Genetics of bipolar disorder

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.

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Neuroinflammation and psychiatric illness

Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Here we used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 individuals with schizophrenia and their matched controls. We detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. Using quantitative real-time PCR we confirmed the changes in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1β and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1β expression. A group of individuals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression. In summary, we have demonstrated changes in an inflammatory response pathway that are present in ∼40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain.

Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia

The immune system and developmental programming of brain and behavior

High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.

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The role of inflammation in schizophrenia

Although an immune dysfunction and the involvement of infectious agents in the pathophysiology of schizophrenia are discussed since decades, the field never came into the mainstream of research. In schizophrenia a blunted type-1 immune response seems to be associated with a dysbalance in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan - kynurenine metabolism resulting in increased production of kynurenic acid in schizophrenia. This is associated with an imbalance in the glutamatergic neurotransmission, leading to an NMDA antagonism in schizophrenia. The immunological effects of antipsychotics rebalance partly the immune imbalance and the overweight of the production of the kynurenic acid. This immunological imbalance results in an inflammatory state combined with increased prostaglandin E(2) (PGE(2)) production and increased cyclo-oxygenase-2 (COX-2) expression. COX-2 inhibitors have been tested in clinical trials, pointing to favourable effects in schizophrenia.

Immune System and Schizophrenia.

Although there is no doubt that the dopaminergic neurotransmission is strongly involved in the pathophysiology of schizophrenia, the exact mechanism leading to dopaminergic dysfunction is still unclear. A disbalance in the immune response associated with a slight inflammatory process of the central nervous system (CNS) has been postulated. Such a mechanism is the basis for the "mild encephalitis" concept. A dysfunction in the activation of the type-1 immune response seems to be associated with decreased activity of the key enzyme of the tryptophan/kynurenine metabolism, indoleamine 2,3-dioxygenase (IDO). Theoretically, a decreased activity of IDO results in the increased production of kynurenic acid, an N-methyl-D-aspartate antagonist in the CNS, and a reduced glutamatergic neurotransmission in schizophrenia. Accordingly, in animal models of schizophrenia, increased levels of kynurenic acid in critical regions of the CNS were described, although studies of peripheral blood levels of kynurenic acid in schizophrenic patients showed controversial results. The immunological effects of a lot of existing antipsychotics, however, rebalance in part the immune imbalance and the overweight of the production of kynurenic acid. The inflammatory state in schizophrenia is associated with increased prostaglandin E(2) production and increased cyclooxygenase-2 (COX-2) expression. Growing evidence from clinical studies with COX-2 inhibitors points to favorable effects of anti-inflammatory therapy in schizophrenia, in particular in an early stage of the disorder. Further options for immunomodulating therapies in schizophrenia will be discussed.

Inflammation in schizophrenia.

Objectives. The influence of infectious agents on the pathogenesis of psychiatric disorders has been discussed for decades. Pre- and postnatal infections are risk factors for schizophrenia. This may be explained by chronic infections or an altered immune status. However most of the studies have only focused on one single pathogen and not on the impact of different infectious agents. We investigated the association between schizophrenia and various neurotophic infectious agents. Methods. A total of 31 schizophrenic patients and 30 healthy matched individuals were included. Antibody titres of cytomegalovirus, herpes simplex virus, Epstein-Barr virus, mycoplasma, chlamydia and toxoplasma were evaluated. For statistical analysis we used Fisher's exact and Wilcoxon test. Results. Significantly elevated positive antibody titres within schizophrenic patients were found only for Chlamydia trachomatis (P=0.005) and a trend to significance for herpes simplex virus (P=0.055). Combining the different agents, ...

The association of infectious agents and schizophrenia

Increased proinflammatory markers like cytokines have been described in the blood and cerebrospinal fluid of patients suffering from schizophrenia. Animal models have shown that a hit in early life to the immune system might trigger a lifelong increased immune reactivity. Many epidemiological and clinical studies show the role of various infectious agents as risk factors for schizophrenia with overlap to other psychoses. The first large-scale epidemiological study in psychiatry from Denmark clearly demonstrates severe infections and autoimmune disorders during lifetime to be risk factors for schizophrenia. Genetic studies have shown the strongest signal for schizophrenia on chromosome 6p22.1, in a region related to the major histocompatibility complex and other immune functions. The vulnerability-stress-inflammation model is important as stress may increase proinflammatory cytokines and even contribute to a lasting proinflammatory state. The immune system itself is considered an important further piece in the puzzle, as in autoimmune disorders in general, which are always linked to three factors: genes, the environment and the immune system. Alterations of dopaminergic, serotonergic, noradrenergic and glutamatergic neurotransmission have been shown with low-level neuroinflammation and may directly be involved in the generation of schizophrenic symptoms. Loss of central nervous system volume and microglial activation has been demonstrated in schizophrenia in neuroimaging studies, which supports the assumption of a low-level neuroinflammatory process. Further support comes from the therapeutic benefit of anti-inflammatory medications in specific studies and the anti-inflammatory and immunomodulatory intrinsic effects of antipsychotics.

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Norbert Müller

Papers

The role of inflammation in schizophrenia

Immune System and Schizophrenia.

Inflammation in schizophrenia.

The association of infectious agents and schizophrenia

Immunology of Schizophrenia