Over the last few decades there has been increasing interest in early intervention and prevention of schizophrenia, a topic recently reviewed by Hashimoto and published in the Current Psychiatry Reports journal.¹ Cognitive impairment is one of the key characteristics of the disease and studies have shown that this kind of impairment appears early, many years before the onset of psychosis and worsens post-psychosis onset.¹ Therefore, early intervention and treatment of the cognitive symptoms may prevent progress to psychosis and offer a promising therapeutic approach.

Studies have looked at the features of early cognitive impairment and they have shown it is associated with a high inflammatory profile.^1,2 In particular, positron emission tomography (PET) A technique that measures physiological function by looking at the blood flow, metabolism or neurotransmission, using radioactive injectable tracers³ studies have demonstrated high microglial activity The activity of the resident immune cells of the central nervous system (CNS), the microglia cells, measured by detection of secreted molecules² in the brain of schizophrenia, which is an indicator of an inflammatory response.² Moreover, researchers working with human cohorts and mouse models have shown that maternal immune activation (MIA), and thereby inflammation, during pregnancy causes long-term cognitive deficits in the offspring in adulthood.¹ Therefore, inflammation is linked to the risk of developing psychosis later in life and this has led to the consideration of a range of anti-inflammatory medications for treatment of the disease.

Recent advances in pre-clinical research have yielded positive findings related to anti-inflammatory treatment of adolescents at high risk of developing schizophrenia. Notably, some compounds might prevent the onset of behavioural abnormalities and parvalbumin A calcium-binding protein expressed in neurons of the CNS that is reduced in schizophrenia and therefore used as a marker to detect abnormal function⁴ immunoreactivity in the medial prefrontal cortex (Figure 1) of adult offspring after MIA.¹ The table below summarises the potential candidate compounds for intervention, their mechanism of action, the animals they have been tested in preclinically and corresponding literature:¹

Reference: Adapted from the National Institute of Mental Health

Potential candidates for intervention in psychosis

MIA, maternal immune activation; DAO, D-amino acid oxidase; NMDAR, N-methyl-D-aspartate receptor

Reference: Adapted from Hashimoto. Current Psychiatry Reports. 21, 75 (2019)¹

In conclusion, given the role of inflammation in prodromal cognitive impairment, early intervention using anti-inflammatory compounds seems to be a promising approach to prevent a subsequent transition to schizophrenia, as illustrated in the diagram below.¹⁴ The pre-clinical findings have set the grounds for the development of new treatments that will revolutionise clinical practice, by preventing progress of schizophrenia for first time, and alleviate the healthcare system from managing patients with a chronic life-long condition. An interesting longitudinal study showed that people at ultra-high risk of psychosis transitioned to psychosis at a rate of 9.6% after 6 months and 29.1% after 3 years, while the rates were lower for people at high risk.¹⁵ These results demonstrate that early intervention with safe anti-inflammatories could be beneficial for the latter group. In the future, it is necessary to conduct further randomized, double-blind, placebo-controlled study of the compounds mentioned above in young people with high risk for psychosis, in order to confirm this hypothesis.¹ Furthermore, further research is required to establish accurate diagnostic methods for identification of cognitive symptoms at early stage.

Proposed mechanism of early intervention using anti-inflammatory compounds

Reference: Adapted from Estes and McAllister. Science. 353:772–7 (2016)¹⁴