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Current - BFoMH [Private] > Neurotransmission defects and mental health: Focus on schizophrenia > Flashcards

Neurotransmission defects and mental health: Focus on schizophrenia Flashcards

1
Q

What is the state of diagnosis for schizophrenia?

A

There’s no diagnostic pathology
- its diagnosis is currently based on clusters of symptoms: positive and negative

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2
Q

What is the relatability of schizophrenia with other psychiatric disorders?

A
  • Similarly to other psychiatric disorders, patients display cognitive impairments
  • However, schizophrenia is characterised by psychotic episodes consisting of both positive and negative symptoms
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3
Q

What are positive symptoms?

A

Additional features that are not ordinarily present.

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4
Q

What are the positive symptoms in schizophrenia?

A
  • Delusions
  • Hallucinations
  • Thought disorder (potentially perceived in the patient’s speech)
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5
Q

What are negative symptoms?

A

Refers to a loss or reduction in normal function.

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6
Q

What are the negative symptoms in schizophrenia?

A
  • 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
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7
Q

What are the cognitive impairments in schizophrenia?

A
  • Working memory
  • Spatial memory
  • Attention span
  • Executive functions
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8
Q

What are the possible life courses of people following a diagnosis of schizophrenia?

A
  • 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%
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9
Q

What are the environmental factors of schizophrenia?

A
  • Obstetric complications (pregnancy and birth)
  • Exposure to infection or inflammation
  • Exposure to social stress (childhood trauma is common)
  • Drug use (cannabis)
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10
Q

What are the genetic factors of schizophrenia?

A
  • Heritability (highly heritable)
  • Rare variants of large effect (DISC1 gene, Nrxn1)
  • Common variants of small effect = ‘polygenic score’
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11
Q

What is the degradation process of dopamine?

A
  • MAO breaks it down presynaptically
  • Cathecol-O-Methyl Transferase (COMT) breaks it down postsynaptically
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12
Q

What is the role of presynaptic auto receptors in dopaminergic neurotransmission?

A

They inhibit further dopamine release in the synaptic cleft.

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13
Q

What are the 4 dopamine pathways of schizophrenia?

A
  1. Mesolimbic pathway - from VTA to nucleus accumbens, striatum, amygdala, hippocampus
  2. Mesocortical pathway - from VTA to PFC
  3. Nigrostriatal pathway - from substantia nigra to striatum
  4. Tuberoinfundibular pathway - from A8 dopamine nucleus, via hypothalamus, to pituitary gland (regulates HPA)
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14
Q

What is the dopamine hypothesis of schizophrenia?

A
  • Increase in dopaminergic neurotransmission in mesolimbic pathway
  • Leads to abnormally high levels of dopamine in nucleus accumbens and striatum
  • These underlie the positive symptoms
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15
Q

What are the first key pieces of evidence that lead to the development of the dopamine hypothesis?

A
  • 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
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16
Q

What is positron emission tomography (PET)?

A

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 3D location of the radiolabelled molecule AND measure the amount of tracer to assess the function of a system or an organ
17
Q

What is the neuroimaging evidence for the dopamine hypothesis?

A
  • 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)
  • showed 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
18
Q

What do the studies of antipsychotic drugs and their binding to the dopamine D2 receptors show?

A
  • 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 effect
  • 80% threshold beyond which patients have extrapyramidal side effects or akathisia
  • Narrow drug therapeutic window
19
Q

What are extrapyramidal symptoms?

A

Reflect the action of antipsychotics on dopamine D2 receptors in other dopamine pathways - such as nigrostriatal pathway, responsible for control of movement

20
Q

What is akathisia?

A

Extrapyramidal movement disorder consisting of difficulty in staying still, and a subjective sense of restlessness

21
Q

What is a drug therapeutic window?

A

Range of doses in which positive effects are seen without adverse side-effects

22
Q

Where can the excess of dopamine activity come from?

A
  • 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
23
Q

What does the stress-diathesis model suggest for the origin of the excess of dopamine activity?

A

An individual inherits several genes that encode for abnormal proteins
- leading to defective dopamine function in mesolimbic pathway -> positive symptoms consequently

24
Q

What is the evidence against the dopamine hypothesis of schizophrenia?

A

Significant proportion of treatment-resistant patients (not responding to anti-psychotics), seeing no improvement in their positive symptoms (30%)
-> dopamine hyperactivity is perhaps only one of the causes for the onset of schizophrenia

25
Q

What is the evidence showing that treatment-resistant patients do not have the same abnormalities of dopaminergic neurotransmission?

A

> Treatment-responders show

  • high dopamine levels in striatum
  • normal levels of Glu in frontal cortex

> Treatment-resistant patients

  • do not have these high dopamine levels in striatum (undistinguishable from controls)
  • show high levels of Glu in the frontal cortex

=> there are other NTs, such as Glu, that play a role in schizophrenia symptoms - not just dopamine
=> we need early identification of treatment-resistant patients to propose alternative drugs - glutamatergic drugs currently in development

26
Q

What are the 2 potential sub-types of schizophrenia?

A
  1. Based on dopamine
  2. Not dopamine-based
27
Q

Do antipsychotic drugs effectively treat the negative symptoms of schizophrenia?

A

Clinical evidence suggest otherwise

28
Q

What are the NTs other than dopamine involved in schizophrenia?

A
  • Treatment-resistant patients have elevated levels of Glutamate NTs in the frontal cortex
  • Atypical antipsychotics have a dual action at dopamine and serotonin receptors
  • Dopamine, Glutamate and GABA interact and regulate each other
29
Q

How is the glutamate-GABA-dopamine circuitry linked to the mesolimbic pathway?

A
  • GABA interneurons in frontal cortex regulate cortical glutamatergic projections
  • Cortical projection neurons send Glu from frontal cortex to dopamine neurons in midbrain - mesolimbic pathway
30
Q

How could alterations of glutamate explain the positive symptoms of schizophrenia?

A

Glutamatergic cortical projection neurons become overactive due to reduction of GABA interneurons
-> activation of mesolimbic pathway at midbrain level -> high levels of dopamine in nucleus accumbens and striatum -> positive symptoms of schizophrenia

=> Inbalances in GABA and Glu may lead to dopamine imbalance

31
Q

What is the evidence for the alteration of glutamate causing the positive symptoms of schizophrenia?

A

Antagonists of N-methyl-D-aspartate (NMDA) receptors (e.g. ketamine) lead to excess glutamate
-> manifestation of positive symptoms in healthy individuals and exacerbates the positive symptoms of schizophrenia patients

32
Q

How could alterations of glutamate explain the negative symptoms of schizophrenia?

A

Deficiency of GABA cortical neurons

  • > overactive glutamate cortical projection neurons -> hyperactivation of GABA interneurons in midbrain -> block activity and firing of dopamine mesocortical projections, which become hypoactive and unable to deliver adequate supplies of dopamine to frontal cortex
  • > hypofrontality -> negative and cognitive symptoms
33
Q

What do the dopaminergic, glutamatergic and GABAergic connections show about neurotransmission and its altered activity?

A

Polysynaptic nature of neurotransmission
-> complex neuronal circuits and networks, which activity defines behavioural outcomes

> Defective activity will lead to behavioural disturbances driven by alterations of dopamine, GABA and glutamate neurotransmission

Current - BFoMH [Private] (15 decks)

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