L19 - Schizophrenia 2 Flashcards
How do genes operate across diagnostic categories?
- Common alleles (polygenes)
- Rare alleles: CNVs
- Increased evidence for familial overlap inc. impairment of cognition and socially, developmental delay, perinatal risk factors
- Significant co-morbidity
- Genes are not for specific conditions, instead are for phentoypes that share characteristics inc. mental retardation, autism, ADHD, schiz, bipolar disorder
- More CNVs = more likely to have disorder
What do specific, recurrent CNVs confer?
- High risk of Schiz
- CNVs are addition/deletion of DNA
- 2.5% of schiz cases carries one prevalent CNV
What evidence is presented to support the polygenic model?
- Purcell et al (2014) - 2,563 schiz cases vs 2543 controls –find a polygenic burden primarily arising from rare mutations distributed across many genes (cluster on synaptic
plasticity/transmission). - Fromer et al (2014) - found that in schiz new (‘de novo’) mutations - these mutations are over-represented among glutamatergic post synaptic proteins (e.g. NMDA receptor complexes). Overlaps with autism and intellectual disability.
- Convergence onto synaptic networks - glutamate hypothesis
Relationship between neuroleptic drugs and Schiz?
- Neuroleptic drugs introduced in the 1950s
- Correlates to the number of patients in mental hospitals
- Important to remember that other things also supported this correlation: societial outlook
- Can have positive/negative side effects
What was the role of anti-psychotic drugs?
- Not targeted to specific brain regions but act generally
- Affect dopaminergic and glutamate systems
- Most people improve with the drug
- But a lot of people also improve with a placebo
What is the Dopamine Hypothesis?
Based on 3 primary observations:
- Pharmacology: chlorpromazine helpful for schiz = blocks dopamine receptors
- Amphetamines: linked to excess dopamine = abuse of amphetamine are more likely to experience paranoia and psychosis
- Parkinsons: low dopamine in basal ganglia = L-Dopa increases dopamine but side effect is psychotic episodes
- Post-mortem: Schiz patients have increased D2 receptors = but they have taken drugs to alter their brain
- Velocardiofacial syndrome: reduced IQ = deletion of genetic material on chromosome 22 = high risk of psychotic episodes
- COMT is candidate gene = involved in metabolism for dopamine
What studies show support for the dopamine hypothesis?
- Early studies = 2x increase in DA receptors – but many confounds, can’t rule out effect of medications.
- Twin studies = Increased D2 receptors in healthy co-twin of person with Dx of schiz
- First episode psychosis (drug free) - found higher levels of presynaptic DA in
striatum - Also, higher striatal
Dopamine in prodromal phase of schizophrenia (Howes et al 2009) - Image evidence of raised DA levels in striatum of 24
prodromal cases showing. Image indicates the synthesis and accumulation of dopamine in the striatum during
PET
What is the Glutamate hypothesis?
- PCP, ketamine (glutamate antagonist) induces hallucinations and cognitive changes consistent with schiz
- DA receptors inhibit release of glutamate leading to underactivity of glutamate receptors
Is schiz related to brain disease?
- Enlarged ventricles: reduction in tissue volume, and brain areas bordering ventricles have shrunk
- MRI studies of people with schiz show 3% reduction in whole brain volume
- Enlarged ventricles not found in all schiz patients
What are neuropsychological tests for schiz indicating brain disease?
- Poor performance on a range of neuropsych tests
- Attention problems on continous performance test (CPT) & eye tracking dysfunction
- Similar deficits observed in 1st degree relatives
- Deficits seen in P’s during 1st episode (rules out effect of medication & hospitalisation
What was a study looking at neuropsychological deficits?
- First episode schiz compared to IQ matched controls – multiple deficits in executive function, processing speed and verbal memory
- Increasing impetus to the idea that cognitive changes
maybe integral to
aetiology of schizophrenia - Brain damage in twins is different when one suffers from schiz
What was a study looking at ventricular volume by time in patients
- 107 first episode schiz. 51 had repeat MRIs at least 12 months later
- T1 and T2 ‘Schiz’ group had greater ventricular volum
- For those whose schiz symptoms did not improve, ventricular volume increased between T1 and T2
- Schiz has a reduction in white matter volume found in first episode
- White matter changes in temporal area predict later social functioning
- Reduction in corpus callosum in the children of people with schiz
What is the structural damage beyond the ventricles?
- Amygdala, hippocampus, thalamus and frontal lobes
- Alterations in brain regions for schiz are also implicated in other dopamine disorders
What are wide spread brain abnormalities (evidence)
- Pet scans show hypoactivity in brain of person with schiz
- Reduced blood in frontal cortex during WISC
- Impaired functioning of frontal lobes during cognitive tasks in early stages at high risk of schiz
What are the critiques of the brain abnormalities theory?
- Time lag in actions of drugs: blockage of dopamine happens in hours but benefit takes weeks
- 1/3 of patients do not respond to treatment
- Pharmacology more effective for positive than neg symptoms
- Not all studies find differences in DA receptors /alterations in brain functioning
- Well-matched stuides show modest differences in ventricular volume which is affected by sex/age/head size/ethnicity/class = ventricular size can change over time
- Dopamine abnormalities could be due to trauma
- Bi-directional influence between brain/chemicals/env
- Twin studies: could MZ rates be overestimated because they share env. MZ who share placenta have 60% concordance, but MZ who do not have 11% concordance
