Comparative table of competing hypotheses in SZ.
| Hypothesis | Key neurobiological mechanism | Supporting evidence | Limitations |
|---|---|---|---|
| Dopamine hypothesis | Dysregulated dopamine signaling (↑ mesolimbic; ↓ mesocortical) | Antipsychotic efficacy targeting D2 receptors; PET imaging; genetic modulation (e.g., COMT) | Does not fully explain cognitive or negative symptoms; not all patients respond to D2 antagonists |
| Glutamate hypothesis | NMDA receptor hypofunction leading to excitotoxicity | NMDA antagonists (PCP, ketamine) mimic SZ symptoms; synaptic pruning disruptions | Clinical translation is inconsistent; poor response to glutamatergic modulators in human trials |
| Inflammatory hypothesis | Elevated cytokines (e.g., IL-6, IFN-γ) affect neurotransmitter systems | Elevated inflammatory markers in FEP and relapsed patients; cytokine-genetic interactions | Biomarker variability; confounding by treatment/phase; few validated causal mechanisms |
| Neurodevelopmental model | Early disruptions in brain development lead to latent vulnerability | Structural brain abnormalities; “two-hit” model; placental gene expression; CNVs | Low specificity; many early-life insults do not lead to SZ without other risk factors |
| Kynurenine hypothesis | Excess KYNA impairs NMDA signaling and alters dopamine balance | Elevated KYNA in CSF/brain; linked to cognitive symptoms; cytokine-driven pathway shifts | Poor spatial resolution; limited in vivo tracking; unclear therapeutic windows |
| Gut-brain axis | Dysbiosis affects glutamate/GABA/tryptophan metabolism and neuroinflammation | Correlation with symptom severity; links to immune response, barrier integrity, and neurotransmitter levels | Limited replication; confounded by diet, medication, and environment |
CNVs: copy number variations; COMT: catechol-O-methyltransferase; CSF: cerebrospinal fluid; FEP: first-episode psychosis; GABA: gamma-aminobutyric acid; IFN-γ: interferon-gamma; IL-6: interleukin-6; KYNA: kynurenic acid; NMDA: N-methyl-D-aspartate; PET: positron emission tomography; SZ: schizophrenia.
TAO: Conceptualization, Investigation. OJO: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. UOA: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. KBO: Conceptualization, Data curation, Investigation, Writing—original draft. SSM: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. MMA: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. AKA: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. ABO: Writing—original draft. JOO: Writing—original draft, Writing—review & editing. GE: Writing—review & editing. DELP: Writing—review & editing, Supervision. All authors have read and approved the submitted version.
The authors declare that they have no conflicts of interest.
Not applicable.
Not applicable.
Not applicable.
Not applicable.
Not applicable.
© The Author(s) 2025.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.