Schizophrenia Flashcards
Genetic causes
50 risk in identical twins.
1 parent has it: 12% risk.
a genome wide study identified 8 rare copies of gene variants that have strong association with schizophrenia, but are not disease specific
Environmental causes
Early lesion hypothesis: event stopping normal foetal development, e.g., maternal virus, hypoxia, or prematurity, or early life neglect
late lesion hypothesis: dysfunction in neuronal maturation during adolescence.
For adolescents, urban rearing, migration, social isolation, drug abuse, and stress associated
Neurobiology
Developmental rather than degenerative.
structural abnormalities present at onset, and do not worsen.
6-10% volume reduction, particularly in the hippocampus.
larger ventricles, smaller temporal lobe
hyperactive mesolimbic (positive)
hypoactive mesocortical (negative)
changes to D2/3 receptors
loss of GABA interneurones and glutamate hypofunction
Maternal immune activation and other early life risk factors
Increase in rate of schizophrenia in children born in winter - association due to maternal infection during pregnancy.
gene C4 has the highest association with schizophrenia. more encoded in schizophrenics
Several factors contributing to inappropriate cytokine cascades associated with increased risk: perinatal infection, preterm birth. For infants: stress, infection, malnutrition, microbiome, neglect, etc…
Antipsychotics
alpha-flupenthixol is a selective D2 antagonist.
Chlorpromazine is a common antipsychotic. causes apathy and reduced initiative. does cause extrapyramidal side effects as a result of D2 antagonism, e.g., spasms/rigidity, parkinsonism, restlessness (akathisia), dyskinesia
The dyskinesia may be associated with up regulation of DA receptors as a result of the treatment. goes on to have effects at other DA receptors. Also as a result of D2 receptors also being found as presynaptic receptors.
Clozapine mechanism
Atypical antipsychotic. Binds more to D3/4. has less extra-pyramidal side effects as a result. also a mAChR and alpha-AR antagonist.
Glutamate and schizophrenia
Associated with negative and cognitive effects.
NMDA hypofunction associated with the cognitive and negative symptoms. NMDA antagonists were found to exacerbate schizophrenia’s negative symptoms..
Several glutamatergic gene mutations (e.g., mGluR3 and neuregulin - NMDA) associated with schizophrenia.
Post-mortem, decreased [glutamate] and [D-serine] (which is associated with NMDAR hypofunction).
GABA (and NMDA mediation) and schizophrenia
Loss of GABA interneurons that innervate the mesolimbic pathway. May contribute to the hyperactivity of the pathway that causes the positive symptoms.
The NMDARs innervate the GABA interneurones. loss of the NMDA pathways leads to less release of GABA -> increased mesolimbic activation
