Schizophrenia

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Kraeplin's term for schizophrenia?
Dementia Praecox
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Bleuler term for schizophrenia
Split mind
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Positive symptoms
Delusions and hallucinations
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Negative symptoms
Anhedonia, flattened affect
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Liddle
Re-examined the positive negative dichotomy, 40 patients with schizophrnia, confirmed positive and negative dichotomy but included a third factor termed disorganisation syndrome
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What 5 factors did Liddle include?
Psychomotor poverty, reality distortion, disorganisation, psychomotor excitation, anxiety and depression
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What was found in twins with schizophrenia?
enlarged ventricles in twin with schizophrenia
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What happens to the frontal cortex during executive tasks?
Brain activation is lower
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What is the N back task test?
Classic test working memory asked to press key if target letter appears (0-back) if target letter is same as 1 before (1-back) 2 letters before (2-back) etc...
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What is another idea?
Connectivity is faulty between brain asreas that make up specific brain networks
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What is the concordance rate for MZ twins?
48%
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What is the approaches to investigating the neurochemistry schizophrenia?
Post mortem studies, peripheral markers, mechanism of action of antipsychotic drugs, in vivo receptor binding
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What does schizophrenia result from?
Overactivity in brain dopamine transmission
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What does hyperactivity in the mesolimbic dopamine give rise to?
Positive symptoms, hypoactivity in frontal cortex gives rise to negative
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What is clinical potency ?
Effective antipsychotics parallels their pharmacological potency in blocking dopamine binding
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What is parkinsonian side effects?
Neuropletics
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What does amphetamine do?
Releases dopamine, induces psychosis that responds to neuropletics
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What receptors are involved in schizophrenia?
D2 but not D1 receptors
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What about D4?
Mixed results: Seeman 6 fold elevation in schiz. other stdies found no D4 receptors in controls
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What can brain DA turnover be reflected by?
Plasma Homovaniliic acid concentrations
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What does Chronic antipsychotic treatment lower?
Plasma HVA which relates to good treatment outcomes
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What are mesolimbic dopamine systems?
Implicated in animal models of disrupted selective attention in schizophrenia
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What does chronic antipsychotic decrease?
Dopamine firing in A9 and A10 striatum
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Latent inhibition is what by amphetamine?
Disrupted: reversed by AP drugs
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PET
In vivo measurement of D2 receptor affinity in humans
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Some studies find what?
Some studies find increase in D2 binding (Wong et al,1986) no change in other studies (eg., Pilowsky, 1994
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Glutamate and Schiz
Drugs that block glutamate receptor such as PCP produce psychosis
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Serotonin and Schiz
Atypical antipsychotic drugs have high affinity for 5HT2 receptor: could be modulatory role on DA function
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GABA and Schiz
Moulatory role on DA function
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Abnormalities of the NMDA and kainate receptors do what?
Found in multiple regions of the prefrontal cortex and are asscoaited with up-regulaton o the NR1 subunit
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Decrease in glutamate synthesis leads to what?
Release in the cortex and also decrease in certain receptor sites for GLU in certain areas of the brain such as the cingulate and hippocampus
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What is PCP?
Induces psychosis is a non competitive NMDA antagonist
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Criteria for a neurotransmitter?
Must be produced within a neuron. must be found within a neuron, when a neuron is stimulated, a neuron must release the chemical, when a chemical is released it must act on post synaptic receptor and cause a biological effect
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After a chemical is released then what?
it must be inactivated, inactivation can be through a reuptake mechanism or by enzyme that stopes the action of the chemical, if the chemical is applied on the post-synaptic membrane. It should have the same effect as when it is released by a neuron
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What are the amino acids?
Glutamate and GABA
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What is dopamine?
Catecholamine
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What is serotonin?
Monoamine
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What are multiple pathways that use glutamate?
Cortical association Cortico-thalamic Cortico-spinal Basal ganglia Hippocampal Cerebellar
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Glutamae is synthesised from?
Glutamine in astrocytes
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What is glutamate removed from
synapse by glutamate transporters
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Subtypes of glutamate?
NMDA, AMPA and Kainate, Metabotropic
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What do Neurotransmitters do?
Enhance synthesis, increase release, block reuptake, reduce metabolism
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Kim (1980)
discovered reduced glutamate in cerebrospinal fluid in patients with schizophrenia (not replicated, but other enzyme markers for glutamate shown to be reduced)
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What did Ketamine lead to?
Symptoms of schizophrenia
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What do postmortem studies show?
show changes in glutamate receptor binding, transcription, and subunit protein expression in the prefrontal cortex, thalamus, and hippocampus of subjects with schizophrenia
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What do glutamate neurons regulate?
regulate the function of other neurons that have been strongly implicated in the pathophysiology of schizophrenia
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Including?
dopamine neurons, which are the target of antipsychotic drugs
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Where are d2 receptors localised?
localized presynaptically on glutamate terminals and work to inhibit the release of glutamate, reduced D2 receptor function produces modest increases in glutamate release
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What does NMDA receptor hypofunction lead to?
Negative, cognitive and affective symptoms of schizophrenia
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Dopamine hypothesis of schizophrenia
Caused by overactivity of dopaminergic synapses likely in the mesolimbic pathway coming from the VTA
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The dopamine synthesis system?
Tyrosine --> Tryosinase hydroxylase --> DOPA --> DOPA DECARBOXYCLASE -->Dopamine -->Monoamine oxidase + dopamine beta hydroxylase --> DOPAC and Noradrenaline
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Where is the dopamine system?
The mesotelencephalic dopamine system in the human brain consisting of the nigrostriatal pathway and the mesocorticolimbic pathway
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According to Weinberger, what is the symptoms of schizophrenia caused by?
Positive symptoms caused by an overactivity of dopaminergic synapses likely in the mesolimbic pathway coming from the VTA
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Consequent to what?
Hypoactivity of dopamine synapses in prefrontal cortical regions (Negative and cognitive symptoms)
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Increase release of dopamine in the nucleus accumbens leads to?
Positive symptoms
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Where is the D1 receptor found?
Cortex, Limbic system, basal ganglia, hypothalamus
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Where is the D5 receptor found?
Basal ganglia, hypothalamus
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Where is the D2 receptor found?
Cortex, limbic system, basal ganglia, pituitry gland
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Where is the D4 receptor found?
Limbic system, basal ganglia
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What is dopamine?
Agonist
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What is chlorpromazine?
Antagonist
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When D1 receptor is bound bydopamine, it stimulates what?
the cell by activating the enzyme adenylate cyclase and the signaling molecule cyclic AMP to turn on gene transcription
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What is D2 receptor?
inhibiting cyclic AMP production and preventing cell activation. A crucial role of the D2-like receptors is the regulation of DA release by acting as autoreceptors on the somatodendritic region of midbrain Dopamine neurons
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What are agonists?
Drugs that occupy receptors and activate them
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What are antagonists?
Drugs that occupy receptors but do not activate them, antagonists block receptor activation by agonists
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What are some examples of typical drugs?
Chorpromazine, haloperidol
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what are some examples of atypical drugs?
Clozapine, Risperidol
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What is the law of thirds?
Respond well to drug therapy, employable; significant time hospitalised, respond well to drug therapy
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What does the degeneration of DA cells in parkinson's disease?
Removes the inhibitory influence on the ACh neuron so it fires more often, causing the movement
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Dopamine binding to DA receptors normally what?
Inhibit the cholinergic cell. Blocking these receptors leads to the same motor effects as degeneration of cells in Parkinson's disease
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What is antcholinergic drugs?
They block ACh receptors and reduce parkinsonian symptoms
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What is a side effect of antipsychotics?
Weight gain and tardive dyskinesia: Clozapine worse!
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What is the indicidence of TD after 25 uears?
68%
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What does PCP do?
Induce hyperactivity
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What is pre-pulse inhibition?
Disrupted by drugs that induce psychosis, amphetamine, PCP
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These distruptions are reversed by?
Antipsychotic drugs haloperidol/clozapine
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How is this disrupted by ?
drugs that increase dopamine injected directly into the nucleus accumbens
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What is latent inhibition ?
Disrupted by amphetamine this disruption is reversed by anti-psychotic drug
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Pre-training?
rat is trained to lick from spout in skinner box
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Preexposure/non-preexposure:
rats in one group exposed to 20-60 tones/rats in other group put into skinner box no tones
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What is conditioning?
Mild foot shock paired with tone twice
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What was the test?
Rats put in skinner box and allowed to drink from spout. The group were not pre-exposed to tone stop drinking when they heard tone as they have associated tone with food shock.
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The group that were pre-exposed keep doing what?
Keep drinking when they hear the tone as it is irrelevant to the tone
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Symptom such as delusions arise as a patient tries to?
Make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of aberrant salience of internal representations
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AP drugs through their actions on D2 receptors do what?
Dampen the salience of these abnormal experiences thus alleviating symtoms
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Card 2

Front

Bleuler term for schizophrenia

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Split mind

Card 3

Front

Positive symptoms

Back

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Card 4

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Negative symptoms

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Card 5

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Liddle

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