It is therefore plausible that the IFN response in people with schizophrenia reflects mild inflammation driven by a low level of infection, autoimmunity, or tissue injury. In previous studies, we used peripheral cytokine mRNA levels alone to stratify people into high and low inflammation groups [ 5 , 18 ].
Here, we took a novel approach and added the commonly used marker CRP to our cluster analysis. We found that IL-6 did not significantly differ between high and low inflammation individuals or between controls and patients in our cohort at the transcriptional level, but IL-6 does typically appear to be elevated at the protein level in people with schizophrenia [ 5 , 16 , 50 , 51 , 52 , 53 ].
Several other studies have, however, found elevated IL-6 mRNA [ 15 , 16 , 17 ] in the blood of patients compared to controls, pointing to multiple cellular contributors to increased blood IL-6 levels in schizophrenia. However, this putative anti-inflammatory effect of antipsychotics [ 54 ] is clearly not sufficient or enduring enough to reduce inflammation in all patients in the long term [ 55 ]. This might suggest that some degree of increased TLR4 expression by leukocytes is inherent to schizophrenia.
Since TLR4 is an innate immune receptor for bacterial glycoproteins and a major activator of the M1 macrophage phenotype [ 58 ], our findings are consistent with high levels of macrophage-derived cytokines in patient blood [ 5 , 39 , 40 , 41 , 42 ], and with other studies finding increased TLR4 mRNA in peripheral mononuclear cells extracted from people with schizophrenia [ 19 , 20 ]. Together with previous findings that TLR4 activation in patient immune cells leads to exaggerated pro-inflammatory cytokine release [ 21 ], higher TLR4 mRNA in white blood cells would be consistent with a higher number of TLR4 receptors at the cell surface in schizophrenia.
Overall, TLR4 up-regulation in patient circulating leukocytes plausibly contributes to increased peripheral inflammation in a subset of people with schizophrenia. However, this raises the interesting question of what else may be inducing increased innate immune receptor TLR4 mRNA in white blood cells in schizophrenia, with the possibility that there may be a higher bacterial load [ 61 , 62 ]. TNFR2 transcript levels were higher in both high and low inflammation patients compared to both high and low inflammation controls.
This suggests that changes in leukocyte expression of TNFR2 mRNA are more related to a diagnosis of schizophrenia than to inflammatory status. Elevated circulating soluble TNF protein is consistently found in chronically-ill people with schizophrenia across multiple cohorts [ 5 , 15 , 35 , 69 ]. Our finding of up-regulated TNFR2 mRNA in the circulating leukocytes of patients may therefore contribute to both pro- and anti-inflammatory processes: if the mRNA findings translated into higher levels of membrane-bound TNFR2 receptors on leukocytes pro-inflammatory or if they translated into higher levels of circulating sTNFR2 pro- or anti-inflammatory.
Thus, the TNF protein elevations found in circulation may derive from cells other than white blood cells. It is possible that this change in RelB mRNA in the blood of people with schizophrenia compared to controls reflects type 1 error. Additionally, further stratifying our cohort based on inflammatory status revealed that this elevation not only occurs in patients with inflammation but also occurs to the same degree in controls with inflammation.
An important consideration in the interpretation of our findings is the magnitude of transcriptional changes in peripheral leukocytes of people with schizophrenia.
Indeed, elevated cytokine transcription and plasma CRP in our patient cohort is associated with worse psychiatric and cognitive symptoms [ 18 , 25 ], strengthening the contention that even minor changes in cytokine transcription clinically relevant in schizophrenia.
Finally, it is also possible that the changes reported here are not occurring universally across all leukocytes but rather in a specific immune subset such as macrophages. Putative cell-specific changes may be dampened in assays containing all peripheral blood leukocytes, and single-cell RNA studies would be needed to address this. Although we were unable to covary for BMI in our analyses given that we had BMI data for only a small number of controls, we were able to assess the relationship between BMI and inflammation markers in the patients, a group in which we would be more likely to find such a relationship since healthy controls would be less likely to have either inflammation or obesity [ 81 ].
However, the findings do not support a strong role for BMI in the differences observed in inflammatory markers in high versus low inflammation within the patient subgroups. BMI did not differ between high and low inflammation groups, and only 3 inflammatory markers were weakly associated with BMI across the entire cohort of schizophrenia patients.
CRP was positively, but weakly, correlated with BMI in patients, consistent with various studies showing CRP is increased in overweight and obese individuals [ 82 ]. Therefore, increased BMI does not seem to be the sole explanation for our findings. Thus, stratifying based on inflammatory status is potentially useful in understanding the mechanisms behind peripheral inflammation in this patient subgroup and may help identify patients who would most benefit from adjunctive anti-inflammatory medication.
Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl Psychiatry. Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression.
Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation. Postmortem transcriptional profiling reveals widespread increase in inflammation in schizophrenia: a comparison of prefrontal cortex, striatum, and hippocampus among matched tetrads of controls with subjects diagnosed with schizophrenia, bipolar or major depressive disorder.
Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation. PubMed Google Scholar. RNA-Seq analysis implicates dysregulation of the immune system in schizophrenia. BMC Genomics. Transcriptome sequencing study implicates immune-related genes differentially expressed in schizophrenia: new data and a meta-analysis.
Schizophrenia Bull Open. Google Scholar. Biol Psychiatry. Regional, cellular and species difference of two key neuroinflammatory genes implicated in schizophrenia. Brain, Behav, Immun. CAS Google Scholar. Nuclear factor kappa B activation appears weaker in schizophrenia patients with high brain cytokines than in non-schizophrenic controls with high brain cytokines.
Serum and gene expression profile of cytokines in first-episode psychosis. Proinflammatory cytokines and their membrane-bound receptors are altered in the lymphocytes of schizophrenia patients.
Schizophrenia Res. The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia. BMC Psychiatry. Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia.
The multiaxial approach was intended to help clinicians and psychiatrists make comprehensive evaluations of a client's level of functioning, because mental illnesses often impact many different life areas. It described disorders using five DSM "axes" or dimensions to ensure that all factors—psychological, biological, and environmental—were considered when making a mental health diagnosis. Axis I consisted of mental health and substance use disorders that cause significant impairment.
Disorders were grouped into different categories such as mood disorders , anxiety disorders , or eating disorders. Axis II was reserved for mental retardation a term which has since been replaced by "intellectual disability" and personality disorders , such as antisocial personality disorder and histrionic personality disorder. Personality disorders cause significant problems in how a person relates to the world, while intellectual disability is characterized by intellectual impairment and deficits in other areas such as self-care and interpersonal skills.
Any social or environmental problems that may impact Axis I or Axis II disorders were accounted for in this axis. These include such things as unemployment, relocation, divorce, or the death of a loved one. Axis V is where the clinician gives their impression of the client's overall level of functioning. Based on this assessment, clinicians could better understand how the other four axes interacted and the effect on the individual's life.
The previous edition of the DSM, the DSM-IV-TR, utilized a multiaxial system that was designed to help clinicians fully evaluate the biological, environmental, and psychological factors that can play a role in a mental health condition. The most immediately obvious change is the shift from using Roman numerals to Arabic numbers in the name. Perhaps most notably, the DSM-5 eliminated the multiaxial system.
Instead, the DSM-5 lists categories of disorders along with a number of different related disorders. Example categories in the DSM-5 include anxiety disorders, bipolar and related disorders, depressive disorders , feeding and eating disorders, obsessive-compulsive and related disorders, and personality disorders.
A few other changes that came with the DSM-5 included:. While the DSM is an important tool, only those who have received specialized training and possess sufficient experience are qualified to diagnose and treat mental illnesses. A number of significant changes were made in the DSM-5 compared to previous editions.
The DSM-5 eliminated the multiaxial system in favor of categories of related disorders. All clinical material on this site is peer reviewed by one or more qualified mental health professionals. Our material is not intended as a substitute for direct consultation with a qualified mental health professional.
Please seek professional advice if you are experiencing any mental health concern. Although individuals with a defined attenuated psychosis syndrome are times more likely than the general population to develop a psychotic disorder in the next year, the vast majority of such individuals do not develop schizophrenia.
Disappointment has been expressed about the fact that this entity was not included in the main body of the DSM-5 manual,[ 23 ] but data necessary to address various questions about its precise nature and nosological status can be generated and this will allow future diagnostic systems to better characterize this condition.
While high reliability and validity were important considerations, changes in the DSM-5 treatment of schizophrenia and other psychotic disorders are principally designed to facilitate clinical assessment and treatment. Hopefully, the revisions in DSM-5 criteria for schizophrenia and related disorders will make them more useful to patients and clinicians, while providing a more useful platform in integrating emerging genetic and other neurobiological information about these conditions.
The addition of psychopathology dimensions with a simple rating scale should encourage the provision of measurement-based care. National Center for Biotechnology Information , U. Indian J Psychol Med. Rajiv Tandon. Author information Copyright and License information Disclaimer. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.
This article has been cited by other articles in PMC. Schizophrenia In view of its fair validity and clinical utility, changes in the diagnostic criteria of schizophrenia are relatively modest, and broad continuity with DSM-IV is maintained. Schizoaffective disorder Characterization of patients with both psychotic and mood symptoms either concurrently or at different points during their illness has always been a nosological challenge, and this is reflected in the poor reliability, low diagnostic stability, and questionable validity of DSM-IV schizoaffective disorder.
Catatonia In DSM-IV, two different sets of criteria are used to diagnose catatonia in different parts of the manual, and the syndrome is treated discrepantly e.
Attenuated psychosis syndrome It is believed that the poor outcome of schizophrenia in many individuals with the disorder is because of the late identification and intervention in the course of the illness by which time patients have experienced a substantial amount of socio-occupational decline and brain damage. American Psychiatric Association. World Health Organization. Geneva: World Health Organization; Tandon R.
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