Biological underpinnings of psychotic illness Flashcards

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1
Q

When and what was the start of modern research into schizophrenia?

A

1976: Tim Crow & Eve Johnstone
- first to apply brain scanning to those with schizophrenia

  • those with chronic schizophrenia had larger fluid-filled space in centre of brain
  • less cortical volume than healthy controls
  • cognitive difficulties
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2
Q

What were the thoughts on aetiology of schizophrenia after the scan study of Tim Crow and Eve Johnstone on chronic schizophrenia (1976)?

A
  • Loss of brain tissue
  • brain was normal until early adult life and then deteriorated
  • > hypothesis of degenerative disorder
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3
Q

What were the thoughts on the aetiology of schizophrenia after the studies of Lewis and Murray (1987) and Danny Weinberger (1987)?

A
  • Developmental problem that increase one’s vulnerability to psychotic symptoms
  • Late 90s: developmental hypothesis largely accepted
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4
Q

What were the thoughts on the aetiology of schizophrenia after the studies of Lieberman and colleagues (2005) and Rene Kahn (2006)?

A
  • There’s an intrinsic degeneration in the brain of those with schizophrenia, which was prevented by olanzapine
  • Progressive brain disorder, maybe caused by Haloperidol
  • schizophrenia patients on haloperidol showed decline in grey matter of the brain compared to controls or those on olanzapine
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5
Q

What did the study led by Nancy Andreasen show on the aetiology of schizophrenia (Ho et al., 2011)?

A

Longitudinal study of first-episode schizophrenia:

  • follow up max 15 years and repeated brain scans
  • smallest dose of antipsychotic Chlorpromazine (115mL) showed smaller decrease in cortical volume
  • > is it the illness or antipsychotic causing this
  • giving animals antipsychotics showed decline in cortex volume
  • > decline cause partly by antipsychotics
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6
Q

What do we know now about the aetiology of schizophrenia?

A

The progressive brain changes in the illness are in part due to:

  • antipsychotics
  • cannabis and other drugs
  • stress and cortisol damage
  • lack of exercise
  • > not an intrinsic degeneration of the brain
  • > improve one’s lifestyle and decrease use of antipsychotics
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7
Q

What was the breakthrough for schizophrenia in molecular genetics?

A

Genetic component in schizophrenia

  • numerous genes involved in the susceptibility of schizophrenia
  • 108 areas of genome associated with developing schizophrenia

Ripke et al., 2014: Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia
- global collaboration (36,989 participants; 113,075 healthy controls)

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8
Q

Which genetic loci impact one’s vulnerability to psychosis?

A
  • Dopamine D2 receptors: antipsychotics
  • Glutamate genes: influence dopamine release
  • Neurodevelopmental genes
  • Immune genes
  • > polygenic risk
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9
Q

What is the polygenic risk score?

A

Calculated by the sum of the involved genetic loci

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10
Q

How could the polygenic risk score of psychosis be used?

A
  • Someone demonstrating signs of psychosis in young age
  • > test polygenic risk score
  • > take steps to prevent/manage first episode of psychosis
  • Examine relationship between genetic factors and environmental risk factors (e.g. cannabis use)
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11
Q

What is the role of the polygenic factor in the onset of schizophrenia?

A
  • Individual risk genes are neither necessary nor sufficient to cause schizophrenia
  • > they increase the risk
  • Polygenic (small) effects accumulate with environmental factors to increase one’s liability to psychosis
  • > threshold of psychosis
  • > we all have a level of risk genes for schizophrenia BUT does not mean we’ll development psychosis or schizophrenia
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12
Q

What does it mean that schizophrenia is polygenic?

A

Requires a combination of gene and environmental factors

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13
Q

What are copy number variants?

A

‘knock-out genes’

  • deletion or duplication of genes resulting in incorrect amount of genes
  • if you lose/duplicate a chunk of your DNA and if these are neurodevelopment genes, this will damage the development of your brain
  • high proportion (10-20%) of those with autism, learning disability and epilepsy have copy number variant
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14
Q

What is the role of copy number variants in schizophrenia (Walsh et al., 2008)?

A

Continuum of neurodevelopment impairment with the same copy number variants causing

  • learning disability (early)
  • then autism
  • schizophrenia (late)
  • CNVs are rare but dramatically increase your liability (possibly 10 times more likely to develop schizophrenia)
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15
Q

What are the genetics involved in schizophrenia?

A
  • Polygenes (96-97%)

- Copy number variants (3-4%)

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16
Q

What is the developmental cascade towards schizophrenia?

A
  • Pre and perinatal events + copy number variants
    + developmental polygenes
    -> subtle motor, cognitive and social deficits
  • Social anxiety, depression (age 5-10)
  • Quasi psychotic ideas (age 10-17)
  • Dopamine dysregulation of salience (age 17-20)
  • > Psychosis (age 20)
17
Q

What is the role of dopamine dysregulation in schizophrenia?

A

Dopaminergic change dysregulates the person and promotes psychosis

  • dopamine “grabs your attention” = salience
  • those with psychosis release too much dopamine
  • > minor events or perceptions become fare more important and promote delusional ideas

= Mesolimbic system
- hyperactive salience -> more sensitive threat evaluation

18
Q

What have PET scans studies shown on the dysregulation of the dopamine system in schizophrenia?

A

Schizophrenia associated with increased dopamine synthesis in striatum
-> striatal dopaminergic abnormality

  • we can’t reduce the dopamine release
    BUT we can block dopamine receptors
    -> reduce effects of increased dopamine release (calming the patient)
19
Q

When does the striatal dopaminergic abnormality arise in the development of schizophrenia (Howes et al., 2009)?

A

In the prodrome
- begins and develops as people are becoming psychotic

  • 25% of those in the ‘at risk mental state’ group (prodrome) will go on to develop psychosis
  • they seem to have the highest levels of dopamine, compared to controls of those already with psychosis
20
Q

What is the observed striatal dopaminergic increase in psychosis (Howes et al., 2011)?

A

Positive correlation between development of psychosis and increase in dopamine levels

  • on average, as patients are developing psychosis, dopamine levels increase
  • more dopamine = increased likelihood of attributing salient importance to insignificant things in your environment
21
Q

What do cannabis studies show?

A

Starting cannabis (active ingredient = THC) use while the brain is developing may cause issues

  • increased risk of schizophrenia (odds ratio > 1)
  • cannabis users age 15: OR = 4.5
    vs
  • cannabis users age 18: OR = 1.6
22
Q

What is the risk associated with different types of cannabis and frequency of use (Di Forte et al., 2015)?

A
  • 90% of users who occasionally use low strength cannabis will not develop any problems
  • THC content of hashish = 3-4%
  • THC content of skunk (high potency cannabis) = 16%
  • odds ratio (first-episode psychosis) for never used cannabis = 1
  • odds ratio for hash everyday = 0.91
  • odds ratio for skunk at weekends = 2.7
  • odds ratio for skunk everyday = 5.4
23
Q

What are synthetic cannabinoids?

A
  • Manufactured, synthetic cannabis
  • has 100% effect on CB1 receptors
    vs partial effect for traditional cannabis
  • known as Spice or K2, can be mixed with traditional cannabis and smoked
  • epidemic use in UK jail system (easy to smuggle, not detectable by routine tests)
24
Q

What is the risk of psychosis associated with synthetic cannabis?

A

Potentially develop psychosis in number of days

25
Q

What did the epidemiological AESOP study show on the social factors in psychosis (Kirkbridge et al., 2006)?

A
  • Where you live is a factor
  • Living in big city increases your risk of developing psychosis
  • Studies in Italy, Spain, Brazil, Ireland also show incidence is lower in rural areas
  • Cities in the North (London, Paris, Amsterdam) seem to have higher incidence rates compared to cities in the South (Barcelona, Palermo, São Paolo)
  • Africa and Caribbean migrants who come to UK/Europe have much higher risk of psychosis, potentially because of their socioeconomic position within their environments
26
Q

How do social factors impact dopamine (Romina et al., 2012)?

A

Increased stress-induced dopamine release in psychosis

- those with schizophrenia release more dopamine during stressful experience (11.4% more than controls)

27
Q

How do childhood experience impact dopamine (Egerton et al., 2015)?

A

Adversity in childhood linked to elevated striatal dopamine in adulthood

  • presynaptic dopamine in associative striatum is elevated in young adults who experienced severe sexual/physical abuse or unstable family arrangements during childhood
  • childhood adversity increases likelihood of releasing dopamine during stressful event
  • > increases risk of psychosis
28
Q

What characterises the development of people with a liability to psychosis or severe psychosis (schizophrenia)?

A
  • Overactive dopamine system

-> Aberrant processing of stimuli
= misinterpreting the environment

  • > Biased cognitive schema
  • if abused as child, more likely to blame others in stressful events
  • > Paranoid interpretation
  • > Psychosis
  • > Acute psychosocial stress
  • > Sensitised (overactive) dopamine system
29
Q

What is the mechanism characteristic of the maintenance of psychosis?

A

Stress is exacerbated by the psychosis
-> further dopamine release

  • > more aberrant processing, more paranoia
  • > further psychotic episodes