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What is the Connection Between Inflammation and Schizophrenia?

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    Current Psychiatry Reports

    Recent Advances in the Early Intervention in Schizophrenia: Future Direction from Preclinical Findings
    Current Psychiatry Reports 2019; 21: 75
    “In the past decade, there has been increasing interest in the potential benefit of early intervention in schizophrenia. Patients with schizophrenia show cognitive impairment for several years preceding the onset of psychosis. The author discusses the recent topics on prevention of schizophrenia.”

    Advances in the Early Intervention in Schizophrenia

    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

    Medial prefrontal cortexMedial prefrontal cortex

    Figure 1. Depiction of the medial prefrontal cortex in the brain

    Reference: Adapted from the National Institute of Mental Health

    Potential candidates for intervention in psychosis

    CompoundMechanism of ActionKey Findings
    D-serineNMDAR agonistSupplementation during adolescence can lead to prevention of the onset of cognitive deficits in adult offspring after MIA5
    Rescue of schizophrenia-like behavioural abnormalities in adulthood caused by neonatal disruption of serine racemase6
    Sodium benzoateDAO inhibitorEfficacy as an adjunctive treatment in early Psychosis (study protocol for a randomized controlled trial)7
    7,8-Dihydroxyflavone (DHF)TrkB agonistTreatment during juvenile and adolescent prodromal phase prevents onset of psychosis in adult offspring after MIA8
    Treatment from pregnancy to weaning prevents cognitive deficits in adult offspring after MIA9
    Prevents increase in levels of C1q in the prefrontal cortex of adult offspring after MIA10
    Sulforaphane (SFN) or its precursor glucoraphaninNrf2 agonistIntake of sulforaphane-rich broccoli sprout extracts during juvenile and adolescence can prevent phencyclidine-induced cognitive deficits at adulthood11
    Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after MIA12
    TPPUSoluble epoxide
    hydrolase inhibitor
    Soluble epoxide hydrolase has a key role in neurodevelopmental disorders of offspring after MIA13

    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

    Maternal Immune ActivationMaternal Immune Activation

    MIA: Maternal Immune Activation

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


    1. Hashimoto. Current Psychiatry Reports. 2019;21:75
    2. Bloomfield et al. Am J Psychiatry. 2016;173:44–52
    3. Berger et al. BMJ. 2003; 326
    4. Hayashida et al. Heliyon 5. 2019; e02037
    5. Fujita et al. Sci Rep. 2016;6:37261
    6. Hagiwara et al. PLoS One. 2013;8:e62438
    7. Ryan et al. Trials. 2017;18:165
    8. Han et al. Sci Rep. 2016;6:36087
    9. Han et al. Eur Arch Psychiatry Clin Neurosci. 2017;267:479–83
    10. Han et al. Clin Psychopharmacol Neurosci. 2017;15:64–7
    11. Shirai et al. PLoS One. 2015;10:e0127244
    12. Matsuura et al. Sci Rep. 2018;8:2158
    13. Ma et al. Proc Natl Acad Sci USA. 2019
    14. Estes and McAllister. Science. 2016;353:772–7
    15. Schultze-Lutter et al. Eur Psychiatry. 2015;30:405–16

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      Negative symptoms are symptoms of loss or absence of normal function relating to motivation and interest, or emotional expression. Evidence does not support theNegative symptoms are symptoms of loss or absence of normal function relating to motivation and interest, or emotional expression. Evidence does not support the

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      Negative symptoms of schizophrenia can occur as primary symptoms that are part of the underlying pathophysiology of schizophrenia or as secondary symptoms that Negative symptoms of schizophrenia can occur as primary symptoms that are part of the underlying pathophysiology of schizophrenia or as secondary symptoms that


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