Biological underpinnings of psychotic illness Flashcards
When and what was the start of modern research into schizophrenia?
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
What were the thoughts on aetiology of schizophrenia after the scan study of Tim Crow and Eve Johnstone on chronic schizophrenia (1976)?
- Loss of brain tissue
- brain was normal until early adult life and then deteriorated
- > hypothesis of degenerative disorder
What were the thoughts on the aetiology of schizophrenia after the studies of Lewis and Murray (1987) and Danny Weinberger (1987)?
- Developmental problem that increase one’s vulnerability to psychotic symptoms
- Late 90s: developmental hypothesis largely accepted
What were the thoughts on the aetiology of schizophrenia after the studies of Lieberman and colleagues (2005) and Rene Kahn (2006)?
- 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
What did the study led by Nancy Andreasen show on the aetiology of schizophrenia (Ho et al., 2011)?
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
What do we know now about the aetiology of schizophrenia?
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
What was the breakthrough for schizophrenia in molecular genetics?
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)
Which genetic loci impact one’s vulnerability to psychosis?
- Dopamine D2 receptors: antipsychotics
- Glutamate genes: influence dopamine release
- Neurodevelopmental genes
- Immune genes
- > polygenic risk
What is the polygenic risk score?
Calculated by the sum of the involved genetic loci
How could the polygenic risk score of psychosis be used?
- 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)
What is the role of the polygenic factor in the onset of schizophrenia?
- 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
What does it mean that schizophrenia is polygenic?
Requires a combination of gene and environmental factors
What are copy number variants?
‘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
What is the role of copy number variants in schizophrenia (Walsh et al., 2008)?
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)
What are the genetics involved in schizophrenia?
- Polygenes (96-97%)
- Copy number variants (3-4%)
What is the developmental cascade towards schizophrenia?
- 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)
What is the role of dopamine dysregulation in schizophrenia?
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
What have PET scans studies shown on the dysregulation of the dopamine system in schizophrenia?
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)
When does the striatal dopaminergic abnormality arise in the development of schizophrenia (Howes et al., 2009)?
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
What is the observed striatal dopaminergic increase in psychosis (Howes et al., 2011)?
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
What do cannabis studies show?
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
What is the risk associated with different types of cannabis and frequency of use (Di Forte et al., 2015)?
- 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
What are synthetic cannabinoids?
- 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)
What is the risk of psychosis associated with synthetic cannabis?
Potentially develop psychosis in number of days
What did the epidemiological AESOP study show on the social factors in psychosis (Kirkbridge et al., 2006)?
- 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
How do social factors impact dopamine (Romina et al., 2012)?
Increased stress-induced dopamine release in psychosis
- those with schizophrenia release more dopamine during stressful experience (11.4% more than controls)
How do childhood experience impact dopamine (Egerton et al., 2015)?
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
What characterises the development of people with a liability to psychosis or severe psychosis (schizophrenia)?
- 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
What is the mechanism characteristic of the maintenance of psychosis?
Stress is exacerbated by the psychosis
-> further dopamine release
- > more aberrant processing, more paranoia
- > further psychotic episodes
