Biological basis of schizophrenia - Y2

A brief history

The term dementia praecox (meaning premature decline, now disused) was popularized by German psychiatrist Dr Emile Kraepelin in 1887

  • Distinguished between this and manic-depressive psychosis - Kraepleinian dichotomy
  • Swiss psychiatrist Bleuler (1908) coined the name ‘schizophrenia’ - comes from ‘schizo’ - split (Greek) to describe the fragmented thinking of those with the disorder
    -> Not meant to convey the idea of split personality
  • Cost of schizophrenia to individuals and society
    -> Associated with high levels of distress and suicide
    -> Unemployment high - 80-90%
    -> Average life expectancy reduced by 10-20 years
    -> Schizophrenia costs £11.8 billion per year in England
    -> Not uniformly negative outcomes - about 20% have chronic symptoms and disability

DSM-5 diagnosis - made on person’s history and mental state

  • At least two characteristic symptoms, each present for a significant portion of time during a 1 month period
  • Is it an umbrella for a range of conditions?

Symptoms - comorbidity, gender and cultural differences and symptom overlap

  • Positive symptoms of schizophrenia -
    -> Hallucinations - appraisal is important; dopamine excess in striate cortexes
    -> Thought disorders
    -> Delusions - persecution, grandeur and control - appraisal
  • Negative symptoms -
    -> Affective flattening
    -> Avolition
    -> Alogia - speech poverty
    -> Social and occupational dysfunction
    -> Catatonic behaviour
    -> Disorganised thinking
    -> Anhedonia
  • Cognitive symptoms -
    -> Difficulty in sustaining attention
    -> Low psychomotor speed
    -> Deficits in learning and memory
    -> Poor abstract thinking
    -> Poor problem solving

Typical age of presentation of symptoms - males most common around 20-24, and females around 24-29; can happen at any age however
Differential diagnosis -

  • Take into account length of illness, pattern and nature of associated substance use, co-occurrence of mania and depression and presence of other illnesses (Owen et al, 2016)
    -> Psychotic disorders induced by alcohol or drugs
    -> Psychotic disorder not otherwise specified
    -> Delusional disorder
    -> Brief psychotic disorder
    -> Schizoaffective disorder
    -> Psychotic disorder caused by general medical illness

Is the definition too wide or too narrow?
Too wide -

  • No unifying symptom
  • Manifestation and outcomes heterogenous
  • Too many different causal mechanisms
    Too narrow -
  • Large genetic overlap between schizophrenia and other conditions
  • Many individuals receive more than one diagnosis, because symptoms do not fall neatly into only one category

Cognitive model of positive symptoms in schizophrenia - Garety et al, 2011 -

  • Biopsychological vulnerability -> stressful events -> cognitive dysfunction and biases <-> emotional changes <-> appraisal of experience -> positive experiences
  • Model proposes that positive symptoms are not pathological - it is how they are appraised that is problematic - reasoning biases influence appraisal and represent the risk factors for illness
  • Reasoning biases associated with positive symptoms -
    -> Jumping to conclusions - a data gathering bias demonstrated by the Beads task
    --> Number of items requested before making a decision - individuals with delusions request fewer beads before making their decision than other psychiatric or non-clinical groups
    -> Externalising attributional style
    -> Poor social understanding or theory of mind

Bias against Disconfirmatory Evidence (BADE)

  • Tendency to dismiss information that disconfirms one’s existing assumptions
  • In adults, BADE is associated with delusion-related symptoms in clinical disorders such as schizophrenia (e.g. Riccaboni et al, 2012)
  • BADE is also associated with hallucinations reported by adolescents in the community (Hollowell and Ronald, 2020)

Dopamine hypothesis of schizophrenia

  • Over four decades old
  • Explains the positive symptoms
  • Overactivity of synapses between dopaminergic neurons of the ventral tegmental area and neurons in the nucleus accumbens and amygdala (mesolimbic pathway)
  • Activity of dopaminergic neurons in these areas involved in process of reinforcement
  • Evidence from drugs
    -> Drugs that act as agonists on these dopaminergic neuron synapses reinforce behaviour
    -> If taken in large doses, drugs that acts as agonists on this pathway induce positive symptoms of psychosis and these drugs worsen symptoms in people with schizophrenia
    -> Drugs that act as antagonists of dopaminergic neuron synapses - block DA receptors - work as antipsychotic medication, they reduce positive symptoms
    -> Side effects of traditional antipsychotic medication were Parkinson-like symptoms; Parkinsons is a disorder caused by lack of DA activity

Other evidence -

  1. Peripheral markers -
  • Increase in schizophrenia symptoms - DA metabolites in CSF and plasma
  1. Ex-vivo studies - dopamine and DA metabolite levels in brain
  2. Brain imaging studies - DA synthesis and DA release capacity and baseline DA levels

Other risk factors

Striatal dopaminergic activity in schizophrenia - Howes et al, 2017

  • Reduced cortical dopamine release leads to increased activity of excitatory glutaminergic neurons projecting to the midbrain which increases striatal dopamine synthesis and release
  • Hypoactive NMDA receptors on GABAergic interneurons lead to reduced GABA release which also leads to increased striatal dopamine synthesis and release

Genetic risk factors

  • Impaired glutamatergic regulation -> increased striatal DA release -> Aberrant Salience -> psychotic symptoms -> acute psychological stress (also increases striatal DA release) -> blunted cortical DA release

Increased dopamine activity associated with positive symptoms of schizophrenia:

  • Relative amount of dopamine released in response to amphetamine and relationship between dopamine release and changes in positive symptoms in those with schizophrenia (Laurelle et al, 1996)

Glutamate dysfunction and schizophrenia

  • Most abundant neurotransmitter in the CNS; has excitatory effect and is present in >90% of synaptic connections
  • Three major classes of synaptic receptors for glutamate - AMPA receptors, NMDA receptors and metabotropic receptors
  • Has key role in learning and memory through its involvement in synaptic plasticity
  • Relevance to schizophrenia -
    -> Several genes associated with schizophrenia code for proteins related to glutamate receptors
    -> Glutamate signalling involved in pathway influencing mesolimbic dopamine activity
    -> Disturbed glutamatergic function may explain the cognitive and negative symptoms

Is schizophrenia a brain disorder?

Supporting evidence -

  • Non-specific symptoms - negative and cognitive symptoms not specific to schizophrenia, seen in those with brain damage, brain trauma and intellectual disability
  • Associated with minor physical anomalies suggesting prenatal neurodevelopmental origin of the condition
  • Several of the environmental risk factors take their effect prenatally (mother having flu during second trimester - major stage of brain development - elevates risk in offspring
    -> Obstetric complications increase risk
  • Home videos (retrospectively viewed) and prospective studies of high risk cases suggest abnormal brain development prior to onset of condition

Schiffman et al, 2002 - minor physical anomalies:

  • Head - two or more hair whorls, head circumference outside normal range
  • Eyes - skin fold at inner corner of eye, wide-set eyes
  • Ears - low-seated ears and asymmetrical
  • Mouth - high-steepled palate furrowed tongue
  • Hands - curved fifth finger and single transverse crease in palm
  • Feet - third toe longer than second toe and partial webbing of two middle toes

Potential problems with the brain disorder hypothesis -

  • Schizophrenia associated with many social and environmental adversity factors e.g. trauma
  • Onset usually not until adolescence
  • Some individuals show no prodrome - pre-disorder cognitive impairments or physical anomalies
  • Monozygotic twin concordance rate is not 100%
  • Non-specific explanation

Brain differences in schizophrenia:

  • Latest research presents a complex picture - decrease in brain volume shown by MRI studies
    -> Enlarged ventricles
    -> Synaptic dysfunction
    -> Hypofrontality - leading to negative and cognitive symptoms

Challenges to this field -

  • Are findings due to the outcome of the illness or an aspect of the cause?
  • How to link new genetic results to established neuroscience findings
  • Converging across results from different methods
  • How do findings link to individual symptoms?

Genetic research on schizophrenia

Kendler et al, 1993 -

  • If immediate family of someone with schizophrenia, your chances are 13 times higher that you too will develop schizophrenia compared to a person selected randomly (relative risk)
  • Absolute risk is 65 out of 1000 rather than 5 out of 1000

Evidence from family studies for polygenic inheritance of schizophrenia

  • High concordance of 48% between MZ twins (Gottesman, 1991)
  • Family and twin studies show that risk of schizophrenia increases with increased relatedness with an affected individual; polygenic model

Sullivan et al, 2003 - heritability of schizophrenia is estimated at 81%, shared environment at 11%, MZ twins higher concordance

Genetic basis -

  • Highly polygenic - lots of genes contribute to risk and different genes contribute in different ways
  • Pleiotropic risk - same genes contribute to several different phenotypes
  • Convergence of genetic findings pointing towards particular biological processes

Reduced fecundity (less children), natural selection and genetics of schizophrenia

  • Schizophrenia is associated with reduced fecundity (Bundy et al, 2011)
  • Geneticists hypotheses that common genes giving high risk for schizophrenia are not found because they have been selected out across generations (evolution through natural selection)
  • This might explain genes associated with schizophrenia tend to be rare and have a small effect size

Psychiatric genomics consortium leads progress in schizophrenia genetics:

  • 108 genes identified to be associated with schizophrenia

Polygenic risk score -

  • Sum of risk alleles identified to be associated with schizophrenia - each risk allele is weighted by the strength of its association with schizophrenia
  • Use the polygenic risk score as a predictor in regression - does polygenic risk predict etc

The Major Histocompatibility Complex (MHC) - Sekar et al, 2016 - - Complex variation in complement component 4 (C4) genes

  • Vary widely between people in how many copies and which forms (C4A and C4B)
  • Schizophrenia associated with C4 variants promoting higher expression (activity) of C4A in brain tissues
  • Explains large signal from MHC

Ultra rare protein altering genetic variants associated with schizophrenia

  • Compared exomes of 4277 individuals with schizophrenia to controls
  • Found gene-disruptive and putatively protein-damaging ultra rare genetic variants more common in individuals with schizophrenia than controls
  • Variants concentrated in brain-expressed genes, specifically in neuron-specific genes and particularly synaptic genes

Non-genetic factors -

  • Prenatal and perinatal events
    -> Subtle motor, cognitive and social deficits - CNVs and SNPs, developmental genes
  • Chronic social adversity in childhood, migration and urbancity - HPA hyperactivity and inflammation
    -> Social anxiety, quais-psychotic ideas, depression
    -> Dopamine dysregulation
  • Drug abuse - glutamatergic and endocannabinoid dysfunction
    -> Dopamine dysregulation - neurotransmitter genes

Should diagnostic categories be used in basic research -

  • In psychotic experiences, it may be better to use continuous scales for individual scales to identify relation

Environmental factors related to onset of schizophrenia

  • Season of birth - people born during late winter and early spring are more likely to develop schizophrenia
  • Viral epidemics - an increased incidence of schizophrenia is seen in people born a few months after an influenza epidemic
  • Population density - likelihood of developing schizophrenia is approximately three times higher in people who live in the middle of large cities than in those who live in rural areas
  • Prenatal malnutrition - low birth weight babies have a higher incidence of schizophrenia
  • Substance abuse - tobacco use during pregnancy is associated with increased risk of schizophrenia in offspring
    -> Cannabis and schizophrenia - increases risk, operates in a dose response manner
    --> Has an odds ratio of 3.9 for risk of schizophrenia and other psychosis related outcomes among heaviest cannabis users compared to nonusers (Marconi et al, 2016)
    -> High rates of tobacco smoking in those with schizophrenia - shared genetic influences, smoking as a risk factor of self-medicating hypothesis (Hunter et al, 2020)
  • Interactions - a person born to a woman who had pyelonephritis during pregnancy is twice as likely to develop schizophrenia and four times more likely to do so if he or she has a family history of schizophrenia
  • Obstetric complications - emergency C section, uterine complications and fetal oxygen deprivation at birth are associated with increased risk of schizophrenia

Limitation of observed associations with environmental factors:

  • Do not control for underlying genetic liability
  • Difficult to control for all confounds
  • Associations do not prove causation, and often do not reveal mechanism underlying association

Other research and treatment

Social defeat hypothesis of schizophrenia: Selten et al, 2013

  • Long term exposure to social defeat -> sensitisation of the mesolimbic dopamine pathways -> increased risk for schizophrenia

Howes and Murray, 2014: An integrated sociodevelopmental-cognitive model of schizophrenia -

  • Genes <-> anomalous neurodevelopmental
    -> neurodevelopmental hazards
    -> sensitised dopamine system <-> socio-developmental adversity -> biased cognitive schema

Subthreshold categories and labels:

  • Traits - psychotic experiences, schizotypy, psychosis-like proneness
  • At risk mental state / ultra high risk
  • The prodrome

Psychotic experiences as traits in the community:

  1. Variations in terminology - positive, negative and cognitive types -
  • Negative symptoms
  • Grandiosity
  • Cognitive disorganisation
  • Hallucinations
  • Paranoia
  1. Multidimensional and quantitative (Ronald et al, 2014)
  2. Common in population (Kelleher et al, 2013)
  3. Increased risk of - suicide attempts and psychiatric conditions
  4. Persistent psychotic experiences show higher odds ratios
  5. They are the most predictive symptom in a polygenic risk score prediction compared to major depressive disorder and bipolar disorder
  6. Taxometric analyses find no categories in positive psychotic experiences

Co-occurring conditions -

  • Depression
  • Anxiety
  • Autism Spectrum Disorder
  • Physical health
  • Epilepsy
  • Intellectual impairment

Reasons for high co-occurrence -

  • Correlated risk factors
  • Alternate forms
  • Overlap of specific symptoms
  • Phenotypic causality
  • Reciprocal causation
  • Three independent disorders
  • Assortative mating - more likely to have children with autistic or schizophrenic partners
  • Ascertainment bias (artifactual explanation)

High genetic correlations between schizophrenia and other psychiatric conditions

The general psychopathology (p-factor): Caspi et al, 2014 and 2018

  • Historically different psychiatric diagnosis and forms of psychopathology considered distinct
  • Recently it has been reported that a single latent factor can encapsulate individuals’ proclivity to develop all of the psychopathology included within broad internalising, externalising and thought disorder dimensions
  • A large number of psychiatric symptoms and traits fall into a single principal component, termed the p-factor
  • Using family and twin models, high genetic overlap is observed between psychiatric symptoms
  • A single polygenic p-factor has been reported
  • Models suggest genetic influences are general across psychopathology (Pettersson et al, 2013 and 2016)

Treatment of schizophrenia:

  • Antipsychotic medication - Typical and atypical
    -> Atypical does positive and negative symptoms by sitting in D2 and D3 receptors but only temporarily - has affinity for D1 and D4
    -> Typical stays in system, leading to negative symptoms
  • Psychological therapy
  • Rehabilitation
  • Social support
  • Three aspects of outcome -
    -> Clinical, social and personal

Refer to mindmap 10 from first year for more

Family explanations -
Family dysfunction -

  • Schizophregenic mother
  • Double bind theory
  • Expressed emotion
    Cognitive explanations -
  • Dysfunctional thought processing
  • Central control issues - metarepresentation

Treatment - family therapy and CBT (psychoeducation)


Areas - Ventral striatum activity negatively correlated with avolition

Heterogeneity of symptoms - 2 patients with completely different symptom profiles could still be classified as having schizophrenia

  • This is an issue - clinical heterogeneity - variation within the same diagnosis
  • If schizophrenia is not a unitary disorder, it should be renamed
  • It acts as an umbrella term that covers groups of patients with diverse symptoms and different underlying causes - but the APA still considers it a diagnostic label
  • More research is needed to identify subtypes, and the causes and treatments for each - changing the label is the start

Traits - psychotic experiences, schizotypy, psychosis-like pronenenss

  • prodrome - what it looks like before it occurs
  • At risk state / ultra-high risk