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Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization.

ABSTRACT: An interaction between external stressors and intrinsic vulnerability is one of the longest standing pathoaetiological explanations for schizophrenia. However, novel lines of evidence from genetics, preclinical studies, epidemiology and imaging have shed new light on the mechanisms that may underlie this, implicating microglia as a key potential mediator. Microglia are the primary immune cells of the central nervous system. They have a central role in the inflammatory response, and are also involved in synaptic pruning and neuronal remodeling. In addition to immune and traumatic stimuli, microglial activation occurs in response to psychosocial stress. Activation of microglia perinatally may make them vulnerable to subsequent overactivation by stressors experienced in later life. Recent advances in genetics have shown that variations in the complement system are associated with schizophrenia, and this system has been shown to regulate microglial synaptic pruning. This suggests a mechanism via which genetic and environmental influences may act synergistically and lead to pathological microglial activation. Microglial overactivation may lead to excessive synaptic pruning and loss of cortical gray matter. Microglial mediated damage to stress-sensitive regions such as the prefrontal cortex and hippocampus may lead directly to cognitive and negative symptoms, and account for a number of the structural brain changes associated with the disorder. Loss of cortical control may also lead to disinhibition of subcortical dopamine-thereby leading to positive psychotic symptoms. We review the preclinical and in vivo evidence for this model and consider the implications this has for treatment, and future directions.

SUBMITTER: Howes OD

PROVIDER: S-EPMC5438023 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization.

Howes O D OD McCutcheon R R

Translational psychiatry 20170207 2

An interaction between external stressors and intrinsic vulnerability is one of the longest standing pathoaetiological explanations for schizophrenia. However, novel lines of evidence from genetics, preclinical studies, epidemiology and imaging have shed new light on the mechanisms that may underlie this, implicating microglia as a key potential mediator. Microglia are the primary immune cells of the central nervous system. They have a central role in the inflammatory response, and are also invo ...[more]

PMID: 28170004

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Project description:Schizophrenia is a serious mental disease with a high mortality rate and severe social consequences. Due to insufficient knowledge about its etiopathogenesis, curative treatments are not available. One of the most promising new research concepts is the mild encephalitis hypothesis of schizophrenia, developed mainly by Karl Bechter and Norbert Müller. According to this hypothesis, a significant subgroup of schizophrenia patients suffer from a mild, but chronic, form of encephalitis with markedly different etiologies ranging from viral infections, traumas to autoimmune diseases. This inflammatory process is thought to occur in the beginning or during the course of the disease. In this article, we investigate the consequences of the mild encephalitis hypothesis of schizophrenia for the scientific community, and evaluate these consequences ethically. The mild encephalitis hypothesis implies that schizophrenia would no longer be considered an incurable psychiatric disorder. Instead, it would be considered a chronic, but treatable, neurological disease. This paradigm shift would doubtlessly have significant consequences: (1) major reforms would be necessary in the theoretical conceptualization of schizophrenia, which would challenge the psychiatric diagnostic systems, Diagnostic and Statistical Manual of Mental Disorders version 5 and ICD-10. (2) Psychotic patients should be treated in interdisciplinary teams, optimally in neuropsychiatric units; additionally, specialists for endocrinology, diabetology, and cardiology should be consulted for the frequently occuring somatic comorbidities. (3) Current diagnostic procedures and (4) therapies would have to be modified significantly. (5) There might be repercussions for the pharmaceutical industry as well: first, because old drugs with expired patent protection could partly replace expensive drugs and, second, because there would be a demand for the development of new anti-inflammatory drugs. (6) Legal evaluation of compulsory treatment orders might have to be reconsidered in light of causal therapies; leading to increased legal approval and reduced need for compulsory treatment orders due to better patient compliance. (7) The social inclusion of patients might improve, if treatment became more effective regarding cognitive and social functioning. (8) The stigmatization of patients and their relatives might decrease.

Dataset Information

Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization.

Publications

Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization.

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