Schizophrenia: Neurobiology and treatment Flashcards
Describe how genes cause schizophrenia
Genetic Risk:
1% general population up to ~50% risk in monozygotic twin
Partial penetrance
Likely to be polygenic multiple susceptibility genes
What is partial penetrance?
Interaction of the genes and environment
What do the genetics of schizophrenia overlap with?
Genetics of autism and other neurodevelopmental disorders
What is the peak age of onset for males?
20-28
What is the peak age of onset for females?
26-32
List some environmental events which may give rise to schizophrenia
Obstetric complications - prenatal infection, nutritional deficiency Adverse life effects Substance abuse (cannabis use 6X risk)
Describe some structural changes of schizophrenia
Ventricular enlargement
Reduced brain volume (less gray matter - temporal lobes, frontal lobes, subcortical structures)
Cytoarchitectural differences in cortex and hippocampus
Which structure in the brain is associated with hallucinations?
Paracingulate sulcus
What is the paracingulate sulcus used in?
Reality monitoring
Describe the neurodevelopmental model of schizophrenia
During adolescence grey matter is lost, if this happens excessively then this may cause early-onset schizophrenia
Describe the wisconsin card soring task
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.
Describe the neurophysiology of schizophrenia
Hypofrontality
Hyper-excitable sensory cortex
Abnormal neural oscillations
What is pruning?
Pruning is a sort of clean-up job conventionally thought to eliminate weak synapses and leave strong ones.
Occurs in adolescence
Describe hypofrontality
Increases on activity in dIPFC seen in healthy volunteers absent in schizophrenics
Correlate with negative and cognitive symptoms
Describe the fMRI evidence of auditory cortex activation during hallucinations
Patients press a button during
auditory verbal hallucinations –
Correlation with BOLD signal
What are oscillations?
important organizers of brain activity, plasticity and connectivity (*maturation)
What is meant by neuronal synchrony?
well-timed coordination and communication between neural populations
What happens to the oscillations during schizophrenia?
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.
How are dopamine neurons arranged in the brain?
Cell bodies in the midbrain which project to the forebrain
What are the components of the dopaminergic system?
Nigrostriatal system -
Mesolimbic system
Mesocortical system
What is the gamma rhythm used for?
Attention
Perception
Working memory
What is the mesocorticolimbic system used for?
Reward and reinforcement, provides stimulus salience
What was the first antipsychotic drug?
Chlorpromazine
What is haloperidol?
More potent than chlorpromazine
Which drugs are given to prevent positive symptoms?
Typical antipsychotic (nuroleptic) drugs
What are typical antipsychotics?
D2 receptor antagonists
What are the side effects of typical antipsychotics?
Parkinsonian-like side effects:
Antipsychotic dosage correlates with their potency as D2 receptor antagonists
Give some examples of dopamine agonists
cocaine, amphetamine, L-DOPA
What can dopamine agonists do?
cause positive symptoms of schizophrenia (e.g. psychosis)
How are drug induced psychosis treated?
treated with the D2 antagonist antipsychotic drugs.
Which G protein is the DR receptor coupled to?
Gi
What are atypical antipsychotics?
Atypical antipsychotics can work in patients resistant to typicals
Atypicals do not have same extra-pyramidal side effects (lower activity at D2 receptor)
What is the main atypical antipsychotic?
Clozapine
Where does clozapine act?
activity mainly at D4 receptors (also binds D3, D1, D2, D5)
5HT receptors
improves positive and negative symptoms
Give the side effects of clozapine
weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia (needs to be watched - blood tests)
List some other atypical antipsychotics
Risperidone, Olanzapine - differing affinities for receptor subtypes, varying levels of side effects.
Give evidence of the glutamate hypothesis in schizophrenia?
PCP Causes many positive, negative and cognitive symptoms of schizophrenia
NMDA receptor antagonist
Genetically engineered mice with
fewer NMDA receptors.
Describe PCP treatment results in animal studies
NMDA antagonism in PFC - less glutamatergic firing to VTA GABA neurons
Less GABAergic inhibition of VTA-NAcc DA neurons
Greater DA release in NAcc
Less activation of VTA-PFC DA neurons - less Glu - hypofrontality
What are dopamine agonists?
Causes psychosis
What are dopamine antagonists?
Antipsychotic
Where do dopamine agonists and antagonists act?
Nucleus accumbens
What do atypical antipsychotic drugs do?
Increase DA activity in PFC
and
Decrease DA in NAcc
How do the different drugs affect the enduring symptoms of the disease?
typical antipsychotics - no effect on these symptoms
atypicals - some improvement, e.g. increase verbal fluency
List the neurocognitive deficits of schizophrenia
Lower IQ Attentional deficits (e.g. Stroop Test) Working memory (e.g. Wisconsin Card Sorting Test) Planning and information processing deficits
How do schizophrenia patients perform on the stroop test?
Patients with schizophrenia are slower and less accurate (hard time inhibiting the other contextual information and attending to the colours)
