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Pharmacy Year 4 > Neuro > Flashcards

Neuro Flashcards

1
Q

Briefly describe the dopamine theory of schizophrenia.

A

Increased dopamine release from the presynaptic neuron in subcortical pathways
Hypersensitivity of DA release to stimuli
(Excess dopamine in mesolimbic pathway and associative striatum leading to psychotic symptoms)
McCutcheon et al., 2015
Advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory

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2
Q

What evidence supports the dopamine theory?

A

Laurelle et al, 1996
Both healthy volunteers and those diagnosed with schizophrenia were given an amphetamine challenge to induces dopamine release
Overlay of PET onto MRI allows brain regions to be identified
Radiolabelled molecule in PET scan (11C-raclopride) binds to D2 receptors
10% reduction in binding of radiolabelled molecule in healthy volunteers
20% reduction in binding of radiolabelled molecule in patients with schizophrenia
Supporting the theory of excessive release of dopamine seen in schizophrenia which can ultimately lead to positive symptoms

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3
Q

Describe the glutamate theory of schizophrenia.

A

Most abundant excitatory transmitter in the brain, GABA is an inhibitory transmitter with an NMDA receptor
The receptor responds to glutamate, so promotes GABA function leading to inhibition
NMDA receptor hypofunctional state can be induced by genetic and non-genetic factors
Glutamate activation of dopamine cell bodies where GABA is not active, therefore leading to too much dopamine and as a result, psychosis
By restoring function of the negative feedback between glutamate and GABA, cognitive pathways may also be restored
Due to their abundance, treatment must be carefully used

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4
Q

Describe the potential association between schizophrenia and parvalbumin.

A

Kv3 channels expressed on PV+ GABAergic interneurons in cortico-limbic circuits where they permit fast firing
Alterations in DLPFC circuitry in schizophrenia
Numerous studies demonstrating deficits in parvalbumin containing GABA-ergic interneurons
Potential target for treating cognitive deficits

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5
Q

What is phencyclidine?

A

NMDA antagonist
Used as a drug of abuse
Renders NMDA receptors hypofunctional, leading to disinhibition of pyramidal cells
Causes patients to experience positive and affective symptoms

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6
Q

Describe the Kv3 novel approach to schizophrenia treatment?

A

Kv3 modulators for the treatment of schizophrenia related cognitive deficit
Potential use in psychosis but different complex pathway, not likely to be studied until evidence in cognition gathered and proven
Acute AUT6 preclinical study
Improved natural forgetting in a 6 hour ITI NOR task

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7
Q

Briefly describe the action of antipsychotics?

A

Antipsychotics inhibit D2
Antagonist then battles with dopamine itself to block the receptor
Therefore only a ‘normal’ amount of dopamine can reach the receptors due to the inhibition
Increased dopamine is not managed with these drugs
If the antagonist is then taken away, the increased dopamine is still present so psychotic symptoms will reoccur

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8
Q

What is the major difference between typical and atypical antipsychotics?

A

Typicals are selective for D2 receptors

Atypicals have richer pharmacology and higher affinity for 5HT2 receptors

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9
Q

Describe the side effect profile of typical antipsychotics.

A

Due to >75-80% blockade of D2 in motor part of striatum
EPSEs: pseudoparkinsonism, akathisia, dystonia, tardive dyskinesia
QT prolongation may occur with quetiapine, haloperidol and amisulpride in particular

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10
Q

Describe the side effect profile of atypical antipsychotics.

A

Antagonism of HT and5HT2c can induce weight gain, increase cBG and lipid levels, particularly with olanzapine and clozapine
Can cause blood disorders such as neutropenia/agranulocytosis

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11
Q

What two serious side effects can be seen with both typical and atypical antipsychotics?

A

Hyperprolactinaemia

Neuroleptic malignant syndrome

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12
Q

Describe the pharmacology of hyperprolactinaemia with antipsychotics.

A

Occurs due to depletion of dopamine in the tuberoinfundibular pathway
Generally occurs over 75% D2 receptor occupancy

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13
Q

What is the threshold for antipsychotic efficacy?

A

Begins as soon as D2 occupancy >60% in striatum, can be within hours
>65% D2 receptor occupancy in the associative striatum

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14
Q

Define concordance.

A

Match between patient and clinician’s views on treatment

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15
Q

Define adherence.

A

How far the users sticks to what is agreed

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16
Q

Define compliance.

A

Whether the user gets medication, voluntarily or involuntarily

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17
Q

What is the key thing predicted by poor adherence?

A

Relapse

Failure to recover from relapse (15% of these patients)

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18
Q

What is accepting the need for treatment of schizophrenia reliant upon?

A 
Awareness
Trust in prescriber (not team)- Day et al, 2004
Self esteem
Accepting risk of relapse
Insight
Family support
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19
Q

What is the estimate for non-adherence in schizophrenia?

A

40%

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20
Q

What is the evidence base for use of depots?

A

Beneficial in poor adherence- Barnes et al.
Large benefit to ‘typical’ patients- Tihonen et al.
In national case register studies (e.g. all Finns starting APS over 11 years, all Swedes over 8 years) those on depot and clozapine relapsed or were readmitted about 20-30% less often

21
Q

What is stigma? Give reference.

A

The association of a negative attribute with a ‘sign’ that distinguishes a person, may be race, gender, religionetc. May not be visible- Goffman, 1963

22
Q

What are the two main opposing opinions regarding stigma in schizophrenia? Give references.

A

Attributing a problem (schizophrenia) to an uncontrollable cause (genetics) reduces blame- Corrigan et al, 2002.
Bioperspectives increased over two decades however attitudes towards schizophrenia worsened, unlike depression and drug dependency- Angermeyer et al, 2013

23
Q

Give 5 key pieces of evidence supporting the fact that schizophrenia is still stigmatised. Give references.

A

47% of people with schizophrenia experience discrimination
Schizophrenia is associated with acts of violence- Bowen et al, 2019.
43% of 1414 Brazilian psychiatrists showed high levels of stigma, 33% showed moderate levels- Loch et al, 2013.
Professionals in Australia endorse more stereotypes than the public- Jorm, 1999
Psychiatrists in Japan endorse more positive attitudes than the public- Hori et al, 2011

24
Q

Briefly describe the pre-clinical test carried out in schizophrenia.
Neill et al, 2010.

A

Animal given amphetamine challenge to induce dopamine release and hyper-locomotion
Treated with APS

25
Q

What are the 3 key assessment domains in schizophrenia pre-clinical testing?
Neill et al, 2010.

A

Visual memory (Novel object recognition)
Problem solving/reasoning (reversal learning)
Attention (5 choice serial reaction)

26
Q

Describe the advantages and disadvantages of acute PCP models.
Neill et al, 2010.

A

Would show cognitive deficits but function would return when drug leaves the system
Most studies showing reversal of deficit involve acute administration immediately prior to testing
When retested in the NOR paradigm, deficit reappears

27
Q

Describe the advantages of sub-chronic PCP models.

Neill et al, 2010.

A

Does not allow function to return
Consistent blocking of NMDA receptors creates pathology for long term assessment
Retained evidence of behavioural deficit
Test in drug free state after acute effects of APS have worn off
Allows for brain analysis post dosing and washout

28
Q

What are the key issues in schizophrenia models?

Neill et al, 2010.

A

Inconsistencies in dosing, rat strains/genders, test procedures
NMDA model doesn’t incorporate neurodevelopment/genetics
Animals are genetically identical and live in optimal conditions, no genetic predisposition of prior drug exposure

29
Q

Describe the parvalbumin theory in schizophrenia. Give reference.

A

Lewis et al, 2012.
Kv3 potassium channels expressed on parvalbumin+ GABA-ergic interneurons in cortico-limbic circuits where they permit fast firing
Studies show PV+ neuron deficits in dorsolateral prefrontal cortex in post-mortem following sub chronic PCP dosing
Ultimately, high spiking release of GABA to synchronise cellular network cannot occur due to lack of parvalbumin

30
Q

What are Kv3 potassium channels?

A

When activated, they depolarise the neuron quickly to allow refiring
Activate/deactivate at speed, high voltage activated at the peak of AP peaks
Located on the soma and axon terminals of specific neurons (kv3.1)
Kv3 channels present on PV interneurons (co-localisation) so may be essential cognition

31
Q

Describe the clinical study of AUT6. Give reference.

A

Cadinu et al, 2017.
AUT6 is a novel and selective Kv3 channel modulator
Acutely, improved natural forgetting in 6 hour IRI NOR task. Function is restored in sub-chronic PCP model with APS
Chronically, consistently rescues deficit but benefits not seen following one week washout
Post mortem evidence matches findings
Initial human studies say it is safe and well-tolerated however no psychiatrist will stop APS to enter a trial for cognitive function

32
Q

Briefly describe the amyloid cascade. Give references.

A

When APP is processed by beta-secretase, it is cleaved in safe areas producing a monomer.
With further processing by gamma-secretase, the beta-amyloid monomer is formed.
Glial cells take beta-amyloid into lysosomes for removal.
The monomer is very sticky and aggregates, forming insoluble oligomers that vary in configuration.
This triggers the formation of plaques and phosphorylation of Tau proteins.
Plaques target synapses and create neurofibrillary tangles acting extracellularly (Bloom et al, 2014)
Tau phosphorylation reduces microtubule assembly in the cytoplasm, causing dysfunction and death (Di et al, 2016)

33
Q

Describe the theory of neuroinflammation in Alzheimer’s.

A

Occurs in response to abnormal presence within the brain
Glial cells are responsible for clearing amyloid, however inflammatory response is slowed in the elderly so can cause accumulation.
At some point, cells stop phagocytosing amyloid and begin a pro-inflammatory response targeting neurons

34
Q

Describe the stages of dementia. Give reference.

A

Leclerc et al, 2013.
Early presymptomatic- astrocyte dysfunction, CSF amyloid-beta, amyloid-beta on PET scans
Late presymptomatic- microglial activation, FDG on PET, MRI hippocampus volume reduction, P-Tau
Early mild cognitive impairment- MRI brain changes begin to be visible
Late mild cognitive impairment- cognition becomes impaired
Dementia- clinical dementia diagnosis and symptoms

35
Q

What are the main models used in AD? What is the major problem?

A

Models for sporadic AD rely on acute pharmacological and transgenic models that mimic certain aspects of AD.
Rodents don’t naturally develop AD, genes inserted to cause the overproduction of amyloid-beta but no evidence of Tau development.

36
Q

Describe the acute model for Alzheimer’s. Give reference.

A

Watremez et al, 2017.
Amyloid is injected acutely and cleared after one off administration so is not reflective of chronic build up.
Acute deficits in NOR were reversed with donepezil and rolipram.
To see physiological changes ASAP, larger quantities must be injected but must consider physiological relevance.
Clearance can be variable.

37
Q

What is the key problem with the acute model for Alzheimer’s.

A

Configuration of isolated amyloid changes in vitro and in vivo.
Consider use of amyloid from human tissue.

38
Q

Describe the transgenic model for Alzheimer’s. Give reference.

A

Oddo et al, 2003.
Combination of acute and transgenic models allows reduction in timeline for answers.
3xTgAD mouse expresses human familial AD transgenes for APP, presenillin and Tau, injected at birth.
Amyloid-beta plaques and NFT pathology seen from 9 months
Decrease in synaptic plasticity and connectivity from 4 months
Subtle cognitive deficits (Morris Walter Maze) from 4-6 months

39
Q

What are the 3 most known novel targets in AD?

A

Secretase modulators- due to the fact that amyloid-beta production largely occurs before symptoms present, this is more beneficial in early onset AD
Anti aggregants- prevent aggregation and toxic compound formation
Immunotherapies- clear amyloid-beta deposits, variable configurations so recognisable sequence may be hidden or altered

40
Q

Describe the use of aducanumab in AD. Give reference.

A

Schneider et al, 2019.
Monoclonal antibody that selectively binds to amyloid β fibrils and soluble oligomers.
In trials, after 12 months nearly half the patients who received the 10 mg/kg dose no longer had positive amyloid PET scans

41
Q

What are NLRP3 inflammasomes?

A

Inflammasomes are defined by the presence of a cytosolic pattern recognition receptor, found in microglial cells.
NLRP3 is relevant to sterile inflammation caused by amyloid.
Senses damage associated molecular patterns, endogenous molecules modified during disease such as amyloid-beta.
NLRP3 interacts with the adaptor protein ASC and procaspase-1 to form inflammasomes
Results in caspase-1 activation and processing of pro-1L-1beta to mature active form, one of the earliest pro-inflammatory cytokines.

42
Q

Describe the preclinical trials of fenmate NSAIDs in AD. Give reference.

A

Daniels et al, 2016.
Mefenamic acid inhibits NLRP3 in vitro via voltage regulated anion channels
Inhibiting this pathway is both protective and therapeutic in animal models of AD related cognitive deficits

43
Q

What are acetylcholinesterase inhibitors? Describe their use.

A

Donepezil is first line in mild to moderate disease.
Increases the availability of ACh in synapses in the brain.
Can prolong current level of function.

44
Q

What are the side effects of acetylcholinesterases?

A 
Nausea and vomiting
Dizziness
Hallucinations
Insomnia
Agitation
Ulceration
Anorexia
Seizures
Heart block
45
Q

Describe the use of NMDA receptor antagonists in AD.

A

Memantine is first line in severe disease.

46
Q

What are the side effects of memantine?

A 
Headache
Dizziness
Constipation
Hypertension
Somnolence
47
Q

What is BPSD?

A

Behavioural and psychological symptoms of dementia.

Experienced by up to 90% of AD patients.

48
Q

What may be given in AD associated agitation?

A

Risperidone is licensed for up to 6 weeks.

49
Q

What are the key benefits of maintenance treatment in schizophrenia? Give reference.

A

Reduces relapse rate substantially in chronic sufferers, from 64% to 27% over 11 months mean follow-up- Leucht et al, 2013.
10-fold decreased suicide risk

Pharmacy Year 4 (3 decks)

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