Young Psychiatrists’ Session: Meet the Expert: Brian Leonard Inflammation, Neurodegeneration and the Psychopathology of Schizophrenia

In recent years, the possible cause of schizophrenia has switched from an emphasis on neurotransmitter dysfunction to possible genetic and neurodevelop-mental abnormalities. Th e link between the loci for insulin-dependent diabetes mellitus type 2,the human lymphocyte antigen system and schizophrenia suggests that a dysfunctional immune system plays a role in this disorder. Th is hypothesis is supported by a link between viral infections in utero and schizophre-nia in the off spring; the negative correlation between rheumatoid arthritis and schizophrenia lends further support to this view. Recent studies have indicated that changes in the adaptive immune system in schizophrenia result in an imbalance between the pro-infl ammatory and anti-infl ammatory cytokines. Of the changes in the pro-infl ammatory cytokines that have been detected in the blood and CSF of schizophrenic patients, inter-leukin-6 (IL-6) has received particular attention. In the plasma, high concentrations of IL-6 are associated with both the duration of the disorder and its resistance to drug treatment while the increase of IL-6 in the CSF is associated with the paranoid symptoms of the disorder.. It is now known that IL-6 increases the activities of dopaminergic and serotonergic neurons in the hippocampus and the frontal cortex. Th ereby linking the immune changes with those neurotrans-mitters reputed to be causally connected to the psy-chopathology of the disorder. IL-6 is suppressed by eff ective treatment of the psychotic state by atypical antipsychotics. Th e link between the immune system and neuro-degenerative changes that frequently occur in those with chronic schizophrenia is provided by the increased synthesis of quinolinic acid, the fi nal product of the tryptophan-kynurenine pathway. Th is pathway involves the activation of indoleamine 2,3 –dioxyge-nase (IDO) by IL-6 and other pro-infl ammatory cy-tokines in many peripheral tissues and in microglia in the brain. In schizophrenia, there appears to be an imbalance between the neurodegenerative component (quinolinic acid, a NMDA glutamate agonist) and the neuroprotective component (kynurenic acid,a NMDA glutamate antagonist) in which the neurode-generative pathway predominates. Th us recent clinical and experimental evidence suggests that a dysfunc-tional immune system contributes to both the acute symptoms and to long-term pathological changes in the brains of those suff ering from schizophrenia.