schizophrenia: causes and treatment
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Schizophrenia: causes and treatment
Robin M MurrayProfessor of Psychiatric ResearchInstitute of Psychiatry, Psychology and Neuroscience,King’s College, London, UK
robin.murray@kcl.ac.uk
65,205 cases and 87,919 controls
256 genome wide significant sites
PGC SCZ wave3
Ripke et al, Nature, July 2014
DRD2 - antipsychoticsGlutamate and GABA genes – which influence dopamine releaseNeurodevelopmental/cognitive genesImmune genes – response to infection/stress
The Polygenic Risk Score
Estimate any individual’s liability to schizophrenia by summing together their risk SNPs
Examine relationship to environmental factors
Striatal Dopamine Synthesis is Elevatedin schizophrenia
Controls
Schizo
phrenia
Bipolar
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P < 0.01d = 1.02
P = 0.04d = 0.91
Jauhar et al JAMAPsychiatry Dec 2017
Dopamine (DA) as the “Wind of PsychoticFire”
When individuals are acutely psychotic, they show an excessive release of DA 1
DA normally mediates the attachment of salience to ideas and objects 2
Heightened DA transmission leads to aberrant assignment of salience to external and internal stimuli3
Delusions arise from attempts to explain this abnormal salience4
1. Laruelle M, et al. Proc Natl Acad Sci USA. 1996;93(17):9235-9240. 2. Berridge KC, Robinson TE. Brain Res Brain Res Rev. 1998;28(3):309-369. 3. Kapur S. Am J Psychiatry. 2003;160(1):13-23. 4. Maher, 1983
How can we make sense of schizophrenia?
“My thoughts get all jumbled up ...things are coming in too fast; I lose my grip and get lost; I am attending to
everything at once and as a result I do not attend to anything”1
“Meaningful connections are created between temporary coincident external impressions … or perceptions with thoughts that happen to be present, or events and recollections happening to occur in consciousness at the same time”2
1. McGhie A, Chapman J. Br J Med Psychol. 1961;34:103-116.2. David Hemsley, 1987, 1994.
Social factors that increase the risk of Psychosis.
Childhood adversity
Migration/ethnic minority
Bullying
Adverse life events/stress
If the Final Common Pathway to Psychosis is Striatal Dopamine Excess, can social factors cause this?
12 Ultra-high risk subjects (6.9%) and 10 drug- naïve schizophrenic patients (11.44%) showed greater release of dopamine* in Associative Striatum in response to Montreal Stress Test compared to 12 controls
* measured using (11C)-(+) - PHNO binding
Biological Psychiatry, 2012,71, 561-567
Controls High Risk Schizophrenia
Drug Use can also increase risk of psychosis by impacting on striatal dopamine
Risk of psychosis in relation to
extent of cannabis use
O R = 4
Marconi et al Schiz Bull 2016
Howes and Murray, Lancet, 2014
Stress, childhood abuse,Migration, and drug abuseall impact on striatal Dopamine
The Final Common Pathway to Psychosis is Dopamine Dysregulation, Social Factors and Drug Abuse
can cause this.
Does the incidence of psychosis vary across Europe, and if so what causes this?
CambridgeAmsterdam
+Leiden region
Paris + Clermont Ferrant
Bologna
Palermo
Barcelona,Madrid +3
EUGEI study: 2011-2013 Incident First Episode Psychosis cases N=1130 & population controls N=1499
London
Verona
Jongsma et al, JAMA Psych 2018
London
What is the explanation for the low rates in Italy/Spain?
Migration
Families v social isolation?
High Potency Cannabis
The effect of daily use of high-potency cannabis on the odds for psychotic was particularly visible in London and Amsterdam
*Adjusted for age, gender, ethnicity, level of Ed, employment status and other drugs (tobacco, alcohol, stimulants, Ketamine, Legal highs, Hallucinogenics).
Di Forti et al, Lancet Psych, On Line March 23 2019
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Prevalence of daily cannabis use in population controls (%)Adjusted psychosis incidence (rate per 100,000)
r=0.8, p=0.0109
Population Attributable Fraction
If nobody smoked high potency cannabis, 12% of all cases of first episode psychosis across Europe would be prevented, rising to 32% in London and 50% in Amsterdam
Di Forti et al, Lancet Psych, On Line March 23 2019
Drug Treatment:
But people need more than drugs
Psychological and social treatments are important
Cognitive Behaviour Therapy
Randomised controlled trials have shown that cognitive behavioural therapy (CBT) can be useful not just for anxiety and depression in patients with psychosis but also for modifying positive symptoms especially delusions
Howes & Murray Lancet 2014
Sensitiseddopamine
system
Dopaminerelease
Aberrantprocessingof stimuli
Paranoidinterpretation Psychosis
Biasedcognitive schema
Acute StressDrug abuse
Reduce stress or drug use
Block dopamine
CBT
New Psychological Therapies eg
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1. “dopamine supersensitivity and functional tolerance to antipsychotics are due in part to changes in striatal
dopamine receptor function”
2. “breakthrough” supersensitivity during antipsychotic treatment undermines treatment efficacy”.
J Neuroscience 2007
Haloperidol D2 occupancy –implications for dose reduction
Switching paliperidone to placebo –effect of formulation
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