Inflammation and glutamate dysregulation: unravelling the aetiology of schizophrenia

Reduced glutamatergic signalling and immune dysregulation are two major aetiological hypotheses in schizophrenia. Investigations aimed at further elucidating the mechanisms of the pathogenesis and symptomology of schizophrenia were presented at SIRS 2022.

Agitation is a challenging symptom in patients with severe mental disorders and closely related to aggression and reduced quality-of-life for those who do not achieve remission, explained Dr Gabriela Hjell, University of Oslo and Østfold Hospital, Grålum, Norway.


Agitation is associated with increased levels of IL-18BP

The Thematically Organized Psychosis (TOP) study is an ongoing cross-sectional study at the NORMENT research centre in Oslo that is investigating the relationship between inflammasome-related systems and agitation (as measured by the positive and negative syndrome scale-excited component; PANSS-EC) in 660 patients with a psychotic or affective disorder.1

Agitation is a clinical phenomenon linked to immune disturbances that are independent to psychotic and affective symptoms

Results showed agitation to be significantly associated with increased circulating levels of IL-18 binding protein (IL-18BP; standardised coefficient=0.13, P=0.0007). This association remained significant even after controlling for confounders, including gender, age, and anti-depressant medication, as well as symptoms of psychosis, mania, and depression.1 These results suggest that agitation is a clinical phenomenon linked to immune disturbances that are independent to psychotic and affective symptoms said Dr Hjell.


Modulation of D2/D3 receptors can significantly increase glutamine levels in vivo

In another study, aimed at evaluating the effects of dopaminergic antipsychotic (AP) drugs on the glutamate system, Uzma Zahid, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, demonstrated for the first time that modulation of dopamine D2/D3 receptors can affect brain glutaminergic neurotransmission in vivo.2

Thalamic glutamate levels may be part of a network affected by D2/D3 receptor modulation

In this double-blind placebo-controlled, cross-over trial conducted in 25 healthy volunteers, 7 days of AP drugs to modulate dopamine D2/D3 receptors significantly increased levels of glutamate in the thalamus compared to placebo (z=1.99; P=0.046). No significant effects were seen in the anterior cingulate cortex or the striatum.2 Thalamic glutamate levels may be a part of network that can be affected by D2/D3 receptor modulation.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

  1. Hjell G, et al. Interleukin-18 signaling system links to agitation in severe mental disorders. Psychoneuroendocrinology 2022;140:105721. 
  2. Zahid U. Oral presentation at SIRS 2022.
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