychopharmacology - Schizophrenia - Dopamine hypothesis – evidence

• 1) Typical Antipsychotic (neuroleptic) Drugs
  
  • D2 receptor antagonists
  • Prevent … symptoms
  • First antipsychotic (discovered in 1950s): C…
  • Haloperidol: more potent than C…
  • Parkinsonian-like side effects: - dopamine mechanism?
  • Antipsychotic dosage correlates with their … as D2 receptor antagonists
• 2) DA … e.g. cocaine, amphetamine, L-DOPA can (in large doses) cause … symptoms of schizophrenia (e.g. …)
  
  • These drug-induced psychoses can be treated with the D2 antagonist antipsychotic drugs.

Answer 23

• 1) Typical Antipsychotic (neuroleptic) Drugs
  
  • D2 receptor antagonists
  • Prevent positive symptoms
  • First antipsychotic (discovered in 1950s): Chlorpromazine
  • Haloperidol: more potent than Chlorpromazine
  • Parkinsonian-like side effects: - dopamine mechanism?
  • Antipsychotic dosage correlates with their potency as D2 receptor antagonists
• 2) DA agonists e.g. cocaine, amphetamine, L-DOPA can (in large doses) cause positive symptoms of schizophrenia (e.g. psychosis)
  
  • These drug-induced psychoses can be treated with the D2 antagonist antipsychotic drugs.

Question 24

First antipsychotic (discovered in 1950s): ?

Answer 24

Chlorpromazine

Question 25

Haloperidol VS Chlorpromazine - which is more potent?

Answer 25

**Haloperidol** VS Chlorpromazine - which is more potent?

Question 26

_Psychopharmacology - Schizophrenia_ * Correlation of drug effective ... in controlling schizophrenia and drug binding ... for D2 receptors

Answer 26

* Correlation of drug effective **dose** in controlling schizophrenia and drug binding **affinity** for D2 receptors

Question 27

_Dopamine hypothesis contd. (schizophrenia)_ * D1 receptor family - (... coupled) * D1 - caudate - putamen, NAcc, olfactory, tubercule * D5 - hippocampus, hypothalamus * D2 receptor family - (... coupled) * D2 - caudate, putamen, NAcc, etc * D3 - NAcc * D4 - frontal cortex * Assessment - But note the non ... distribution of ... in the caudate, putamen, Nacc, and ... in the frontal cortex

Answer 27

* D1 receptor family - (**Gs** coupled) * D1 - caudate - putamen, NAcc, olfactory, tubercule * D5 - hippocampus, hypothalamus * D2 receptor family - (**Gi** coupled) * D2 - caudate, putamen, NAcc, etc * D3 - NAcc * D4 - frontal cortex * Assessment - But note the non **overlapping** distribution of **D2Rs** in the caudate, putamen, Nacc, and **D4R** in the frontal cortex

Question 28

note the non overlapping distribution of D..R in the caudate, putamen, Nacc, and D..R in the frontal cortex

Answer 28

note the non overlapping distribution of D2Rs in the caudate, putamen, Nacc, and D4R in the frontal cortex

Question 29

_Typical vs. atypical antipsychotics (Schizophrenia)_ * Atypical antipsychotics can work in patients ... to typicals * Atypicals do not have same ...-... side effects (lower activity at D2 receptor) * C... activity mainly at D4 receptors (also binds D3, D1, D2, D5) 5HT receptors * improves positive and negative symptoms * side effects - weight ..., S..., Hyper..., tachycardia, hypo..., neutro... (needs to be watched - blood tests) * Other atypicals: * Risperidone, O... - differing affinities for receptor subtypes, varying levels of side effects.

Answer 29

* Atypical antipsychotics can work in patients **resistant** to typicals * Atypicals do not have same **extra-pyramidal** side effects (lower activity at D2 receptor) * **Clozapine** activity mainly at D4 receptors (also binds D3, D1, D2, D5) 5HT receptors * improves positive and negative symptoms * side effects - **weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia** (needs to be watched - blood tests) * Other atypicals: * Risperidone, **Olanzapine** - differing affinities for receptor subtypes, varying levels of side effects.

Question 30

_Typical vs. atypical antipsychotics (Schizophrenia)_ * Atypical antipsychotics can work in patients resistant to typicals * Atypicals do not have same extra-pyramidal side effects (lower activity at ... receptor) * Clozapine activity mainly at ... receptors (also binds D3, D1, D2, D5) 5HT receptors * improves ... and ... symptoms * side effects - weight gain, sedation, hypersalivation,...cardia, hypotension, neutropenia (needs to be watched - blood tests) * Other atypicals: * R..., Olanzapine - differing affinities for receptor subtypes, varying levels of side effects.

Answer 30

* Atypical antipsychotics can work in patients resistant to typicals * Atypicals do not have same extra-pyramidal side effects (lower activity at **D2** receptor) * Clozapine activity mainly at **D4** receptors (also binds D3, D1, D2, D5) 5HT receptors * improves **positive** and **negative** symptoms * side effects - weight gain, sedation, hypersalivation, **tachycardia**, hypotension, neutropenia (needs to be watched - blood tests) * Other atypicals: * **Risperidone**, Olanzapine - differing affinities for receptor subtypes, varying levels of side effects.

Question 31

List 3 atypical antipsychotics

Answer 31

Risperidone, Olanzapine, Clozapine

Question 32

_Psychopharmacology - Schizophrenia - Gluamate Hypothesis evidence_ * 1) PCP (phencyclidine, angel dust) * Causes many positive, negative and ... symptoms of schizophrenia * ... receptor antagonist * 2) Genetically engineered mice with fewer ... receptors. (social ... - same as in schizophrenia - faulty glutamate)

Answer 32

* 1) PCP (phencyclidine, angel dust) * Causes many positive, negative and **cognitive** symptoms of schizophrenia * **NMDA** receptor antagonist * 2) Genetically engineered mice with fewer **NMDA** receptors. (social **isolation** - same as in schizophrenia - faulty glutamate)

Question 33

_PCP treatment used to model schizophrenia in animal studies:_ * 1) NMDA antagonism in PFC - less ... firing to VTA GABA neurons * 2) Less ... inhibition of VTA-NAcc DA neurons * 3) Greater ... release in NAcc * 4) Less activation of VTA-PFC DA neurons - less Glu - hypo...

Answer 33

* PCP treatment used to model schizophrenia in animal studies: * 1) NMDA antagonism in PFC - less **glutamatergic** firing to VTA GABA neurons * 2) Less **GABAergic** inhibition of VTA-NAcc DA neurons * 3) Greater **DA** release in NAcc * 4) Less activation of VTA-PFC DA neurons - less Glu - **hypofrontality**

Question 34

* Dopamine ... - antipsychotic * Dopamine ... or ... drugs - cause psychosis

Answer 34

* Dopamine **antagonists** - antipsychotic * Dopamine **agonists** or boosting drugs - cause psychosis

Question 35

Where to antipsychotics work?

Answer 35

nucleus accumbens (and amygdala)

Question 36

... antagonists(PCP) - positive + negative + cognitive symptoms

Answer 36

**Glutamate** antagonists(PCP) - positive + negative + cognitive symptoms

Question 37

Glutamate antagonists(PCP) - ... + negative + ... symptoms

Answer 37

**Glutamate antagonists(PCP) - positive + negative + cognitive symptoms**

Question 38

* Glutamate antagonists(PCP) - positive + negative + cognitive symptoms * Action in PFC (feedback to DA system - ... active in NAcc and ...active in PFC)

Answer 38

* Glutamate antagonists(PCP) - positive + negative + cognitive symptoms * Action in PFC (feedback to DA system - **hyperactive** in NAcc and **hypoactive** in PFC)

Question 39

* Atypical antipsychotic drugs seem to: * ... DA activity in PFC and ... DA in NAcc

Answer 39

* Atypical antipsychotic drugs seem to: * **Increase** DA activity in PFC and **Decrease** DA in NAcc

Question 40

_Neurocognitive Deficits - Schizophrenia_ * Enduring symptom of the disease - * ... antipsychotics - no effect on these symptoms * ... - some improvement, e.g. increase verbal fluency * Lower ... * Attentional ... (e.g. Stroop Test) * ... memory (e.g. Wisconsin Card Sorting Test) * Planning and information processing deficits

Answer 40

* Enduring symptom of the disease - * **typical** antipsychotics - no effect on these symptoms * **atypicals** - some improvement, e.g. increase verbal fluency * Lower **IQ** * Attentional **deficits** (e.g. Stroop Test) * **Working** memory (e.g. Wisconsin Card Sorting Test) * Planning and information processing deficits

Question 41

_Neurocognitive Deficits - Schizophrenia_ * Enduring symptom of the disease - * typical antipsychotics - no effect on these symptoms * atypicals - some ..., e.g. increase verbal fluency * Lower IQ * ... deficits (e.g. Stroop Test) * Working memory (e.g. ... Card Sorting Test) * ... and ... processing deficits

Answer 41

* Enduring symptom of the disease - * typical antipsychotics - no effect on these symptoms * atypicals - some **improvement**, e.g. increase verbal fluency * Lower IQ * **Attentional** deficits (e.g. Stroop Test) * Working memory (e.g. **Wisconsin** Card Sorting Test) * **Planning** and **information** processing deficits

Question 42

_Stroop task_ * Patients with schizophrenia are ... and ... accurate

Answer 42

* Patients with schizophrenia are **slower** and **less** accurate (hard time inhibiting the other contextual information and attending to the colours)