Schizophrenia Flashcards
Symptoms
Positive symptoms: delusions, hallucinations, reality distortion, thoughts disorder.
Negative symptoms: social withdrawal, decreased emotional response
Cognitive dysfunction such as dementia may also occur.
Neurotransmission
Positive symptoms are caused by a hyperactivity of mesolimbic dopamine neurons.
Negative symptoms are caused by a hypoactivity of mesocortical dopamine neurons.
Changes in dopamine D2 and D3 receptors are seen. These could be due to genetic factors or drug use.
Cognitive effects may be caused by glutamate hypofunction and a loss of GABAergic interneurons in the striatum.
Characteristics
Neurodevelopmental disorder.
Brain structure abnormalities are present at the onset of psychosis.
6-10% reduction in brain volume, particularly in the hippocampus.
Reduced temporal lobe
Enlarged ventricles.
Risk factors
12% risk if one parent has it and 50% risk in identical twins
The early lesion hypothesis suggests that foetal or perinatal events, such as a maternal viral infection, hypoxia or premature birth, interacting with normal development and synapse formation are associated with an increased risk. This is altered by early life stress affecting development, such as neglect.
The late lesion hypothesis suggests that deviation in neuronal maturation during adolescence is involved.
Compared with non-cannabis users, daily use of high-potency, skunk-like cannabis is associated with a fivefold increase of developing psychosis.
Maternal immune activation
There is a 2-fold increase in risk for babies born in the winter, possibly due to maternal infection and increased inflammation during pregnancy.
Prenatal exposure to infection can lead to an immune hyperesponse in genetically predisposed individuals. This may affect the meninges and alter the BBB, impacting neurodevelopment.
Genetic risk factors
C4 (complement component 4) is associated with a significant increase in risk. C4 expression is higher in SZ.
SNP most significantly associated with SZ lies within the major histocompatibility complex near C4 → affects immunity.
C4 promotes expression of C3 in developing brain and and C4 knock-out mice show altered synaptic pruning.
Other genes strongly associated with an increased risk include: neuregulin, dysbindin, D-amino acid oxidase, proline dehydrogenase, COMT, regulator of G protein signalling (RGS-4), 5HT2A and dopamine D3 receptor → many are associated with 5-HT and DA signalling.
Development and symptoms
Impacting on neurogenesis mid-development in mice leads to the positive symptoms of schizophrenia.
Negative symptoms are caused by later interference in development affecting synaptogenesis.
Dopamine signalling
Difficult to specifically target mesocortical and mesolimbic pathways implicated in SZ.
Amphetamine, which increases DA levels in the brain, induces psychosis. It inhibits DAT and reverses DAT transport, and inhibits VMAT2. Its action is therefore firing-rate independent.
PET studies show increased D2 expression in SZ.
a-Flupenthixol blocks D2 receptors and is clinically effective as a form of treatment. β-Flupenthixol is not active clinically and not a D2 antagonist.
Chlorpromazine
Typical antipsychotic, binds to D2-like receptors. Treats positive symptoms but worsens negative ones.
Causes apathy and reduced initiative.
D2 antagonismin in the mesolimbic pathway causes reduced emotion and aggression.
Antagonism in the tuberoinfundibular pathway causes neuroendocrine effects, increasing the release of prolactin.
Extrapyramidal D2 antagonism in the striatum can cause acute Parkinson-like symptoms and long-term tardive dyskinesia.
Antagonism in the CTZ has antiemetic effects
5HT2C antagonism causes weight gain.
Atypical antipsychotics
Clozapine, risperidone, aripiprazole.
Broader range: still mostly targets dopamine receptors, but also have some action at 5-HT receptors, as well as α1, H1 and M1 receptors.
Clozapine has a high affinity for D3 and 4 receptors, but a low affinity for D2 and so low extrapyramidal side effects. Muscarinic and α-AR antagonism can cause systemic side effects.
Glutamate hypofunction hypothesis
NMDA antagonists, such as ketamine and phencyclidine, induce psychosis, exacerbate schizophrenia and cause negative symptoms and cognitive impairments.
Several gene mutations associated with schizophrenia involve glutamate transmission → D-amino acid oxidase, mGluR3, neuregulin.
Post-mortem studies show a reduction in D-serine, indicating NMDA hypofunction, and reduced CSF levels of glutamate.
Decreases in NMDA receptor expression in the prefrontal cortex.
Glutamate hypofunction is therefore involved in SZ.
NMDA receptor hypofunction results in decreased glutamate activation of the GABA inhibitory output onto dopamine neurones in the VTA, resulting in DA hyperactivity → hypoglutamatergic activity exacerbates hyperdopaminergic activity in mesolimbic areas.
