Study of the Activation of Proinflammatory Pathways of Toll-like Receptors in Schizophrenia Patients
Condition: Schizophrenia; Mental Disorders; Psychotic Disorders
MeSH terms: Schizophrenia; Mental Disorders; Psychotic Disorders
Study type: Observational

Summary: 
      The study of immune pathways involved in the etiopathogeny of schizophrenia would be an
      important advance to understand the mechanisms involved in the development of this disease
      and it would be a turning point in drug therapy. Until now, the mechanism of action of
      antipsychotics focused on the blockade or modulation of brain dopaminergic pathways. If
      immunological pathways responsible for neuroinflammation and neurodegeneration which involve
      alterations in different areas and brain pathways (including dopaminergic pathways) are
      discovered, investigators could develop new treatments that act on these new targets,
      allowing to delay the onset of the first psychotic episode and improve the evolution and
      impact of this disease.
    

Detailed description: 
      Schizophrenia is a mental illness that affects approximately 1% of the population. It
      supposes an important impact on patients and the socio-health system, since most patients
      will have difficulty to have an autonomous and independent life and they will need health,
      economic and social resources for lifetime.

      Until recently, the etiopathogeny of schizophrenia was explained by the combination of
      genetic and environmental factors. However, in recent years there are increasing evidence of
      the involvement of the immune system in the development and evolution of schizophrenia in at
      least a subset of patients. Although several meta-analyzes have been published where the
      increases or decreases in some interleukins and other proinflammatory molecules are
      described, immune pathways involved in the development and evolution of schizophrenia are
      still unknown.

      The first observations that relate the immune system disorders with the development of
      non-affective psychosis were made a century ago where it is described the association between
      pathogen infections (viruses, protozoa or spirochetes) and the occurence of psychosis.
      Pathogens can directly affect neurons and brain structures, increasing the release of free
      radicals of oxygen and nitrogen or indirectly altering the activation of the innate or
      adaptive immune system. They have been published current epidemiological studies that support
      this theory and they argue that there is an increased risk of having a psychotic
      decompensation after hospitalization. Furthermore, it is known that many of the genes
      involved in schizophrenia match those genes involved in the defense against pathogens attack.

      Several epidemiological studies have objectified the association of autoimmune diseases
      and/or chronic inflammatory diseases (intestinal, vasculitis, etc.) with some mental
      disorders such as schizophrenia, being stress one of the most important triggers factors in
      the development of both pathologies. Considering that in most cases the onset of autoimmune
      disease or chronic inflammatory precedes the first psychotic episode, it is hypothesized the
      autoimmune reaction as a trigger for psychotic symptoms. However, although these studies show
      statistically significant the involvement of some interleukins (increase in interleukin 6
      (IL-6) mainly) in the development or exacerbation of schizophrenia, the levels of
      interleukins can be altered by other causes such as cardiovascular diseases, obesity and
      metabolic syndrome; conditions highly prevalent in patients with schizophrenia.

      The innate immune system consists of various immune cells (macrophages, mast cells, dendritic
      cells, microglia, leukocyte, etc.) that recognize pathogen-associated molecular patterns
      (PAMPs) or damage-associated molecular pattern molecules (DAMPs) through a receptorial system
      called pattern-recognition receptors (PRRs), located on the cell surface or in cytoplasm.
      Toll-like receptors (TLRs) are one of the most important families of PRRs. They are
      transmembrane proteins that have an extracellular domain which binds to the ligands and other
      intracellular domain which binds to other protein complexes to initiate intracellular
      transduction pathways. Among the 11 known, the TLRs most studied in schizophrenia has been
      the TLR-4. Multiple studies have objectified that TLRs are expressed during neurodevelopment
      in early stages of life and they also have an important role in neurodevelopment and neuronal
      plasticity during adulthood. Microglia are phagocytic cells located in the central nervous
      system (CNS) and it is known that they express various types of TLRs. Its role as regulatory
      cells of CNS is done via intracellular signaling pathways that initiate TLRs. Depending the
      activated signaling routes, microglia perform different functions: involved positively in the
      immune response, in neurodevelopmental, in neuronal plasticity and in synaptogenesis, or
      otherwise through production of proinflammatory cytokines and free radicals of oxygen and
      nitrogen that favors both neuroinflammation and cerebral neurotoxicity.

      Some epidemiological and experimental studies in both animals and humans suggest that
      infections by viruses, bacteria and protozoa in the prenatal phase (especially in the first
      quarter) represent a major risk factor for prenatal inflammation, abnormalities in
      neurodevelopment, obstetric complications and behavioral changes similar to those observed in
      schizophrenia patients. TLRs can cause neuronal damage in the fetus through two intracellular
      signaling pathways: increasing cytokine production and/or antimicrobial factors and producing
      a maintained activation of microglia. Both increased cytokines and antimicrobial factors such
      as maintained activation of microglia will cause the accumulation of free radicals of oxygen
      and nitrogen, resulting in neurodegeneration, necrosis and/or apoptosis, which will lead to
      changes both in the structure and brain function, and in the normal process of child
      neurodevelopment. It is known that excessive activation of microglia may lead to a reduction
      in the synapses between glutaminergic neurons in some brain areas such as cerebral cortex,
      hippocampus and basal ganglia, similar to glutamatergic hypofunction found in brains of
      schizophrenia patients. In addition, several studies have been published demonstrating the
      anti-inflammatory and antioxidant properties of antipsychotics, suggesting that its
      effectiveness is not only due to its action on dopaminergic receptors (classical theory) but
      they also have a modulatory effect on the immune system.
    

Intervention name(s): Retrospective study of frozen samples; Prospective study of fresh samples
Intervention type(s): Genetic; Genetic
Intervention description(s): Frozen samples of serum and peripheral blood mononuclear cell (PBMC) stored in the Biobank Valdecilla will be selected.; Samples of serum and cells will be drawn.
Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Individuals included in the First Episode Psychosis Clinical Program (PAFIP) at the
        University Hospital Marqués de Valdecilla (Santander - Cantabria, Spain) between June 2011
        and September 2017.
      
Biospecimen description: 
      Serum and peripheral blood mononuclear cell (PBMC)
    
Keywords: Psychosis; Antipsychotic Agents; Immunology; Schizophrenia Spectrum and Other Psychotic Disorders