Hypotheses of Psychosis

A Comprehensive Review of Theories

Introduction

Psychosis, characterized by symptoms like hallucinations and delusions, is a hallmark of disorders such as schizophrenia. It is a heterogeneous syndrome arising from multiple interacting factors. Contemporary models fall into biological, psychological, and social/environmental categories, each offering insights into potential causes and treatments. Integrative approaches, such as the vulnerability-stress framework, suggest that genetic vulnerability interacts with neurodevelopmental insults, cognitive biases, and social stress to trigger psychotic symptoms [PMC] [Nature]. This article provides a comprehensive overview of these hypotheses, tailored for clinicians and students in clinical settings.

Biological Hypotheses

  • Dopamine Hypothesis:
    • Description: Proposes that excessive dopamine activity, particularly via D₂ receptors in the mesolimbic pathway, underlies psychotic symptoms, with prefrontal dopamine deficits contributing to negative and cognitive symptoms [PMC] [PubMed].
    • Evidence:
      • Antipsychotics (e.g., chlorpromazine) that block dopamine D₂ receptors reduce symptoms, with efficacy correlating to 70–80% D₂ receptor occupancy in the striatum [PMC].
      • Imaging studies show increased presynaptic dopamine synthesis and release in schizophrenia patients (meta-analysis: Hedges’ g ≈ 0.68 for striatal dopamine synthesis capacity) [PMC].
      • Stimulants like amphetamine, which boost dopamine, can induce psychosis-like states in healthy individuals [PMC].
      • Genetic polymorphisms in dopamine-related genes and animal models link hyperdopaminergia to psychosis-like behaviors.
    • Critiques and Limitations:
      • Mixed evidence for inherent dopamine overactivity; some PET studies show abnormalities only under challenge conditions, and post-mortem dopamine measures are inconclusive [PubMed].
      • Antipsychotics may broadly suppress neural activity rather than specifically addressing a dopamine defect [PubMed].
      • Not all patients respond to D₂ antagonists, and negative/cognitive symptoms often persist despite dopamine blockade [PMC].
    • Clinical Relevance: Guides the use of antipsychotics but highlights the need for broader treatment approaches targeting other systems.
  • Glutamate Hypothesis:
    • Description: Suggests that hypofunction of NMDA-type glutamate receptors (NMDARs) leads to cortical and hippocampal dysconnectivity, contributing to negative and cognitive symptoms of psychosis [PMC].
    • Evidence:
      • NMDA antagonists (e.g., ketamine, PCP) induce schizophrenia-like symptoms, including positive, negative, and cognitive features [PMC].
      • Imaging shows reduced NMDA receptor tracer binding in the hippocampus of unmedicated patients, consistent with hypofunction [PMC].
      • Post-mortem studies reveal morphological changes in pyramidal neuron dendrites and reduced presynaptic boutons in the cortex, suggesting a loss of glutamatergic synapses [PMC].
      • Elevated kynurenic acid (an NMDA receptor inhibitor) in CSF of patients supports glutamate dysregulation [PMC].
      • Genetic mutations affecting glutamatergic synapse proteins (e.g., GRIN2A) are linked to schizophrenia [PMC].
      • Disrupted NMDA signaling may disinhibit dopamine neurons, linking glutamate and dopamine hypotheses [PMC].
    • Critiques and Limitations:
      • Ketamine and PCP also interact with other receptors (e.g., ketamine has D₂ receptor affinity), complicating the attribution of effects to glutamate [PMC].
      • Not all patients show clear glutamatergic deficits; genetic findings apply to a minority of cases.
      • Therapeutic targeting of NMDA receptors has shown mixed results, lacking a straightforward treatment approach.
    • Clinical Relevance: Promising for explaining negative and cognitive symptoms; supports research into glutamate-based treatments like glycine modulators.
  • Neuroinflammation Hypothesis:
    • Description: Suggests that immune and inflammatory processes, such as cytokine elevation and microglial activation, contribute to psychosis by perturbing neurodevelopment and neurotransmission [PMC].
    • Evidence:
      • Maternal infection during pregnancy increases offspring psychosis risk (meta-analyses: ~1.25× higher odds) via cytokine exposure disrupting fetal brain maturation [PMC].
      • Elevated pro-inflammatory cytokines (e.g., IL-6, IL-1β) in blood and CSF of schizophrenia patients correlate with worse symptoms [PMC].
      • TSPO PET imaging shows increased microglial activation in patients compared to controls [PMC].
      • Post-mortem studies find increased microglial markers and cytokine expression in specific brain regions [PMC].
      • Genetic overlap: GWAS signals for schizophrenia include immune-related genes (e.g., complement component C4) [PMC].
    • Critiques and Limitations:
      • TSPO PET findings may not exclusively reflect microglia, as TSPO is expressed in various glial cells [PMC].
      • Meta-analyses of cytokine levels show heterogeneity; inflammation may be a consequence rather than a cause (e.g., influenced by medication, stress) [PMC].
      • No clear “inflammatory subtype” identified after correcting for confounders [PMC].
    • Clinical Relevance: Suggests potential for anti-inflammatory treatments; highlights the role of prenatal immune insults in risk.
  • Genetic Vulnerability:
    • Description: Psychosis, particularly schizophrenia, has a strong genetic component, with twin studies estimating heritability at ~80% [Nature].
    • Evidence:
      • GWAS identifies hundreds of common SNPs associated with schizophrenia, each with small effects (odds ratios ~1.05–1.20), explaining <10% of liability [Nature].
      • Rare variants like 22q11.2 deletions confer higher risk (e.g., ~20-fold increased risk of schizophrenia) [Nature].
      • Common variants account for 2–3% of variance in liability; rare variants add further risk, explaining elevated rates in families [Nature].
      • Genes converge on pathways involved in synaptic plasticity, neuronal development, and immune regulation [Nature].
    • Critiques and Limitations:
      • Monozygotic twin concordance is ~40–50%, indicating significant non-genetic factors [Nature].
      • Known genetic variants have small or rare effects, making predictive testing impractical [Nature].
      • Gene-environment interactions are critical but not fully understood [PMC].
    • Clinical Relevance: Provides a background vulnerability; emphasizes the need to consider environmental triggers in risk assessment.

Psychological Hypotheses

  • Cognitive Biases:
    • Description: Proposes that information-processing biases, such as external attributional bias and jumping to conclusions (JTC), contribute to delusions [PubMed].
    • Evidence:
      • Patients with psychosis require less evidence to make decisions (meta-analysis: effect size g ≈ -0.53) [PubMed].
      • Odds of extreme JTC (deciding after 1-2 beads in the beads task) are 4–6 times higher in psychotic individuals [PubMed].
      • Source-monitoring deficits (confusing internal thoughts with external events) are common in hallucinating patients [PubMed].
      • CBT targeting these biases can reduce delusional conviction [PubMed].
    • Critiques and Limitations:
      • Biases are not unique to psychosis; they occur in anxiety, depression, and healthy individuals under stress [PubMed].
      • Unclear if biases cause psychosis or result from delusional beliefs [PMC].
      • Some patients with biases do not develop psychosis, and some psychotic patients perform normally on cognitive tasks [PubMed].
    • Clinical Relevance: Useful for understanding symptom formation; informs CBT approaches to reduce delusional thinking.
  • Trauma-Related Models:
    • Description: Suggests that early-life adversity (e.g., abuse, neglect) increases psychosis risk by altering brain development and cognitive schemas [PMC].
    • Evidence:
      • Developmental trauma doubles the odds of psychosis (meta-analysis) [PMC].
      • Up to one-third of schizophrenia cases may involve significant childhood adversity [PMC].
      • Trauma-exposed patients have more severe symptoms, often with mood or dissociative features [PMC].
      • Hallucinations and delusions may reflect traumatic themes; high rates of undiagnosed PTSD in psychosis patients [PMC].
      • Dose-response relationship: More severe/multiple traumas increase risk [PMC].
    • Critiques and Limitations:
      • Relies on retrospective self-reports, prone to recall bias and confounding (e.g., socioeconomic status, substance use) [PMC].
      • Trauma may predispose to multiple outcomes (e.g., PTSD, depression) on a continuum, not specific to psychosis [PMC].
    • Clinical Relevance: Highlights the importance of trauma history in assessment; supports trauma-focused therapies.

Social and Environmental Hypotheses

  • Urbanicity:
    • Description: Living in urban environments increases psychosis risk, possibly due to social stress, isolation, and environmental factors [PMC].
    • Evidence:
      • Meta-analysis: Urban dwellers have a 2.3× higher schizophrenia incidence than rural dwellers [PMC].
      • Dose-dependent effect: Higher population density and social fragmentation correlate with increased risk [PMC].
      • Longitudinal studies confirm higher first-episode psychosis rates in urban cohorts [PMC].
    • Critiques and Limitations:
      • Urbanicity is a proxy for multiple factors (e.g., migration, inequality, drug availability) [PMC].
      • Higher rates may be concentrated in deprived neighborhoods rather than urban areas broadly.
      • Unclear which specific urban factors (e.g., pollution, noise) are most influential.
    • Clinical Relevance: Suggests environmental interventions (e.g., access to green spaces) may mitigate risk in urban settings.
  • Social Defeat and Migration:
    • Description: Chronic social exclusion or subordinate status (e.g., in immigrants, minorities) sensitizes the dopamine system, increasing psychosis risk [PMC].
    • Evidence:
      • First- and second-generation migrants, especially visible minorities, have 2–3× higher psychosis risk [PMC].
      • African-Caribbean second-generation immigrants in the UK have among the highest schizophrenia rates [PMC].
      • Social defeat may activate stress pathways and mesolimbic dopamine, predisposing to psychosis [PMC].
      • Altered HPA axis and dopaminergic responses to stress observed in high-risk groups [PMC].
    • Critiques and Limitations:
      • “Social defeat” is vaguely defined and hard to measure objectively [PMC].
      • Not all marginalized groups show increased risk; strong community support may mitigate effects [PMC].
      • Migration involves confounding factors like trauma and economic disadvantage [PMC].
    • Clinical Relevance: Highlights the need to address social stressors and support marginalized patients in treatment plans.
  • Family and Social Dynamics:
    • Description: High levels of Expressed Emotion (EE) in families, such as criticism or hostility, predict relapse in schizophrenia [PubMed].
    • Evidence:
      • Meta-analyses show higher relapse rates in high-EE households compared to low-EE environments [PubMed].
      • Family interventions reducing EE (via education and communication training) lower relapse rates [PubMed].
      • Early theories like the “schizophrenogenic mother” have been discredited due to lack of evidence [AMA].
    • Critiques and Limitations:
      • EE predicts relapse but is not a sole cause; many patients in high-EE settings do not relapse [PubMed].
      • No unique “schizophrenogenic” parenting style exists; general stress and criticism contribute [AMA].
      • Blaming families is unhelpful and unsupported by evidence [AMA].
    • Clinical Relevance: Family interventions to reduce EE can improve outcomes; focus on communication and stress reduction.

Conclusion

Psychosis arises from multiple converging causes rather than a single root. Biological vulnerabilities (genetic risk, neurotransmitter imbalances, inflammation) set the stage, while psychological (cognitive biases, trauma) and social (urbanicity, social defeat, family dynamics) factors modulate expression. Dopamine and glutamate dysregulation underlie core symptoms, immune activation contributes to neural dysfunction, and genetics provides background liability [PMC] [Nature]. Psychological and social hypotheses explain phenomenology and epidemiology, with chronic social stress potentially triggering dopamine release in a genetically susceptible brain, and cognitive biases shaping delusional content [PMC]. A biopsychosocial approach, integrating brain, mind, and environment, remains the most comprehensive framework for understanding and addressing psychotic disorders [PMC] [Nature].

References