Schizophrenia Flashcards
Define schizophrenia
- 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
How is schizophrenia diagnosed
- 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
What are the symptoms from which 2 need to present for over 1 month
- delusions
- hallucinations
- disorganised speech
- grossly disorganised/catatonic behaviour
- affective flattening, alogia, or avolition (negative symptoms)
What are the positive symptoms of schizophrenia
- increase in abnormal active behaviours including
- hallucinations
- delusions
- disordered thoughts
- language abnormality
- motor disorders
What are the negative symptoms of schizophrenia
- absence of normal active behaviours occur prior to positive symptoms
- affective blunting- emotional responses
- avolition
- anhedonia
- poverty of speech
- social withdrawal
- neglect of hygiene
What are the Cognitive symptoms of schizophrenia
- disturbance of normal thought processes
- poor executive function and decision making
- recognition deficits
- memory problems
- attention deficits
What is the prognosis for schizophrenia
- 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
Describe schizophrenia epidemiology
- Prevalence ~1%
- 10% suicide risk – 40% single attempt
- Onset
- ♂: median 26 yrs
- ♀: median 29 yrs
- ♂:♀ ~1.3:1
- Increased prevalence in lower economic strata
What are the different courses of schizophrenia
- Relapsing and remitting: episodic
2. Chronic and progressive
What is the Aetiology of schizophrenia
- Clearly complex but largely unknown
- genetic
- environmental
- structural brain changes
Why is schizophrenia thought to have genetic factor
- strongly inherited – 50% in monozygotic twins
2. no specific gene identified - many genes implicated
What are the environmental factors of schizophrenia
- no specific factors implicated
- pregnancy and delivery complications
- prenatal and childhood virus infection
- urban birth and residence
- psychosocial factors (dysfunctional family environment)
What are the structural brain changes that can lead to schizophrenia
- developmental disruption of neuronal migration
- enlarged ventricles
- reduced regional cerebral volumes
- loss of neurones
- reduced network and functional activity
What are structural changes that act as biomarkers in MRI scans
- Ventricles in in schizophrenic patients are enlarged
- With chronic schizophrenia- lateral ventricles continue to increase over time
- Loss of neuronal tissue associated with schizophrenia
What are biomarkers in EEG and how do you carry out an EEG
- 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
What pathways are involved with schizophrenia
- All about excess dopamine
- nigrostriatal pathway
- Mesolimbic pathway (A10 from VTA)
- Mesocortical pathway (A10 from Ventral Tegmental Area)
5 . Retrorubral field (A8)
How is the nigrostriatal pathway involved
- motor actions (A9 from substantia nigra pars compacta)
How is the Mesolimbic pathway involved
- nucleus accumbens amygdala
- hippocampus
- entorhinal cortex
- cingulate cortex
- Positive symptoms
- perception
- emotions
- memory
How is the Mesocortical pathway involved
- prefrontal cortex
- cingulate gyrus
- Negative symptoms
- motivation
- volition
- cognition
- planning
- social behaviour
How can drugs cause schizophrenia
- cocaine and amphetamine release DA
- chronic abuse can elicit toxic psychosis
- paranoid delusions
- hallucinations
- compulsive behaviour
- exacerbates positive symptoms
What does L-DOPA do
- L-DOPA increases DA levels
2. delusions and hallucinations
Describe how antipsychotic/neuroleptic drug are associated with schizophrenia
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
Describe how antipsychotic/neuroleptic drug are associated with schizophrenia
- 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
What does Neuroleptic efficacy correlate with
- 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
What are some typical (first generation) antipsychotics
- High affinity D2-receptor antagonists
- phenothiazines - chlorpromazine, thioridazine, fluphenazine
- butyrophenones - haloperidol
- thioxanthenes – chlorprothixene
- dibenzodiazepines – clozapine
- Serious side effects
What are typical (first generation) antipsychotics effective against
- Effective ONLY against positive symptoms
What are some DA associated side effects of typical (first generation) antipsychotics
- DA related include hormonal and extrapyramidal motor
- pseudoparkinsonism (early Parkinson’s like)
- tardive dyskinesia (late Huntington’s like)
- other motor effects (akathisia, dystonia)
- increased prolactin release – sexual dysfunction
What are some Non-DA associated side effects of typical (first generation) antipsychotics
- sedation - antihistamine, anticholinergic
- hypotension – central adrenergic
- peripheral autonomic – blurred vision, dry mouth, constipation
What are some Atypical (second generation) antipsychotics
- Relatively low affinity for D2
- Benzamides: lanzapine, Quetiapine, Risperidone, Ziprasidone, Quitiapine, Aripiprazole
- Also Clozapine
What symptoms are Atypical (second generation) antipsychotics effective against
- Effective against both positive and negative
- High affinity at 5HT2
- High ratio 5HT2:DA may be desirable
What are side effects of Atypical (second generation) antipsychotics
- Less side effects than Typicals, especially motor effects.
- but other side effects
- weight gain
- diabetes
What are problems with DA treatments
- Serious dopaminergic side effects
- many neuroleptics only control positive symptoms
- DA block immediate – clinical onset 6-8 weeks – adapative changes
- drugs block many other receptors
- muscarinic, histaminergic, alpha-noradrenergic
What role does 5HT play in schizophrenia and how could this be used
- Increased levels in schizophrenics
- LSD - 5HT agonist induces hallucinations, cognitive impairment, aggression
- 5HT metabolites (Dimethyltryptamine) hallucinogenic
- many neuroleptics are potent 5HT2 receptor blockers
What happens in typical antipsychotics
- Typical antiphsycotic have high affinity for D2
- When complete D2 blockade can see antipshycotic affect + motor side effects
- 5HT neurones impinge on dopanergic nerve terminals
- When releases 5HT it reduces release of dopamine from nerve terminal
What happens with atypical antipsychotics
- Low affinity for D2
- High affinity for 5HT2A
- Antipsychotic will block 5HT2A Heteroreceptors on dopaminergic nerve terminals
- Reduces the signal from receptors which under normal circumstances would induce dopamine release
- Break on dopamine release is removed
- Increase dopamine release
- Partial blockade- achieves antipsychotic effects but with reduced motor side effects
How could glutamate affect schizophrenia and be used to treat
- Neurodevelopmental change – glutamate neurones affected
- Disordered migration - abnormal circuits
- Neuronal and synaptic loss
- NMDA antagonists e.g. ketamine, phencyclidine are psychotomimetic
- NMDA receptor knockout - social withdrawal in mice
- Reduced glutamate in CSF
- Loss of cortical glutamate receptors in post mortem schizophrenics- suggests that blockade of glutamergic system in brain may induce psychotic episode
Describe DA-glutamate interaction and how this can lead to positive symptoms
- DA-glutamate interaction – positive symptoms
- glutamate neurons in cortex excite GABA in VTA by NMDA receptors
- input from NMDA which is stimulatory stimulates inhibitory GABAergic neuron
- This reduces activity in mesolimbic dopamine neurone into nucleus accumbens
- In schizophrenia Glutamatergic neurons are reduced
- loss of excitation reduces inhibition in VTA, Less inhibitory effect on GABAergic interneuron
- loss of inhibition causes excess DA release in mesolimbic path
What is lost in a schizophrenic
- Ordered distribution of neurons is lost in schizophrenic
- Individual neurons in schizophrenic brains show shorter branches in dendritic tree than normal
- The number of spines – sites of incoming synaptic contact from other neurons- far fewer in schizophrenic subjects
Describe how DA-glutamate interaction could result in negative symptoms
- Glutamatergic neuron makes direct contact with mesocortical dopanergic neuron – excitatory
- Maintains activity of dopanergic output
- In Schizophrenia Glutamatergic neurons lost
4 Excitation of dopanergic neuron goes down - Suggests reduction of dopamine
