Meta-analysis of lymphocytes in schizophrenia: Clinical status and antipsychotic effects

Brian J. Miller; Bintou Gassama; Dale Sebastian; Peter Buckley; Andrew Mellor

doi:10.1016/j.biopsych.2012.09.007

Meta-analysis of lymphocytes in schizophrenia: Clinical status and antipsychotic effects

Brian J. Miller, Bintou Gassama, Dale Sebastian, Peter Buckley, Andrew Mellor

Research output: Contribution to journal › Article › peer-review

170 Scopus citations

Abstract

Background: Schizophrenia is associated with immune system dysfunction, including abnormal blood immune cell parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment following an acute exacerbation of psychosis. Methods: We identified articles by searching PubMed, PsycINFO, and Thomson Reuters (formerly ISI) Web of Knowledge and the reference lists of identified studies. Results: Sixteen studies of blood lymphocytes met the inclusion criteria. There was insufficient data for a meta-analysis of the mononuclear phagocytic system. In cross-sectional studies, there was a significant increase in the CD4% and CD56% in acutely relapsed inpatients. Absolute levels of total lymphocytes, CD3, and CD4, and the CD4/CD8 ratio were significantly increased, and the CD3% was significantly decreased in drug-native first-episode psychosis. In longitudinal studies, the CD4/CD8 ratio appeared to be state-related markers, as it decreased following antipsychotic treatment for acute exacerbations of psychosis. Absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment for relapse. Conclusions: Blood lymphocyte abnormalities in drug-naïve first-episode psychosis suggest an effect that may be independent of antipsychotic medications. While some parameters (CD4/CD8) may be state markers for acute exacerbations of psychosis, others (CD56) may be trait markers; however, more longitudinal studies are needed. Although these findings could provide the basis for future hypothesis testing, a relatively small number of studies and subjects, lack of correlative data with clinical features, and inadequate consideration of potential confounding factors limit the results.

Original language	English (US)
Pages (from-to)	993-999
Number of pages	7
Journal	Biological Psychiatry
Volume	73
Issue number	10
DOIs	https://doi.org/10.1016/j.biopsych.2012.09.007
State	Published - May 15 2013

Keywords

First-episode psychosis
lymphocytes
meta-analysis
monocytes
relapse
schizophrenia

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2012.09.007

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@article{c4037616210546f9a6705c106fe9ccc7,

title = "Meta-analysis of lymphocytes in schizophrenia: Clinical status and antipsychotic effects",

abstract = "Background: Schizophrenia is associated with immune system dysfunction, including abnormal blood immune cell parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment following an acute exacerbation of psychosis. Methods: We identified articles by searching PubMed, PsycINFO, and Thomson Reuters (formerly ISI) Web of Knowledge and the reference lists of identified studies. Results: Sixteen studies of blood lymphocytes met the inclusion criteria. There was insufficient data for a meta-analysis of the mononuclear phagocytic system. In cross-sectional studies, there was a significant increase in the CD4% and CD56% in acutely relapsed inpatients. Absolute levels of total lymphocytes, CD3, and CD4, and the CD4/CD8 ratio were significantly increased, and the CD3% was significantly decreased in drug-native first-episode psychosis. In longitudinal studies, the CD4/CD8 ratio appeared to be state-related markers, as it decreased following antipsychotic treatment for acute exacerbations of psychosis. Absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment for relapse. Conclusions: Blood lymphocyte abnormalities in drug-na{\"i}ve first-episode psychosis suggest an effect that may be independent of antipsychotic medications. While some parameters (CD4/CD8) may be state markers for acute exacerbations of psychosis, others (CD56) may be trait markers; however, more longitudinal studies are needed. Although these findings could provide the basis for future hypothesis testing, a relatively small number of studies and subjects, lack of correlative data with clinical features, and inadequate consideration of potential confounding factors limit the results.",

keywords = "First-episode psychosis, lymphocytes, meta-analysis, monocytes, relapse, schizophrenia",

author = "Miller, {Brian J.} and Bintou Gassama and Dale Sebastian and Peter Buckley and Andrew Mellor",

note = "Funding Information: Taken together, our findings suggest that immune cell parameters in schizophrenia may vary with clinical status. The CD4/CD8 ratio appeared to be a state-related marker, as it was significantly increased in FEP and significantly decreased following antipsychotic treatment for acute psychosis. In contrast, absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment. The percentage of CD3 lymphocytes may also be a trait marker, as this proportion was significantly decreased in stable medicated outpatients. A paucity of studies investigated correlations between immune cell parameters and clinical features in schizophrenia, which is an important gap in this literature. We believe ours to be the first systematic, quantitative review of immune cell parameters in schizophrenia. An important strength of our study is that we considered the effects of clinical status and antipsychotic treatment following an acute illness exacerbation. Nonetheless, our results should be interpreted with caution in light of small numbers of studies and subjects, as well as significant heterogeneity across studies (including different assay methodologies and nonstandardized antipsychotic treatment). All immune cell parameters were assessed in fewer than 200 patients (and many in fewer than 100 patients) and in 6 or fewer different studies. However, the alterations in drug-na{\"i}ve first-episode psychosis suggest an association between abnormalities in immune cell parameters and acute exacerbations of schizophrenia that is independent of antipsychotic medications. There are several other limitations of the present study. Many studies were excluded because either the patient{\textquoteright}s clinical status or summary data on immune cell parameters were not available. Many of these studies would have otherwise been included in the meta-analysis, and their influence on the results is uncertain. Furthermore, many studies did not control for potential confounding factors that could account for differences in immune cell parameters between different populations at different stages of illness, including age, race or ethnicity, body mass index, smoking, socioeconomic status, and cortisol (67–70) . For example, effects of age and gender were considered in 100% of studies. By contrast, blood was collected at a standardized time of day in only 38% of studies. Even fewer studies considered potential effects of smoking (13%), cortisol (6%), and body mass index (0%). One study that controlled for many potential confounders reported a significant difference in several immune cell parameters between patients and control subjects (16) . However, this study found that CD19 numbers were positively correlated with the free cortisol index (as a measure of stress), and CD56 levels were negatively correlated with cotinine (as a measure of smoking). The latter result raises the possibility that smoking could confound our findings for CD56. Another limitation is the potential effect of medication status of the subjects in the AR group. In these studies, blood samples were taken while subjects were still acutely ill, generally on admission or within days of admission. Medication nonadherence would be expected to be common in acutely relapsed inpatients, and indeed many of the studies reported that a large proportion of subjects were drug-free at the time of sampling. However, stratified data based on medication status were generally not available. Two longitudinal studies included in the meta-analysis (20,56) did not find any significant changes in lymphocyte parameters between baseline and day 7 of antipsychotic treatment, suggesting that the effect of medication in the AR group might have been minimal. We were not able to perform a meta-analysis of the blood mononuclear phagocytic system; however, there is evidence that it may play a role in the pathophysiology of schizophrenia (reviewed in [71] ). One study (21) also found increased blood levels of IL-1β, IL-6, and TNF-α and increased levels of S100B, a marker of blood-brain barrier disruption. Another study found a significant decrease (to the same level as in control subjects) in IL-1β and TNF-α secretion from isolated blood monocytes following 1 month of first-generation antipsychotic treatment for an acute relapse of schizophrenia (72) . Drexhage et al. (73) found evidence of a proinflammatory gene expression signature in monocytes of patients with recent-onset schizophrenia. Furthermore, a retrospective analysis of serial blood samples in patients with schizophrenia found that monocytosis was associated with a worsening of psychotic symptoms, and in some cases, the monocytosis resolved with a change in antipsychotic treatment during hospitalization (28) . Thus, further studies of the mononuclear phagocyte system, an important source of many proinflammatory cytokines that are increased in schizophrenia (14) , are warranted. This study focused only on blood immune cell parameters in schizophrenia, but there is evidence for immune abnormalities in the CSF and brain as well. Nikkila et al. (47) found a significantly increased proportion of CSF macrophages and activated lymphocytes in patients with acute psychosis compared with control subjects. Another study by the same group also found a significantly increased proportion of CSF macrophages in patients with acute psychosis compared with control subjects (46) . Evidence from positron emission tomography (74,75) and postmortem (76,77) studies also support a role for neuroinflammation/microglial activation in schizophrenia. Several other studies support an association between changes in immune cell parameters and acute exacerbations of psychosis. Muller et al. (12) found a significant decrease in CD19 B-lymphocytes in patients treated with risperidone plus placebo and those treated with risperidone plus celecoxib, with a more pronounced decrease in the celecoxib group. Furthermore, in the celecoxib group only, the decrease in CD19 cells was significantly positively correlated with the decrease in Positive and Negative Syndrome Scale negative scale scores. Another study found that at baseline a relative granulocytosis and lymphopenia prospectively predicted poorer recovery in positive, but not negative, symptoms after 6 months of antipsychotic treatment (66) . Thus, given the efficacy of adjunctive nonsteroidal anti-inflammatory drugs in improving psychopathology in relapsed patients (7–11) , these findings support the plausibility of the hypothesis that immune changes are not merely an artifact of increased stress associated with acute psychosis but may play a role in the pathophysiology of relapse in schizophrenia. In addition to the association between monocytosis and worsening psychosis mentioned above (28) , other studies have found that intraindividual changes in other immune parameters, including CSF IL-2 levels and in vitro IL-2 production, may predict relapse in some patients (78,79) . Further investigation of potential relapse predictive markers is needed. Three hypotheses regarding an immune-cytokine basis for schizophrenia have been postulated. The macrophage-T-lymphocyte theory proposed that cytokines produced by chronically activated macrophages and T-lymphocytes are the fundamental mediators of schizophrenia (80) . Schwarz et al. (81) proposed the Th2-hypothesis, which postulates that a shift from T-helper (Th)1-cell (cytotoxic) toward Th2-cell (antibody-dependent) immune responses predominates in schizophrenia. Lastly, the microglial hypothesis proposed that activated central nervous system microglia release proinflammatory cytokines and free radicals that cause abnormal neurogenesis, neuronal degradation, and white matter abnormalities contributing to the pathophysiology of schizophrenia (82) . Our results inform on these hypotheses. We found abnormal blood lymphocyte parameters, including increased CD4/CD8 ratio in FEP, as well as increased CD56 levels and decreased CD4/CD8 following antipsychotic treatment for relapse. CD4 T-lymphocytes are important sources of IFN-γ and IL-12. Interleukin-12 is also involved in natural killer cell (CD56) activation, and these cells secrete TNF-α and IFN-γ. All of these cytokines were abnormal in our previous meta-analysis (14) . Thus, these findings are not inconsistent with the macrophage-T-lymphocyte theory. While we found evidence for abnormalities in the CD4/CD8 ratio, studies did not distinguish between Th1 versus Th2 CD4 lymphocytes, limiting our ability to make inferences regarding the Th2-hypothesis. We were not able to perform a meta-analysis of the mononuclear phagocyte system, although as noted above, there is evidence of dysfunction broadly consistent with the microglial hypothesis. We emphasize that our results should be interpreted with caution in light of a limited number of studies and small sample sizes, between-study heterogeneity, and a general lack of consideration of potential confounding factors. However, these findings are of importance, as acute relapse of psychosis is common and is associated with adverse outcomes, including increased treatment-resistant symptoms, cognitive decline, and functional disability (83–85) . More longitudinal studies of immune cell parameters in schizophrenia are needed to evaluate if these abnormalities are specific to illness exacerbations or schizophrenia in general and whether they are a temporal predictor of relapse and should control for potential confounding factors. Studies should also simultaneously measure blood cytokines and immune cell subsets, toward better identification of the source(s) of specific cytokines in schizophrenia. For example, one recent study measured intracellular cytokine levels in monocytes of patients with schizophrenia (86) . They found significantly lower baseline monocytic IL-6 levels but significantly increased monocytic intracellular IL-6 production after stimulation with lipopolysaccharide in patients with schizophrenia compared with control subjects. Correlations between immune cell parameters and clinical features should be routinely assessed in studies, toward a better understanding of potential mechanisms between immune dysfunction and psychopathology. Well-replicated findings might suggest novel immunomodulatory treatment strategies. Additionally, stratifying patients based on immune alterations may increase the signal-to-noise ratio of treatment trials of adjunctive anti-inflammatory agents in schizophrenia. Taken together, immune cell parameters may serve as potential biomarkers and therapeutic targets in the etiopathophysiology and clinical course of schizophrenia. We thank Linda H. Young for assistance. Dr. Miller, in the past 3 years, has received grant support from the National Institute of Mental Health (1K23MH098014-01), the Georgia Health Sciences University Intramural Scientist Training Program, the GHSU Brain & Behavior and Immunotherapy Discovery Institutes, the University of Oulu (Finland), the Thule Institute of the University of Oulu, and Oy H. Lundbeck Ab; research support from the National Institutes of Health Clinical Loan Repayment Program; consultancy fees for surveys from Medefied Europe and Plaza Research, on behalf of Genetech/Roche; speaker fees for grand rounds lectures from the Maryland Psychiatric Research Center and the Texas A&M University and Scott and White Hospital Department of Psychiatry; and payment for a survey from e-Rewards Medical Market Research. Dr. Buckley received grant/research support from the National Institute of Mental Health, Janssen Pharmaceutica, Pfizer, and Sunovion and is a Consultant (Honorarium/Expenses) for the National Institute of Mental Health. Dr. Mellor received funding support from the National Institutes of Health (AI083005, AI075165), the Juvenile Diabetes Research Foundation, and the Carlos and Marguerite Mason Trust. Dr. Mellor is a member of the Scientific Advisory Board of NewLink Genetics Inc., and receives compensation for this service. Ms. Gassama and Dr. Sebastian report no biomedical financial interests or potential conflicts of interest. Appendix A ",

year = "2013",

month = may,

day = "15",

doi = "10.1016/j.biopsych.2012.09.007",

language = "English (US)",

volume = "73",

pages = "993--999",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "10",

}

TY - JOUR

T1 - Meta-analysis of lymphocytes in schizophrenia

T2 - Clinical status and antipsychotic effects

AU - Miller, Brian J.

AU - Gassama, Bintou

AU - Sebastian, Dale

AU - Buckley, Peter

AU - Mellor, Andrew

N1 - Funding Information: Taken together, our findings suggest that immune cell parameters in schizophrenia may vary with clinical status. The CD4/CD8 ratio appeared to be a state-related marker, as it was significantly increased in FEP and significantly decreased following antipsychotic treatment for acute psychosis. In contrast, absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment. The percentage of CD3 lymphocytes may also be a trait marker, as this proportion was significantly decreased in stable medicated outpatients. A paucity of studies investigated correlations between immune cell parameters and clinical features in schizophrenia, which is an important gap in this literature. We believe ours to be the first systematic, quantitative review of immune cell parameters in schizophrenia. An important strength of our study is that we considered the effects of clinical status and antipsychotic treatment following an acute illness exacerbation. Nonetheless, our results should be interpreted with caution in light of small numbers of studies and subjects, as well as significant heterogeneity across studies (including different assay methodologies and nonstandardized antipsychotic treatment). All immune cell parameters were assessed in fewer than 200 patients (and many in fewer than 100 patients) and in 6 or fewer different studies. However, the alterations in drug-naïve first-episode psychosis suggest an association between abnormalities in immune cell parameters and acute exacerbations of schizophrenia that is independent of antipsychotic medications. There are several other limitations of the present study. Many studies were excluded because either the patient’s clinical status or summary data on immune cell parameters were not available. Many of these studies would have otherwise been included in the meta-analysis, and their influence on the results is uncertain. Furthermore, many studies did not control for potential confounding factors that could account for differences in immune cell parameters between different populations at different stages of illness, including age, race or ethnicity, body mass index, smoking, socioeconomic status, and cortisol (67–70) . For example, effects of age and gender were considered in 100% of studies. By contrast, blood was collected at a standardized time of day in only 38% of studies. Even fewer studies considered potential effects of smoking (13%), cortisol (6%), and body mass index (0%). One study that controlled for many potential confounders reported a significant difference in several immune cell parameters between patients and control subjects (16) . However, this study found that CD19 numbers were positively correlated with the free cortisol index (as a measure of stress), and CD56 levels were negatively correlated with cotinine (as a measure of smoking). The latter result raises the possibility that smoking could confound our findings for CD56. Another limitation is the potential effect of medication status of the subjects in the AR group. In these studies, blood samples were taken while subjects were still acutely ill, generally on admission or within days of admission. Medication nonadherence would be expected to be common in acutely relapsed inpatients, and indeed many of the studies reported that a large proportion of subjects were drug-free at the time of sampling. However, stratified data based on medication status were generally not available. Two longitudinal studies included in the meta-analysis (20,56) did not find any significant changes in lymphocyte parameters between baseline and day 7 of antipsychotic treatment, suggesting that the effect of medication in the AR group might have been minimal. We were not able to perform a meta-analysis of the blood mononuclear phagocytic system; however, there is evidence that it may play a role in the pathophysiology of schizophrenia (reviewed in [71] ). One study (21) also found increased blood levels of IL-1β, IL-6, and TNF-α and increased levels of S100B, a marker of blood-brain barrier disruption. Another study found a significant decrease (to the same level as in control subjects) in IL-1β and TNF-α secretion from isolated blood monocytes following 1 month of first-generation antipsychotic treatment for an acute relapse of schizophrenia (72) . Drexhage et al. (73) found evidence of a proinflammatory gene expression signature in monocytes of patients with recent-onset schizophrenia. Furthermore, a retrospective analysis of serial blood samples in patients with schizophrenia found that monocytosis was associated with a worsening of psychotic symptoms, and in some cases, the monocytosis resolved with a change in antipsychotic treatment during hospitalization (28) . Thus, further studies of the mononuclear phagocyte system, an important source of many proinflammatory cytokines that are increased in schizophrenia (14) , are warranted. This study focused only on blood immune cell parameters in schizophrenia, but there is evidence for immune abnormalities in the CSF and brain as well. Nikkila et al. (47) found a significantly increased proportion of CSF macrophages and activated lymphocytes in patients with acute psychosis compared with control subjects. Another study by the same group also found a significantly increased proportion of CSF macrophages in patients with acute psychosis compared with control subjects (46) . Evidence from positron emission tomography (74,75) and postmortem (76,77) studies also support a role for neuroinflammation/microglial activation in schizophrenia. Several other studies support an association between changes in immune cell parameters and acute exacerbations of psychosis. Muller et al. (12) found a significant decrease in CD19 B-lymphocytes in patients treated with risperidone plus placebo and those treated with risperidone plus celecoxib, with a more pronounced decrease in the celecoxib group. Furthermore, in the celecoxib group only, the decrease in CD19 cells was significantly positively correlated with the decrease in Positive and Negative Syndrome Scale negative scale scores. Another study found that at baseline a relative granulocytosis and lymphopenia prospectively predicted poorer recovery in positive, but not negative, symptoms after 6 months of antipsychotic treatment (66) . Thus, given the efficacy of adjunctive nonsteroidal anti-inflammatory drugs in improving psychopathology in relapsed patients (7–11) , these findings support the plausibility of the hypothesis that immune changes are not merely an artifact of increased stress associated with acute psychosis but may play a role in the pathophysiology of relapse in schizophrenia. In addition to the association between monocytosis and worsening psychosis mentioned above (28) , other studies have found that intraindividual changes in other immune parameters, including CSF IL-2 levels and in vitro IL-2 production, may predict relapse in some patients (78,79) . Further investigation of potential relapse predictive markers is needed. Three hypotheses regarding an immune-cytokine basis for schizophrenia have been postulated. The macrophage-T-lymphocyte theory proposed that cytokines produced by chronically activated macrophages and T-lymphocytes are the fundamental mediators of schizophrenia (80) . Schwarz et al. (81) proposed the Th2-hypothesis, which postulates that a shift from T-helper (Th)1-cell (cytotoxic) toward Th2-cell (antibody-dependent) immune responses predominates in schizophrenia. Lastly, the microglial hypothesis proposed that activated central nervous system microglia release proinflammatory cytokines and free radicals that cause abnormal neurogenesis, neuronal degradation, and white matter abnormalities contributing to the pathophysiology of schizophrenia (82) . Our results inform on these hypotheses. We found abnormal blood lymphocyte parameters, including increased CD4/CD8 ratio in FEP, as well as increased CD56 levels and decreased CD4/CD8 following antipsychotic treatment for relapse. CD4 T-lymphocytes are important sources of IFN-γ and IL-12. Interleukin-12 is also involved in natural killer cell (CD56) activation, and these cells secrete TNF-α and IFN-γ. All of these cytokines were abnormal in our previous meta-analysis (14) . Thus, these findings are not inconsistent with the macrophage-T-lymphocyte theory. While we found evidence for abnormalities in the CD4/CD8 ratio, studies did not distinguish between Th1 versus Th2 CD4 lymphocytes, limiting our ability to make inferences regarding the Th2-hypothesis. We were not able to perform a meta-analysis of the mononuclear phagocyte system, although as noted above, there is evidence of dysfunction broadly consistent with the microglial hypothesis. We emphasize that our results should be interpreted with caution in light of a limited number of studies and small sample sizes, between-study heterogeneity, and a general lack of consideration of potential confounding factors. However, these findings are of importance, as acute relapse of psychosis is common and is associated with adverse outcomes, including increased treatment-resistant symptoms, cognitive decline, and functional disability (83–85) . More longitudinal studies of immune cell parameters in schizophrenia are needed to evaluate if these abnormalities are specific to illness exacerbations or schizophrenia in general and whether they are a temporal predictor of relapse and should control for potential confounding factors. Studies should also simultaneously measure blood cytokines and immune cell subsets, toward better identification of the source(s) of specific cytokines in schizophrenia. For example, one recent study measured intracellular cytokine levels in monocytes of patients with schizophrenia (86) . They found significantly lower baseline monocytic IL-6 levels but significantly increased monocytic intracellular IL-6 production after stimulation with lipopolysaccharide in patients with schizophrenia compared with control subjects. Correlations between immune cell parameters and clinical features should be routinely assessed in studies, toward a better understanding of potential mechanisms between immune dysfunction and psychopathology. Well-replicated findings might suggest novel immunomodulatory treatment strategies. Additionally, stratifying patients based on immune alterations may increase the signal-to-noise ratio of treatment trials of adjunctive anti-inflammatory agents in schizophrenia. Taken together, immune cell parameters may serve as potential biomarkers and therapeutic targets in the etiopathophysiology and clinical course of schizophrenia. We thank Linda H. Young for assistance. Dr. Miller, in the past 3 years, has received grant support from the National Institute of Mental Health (1K23MH098014-01), the Georgia Health Sciences University Intramural Scientist Training Program, the GHSU Brain & Behavior and Immunotherapy Discovery Institutes, the University of Oulu (Finland), the Thule Institute of the University of Oulu, and Oy H. Lundbeck Ab; research support from the National Institutes of Health Clinical Loan Repayment Program; consultancy fees for surveys from Medefied Europe and Plaza Research, on behalf of Genetech/Roche; speaker fees for grand rounds lectures from the Maryland Psychiatric Research Center and the Texas A&M University and Scott and White Hospital Department of Psychiatry; and payment for a survey from e-Rewards Medical Market Research. Dr. Buckley received grant/research support from the National Institute of Mental Health, Janssen Pharmaceutica, Pfizer, and Sunovion and is a Consultant (Honorarium/Expenses) for the National Institute of Mental Health. Dr. Mellor received funding support from the National Institutes of Health (AI083005, AI075165), the Juvenile Diabetes Research Foundation, and the Carlos and Marguerite Mason Trust. Dr. Mellor is a member of the Scientific Advisory Board of NewLink Genetics Inc., and receives compensation for this service. Ms. Gassama and Dr. Sebastian report no biomedical financial interests or potential conflicts of interest. Appendix A

PY - 2013/5/15

Y1 - 2013/5/15

N2 - Background: Schizophrenia is associated with immune system dysfunction, including abnormal blood immune cell parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment following an acute exacerbation of psychosis. Methods: We identified articles by searching PubMed, PsycINFO, and Thomson Reuters (formerly ISI) Web of Knowledge and the reference lists of identified studies. Results: Sixteen studies of blood lymphocytes met the inclusion criteria. There was insufficient data for a meta-analysis of the mononuclear phagocytic system. In cross-sectional studies, there was a significant increase in the CD4% and CD56% in acutely relapsed inpatients. Absolute levels of total lymphocytes, CD3, and CD4, and the CD4/CD8 ratio were significantly increased, and the CD3% was significantly decreased in drug-native first-episode psychosis. In longitudinal studies, the CD4/CD8 ratio appeared to be state-related markers, as it decreased following antipsychotic treatment for acute exacerbations of psychosis. Absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment for relapse. Conclusions: Blood lymphocyte abnormalities in drug-naïve first-episode psychosis suggest an effect that may be independent of antipsychotic medications. While some parameters (CD4/CD8) may be state markers for acute exacerbations of psychosis, others (CD56) may be trait markers; however, more longitudinal studies are needed. Although these findings could provide the basis for future hypothesis testing, a relatively small number of studies and subjects, lack of correlative data with clinical features, and inadequate consideration of potential confounding factors limit the results.

AB - Background: Schizophrenia is associated with immune system dysfunction, including abnormal blood immune cell parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment following an acute exacerbation of psychosis. Methods: We identified articles by searching PubMed, PsycINFO, and Thomson Reuters (formerly ISI) Web of Knowledge and the reference lists of identified studies. Results: Sixteen studies of blood lymphocytes met the inclusion criteria. There was insufficient data for a meta-analysis of the mononuclear phagocytic system. In cross-sectional studies, there was a significant increase in the CD4% and CD56% in acutely relapsed inpatients. Absolute levels of total lymphocytes, CD3, and CD4, and the CD4/CD8 ratio were significantly increased, and the CD3% was significantly decreased in drug-native first-episode psychosis. In longitudinal studies, the CD4/CD8 ratio appeared to be state-related markers, as it decreased following antipsychotic treatment for acute exacerbations of psychosis. Absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment for relapse. Conclusions: Blood lymphocyte abnormalities in drug-naïve first-episode psychosis suggest an effect that may be independent of antipsychotic medications. While some parameters (CD4/CD8) may be state markers for acute exacerbations of psychosis, others (CD56) may be trait markers; however, more longitudinal studies are needed. Although these findings could provide the basis for future hypothesis testing, a relatively small number of studies and subjects, lack of correlative data with clinical features, and inadequate consideration of potential confounding factors limit the results.

KW - First-episode psychosis

KW - lymphocytes

KW - meta-analysis

KW - monocytes

KW - relapse

KW - schizophrenia

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Meta-analysis of lymphocytes in schizophrenia: Clinical status and antipsychotic effects

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