Schizophrenia Flashcards
What is the overall genetic basis of schizophrenia?
Polygenic - inherit a vulnerability, not the disorder itself
What are the genes contributing to schizophrenia associated with?
▪️ All expressed in the brain
▪️ Particularly involved in neurodevelopment, cortical GABAergic interneurons, and glutamatergic neurons (control of dopamine!)
What is polygenic risk score?
Summation of all someone’s risk alleles weighted by significance
How does the polygenic risk score for schizophrenia compare to the polygenic risk score for bipolar and what does this tell us?
PRS-SCZ and PRS-BP high in both disorders indicating a large genetic overlap (~2/3 of genes)
How does PRS for psychotic depression relate to schizophrenia and bipolar?
▪️ Biggest overlap with bipolar disorder
▪️ Not very similar to schizophrenia - are they two ends of a spectrum with bipolar in the middle?
When environmental factors may also contribute to risk of SCZ?
▪️ Urbanicity, particularly big cities in north Europe
▪️ Cannabis use
▪️ Childhood abuse
▪️ Migration
▪️ Adverse life events
How do genetic risk factors differ between psychotic disorder and what might this suggest?
All very similar genes and environmental risk factors involved suggesting it is a spectrum of severity, with schizophrenia on the severest end?
How does dopamine level differ in people with SCZ and bipolar/mania compared to healthy controls?
Excess of dopamine in the striatum suggestive of elevated dopamine synthesis
(Excess synaptic dopamine)
Why is it so difficult to differentiate between SCZ and bipolar/mania?
There is significant genetic and neurochemical overlap
How does abnormal striatal dopamine give rise to psychotic symptoms?
Increased prediction error abnormalities:
▪️ Constantly predict what we expect to happen
▪️ Learn and update beliefs through prediction error
▪️ Dopamine neurons fire to unexpected events
▪️ This facilitates learning from the experience so that the event is remembered with enhanced value
▪️ Increased dopamine signalling leads to aberrant assignment of importance to unimportant stimuli
What is the main goal of antipsychotics?
To block D2 receptors which normalises dopamine dysfunction and abnormal learning
What happens to the “locus” of abnormality as SCZ progresses?
Can be thought of as migrating from the striatum to the cortex as idea become embedded and more strongly believed
Begin to “expect” things which may outweigh actual environmental stimuli
How are hallucinations thought to arise?
When strong prior beliefs exert inordinate influence over the inferences we make about our environment, creating perceptions where there are no corresponding stimuli
(Beliefs overwhelm reality)
What is the main problem with the current state of psychosis treatment with antipsychotics?
They don’t actually address the problem of excessive dopamine synthesis, just prevents it from acting
How could we subdivide psychosis for an aetiological approach to treatment?
On a spectrum from genetic predisposition to SCZ to genetic predisposition to mood instability
What subtypes of SCZ have been proposed by the aetiological approach?
▪️ Rare organic causes (e.g, TLE, NMDAR)
▪️ Neurodevelopmental pathway
▪️ Drug induced (stimulants vs cannabis)
▪️ Social adversity pathway
▪️ Affective psychosis (bipolar, depression)
▪️ Hormonal (post partum, menopause)
What factors may be considered in the neurodevelopmental pathway to psychosis?
▪️ Copy number variants
▪️ Polygenic score for low IQ (majority of cases)
▪️ Obstetric complications (e.g, premature birth, hypoxia, maternal rubella)
How might lower IQ be associated with risk of SCZ?
More likeLy to misinterpret events
(Average IQ in SCZ = 95)
Is SCZ a neurodevelopmental disorder?
Yes in a proportion of cases, but not all
What signs are associated with neurodevelopmental psychosis?
▪️ Poor premorbid functioning
▪️ Minor physical abnormalities and/or neurological soft signs
▪️ Brain structural abnormalities
▪️ Negative symptoms and neuropsychological deficits
▪️ Worse outcome with excess of treatment resistance
What factors may be considered in the social adversity pathway to psychosis?
▪️ Childhood trauma
▪️ Migration discrimination
▪️ Adverse life events (particularly if already genetic vulnerability)
What often mediates the social adversity pathway to psychosis?
Depression and anxiety
If psychosis is mediated by depression and anxiety, what is the best option for treatment?
▪️ Psychological approaches, such as integrated therapy for PTSD and psychosis
▪️ Antipsychotics might make depression worse
Why is psychosis incidence highest in cities such as London, Amsterdam, and Paris?
▪️ Greater frequency of cannabis use
▪️ Higher potency cannabis (greater THC content)
What are the main contributors to the substance-induced pathway to psychosis?
▪️ Cannabis
▪️ Stimulants (e.g., cocaine)
How has the incidence of SCZ in London changed since the 60s and why?
Massively increased (3x higher in 2012)
▪️ Migration?
▪️ Percentage using cannabis increased?
BUT correlation not causation
What treatment options can be offered for individuals with cannabis-induced psychosis?
▪️ Cannabis clinic at the Maudsley (group sessions, 1-to-1s, goals and incentives)
▪️ Cannot use high D2 blockers like haloperidol or risperidone due to low ventral striatal dopamine release
▪️ Monitor for withdrawal
