Schizophrenia Flashcards
1
Q
Define schizophrenia
A
- A long-term mental disorder of a type involving a breakdown in the relation between thought, emotion, and behaviour, leading to faulty perception, inappropriate actions and feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a sense of mental fragmentation
2
Q
How is schizophrenia diagnosed
A
- No reliable, consistent or useful body fluid biomarker
- Principally clinical observation and history (DSM)
- Symptoms - presence of 2 or more over 1 month
- Social - one or more major areas (work, interpersonal relationships, self-care) below level prior to illness.
- Duration - signs persist for at least 6 months
- Other possible diagnostic markers – see later
- Biomarker changes in brain electrical activity
- Biomarker changes in brain structure
3
Q
What are the symptoms from which 2 need to present for over 1 month
A
- delusions
- hallucinations
- disorganised speech
- grossly disorganised/catatonic behaviour
- affective flattening, alogia, or avolition (negative symptoms)
4
Q
What are the positive symptoms of schizophrenia
A
- increase in abnormal active behaviours including
- hallucinations
- delusions
- disordered thoughts
- language abnormality
- motor disorders
5
Q
What are the negative symptoms of schizophrenia
A
- absence of normal active behaviours occur prior to positive symptoms
- affective blunting- emotional responses
- avolition
- anhedonia
- poverty of speech
- social withdrawal
- neglect of hygiene
6
Q
What are the Cognitive symptoms of schizophrenia
A
- disturbance of normal thought processes
- poor executive function and decision making
- recognition deficits
- memory problems
- attention deficits
7
Q
What is the prognosis for schizophrenia
A
- 25% Remit completely; no further symptoms
- 25% Good social recovery; some symptoms persist
- 25% Partial social recovery; persistence of symptoms
- 25% Steady downhill course; social and personality deterioration
8
Q
Describe schizophrenia epidemiology
A
- Prevalence ~1%
- 10% suicide risk – 40% single attempt
- Onset
- ♂: median 26 yrs
- ♀: median 29 yrs
- ♂:♀ ~1.3:1
- Increased prevalence in lower economic strata
9
Q
What are the different courses of schizophrenia
A
- Relapsing and remitting: episodic
2. Chronic and progressive
10
Q
What is the Aetiology of schizophrenia
A
- Clearly complex but largely unknown
- genetic
- environmental
- structural brain changes
11
Q
Why is schizophrenia thought to have genetic factor
A
- strongly inherited – 50% in monozygotic twins
2. no specific gene identified - many genes implicated
12
Q
What are the environmental factors of schizophrenia
A
- no specific factors implicated
- pregnancy and delivery complications
- prenatal and childhood virus infection
- urban birth and residence
- psychosocial factors (dysfunctional family environment)
13
Q
What are the structural brain changes that can lead to schizophrenia
A
- developmental disruption of neuronal migration
- enlarged ventricles
- reduced regional cerebral volumes
- loss of neurones
- reduced network and functional activity
14
Q
What are structural changes that act as biomarkers in MRI scans
A
- Ventricles in in schizophrenic patients are enlarged
- With chronic schizophrenia- lateral ventricles continue to increase over time
- Loss of neuronal tissue associated with schizophrenia
15
Q
What are biomarkers in EEG and how do you carry out an EEG
A
- Changes in gamma behaviour
- Take individual and subject to a buzzer sound and measure EEG
- Can’t discern common change in EEG from individual EEG
- But if you add repeated EEG recordings together- noise cancels out and left with common wavelength related to buzzer
- Deficit in power in areas associated with memory and recall
16
Q
What pathways are involved with schizophrenia
A
- All about excess dopamine
- nigrostriatal pathway
- Mesolimbic pathway (A10 from VTA)
- Mesocortical pathway (A10 from Ventral Tegmental Area)
5 . Retrorubral field (A8)
17
Q
How is the nigrostriatal pathway involved
A
- motor actions (A9 from substantia nigra pars compacta)
18
Q
How is the Mesolimbic pathway involved
A
- nucleus accumbens amygdala
- hippocampus
- entorhinal cortex
- cingulate cortex
- Positive symptoms
- perception
- emotions
- memory
19
Q
How is the Mesocortical pathway involved
A
- prefrontal cortex
- cingulate gyrus
- Negative symptoms
- motivation
- volition
- cognition
- planning
- social behaviour
20
Q
How can drugs cause schizophrenia
A
- cocaine and amphetamine release DA
- chronic abuse can elicit toxic psychosis
- paranoid delusions
- hallucinations
- compulsive behaviour
- exacerbates positive symptoms
21
Q
What does L-DOPA do
A
- L-DOPA increases DA levels
2. delusions and hallucinations
22
Q
Describe how antipsychotic/neuroleptic drug are associated with schizophrenia
A
9) action correlates with D2 DA receptor block – increase in dopamine receptors- a factor in schizophrenia or increased because of it
a) D2 DA gene - risk factor in schizophrenia
b) DA receptors may be increased in schizophrenics
23
Q
Describe how antipsychotic/neuroleptic drug are associated with schizophrenia
A
- action correlates with D2 DA receptor block –
- increase in dopamine receptors- a factor in schizophrenia or increased because of it
- D2 DA gene - risk factor in schizophrenia
- DA receptors may be increased in schizophrenics
24
Q
What does Neuroleptic efficacy correlate with
A
- Neuroleptic efficacy correlates with D2 receptor blockade
- Tight correlation between average clinical dose of antipsychotic compounds and D2 binding affinity
- Lower affinity- need higher dosage
- No correlation with other receptors
25
What are some typical (first generation) antipsychotics
1. High affinity D2-receptor antagonists
2. phenothiazines - chlorpromazine, thioridazine, fluphenazine
3. butyrophenones - haloperidol
4. thioxanthenes – chlorprothixene
5. dibenzodiazepines – clozapine
6. Serious side effects
26
What are typical (first generation) antipsychotics effective against
1. Effective ONLY against positive symptoms
27
What are some DA associated side effects of typical (first generation) antipsychotics
1. DA related include hormonal and extrapyramidal motor
2. pseudoparkinsonism (early Parkinson’s like)
3. tardive dyskinesia (late Huntington’s like)
4. other motor effects (akathisia, dystonia)
5. increased prolactin release – sexual dysfunction
28
What are some Non-DA associated side effects of typical (first generation) antipsychotics
1. sedation - antihistamine, anticholinergic
2. hypotension – central adrenergic
3. peripheral autonomic – blurred vision, dry mouth, constipation
29
What are some Atypical (second generation) antipsychotics
1. Relatively low affinity for D2
2. Benzamides: lanzapine, Quetiapine, Risperidone, Ziprasidone, Quitiapine, Aripiprazole
3. Also Clozapine
30
What symptoms are Atypical (second generation) antipsychotics effective against
1. Effective against both positive and negative
2. High affinity at 5HT2
3. High ratio 5HT2:DA may be desirable
31
What are side effects of Atypical (second generation) antipsychotics
1. Less side effects than Typicals, especially motor effects.
2. but other side effects
3. weight gain
4. diabetes
32
What are problems with DA treatments
1. Serious dopaminergic side effects
2. many neuroleptics only control positive symptoms
3. DA block immediate – clinical onset 6-8 weeks – adapative changes
4. drugs block many other receptors
5. muscarinic, histaminergic, alpha-noradrenergic
33
What role does 5HT play in schizophrenia and how could this be used
1. Increased levels in schizophrenics
2. LSD - 5HT agonist induces hallucinations, cognitive impairment, aggression
3. 5HT metabolites (Dimethyltryptamine) hallucinogenic
4. many neuroleptics are potent 5HT2 receptor blockers
34
What happens in typical antipsychotics
1. Typical antiphsycotic have high affinity for D2
2. When complete D2 blockade can see antipshycotic affect + motor side effects
3. 5HT neurones impinge on dopanergic nerve terminals
4. When releases 5HT it reduces release of dopamine from nerve terminal
35
What happens with atypical antipsychotics
1. Low affinity for D2
2. High affinity for 5HT2A
3. Antipsychotic will block 5HT2A Heteroreceptors on dopaminergic nerve terminals
4. Reduces the signal from receptors which under normal circumstances would induce dopamine release
5. Break on dopamine release is removed
6. Increase dopamine release
7. Partial blockade- achieves antipsychotic effects but with reduced motor side effects
36
How could glutamate affect schizophrenia and be used to treat
1. Neurodevelopmental change – glutamate neurones affected
2. Disordered migration - abnormal circuits
3. Neuronal and synaptic loss
4. NMDA antagonists e.g. ketamine, phencyclidine are psychotomimetic
5. NMDA receptor knockout - social withdrawal in mice
6. Reduced glutamate in CSF
7. Loss of cortical glutamate receptors in post mortem schizophrenics- suggests that blockade of glutamergic system in brain may induce psychotic episode
37
Describe DA-glutamate interaction and how this can lead to positive symptoms
1. DA-glutamate interaction – positive symptoms
2. glutamate neurons in cortex excite GABA in VTA by NMDA receptors
3. input from NMDA which is stimulatory stimulates inhibitory GABAergic neuron
4. This reduces activity in mesolimbic dopamine neurone into nucleus accumbens
5. In schizophrenia Glutamatergic neurons are reduced
6. loss of excitation reduces inhibition in VTA, Less inhibitory effect on GABAergic interneuron
7. loss of inhibition causes excess DA release in mesolimbic path
38
What is lost in a schizophrenic
1. Ordered distribution of neurons is lost in schizophrenic
2. Individual neurons in schizophrenic brains show shorter branches in dendritic tree than normal
3. The number of spines – sites of incoming synaptic contact from other neurons- far fewer in schizophrenic subjects
39
Describe how DA-glutamate interaction could result in negative symptoms
1. Glutamatergic neuron makes direct contact with mesocortical dopanergic neuron – excitatory
2. Maintains activity of dopanergic output
3. In Schizophrenia Glutamatergic neurons lost
4 Excitation of dopanergic neuron goes down
5. Suggests reduction of dopamine
