Is inflammation the missing piece in schizophrenia?
Could the immune system play a larger role in schizophrenia than previously recognised? A growing body of research suggests that inflammation may quietly shape the very symptoms that challenge thinking, motivation, and day-to-day functioning.1 This emerging science is beginning to explain why some patients struggle more than others, and why treatments do not address all symptom domains.
In this article we explore how inflammation fits into the bigger picture of schizophrenia and why recognising immune involvement may be reshaping our understanding of the disorder.
The immune system: an overlooked player in schizophrenia
For decades, schizophrenia was understood mainly through neurodevelopmental and neurotransmitter frameworks.1 Yet a growing body of evidence suggests that the immune system, once considered a peripheral factor, may also contribute to the pathophysiology of schizophrenia in some individuals.1 Research indicates that inflammatory and oxidative mechanisms may influence synaptic function and modulate neural connectivity during critical stages of brain development, providing additional insights into the biological complexity of the disorder.1
People living with schizophrenia often show elevated inflammatory markers, including cytokines, interleukins, tumour necrosis factor–α and C–reactive protein (CRP).2,3 These are not just laboratory curiosities: they signal biological activity capable of influencing neurotransmission, synaptic plasticity, and the integrity of large-scale brain networks.4
Emerging genetic studies add another layer. Higher expression of inflammation-related genes has been linked to cortical thinning, a structural change associated with cognitive and functional decline.4 Microglia, the brain’s resident immune cells, appear to play a key role. When excessively activated, they may disrupt synaptic pruning and neural connectivity, contributing to both symptom emergence and illness progression.2,5,6
In other words, inflammation may not simply accompany schizophrenia – it may help drive it.
Why motivation drops: inflammation inside the reward system
One of the most clinically challenging aspects of schizophrenia is the persistence of negative symptoms.7 Increasing evidence suggests inflammation may be part of the reason these symptoms are so difficult to treat.7
Elevated cytokines and CRP have been associated with reduced activation in reward-related brain circuits.7 This biological disruption aligns with experiences such as reduced motivation, diminished goal-directed behaviour, and social withdrawal – symptoms that can profoundly affect education, employment, and relationships.7
Notably, patients with higher inflammatory markers frequently show more severe negative symptoms, and these individuals often respond poorly to dopamine-targeted treatments.7
This has important clinical implications: If dopamine is not the only system involved, further research into non-dopaminergic treatments, including those that modulate inflammatory processes, may be warranted.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet 2016;388:86–97.
Marques TR, Ashok AH, Pillinger T et al. Neuroinflammation in schizophrenia: Meta-analysis of in vivo microglial imaging studies. Psychol Med 2018;49(13):2186–96.
Ford TJ, Morris D, Gass A et al. Neuroimmune interactions in schizophrenia. Front Psychiatry 2018;9:46.
Cui Y, Zhang X, Wang H et al. Transcriptional inflammation markers and brain structural changes in first-episode schizophrenia. BMC Med 2023;21:250.
Yan L, Li Y, Fan F et al. CSF1R regulates schizophrenia-related stress response and microglia/macrophage activity. BMC Med 2023;21:286.
Bloomfield MAP, Selvaraj S, Veronese M et al. Microglial activity in people at ultra-high risk of psychosis. Am J Psychiatry 2016;173(1):44–52.
Goldsmith DR, Rapaport MH. Inflammation and negative symptoms of schizophrenia: implications for reward processing and motivational deficits. Front Psychiatry 2020;11:46.
