Neurotransmission defects and mental health: Focus on schizophrenia Flashcards
What is the state of diagnosis for schizophrenia?
There’s no diagnostic pathology
- its diagnosis is currently based on clusters of symptoms: positive and negative
What is the relatability of schizophrenia with other psychiatric disorders?
> Similarly to other psychiatric disorders, patients display cognitive impairments
However, schizophrenia is characterised by psychotic episodes consisting of both positive and negative symptoms
What are positive symptoms?
Additional features that are not ordinarily present.
What are the positive symptoms in schizophrenia?
> Delusions
Hallucinations
Thought disorder (potentially perceived in the patient’s speech)
What are negative symptoms?
Refers to a loss or reduction in normal function.
What are the negative symptoms in schizophrenia?
> Alogia: reduced speech
Affective flattening: lack of emotional facial expression
Avolition: diminished ability to begin and sustain an activity
Anhedonia: inability to find pleasure in something previously enjoyable
Asociality: social withdrawal
What the cognitive impairments in schizophrenia?
> Working memory
Spatial memory
Attention span
Executive functions
What are the possible life courses of people following a diagnosis of schizophrenia?
> Group 1: one episode with no impairment
- 22% of patients
> Group 2: several episodes with minimal or no impairment
- 35%
> Group 3: Impairment after the first episode, with exacerbation and no return to normality
- 8%
> Group 4: Increasing impairment with each episode, and no return to normality
- 35%
What are the environmental factors of schizophrenia?
> Obstetric complications (pregnancy and birth)
Exposure to infection or inflammation
Exposure to social stress (childhood trauma is common)
Drug use (cannabis)
What are the genetic factors of schizophrenia?
> Heritability (highly heritable)
Rare variants of large effect (DISC1 gene, Nrxn1)
Common variants of small effect = ‘polygenic score’
What is the degradation process of dopamine?
> MAO breaks it down presynaptically
> Cathecol-O-Methyl Transferase (COMT) breaks it down postsynaptically
What is the role of presynaptic autoreceptors in dopaminergic neurotransmission?
They inhibit further dopamine release in the synaptic cleft.
What are the 4 dopamine pathways of schizophrenia?
- Mesolimbic pathway
- from VTA to nucleus accumbens, striatum, amygdala, hippocampus - Mesocortical pathway
- from VTA to PFC - Nigrostriatal pathway
- from substantia nigra to striatum - Tuberoinfundibular pathway
- from A8 dopamine nucleus, via hypothalamus, to pituitary gland (regulates HPA)
What is the dopamine hypothesis of schizophrenia?
- Increase in dopaminergic neurotransmission in mesolimbic pathway
- Leads to abnormally high levels of dopamine in nucleus accumbens and striatum
- These underlie the positive symptoms
What are the first key pieces of evidence that lead to the development of the dopamine hypothesis?
> 1950s: clinical observations
- chlorpromazine decreased the positive symptoms of schizophrenia
- other antipsychotic drugs developed
> 1963:
- Study shows antipsychotic drugs increased the amount of dopamine metabolites in the cerebral spinal fluid of patients
> 1980s to 2000s: PET scans on schizophrenia patients prescribed with amphetamines vs. healthy controls
- > Amphetamines increased dopamine neurotransmission which induced schizophrenia-like symptoms in healthy people
- > Amphetamines increased severity of patients’ symptoms
What is positron emission tomography (PET)?
Non-invasive molecular imaging technique that allows characterisation and measurement of biologic processes in living systems
- by combining a biologically active molecule to a radionuclide tracer that emits photons detected by the scanner
- > visualisation of the three dimensional location of the radiolabelled molecule AND measure the amount of tracer to assess the function of a system or an organ
What is the neuroimaging evidence for the dopamine hypothesis?
> Use of the radiolabelled analogue of dopamine 18 fluorodopa (18F-DOPA) to visualise dopamine synthesis and storage pathways
- proxy measure of dopamine synthesis capacity (rate of dopamine synthesis)
- > Increase of dopamine synthesis capacity in striatum correlates positively with the severity of positive symptoms
> More than 50 studies replicated these findings with different groups of schizophrenia patients around the world
=> robust evidence of dopamine dysfunction in schizophrenia
What do the studies of antipsychotic drugs and their binding to the dopamine D2 receptors show?
> All antipsychotic drugs bind to the dopamine D2 receptors
However: clozapine has low affinity for D2 receptor yet its the most effective antipsychotic drug
- other antipsychotics bind to other NTs in the brain
=> Alteration of dopamine neurotransmission might not be the only factor in schizophrenia
> PET studies suggest that between 60% to 80% of D2 receptors must be blocked for maximum therapeutic effet
- > 80% threshold beyond which patients have extrapyramidal side effects or akathisia
- > Narrow drug therapeutic window
What are extrapyramidal symptoms?
Reflect the action of antipsychotics on dopamine D2 receptors in other dopamine pathways
- such as nigrostriatal pathway, responsible for control of movement
What is akathisia?
Extrapyramidal movement disorder consisting of difficulty in staying still, and a subjective sense of restlessness
What is a drug therapeutic window?
Range of doses in which positive effects are seen without adverse side-effects
Where can the excess of dopamine activity come from?
> Excess of dopamine production
Dopamine metabolising is not quick enough
Patient’s D2 receptors have been altered so they respond differently to dopamine binding - more sensitive to dopamine
What does the stress-diathesis model suggest for the origin of the excess of dopamine activity?
An individual inherits several genes that encode for abnormal proteins
- leading to detective dopamine function in mesolimbic pathway -> positive symptoms consequently
What is the evidence against the dopamine hypothesis of schizophrenia?
Significant proportion of treatment-resistant patients (not responding to anti-psychotics), seeing no improvement in their positive symptoms (30%)
-> dopamine hyperactivity is only one of the causes for the onset of schizophrenia
