Week 1 part 1 Flashcards
1
Q
How much is spent on treatment for mental disorder in England in 2011/2012 DH?
A
£12 billion
11% of NHS budget
2
Q
What is the percentage of burden of disease in UK due to mental disorder WHO?
A
30.3%
3
Q
Wha is one of the most impactful component of the cost of healthcare?
A
Burden of mental disorders
4
Q
Where is there a lot of investment in?
A
Cancer
Catch up with the impact of cancer on awareness
5
Q
Why do we need to address the issue of mental disorders?
A
Alleviate the suffering
Cost of quality of life
Integrate into society and have a meaningful life
6
Q
What are the challenges in the development of successful therapies in neurology and psychiatry?
A
- Understanding disease cause and evolution
- Understanding the pathophysiology
- Availability of adequate animal models of the disease
- Do the drugs teach the target?
- Patient response variability
- Identification of novel targets
7
Q
What does the challenges in the development of successful therapy in 2019 span?
A
Neurology and psychiatry
8
Q
What is treated by a psychiatry?
A
Schizophrenia and Depression
9
Q
What is treated by a neurologist?
A
Parkinson disease
10
Q
What is found in neurological disease?
A
Neural inflammation
11
Q
What is found in psychiatric and many more evolutionary diseases?
A
Demyelination signal
12
Q
Availability of adequate animal models of the disease?
A
Superimposed ethical issues
Are they good or bad?
Can we use lower species to model human conditions
Is it ethical in terms of harming the animals
How we have control of the animals for medical research
Validity done on each model
13
Q
How are drugs prescribed?
A
In a very routine manner
Quite stereotype manner
14
Q
What is schizophrenia?
A
Severe psychiatric disorder characterised by psychotic and cognitive symptoms
Leading cause of global disease burden
15
Q
What is schizophrenia preceded by?
A
Prodromal phase of attenuated psychotic symptoms and functional impairment
16
Q
What is increasing evidence of schizophrenia?
A
Involvement of neuroinflammatory processes
17
Q
History of schizophrenia: where was patients submitted to?
A
Very strange paradigms of treatment
18
Q
What is schizophrenia a disease of?
A
Changes life significantly by individuals affected by it
It affects personal life
Cost of worldwide and it is not going away
19
Q
What age group does schizophrenia affect?
A
People in their early 20’s
Age 16-30 (women tend to have a later onset)
20
Q
What percentage of population is affected by schizophrenia?
A
1%
21
Q
The percentage of population is similar across what?
A
Different countries
Cultural groups
Sexes
22
Q
The evolution of schizophrenia is what?
A
Heterogenous
The condition persists throughout a patients lifetime
23
Q
What is schizophrenia characterised by?
A
Triad of core symptoms:
Positive
Negative
Cognitive
24
Q
What are the positive symptoms?
A
Hallucination
Delusion
Agitation
Disorganised thinking/speech
25
What are the negative symptoms?
```
Introversion
Apathy
Low self-esteem
Personal neglect
Total lack of interest in anything
```
26
What are the cognitive symptoms?
Poor memory
Attention Deficit
Executive dysfunction
27
What are the structural and functional changes in schizophrenia?
Larger ventricles
| Smaller mesial temporal lobe structures
28
What does structural FMRI of schizophrenia patients show?
Shrinkage of Brain
Some loss of brain matter
Some loss of white matter
29
What has been possible to do in the past 15 years?
A more dynamic assessment of the progression of structural changes in schizophrenia
30
What happens as you grow up and your brain matures?
Lose some percentage of brain matter in particular as the brain continues to sculpture itself
31
What does the normal adolescent show in a structural FMRI?
Loss of brain matter due to sculpturing of the brain measured by an average annual loss from blue to purple
32
What does schizophrenic patients such in a structural FMRI?
Colours are more vivid and more intense
33
What can be used for parameters to be measured objectively to get a stimulation response?
Event related potential (ERP)
| Simple electrical signature when exposed to a sensory stimulus
34
What does computerised tomography show?
Ventricular enlargement
| Generalised loss of brain tissue in patients
35
What does structural MRI show?
Additional volume deficit in the prefrontal and temporal lobes
Thalamus is also reduced in volume
36
What is schizophrenia characterised by?
Abnormal PFC interaction with other cortical areas
37
What is an important concept of schizophrenia?
Hypofrontality
38
What is used to see hypofrontality in schizophrenia patients?
FMRI
- interrogate the brain to see how the brain mobilises in its resources to perform a certain task
39
What is observed for schizophrenic patients when FMRI is used?
Much more difficulty in recruiting brain areas which are necessary to perform well at a certain task
40
What is Hypofrontality?
A state of decreased blood flow in the prefrontal cortex of the brain
41
Hypofrontality - schizophrenic patient - what does it show?
There is a performing metabolic deficit
| You can’t really recruit blood flow, glucose and metabolites
42
What is the earliest seed of neurodevelopment?
Intellectual activity are extremely limited
43
What causes schizophrenia?
A combination of physical, genetic, psychological and environmental factors can make a person more likely to develop the condition
-stressful or emotional life event might trigger a psychotic episode
44
What is the abnormalities in schizophrenia which suggest an impaired neurodevelopment
```
Brain asymmetry
Corpus callosum dysgenesis
Abnormal correlation between regional cortical volume measurements
Absence of gliosis
Minor physical anomalies
Early childhood behaviour abnormalities
```
45
What is gliosis?
Nonspecific reactive change of glial cells in response to damage to the CNS
46
What increases the risk of later schizophrenia?
Prenatal and birth complications
| Unfavourable changes e.g extreme hypoxia of the foetus
47
What does schizophrenia till this day remain?
Polymorphic disease
48
What does the node diagram for schizophrenia patient show?
Emergence of the condition and you can see any pattern
How variable the disease is
49
What component is found in schizophrenia?
Genetic
| The more related you are to someone who is schizophrenic, the more of a risk you will have it yourself
50
After the genome project was completed, there was an enrichment in the understanding of what?
Genetic components of disease
51
Whole chromosomal complement
Gene changes scattered all over
52
Genetics of schizophrenia - examples
Try and understand the biological plausibility
| What is in the gene that will increase the risk of schizophrenia disorder
53
What doesn’t the genetic component of schizophrenia show?
Where the final product is
| If the protein is really changed
54
What are examples of genes and function?
```
PRODH
NRG1
RGS4
EPN4
COMT
```
55
PRODH
Involved in the metabolism of proline (proline oxidase)
| Dysfunction in glutamate transmission
56
NRG1
Involved in neuronal development and survival
57
RGS4
Linked to GTPase activation
| Involved in the activity of several receptor families
58
EPN4
Epsin 4
| Involved in the intracellular trafficking of proteins
59
COMT
Involved in the metabolism of dopamine
60
DISC1
Gene that confers risks
Discovered in Scottish population
When you manipulate these genes experimentally, you reduce neuronal growth
61
What is the function of DISC1
Restricted expression in adult breaks
- dentate gyrus granule cells
- olfactory bulb
DISC1 binds to molecules involved in neural development (e.g. NDEL1)
62
What is the In vitro impairment of DISC1?
Reduced neurite growth
63
What is the In utero interference with DISC1?
Retarded migration and mis-orientation of dendrites of cortical cells
64
What will occur when you have variation of DISC1 and an individual in a cognition test?
An engagement of the brain
65
What is observed in the variation of DISC1?
Decrease in grey matter in the hippocampus
What you can measure functionally is a decrease in engagement of the hippocampus in an episodic memory task
66
What progressed schizophrenia into a full blown disease ?
Genetic predisposition
| Environmental risk factor
67
What is one strong association of risk linked to schizophrenia?
The use of cannabis during adolescence
68
What happens when you have a certain mutation in the COMT gene?
It will take you over the threshold to develop schizophrenia
69
What was the accidental discovery for the treatment of schizophrenia?
Looking at antihistamine and sedative compounds
70
What was the greatest accidental discovery in medicine?
Chlorpromazine
Has a characteristic of blocking dopamine receptors of D2 types
Essential for antipsychotic activity
71
What do all antipsychotic drugs have?
Efficacy
72
What is activity and efficacy correlated with?
Plasma concentration of the drug
| Ability to block the receptors
73
Where do we have antagonist activity at?
5-HT2 receptors
74
Why is clozapine unique?
Allows treatment of resistance to schizophrenic patients
75
Why can’t clozapine be used in all patients?
Decreases in white blood cells count
76
Aripiprazole
Complex pharmacodynamics
| Partial agonist
77
What does every country have in treating schizophrenia?
It’s own guidelines
| Put forward by organisation NICE
78
What are examples of typical antipsychotics
```
Chlorpromazine
Thioridazine
Fluphenazine
Haloperidol
Flupenthixol
```
79
What are examples of atypical antipsychotics ?
```
Risperidone
Olanzapine
Clozapine
Queriapine
Paliperidone
Aripiprazole
```
80
What does clozapine block?
D4 receptors with high affinity
81
What can atypical antipsychotics improve?
Cognition in some patients
82
What is the issue of schizophrenia?
Due to hyperdopaminergic state subcortically (ventral stratium)
But there is hypodopaminergic state in the prefrontal region
83
What are other neurotransmitter abnormalities in schizophrenic patients?
Alteration in glutamatergic and GABAergic transmission
84
Cytoarchitectural defects in schizophrenia?
```
Abnormalities in the cortical layers:
Decreased layer thickness
Decreased size of pyramidal cells
Decreases in GABAergic interneurons
Decreased complexity of dendritic arbors
```
85
Prefrontal pyramidal neurons in schizophrenia
Fewer spines on dendrites
86
What is small changes of schizophrenia?
Reduced interneuron activity
| Excessive excitatory pruning
87
What is criteria for validity of animal models?
Face validity - “looks like the disease”
Construct validity - “has a sound casual rationale”
Predictive validity - “drugs work in it”
88
What is the overview of models of schizophrenia?
1. Early lesion models
2. Stress models
3. Prenatal viral infections or evoked immune response
4. Perinatal treatment with phencyclidine
5. Disruption of Neurogenesis
89
Disruption of neurogenesis
Methylazoxymenthanol exposure (man model)
90
What is man model based on?
Disruption of neurodevelopment with a toxin
91
Method of man model
Inject at day 17 in rat dams and this can be also be done in nice
They then give birth
Look at brain characteristics
They have a smaller brain size
92
Non-exposed rats and schizophrenic patients have anatomical abnormalities which are similar
Increased ventricular size
| Decreased size of key brain regions cortical network
93
Behavioural changes: amphetamine
Inject amphetamine in animals and get them to present with a high sensitivity
94
What is amphetamine?
Psycholytic compound
95
Schizophrenia patients
Hyper-sensitive to amphetamine
96
MAM-animals give amphetamine
Much more active
| They will mimic hyper-sensitivity to amphetamine
97
What is disrupted in schizophrenic patients?
Social behaviours
Impaired interaction
Mimicked in rodents
98
What can cognition modelling in rodents be supported by?
Morris water maze
Put rodent in a little bath of Luke-warm water
Ask them to remember the location of the platform
See how fast they learn
Simple way to test their learning and memory
Twist in the maze - show flexibility cognitive
99
Morris water maze - reference memory
No difference between normal and MAM-exposed animals
Cognition function of schizophrenic patients are perfectly normal
Their flexibility is problematic
100
Morris water maze - reversal memory
Adolescence rats have a problem for reverse memory
Much difficult task as learn platform changes
Animal with MAM-exposure are much more confused by it
101
What is the difficulty in having cognitive ability and making decisions reminiscent of?
Difficulties experienced by patients in the Wisconsin Card Test
102
Schizophrenic patients
Diminished abilities to change rules
Cannot focus
No cognitive abilities
Cannot make decisions faster
103
In schizophrenia what is affected?
Interneurons
104
What is “PV-expressing neurons?”
In the prefrontal cortex
Protein that is enriched in interneurons
Detected in the PFC and hippocampus
105
What are parvalbumin neuron involved in?
Gamma alteration in the brain
| Electrical manifestation of cognitive processing
106
What is schizophrenia associated with?
Demyelination
107
Overview of the MAM model of schizophrenia
The model is based on the neurodevelopmental theory of schizophrenia
The model reproduced regional abnormalities in corticolimbic circuits
Fundamental abnormalities such as decreased density of synaptic spines
Animals also display a behaviour which reproduces the positive, negative and cognitive spectrum of symptoms
108
Why may patient not respond well to existing drug?
Variation in metabolism of drug e.g. cytochrome P450
