Treatment-Resistant Schizophrenia: Clinical and Neurobiological Perspectives

Treatment-resistant schizophrenia (TRS) affects up to a third of people diagnosed with schizophrenia and is defined by persistent psychotic symptoms despite trials of at least two antipsychotic drugs at adequate dose and duration. Clinically, these patients experience more severe positive and negative symptoms, increased functional disability and higher rates of hospitalisation. The mainstay of evidence-based management is clozapine, which is uniquely effective but under‐utilised owing to concerns about adverse effects and the need for blood monitoring. Neurobiologically, TRS diverges from treatment-responsive illness in several respects. Dopamine supersensitivity and differences in striatal dopamine synthesis capacity are less pronounced in TRS, whereas glutamatergic abnormalities—particularly elevated glutamate levels in the anterior cingulate cortex—and changes in synaptic plasticity have been implicated. Structural neuroimaging has revealed greater grey matter reductions in the frontal cortex and temporal lobes, while neuropsychological assessments show early deficits in verbal memory and executive function. Genetic studies indicate that TRS carries a distinct polygenic signature with links to cognitive traits. Together, these findings reflect heterogeneous pathogenic pathways that converge on resistance to typical dopamine‐blocking strategies, underscoring the need for biomarker-driven stratification and personalised interventions.

Research from Nature Portfolio

Recent work employing polygenic risk scores and Mendelian randomization has begun to map causal relationships between biomarkers and TRS. In a large population cohort, researchers used genome-wide data to generate a TRS polygenic risk score and correlated this with routinely collected blood and urine biomarkers. They identified modest but significant associations between the genetic liability for TRS and serum phosphate, total protein and mean corpuscular volume, suggesting that peripheral biochemistry may reflect central neuropathology. Bidirectional causal analyses indicated that lower cholesterol levels may be a consequence of TRS, whereas elevated protein and cell-volume markers could contribute to symptom persistence. These insights offer a blueprint for integrating genetic risk profiling with simple laboratory tests to flag individuals at high risk of non-response and to reveal targets for novel therapeutic approaches.

Treatment-Resistant Schizophrenia: Clinical and Neurobiological Perspectives publication trend

The graph below shows the total number of articles in treatment-resistant schizophrenia: clinical and neurobiological perspectives across all publications each year (not limited to Nature Index journals).

Technical terms

Treatment-resistant schizophrenia (TRS): Schizophrenia that fails to respond to at least two adequate antipsychotic trials.

Polygenic risk score (PRS): A quantitative estimate of an individual’s genetic predisposition to a trait, calculated by summing the effects of many genetic variants.

Mendelian randomization (MR): A method using genetic variants as proxies for environmental or biological exposures to infer causal relationships.

microRNA (miRNA): Small non-coding RNA molecules that regulate gene expression post-transcriptionally and can serve as peripheral biomarkers.

Glutamate dysregulation: Alterations in glutamate neurotransmission, often measured by elevated levels in key brain regions, implicated in TRS pathology.

References

1. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. Schizophrenia (2020).
2. Does clozapine treat antipsychotic-induced behavioural supersensitivity through glutamate modulation within the striatum?. Molecular Psychiatry (2023).
3. Patients with Poor Response to Antipsychotics Have a More Severe Pattern of Frontal Atrophy: A Voxel‐Based Morphometry Study of Treatment Resistance in Schizophrenia. BioMed Research International (2014).
4. Neuropsychological function at first episode in treatment-resistant psychosis: findings from the ÆSOP-10 study. Psychological Medicine (2018).
5. Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia. JAMA Psychiatry (2022).
6. Mendelian randomization study of the relationship between blood and urine biomarkers and schizophrenia in the UK Biobank cohort. Communications Medicine (2024).
7. Development of an individualized risk calculator of treatment resistance in patients with first-episode psychosis (TRipCal) using automated machine learning: a 12-year follow-up study with clozapine prescription as a proxy indicator. Translational Psychiatry (2024).
8. MiRNA Differences Related to Treatment-Resistant Schizophrenia. International Journal of Molecular Sciences (2023).