These authors contributed equally to this work.
Schizophrenia (SZ) has been associated with the inflammatory-related and immunological pathogenesis. This study investigates the aberration of cytokines in patients with SZ.
Thirty patients with SZ without antipsychotic treatment for at least two weeks participated. We measured the serum levels of fourteen cytokines at hospital admission and after 8-week antipsychotic treatment. Severity was measured by expanded version of 24-items brief psychiatric rating scale (BPRS-E). Repeated measure analyses of variance were conducted.
The interleukin-1 receptor antagonist (IL-1ra) was significantly decreased after 8-week antipsychotic treatment than those of before antipsychotic treatment (F=12.15, df=1/30, p=0.002). Neural cell adhesion molecule 1/CD56 (NCAM-1/CD56) was significantly decreased (F=6.61, df=1/30, p=0.016) among those with second-generation antipsychotics but not first-generation antipsychotics treatment. The changes of BPRS-E-manic and BPRS-E-anxiety scores correlated with the baseline IL-1ra (r=-0.393), IL-6 (r=-0.407), and insulin like growth factor binding protein 3 (r=-0.446). Additionally, the changes of BPRS-E and BPRS-E-negative scores correlated with the changes of brain-derived neurotrophic factor (r=0.372) and interferon-gamma (r=0.375).
Our study supports that IL-1ra and NCAM-1/CD56 may be considered as markers of developing SZ.
Schizophrenia (SZ) is a severe and chronic psychiatric disorder that affects approximately 0.30% to 0.66% cases per 10,000 person-years [
In addition to inflammatory cytokines, researchers have become interested in neurotrophic factors. Because SZ is considered a neurodevelopmental disorder [
To date, SZ is a disorder that is clinically diagnosed using the Diagnostic and Statistical Manual of Mental Disorder, 5th edition (DSM-5) [
Thirty patients from a medical center in Southern Taiwan who were admitted from August 2014 to August 2015 were enrolled in the present study. All patients met the diagnostic criteria for SZ according to DSM-5 [
The Brief Psychiatric Rating Scale (BPRS), which is one of the most frequently used screening tools, is used to quickly assess psychopathology in various psychiatric disorders. The original BPRS, which consists of 16 item, was developed in 1962 [
During the eight-week follow-up period, the classification and dosage of the antipsychotic agents were flexibly adjusted according to the clinical judgment of the treating psychiatrists. Drug adherence was monitored and ensured by psychiatric nurses.
Venous blood (5 mL) was collected between 7:00 and 8:00 AM to avoid circadian fluctuations of the measured cytokines. After centrifugation at 3,000 rpm for 10 min, the serum was separated from the blood and stored at -70°C prior to the assay. The serum levels of the following 14 cytokines were examined in the present study: IFN-γ, IL-1β, IL-1ra, IL-2, IL-6, IL-8, IL-10, IGF binding protein 1 (IGFBP-1), IGFBP-2, IGFBP-3, BDNF, GDNF, NGF-β, and neural cell adhesion molecule 1/CD56 (NCAM1/CD56). These cytokines were measured using sandwich enzyme-linked immunosorbent assay kits (R&D Systems, Inc., Minneapolis, MN, USA) according to the manufacturer’s protocol. All experiments were performed in duplicate. The intra- and inter-assay variations were less than 10%. The blood of all patients was assayed at admission baseline (week 0) and after antipsychotic treatment (week 8).
The data for the patient demographics and clinical characteristics are presented as mean±standard deviation for continuous variables and percentages for categorical variables. The primary analysis examined the effects of the eight weeks of antipsychotic treatment on the cytokines levels. Additionally, because second-generation antipsychotics (SGAs) have different binding profiles and mechanisms of action compared with first-generation antipsychotics (FGAs), we examined if the effects of SGAs differed from those of FGAs on cytokine levels [
Although several studies have reported an association between cytokine levels and SZ, our study compared the levels of multiple cytokines in patients with SZ before and after antipsychotic treatment. Together with the BPRS-E assessment of severity, we examined cytokines among the multiple domains of inflammatory factors, neurotrophic factors, growth factors, and immunoacting factors. One of the main findings in our study was that IL-1ra levels were significantly decreased after the eight-week antipsychotic treatment, which was similar to previous report [
Another main result was that the levels of NCAM-1/CD56 were significantly decreased in the patients with SZ who were treated with SGAs but not FGAs. However, the differences in the levels of NCAM-1/CD56 were not significant regardless of the type of antipsychotic. NCAM-1, which is also known as CD56, is a member of the immunoglobulin superfamily, which is often considered a marker of neural lineage commitment and which is associated with natural killer cells [
Several investigations have suggested a connection between SZ and changes in growth factors and/or neurotrophic factors, including BDNF, IGF-1, and IGFBP [
We reported the results of the comparisons of multiple groups of cytokines and assessments of psychotic severity. Thus, our results will be helpful for understanding the changes in the immunological, inflammatory, and neurodevelopment mechanisms that have been observed in patients suffering from chronic SZ. Furthermore, our eight-week study period extended across the acute and maintenance stages, which was a strength of the study. However, the following limitations of the study should be considered. First, the lack of a healthy control group and drug-naïve control group was a problem because placebo effects and other confounding factors might have affected our results. Second, because this was a naturalistic study, the antipsychotic agents were adjusted flexibly and therefore not well controlled. Finally, the relatively small number of patients enrolled in the study limits the generalizability of the results.
In conclusion, in this study, we found that the levels of IL-1-ra were significantly decreased after eight weeks of antipsychotic treatment and that levels of NCAM-1/CD56 were significantly decreased in patients with SZ who received SGAs but not FGAs. Further studies are needed to confirm our results.
We are grateful to our patients and their parents who voluntarily participated in our study and gave valuable information. This work was supported by grants VGHKS13-CT5-08 from Kaohsiung Veterans General Hospital, Taiwan.
Clinical characteristics of patients with schizophrenia (N=30)
Variables | Mean (SD) |
---|---|
Age | 47.3 (8.7) |
Gender (M/F) | 17/13 |
Age of onset | 25.9 (8.9) |
Duration of illness (years) | 21.5 (9.6) |
Education | 10.13 (3.501) |
BMI | 26.25 (5.835) |
Smokers (Y/N) | 4/26 |
FGAs/SGAs | 9/21 |
Chlorpromazine equivalent dose (mg/day) during study | 490.1 (225.8) |
Data are presented as mean (SD). BMI: body mass index, FGAs: first-general antipsychotics, SGAs: second-general antipsychotics, SD: standard deviation
Effects of antipsychotic treatment on the psychopathology and serum cytokine levels
Pre-treatment | Post-treatment | Time |
Time×antipsychotic |
|||
---|---|---|---|---|---|---|
F, df | p value | F, df | p value | |||
BPRS-E-total | 66.00 (11.24) | 46.73 (7.31) | 109.27, 1 | <0.001 |
<0.001, 1 | 0.986 |
BPRS-E-manic | 20.9 (7.12) | 13.43 (3.22) | 28.23, 1 | <0.001 |
0.01, 1 | 0.920 |
BPRS-E-anxiety | 13.37 (4.74) | 9.53 (2.30) | 19.39, 1 | <0.001 |
7.04, 1 | 0.013 |
BPRS-E-negative | 12.67 (4.09) | 11.17 (2.56) | 12.85, 1 | 0.001 |
1.87, 1 | 0.183 |
BPRS-E-positive | 19.07 (3.12) | 12.60 (2.40) | 211.68, 1 | <0.001 |
4.63, 1 | 0.040 |
CGI-S | 4.97 (1.13) | 3.60 (0.86) | 50.62, 1 | <0.001 |
0.08, 1 | 0.778 |
IFN-γ | 0.57 (1.02) | 0.40 (0.43) | 0.64, 1 | 0.431 | 0.02, 1 | 0.892 |
IL-1β | 0.22 (0.21) | 0.21 (0.21) | 0.13, 1 | 0.772 | 0.01, 1 | 0.918 |
IL-1ra | 0.95 (0.61) | 0.70 (0.31) | 12.15, 1 | 0.002 |
3.93, 1 | 0.057 |
IL-2 | 4.26 (21.44) | 0.28 (0.37) | 0.46, 1 | 0.501 | 0.39, 1 | 0.539 |
IL-6 | 1.73 (2.13) | 1.36 (1.94) | 0.58, 1 | 0.452 | 0.43, 1 | 0.517 |
IL-8 | 5.34 (8.84) | 3.60 (1.49) | 0.70, 1 | 0.411 | 0.15, 1 | 0.702 |
IL-10 | 3.26 (10.23) | 0.92 (0.89) | 0.98, 1 | 0.330 | 0.12, 1 | 0.736 |
IGFBP1 | 9.47 (11.45) | 10.47 (14.55) | 0.19, 1 | 0.890 | 0.24, 1 | 0.627 |
IGFBP2 | 122.96 (62.26) | 119.59 (68.53) | 0.14, 1 | 0.711 | 0.02, 1 | 0.882 |
IGFBP3 | 2.32 (0.67) | 2.29 (0.64) | 0.15, 1 | 0.703 | 0.06, 1 | 0.813 |
BDNF | 1.29 (2.31) | 0.76 (1.64) | 2.00, 1 | 0.169 | 1.76, 1 | 0.195 |
GDNF | 0.019 (0.046) | 0.017 (0.033) | 0.469, 1 | 0.499 | 0.469, 1 | 0.499 |
Beta-NGF | 0.023 (0.095) | 0.018 (0.068) | 0.365, 1 | 0.550 | 0.365, 1 | 0.550 |
NCAM-1/CD56 | 0.266 (0.113) | 0.260 (0.090) | 0.063, 1 | 0.804 | 6.610, 1 | 0.016 |
significant differences.
BDNF: brain-derived neurotrophic factor, BPRS-E: the expanded 24-items BPRS, CGI-S: clinical global impressionseverity, GDNF: glial-derived neurotrophic factor, IFN: interferon, IGFBP: insulin-like growth factor-binding protein, IL: interleukin, NCAM: neural cell adhesion molecule, NGF: nerve growth factor
Correlation of the baseline and cytokine level changes and BPRS-E scores after eight weeks of antipsychotic treatment
IL-1ra, T0 | IL-6, T0 | IGFBP3, T0 | △IFN | △BDNF | |
---|---|---|---|---|---|
△BPRS-total | -0.333 | -0.350 | -0.315 | 0.335 | 0.372 |
△BPRS-manic | -0.393 |
-0.407 |
-0.118 | 0.322 | 0.263 |
△BPRS-anxiety | 0.128 | -0.229 | -0.446 |
-0.056 | 0.283 |
△BPRS-negative | -0.010 | -0.028 | 0.024 | 0.375 |
0.184 |
△BPRS-positive | -0.276 | -0.058 | -0.015 | 0.142 | -0.086 |
p<0.05,
T0: data at admission, △: change psychopathology and serum cytokines of before and after antipsychotic treatment. BDNF: brainderived neurotrophic factor, BPRS-E: the expanded 24-items BPRS, IFN: interferon, IGFBP: insulin-like growth factor-binding protein, IL: interleukin