Schizophrenia – Aetiology and neurobiology

Slide introducing the slide deck for Schizophrenia Schizophrenia - Aetiology and neurobiology

Slide showing the aetiology of schizophrenia

Slide introducing the chapter Genetic risk factors for schizophrenia

Slide showing the heritability of schizophrenia

Slide showing the genetics of schizophrenia

Slide showing rare genetic variants in schizophrenia risk

Slide showing rare CNVs associated with schizophrenia risk

Slide showing convergence of schizophrenia risk variants on shared biological pathways.

Slide introducing the Environmental risk factors for schizophrenia chapter

Slide showing prenatal and perinatal environmental risk factors associated with psychotic disorders.

Slide showing premorbid markers and early risk indicators associated with later psychotic symptoms.

Slide showing associations between childhood psychosocial adversities and increased risk of psychotic disorders.

Slide showing adulthood psychosocial risk factors associated with psychotic disorders, including migration and adverse life events.

An overview of the relationship between substance use and schizophrenia, including transition rates following substance-induced psychosis.

Slide showing the association between amphetamine use, dose, and risk of psychosis or mania.

Slide showing the association between cannabis use and increased risk of psychotic symptoms and psychosis, including effects of use frequency and THC potency.

Slide illustrating how genetic and environmental risk factors may interact to contribute to schizophrenia and psychosis risk.

Slide introducing the Neurobiology of schizophrenia chapter

Slide outlining key principles of neurobiological models of schizophrenia, including symptom domains and sources of evidence used to study underlying mechanisms.

Slide introducing the Structural brain abnormalities in schizophrenia chapter

Slide showing structural brain findings in schizophrenia, highlighting enlarged ventricles, reduced grey matter volume and cortical thickness.

Slide showing MRI evidence of structural brain changes before and after psychosis onset.

Slide showing converging structural and functional brain abnormalities in schizophrenia across frontal, cingulate, insular, and striatal regions.

Slide introducing the Core neurotransmitter systems in schizophrenia chapter

Slide summarizing evidence for glutamatergic dysfunction in schizophrenia from drug challenge and imaging studies.

Slide summarizing evidence for GABAergic dysfunction in schizophrenia from post-mortem, gene-expression, and imaging studies.

Slide summarizing evidence for dopaminergic dysfunction in schizophrenia from MRI, PET, and SPECT studies.

Slide showing the relationship between dopamine D₂ receptor occupancy, antipsychotic response, and risk of extrapyramidal side effects

Slide illustrating a proposed model linking glutamate, GABA, and dopamine dysfunction in schizophrenia.

Slide showing how environmental stressors may contribute to dopamine dysregulation in schizophrenia.

Slide showing evidence for altered serotonergic neurotransmission in schizophrenia, including changes in serotonin receptor measures.

Slide showing evidence for muscarinic neurotransmission dysfunction in schizophrenia and cholinergic brain projections.

Slide introducing the Other neurobiological mechanisms in schizophrenia chapter

Slide showing evidence of reduced synaptic density and synaptic markers in schizophrenia.

Slide showing evidence for immune dysregulation in schizophrenia, including increased inflammatory markers and microglial activity.

Slide summarizing key genetic, environmental, and neurobiological factors implicated in schizophrenia.

Slide outlining limitations of current neurobiological models of schizophrenia.

Summary slide of the Schizophrenia Aetiology and neurobiology slide deck

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Schizophrenia is a complex, heterogeneous disorder with multifactorial aetiology. Genetic and environmental factors, and interactions between these factors, contribute to the risk of developing schizophrenia. These risk factors likely act across development and may converge on shared biological processes that influence early brain development and neural functioning. These factors can also shape the biological response to life experiences, further increasing vulnerability to the onset and progression of schizophrenia.

This slide deck was developed by Professor Dr. Oliver Howes, King’s College London, United Kingdom; and Professor Dr. Christoph Correll, Charité – Universitätsmedizin Berlin, Germany, in collaboration with Cambridge (a division of Prime, Cambridge, UK).

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Index for
slide deck

Aetiology and neurobiology

Aetiology and neurobiology

Aetiology and neurobiology

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The aetiology of schizophrenia

The aetiology of schizophrenia

In addition to the factors outlined on the slide, research also highlights the role of epigenetic mechanisms, which may mediate the interplay between genetic predisposition and environmental influences.⁴ These mechanisms include processes such as DNA methylation, histone …

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Genetic risk factors for schizophrenia

Genetic risk factors for schizophrenia

Genetic risk factors for schizophrenia

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The heritability of schizophrenia

The heritability of schizophrenia

Differences between heritability estimates and concordance rates arise due to heritability and concordance rates capturing different aspects of genetic contribution to schizophrenia risk, with heritability reflecting population-level variance in risk and concordance refle…

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The genetics of schizophrenia

The genetics of schizophrenia

The figure summarizes how common‑variant genetic risk is shared across 8 psychiatric disorders, using genome-wide genetic correlations calculated with LD score regression.² Within this structured pattern of shared genetic risk, schizophrenia and bipolar disorder show stro…

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Rare genetic variants in the risk of schizophrenia

Rare genetic variants in the risk of schizophrenia

References:
1. Singh T, Walters JTR, Johnstone M, et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat Genet 2017; 49: 1167–1173.
2. Tansey KE, Rees E, Linden DE, et al. Common alleles contribute to…

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Rare CNVs associated with schizophrenia risk

Rare CNVs associated with schizophrenia risk

This figure illustrates examples of rare CNVs that are associated with increased risk of schizophrenia. Each panel shows the chromosomal region affected (22q11.2 deletion, 15q11.2 microdeletion, and 1q21.1 microdeletion or microduplication), alongside characteristic neuro…

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Genetic risk for schizophrenia converges on specific biological pathways

Genetic risk for schizophrenia converges on specific biological pathways

References:
1. Rosato M, Stringer S, Gebuis T, et al. Combined cellomics and proteomics analysis reveals shared neuronal morphology and molecular pathway phenotypes for multiple schizophrenia risk genes. Mol Psychiatry 2021; 26: 784‒799.
2. Sullivan PF, Yao S, Hjerling-Le…

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Environmental risk factors for schizophrenia

Environmental risk factors for schizophrenia

Environmental risk factors for schizophrenia

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In utero environmental risk factors for psychotic disorders

In utero environmental risk factors for psychotic disorders

Reference:
1. Davies C, Segre G, Estradé A, et al. Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry 2020; 7: 399‒410.

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Premorbid markers and early risk indicators for psychotic symptoms

Premorbid markers and early risk indicators for psychotic symptoms

The study by ENIGMA Clinical High Risk for Psychosis Working Group pooled MRI data from 31 international sites, including 1,792 individuals at CHR and 1,377 healthy controls, giving a total sample of 3,169 participants. Among the CHR group, longitudinal clinical follow‑up…

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Childhood psychosocial risk factors for psychotic disorders

Childhood psychosocial risk factors for psychotic disorders

References:
1. Zhou L, Sommer IEC, Yang P, et al. What do four decades of research tell us about the association between childhood adversity and psychosis: an updated and extended multi-level meta-analysis. Am J Psychiatry 2025; 182: 360–372.
2. Vassos E, Pedersen CB, Mur…

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Adulthood psychosocial risk factors for psychotic disorders

Adulthood psychosocial risk factors for psychotic disorders

References:
1. Henssler J, Brandt L, Müller M, et al. Migration and schizophrenia: meta-analysis and explanatory framework. Eur Arch Psychiatry Clin Neurosci 2020; 270: 325–335.
2. Selten JP, van der Ven E, Termorshuizen F. Migration and psychosis: a meta-analysis of inci…

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Substances and schizophrenia: an overview

Substances and schizophrenia: an overview

References:
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.
2. Murrie B, Lappin J, Large M, Sara G. Transition of substance-induced, brief, and atypical psychoses…

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Amphetamine drugs and psychosis risk

Amphetamine drugs and psychosis risk

The study used electronic health record data from a large US healthcare system (Mass General Brigham), including individuals aged 16–35 years admitted for a first psychiatric hospitalization between 2005 and 2019.¹

A case–control design was employed: cases were patients w…

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Cannabis as a risk factor for developing psychosis

Cannabis as a risk factor for developing psychosis

References:
1. D’Souza DC, DiForti M, Ganesh S, et al. Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis. World J Biol Psychiatry 2022; 23: 719–742.

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How do risk factors in the development of schizophrenia interact?

How do risk factors in the development of schizophrenia interact?

References:
1. McCutcheon RA, Reis Marques T, Howes, OD. Schizophrenia-an overview. JAMA psychiatry 2020; 77: 201–210.
2. Jauhar S, Johnstone M, McKenna PJ. Schizophrenia. Lancet 2022; 399: 473–486.
3. Leucht S, Siafis S, McGrath JJ, et al. Schizophrenia. Nat Rev Dis Prim…

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