Schizophrenia Flashcards
What is schizophrenia?
- Mental disorder chracterised by episodes by psychosis
- Prevalence of ~0.5-1% of population
- Typical onset in early twenties (males) and late twenties (females)
What are the ‘Positive symptoms’ of schiczophrenia?
- Positive Symptoms: Experiences that add to normal function
Hallucinations
* Sensory experiences that are not real
* Sounds, visions, smells, tastes, touch
Illusions
* Distortions of visual input (e.g. moving patterns in carpets)
Delusions
* Beliefs not based on evidence
* Paranoia, grandiosity
What are the ‘negative symptoms’ of Schizophrenia?
Experiences that detract from normal function.
Avolition
* Lack of motivation
* Apathy
Anhedonia
* Inability to feel pleasure
* Social withdrawal
Flat affect
* Reduced emotional range
* Poverty of speech
What are the cognitive symptoms?
Decreased performance in key aspects of cognition
* Verbal fluency
* Problem solving
* Memory and learning
* Visual processing (facial recognition, optical illusions)
* Social cognition
- Reduction of IQ by 20-30%
- Often has the bigest impact on life outcomes
What causes Schizophrenia to develop?
- Heritability of risk ~10% with one parent, ~50% with both parents
- Numerous other risk factors identified
1. Obstetric complications
2. Birth season (winter, spring)
3. Viral infection
4. Childhood trauma
5. Substance abuse
6. Urban living
7. Social isolation or alienation
What was the hunt for genes?
- Genome-wide association study identified 108 risk-linked loci
What is the neurodevelopmental hypothesis?
- Combination of genes and environment
- Individuals at genetic risk are exposed to an environmental trigger during key stages of development
- Disruption of brain development in early life leads to psychosis in adulthood
What are the schizophrenia disease mechanisms?
Dopamine hypothesis
- Hyperactivity in mesolimbic tract
1. Positive symptoms - Hypoactivity is mesocortical tract
1. Negative symptoms
How are rewards and movement processed in striatum?
- Integrates inputs from multiple brain regions
- Interpretation of sensory inputs and emotional context
Ventral striatum
* Nucelus accumbens
* Reward and motivation
Dorsal striatum
* Caudate mucleus and putamen
* Movement
What stimulus salience and delusion?
- Subvisions of striatum for diff functions
- Associative striatum is linked to goal-directed action and stimulus salience
- Increased dopamine synthesis and release in patients
What are the classes of antipsychotics?
- First generation (typical)
- Second generation (atypical)
What are first generation antipsychotics?
- Positive symptom treatment, but negative symptoms can worsen
- Dopamine receptor antagonists
- Common extrapyrimidal side effects (parkinsonism etc)
- E.G. Chlorprozamine
What are second generation antipsychotics?
- Reduced extrapyrimidal side effects
- Treat both positive and negative symptoms
- Variable pharmacological targets profiles
- E.g. Risperidone
What are D2 receptor antagonists?
- Inc Dopamine release and inc D2 receptor density in schizophrenic patients
- Dopamine ‘supersensitivity’ in response to amphetamines (Inc risk of positive symp in schizophrenic patients)
- Antagonists to reverse this hyperactivity
- Principal mechanism of all approved antipsychotics
- Close correlation between binding affintiy and therapeutic dose
What are D2R roles in the striatum?
- Presynaptic D2 receptors on inputs (Dec NT release)
- Postsynaptic D2 receptors on a subclass of spiny projection neurons (SPN)
- Postsynpatic D2 receptors on cholinergic interneurons (CIN)
What is D2 receptor signalling?
- Classical route through Gi/o inhibition of adenylyl cyclase
- Alternate pathways via PLC and Akt
- Downstream targets vary in cell types and location
- High and low affinity states for D2R proposed
What are New Horizons for schizophrenia?
Glutamate hypothesis
* NMDA receptor anagonsits cause schizophrenia symptoms
* Altered glutamine/glutamate metabolism in patients
Neuroinflammation
* Inc microgial activation in patients
* D2 receptor expression on lymphocytes
- LIkely to be multifactorial, as with most CNS problems
Summarise schizophrenia
- Schzophrenia has positive, negative and cognitive symptoms
- Genetic and environmental factors can increase risk
- Disruption at early developmental stages leads to onset in adulthood
- Dopamine transmission to striatum (mesolimbic) incd, and to cortex (mesocortical) decreased
- Antipsychotics classed as typical and atypicla according to receptor targets and side effect profile
- D2 receptor antagonists effective at treating positive symptoms.
