Cytokine levels in symptomatic patients undergoing anti-psychotic treatment for First Episode Psychosis: a cross-sectional study.

Cytokine levels in symptomatic patients undergoing anti-psychotic treatment for First Episode Psychosis: a cross-sectional study. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cytokine levels in symptomatic patients undergoing anti-psychotic treatment for First Episode Psychosis: a cross-sectional study. Valentina Morgera, Frederick Sundram, Bruce Russell, Ian Soosay, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7746547/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Cytokines in first-episode psychosis (FEP) appear to be activated as part of an Inflammatory Response System (IRS) or a Compensatory Inflammatory Response System (CIRS) and have been proposed as clinical (state and trait) markers of psychosis. Antipsychotic medication normalizes the IRS/CIRS ratio despite a predominant activation of the IRS. The current study examined blood levels of IRS/CIRS cytokines proposed as clinical markers in symptomatic medicated patients with FEP. We screened all co-diagnoses and immunomodulating factors that have been linked to cytokine changes to increase the accuracy of findings. Methods We compared cytokines (n = 16) levels in the blood serum of patients with FEP (n = 20) recruited from a specialized FEP clinical service with a matched (age, gender, body mass index) group of healthy control subjects (HC)( n = 20). We screened for tobacco smoking, cannabis use, medications, and the absence of fever. Best-fitting regression models were used to identify differences in FEP vs HCs per diagnosis and additional variables of age, gender, and BMI. We correlated cytokine levels to Positive and Negative Symptoms Scale (PANSS) scores and antipsychotic load, recorded as chlorpromazine equivalents. Results We found elevated levels of IRS (IL-2 and IL-6), and reduced levels of IRS (IL-1, IL-8, IL-12), and CIRS (IL-4) in FEP vs HC. No significant differences in the IRS/CIRS ratio or a correlation between cytokine levels and PANSS scores were found. Lower levels of IL-2, IL-6 and IL-8 correlated to higher amounts of antipsychotics. Conclusion Our study on well-controlled moderately symptomatic patients with FEP taking antipsychotic treatment found that the IRS/CIRS ratio was not altered, while some alterations in cytokine levels were found. IL-2 and IL-6 remain elevated despite the immune-modulatory action of the antipsychotic agents; we suggest they could be used as screening tools for either trait (IL-6) and/or state (IL-2) markers of psychosis, in combination with C-reactive protein, to identify people with FEP that could potentially benefit from an adjuvant anti-inflammatory therapy alongside antipsychotics. Clinical trial registration number: Not applicable psychosis first episode psychosis inflammatory response cytokines IRS/CIRS activation Background Cytokines, small proteins involved in cell signalling and inflammation, have been reportedly elevated in the peripheral blood of people with psychosis and schizophrenia since the 1990s. 1,2 . Altered cytokine levels have been reported in people at high risk of psychosis 3 , during acute psychotic episodes, and in people with chronic schizophrenia 4 . While these changes have been reported across the schizophrenia spectrum, there have been a number of contrasting findings 5 , 6 due in part to the inclusion of schizoaffective disorders, the severity and duration of symptoms, the antipsychotic treatment received, and the influence of co-variants that may influence cytokine expression, such as smoking and body mass index (BMI) 7 , 8 . Differences in blood sampling procedures and analytical methodologies, including the fasting status of participants and the time of day at which samples are taken, may also influence cytokine levels 4 , 9 . Further, the interpretation of results may be difficult due to the complexity of immune response mechanisms; there is an intricate functional correlation between cytokines (10), and individual cytokines are reported to have both pro- and anti-inflammatory properties 11 , 12 , 13 . To assist the interpretation of cytokine changes in psychotic disorders, Maes and colleagues proposed grouping cytokines as belonging to either an Inflammatory Response System (IRS) or a Compensatory Inflammatory Response System (CIRS), that exert pro- or anti-inflammatory functions, respectively. They hypothesised that increased IRS activity promotes an incremental compensatory response from the CIRS, establishing a new set-point balancing the activity of the two systems that can be estimated by calculating the IRS/CIRS ratio 14 . Other research groups have attempted to characterise cytokine changes in psychosis and schizophrenia as either trait markers, altered irrespective of the stage of the disorder, or as state markers, that accompany acute psychotic symptoms 15 , 16 . Recently, Halstead and colleagues presented a comprehensive network-meta-analysis of reported changes in inflammatory proteins in people with schizophrenia spectrum disorders (SSD), including those with FEP 17 . They proposed that cytokines that are consistently elevated across both acute and chronic stages of schizophrenia were potential trait markers for the condition, placing IL-1β, IL-1 receptor antagonist (IL-1RA), soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8, IL-10, and tumour necrosis factor (TNF)-α in this category, while IL-2 and interferon-gamma (IFN-γ) that changed only in symptomatic individuals ‒ were potential state markers. In the current study, we examined the inflammatory response in the peripheral blood of people experiencing symptoms during their FEP and receiving antipsychotic treatment from a specialised first-episode clinical service, compared to an age and gender-matched healthy control group. Other variables that might influence cytokine levels were controlled for, and blood samples were taken at the same time each day under the same conditions 9 . We analysed a large panel of cytokines (n = 16), including most of those suggested in the meta-analysis by Halstead and colleagues. Because our patients with FEP were still symptomatic, we anticipated that both state and trait markers would be altered. We also grouped cytokines based on their IRS and CIRS function in FEP 18 . As the study group was receiving antipsychotic treatment, we did not anticipate finding significant alterations in the IRS/CIRS ratio, as an earlier study showed this might be normalised by antipsychotic therapy 19 . It has also been shown that antipsychotic agents have a non-specific anti-inflammatory effect on most cytokines 6 , 20 , 21 . Methods Recruitment and Study design This was a cross-sectional study comparing cytokine levels in a group of people experiencing their FEP with an age and gender-matched healthy control group. The study was conducted between February 2018 and June 2020 at the Te Toka Tumai ‒ Hāpai Ora Early Intervention Psychosis service in central Auckland. The study was approved by the Northern A Health and Disabilities Ethics Committees of New Zealand (reference: 16/NTA/120/AM01). Treating clinicians briefed potential FEP participants about the study and referred those interested to the principal investigator, VM, who was embedded in the service, to proceed with preliminary screening against inclusion/exclusion criteria. Eligible people then reviewed participant information sheets and, if they were willing to proceed, written consent was obtained and an assessment date/time with the VM agreed. The inclusion criteria for the FEP group were age between 18 and 35 years, a FEP diagnosis and taking antipsychotic medication for no longer than 12 months. A mentally healthy control group recruited by email advertisement at the University of Auckland was matched by age (+/- 5 years) and gender and body mass index (BMI) to FEP participants. This comprised people with no history of any psychiatric condition or treatment with an antipsychotic or any other psychotropic agent. Exclusion criteria for both groups were a history of head injury, neurological disorders or psychiatric comorbidities; current thoughts of self-harm; current suicidal risk; documented cognitive impairment; diagnoses of a substance-induced psychotic disorder (SIPD), a Brief Psychotic Episode, or a psychotic episode with affective features; current use of medication with immunomodulatory effects (e.g., steroids, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, immune-suppressant therapy); the presence of current fever or within the last week before assessment. The last piece of information was gathered later, during the study assessment, and all the others during the eligibility criteria screening. For methodological consistency and preserving the circadian rhythm of cytokine production 21 , 22 , all assessments were conducted in the morning and consisted of a structured clinical interview conducted by a trained interviewer (VM) and blood sampling between 08:30 and 10:00 a.m. Clinical interview During the clinical interview, VM gathered information about the severity of symptoms using the Positive and Negative Symptom Scale (PANSS) 23 and the duration of treatment under the care of the specialized service, from the time admitted to the service till the date of study assessment. This information was supplemented by consulting the participant’s treating team and clinical notes. Substance use was recorded using the Alcohol, Smoking and Substance Involvement Screening test-ASSIST 24 and people who used cannabis occasionally (up to once per week) were included in the study although some in-vivo studies have reported immune-modulatory effects of cannabinoids on cytokines 25 . Cannabinoids are undetectable in the blood in ~ 31 hours in occasional users 26 . For analysis, we computed the antipsychotic load variable in chlorpromazine equivalents (CPZE) by multiplying the daily antipsychotic dosage in CPZE by the number of days the person had been receiving antipsychotics from the initiation of treatment at the clinical service until the date of study clinical assessment. Dosages equivalent to 100 mg/day of CPZE were estimated at 1 mg/day for risperidone, 5 mg/day for olanzapine, 7.5 mg/day for aripiprazole and 75 mg/day for quetiapine 27 . This information was retrieved from the participants' clinical notes. Blood sampling Participants refrained from alcohol and tobacco use for 24 hours, and from cannabis use for 48 hours before blood sampling, to ensure sufficient cannabinoid metabolism 28 . They also fasted on the morning of the assessment. All blood samples were drawn between 10:00 and 10:30 a.m. by VM, a certified phlebotomist. Within an hour of collecting, the blood sample was centrifuged at 1600 rpm for 10 minutes at room temperature. Following centrifugation, the liquid component (serum) was immediately transferred to a clean polypropylene tube 0.5 mL aliquot using a Pasteur pipette and stored in a minus 80-degree Celsius freezer (29) in the premises of the Research Clinical Centre (RCC) at the University of Auckland. All blood samples were shipped frozen to iPath laboratories in Melbourne in thermal parcels with dry ice packs and kept at minus 80° C until analyzed in two batches within a year of collection. Dispatch to iPath laboratories was organized in collaboration with CompoundLabs, an Auckland-based company ( https://compoundlabs.co.nz ). Cytokine analyses were completed using the Luminex XMAP Assay, a multiplex assay technology that permits the simultaneous evaluation of numerous cytokines in several types of biological fluid (30) . This technology is derived from the classic Enzyme-linked immunosorbent assay (ELISA) technology (31). A panel of 16 cytokines was analyzed (IL-1, IL-2, IL-6, IL-12, IL-17, IL-8, TNF-α, TNF-β, INF-γ, GM-CSF, IL-4, IL-13, TGF-β, IL-10, IL-5, IL-7). Statistical analysis Descriptive statistics were completed for demographic and clinical variables, and the results of cytokine multi-assay analyses. As the observed cytokine parameters did not meet the assumptions of normality and homogeneity, the values were logarithmically transformed, as recommended for immune parameters such as cytokines 32 . Once transformed, all cytokine variables met the assumption of linearity. To standardize our scores and facilitate cytokine comparisons, we computed z-scores of all cytokine values 33 . We also computed a total score for the IRS and CIRS cytokine groups following Maes and Carvalho’s recommendations (14): IRS group value was computed as the sum of the z score of the logarithm of IL.1, IL.2, IL.6, IL.8, IL.12, IL.17, TNF-α, TNF-β, INF-γ, GM-CSF; and CIRS group as the sum of z scores of the logarithm of IL.4, IL.5, IL.7, IL.10, IL.13, TGF- β. To determine the influence of diagnosis (FEP) and demographic variables (age, gender, and BMI) on each cytokine in our sample, the best-suited univariate or multiple regression model based on the minimum Akaike Information Criterion (AIC) value for each cytokine (including all the interaction terms) was estimated using the method of Burnham et al. 1998 34 . To investigate the IRS/CIRS balance in our FEP sample, as proposed by Maes and colleagues 35 , the IRS/CIRS ratio was computed as the z score of the IRS group minus the z scores of the CIRS group value [z (IRS group value) – z (CIRS group value)]. A univariate regression linear model was then used to investigate the differences between the IRS cytokines the CIRS cytokines, and the IRS/CIRS ratio, in FEP and HC. The Pearson’s correlation coefficient was used to study the relationship between each cytokine (logarithmic value) and the clinical variables’ severity of symptoms (measured by PANSS score) and antipsychotic load. Probability (p) values were calculated based on two-tailed analyses. P-values < 0.05 were considered indicative of statistical significance. All statistical analyses were run using R Analysis conducted using R version 4.3. R Core Team (2023), the lmerTest package and package DHARMa 36 . Results Recruitment Clinicians on the FEP unit referred 46 people for potential inclusion to the study. Of these, 26 were excluded for the following reasons: one had a neurological disorder, two were at current suicidal risk, three had psychiatric co-morbidities, four experienced a worsening of symptoms requiring urgent intervention such as hospital admission and 16 were lost to follow up. Twenty patients with FEP were recruited and completed the assessments. Twenty HCs were matched per age and gender and completed the assessment. Clinical and demographic variables Each group (FEP and HC) contained 11 males and 9 females who did not significantly differ in age (FEP range 19–31 mean = 22.6, SD = 3.424; HC 19–30 M = 22.8, SD = 2.94) and BMI (FEP M = 25.64, SD = 4.96; HC M = 24.30, SD = 1.46). PANSS total scores ranged between 61 and 89 ( M = 76.7, SD = 7.26), positive subscale scores from 19 to 34 ( M = 24.65, SD 4.01), and the negative scale from 19 to 34 ( M = 26.45, SD = 7.26), showing that FEP participants were moderately symptomatic (37). All participants had been receiving antipsychotic medication in the range of 1 to 12 months ( M = 5.55, SD = 3.76). Dosage in CPZ-equivalents ranged between 100 to 250 mg per day, with most participants (n = 10) on 100 mg; total amount of antipsychotic load received ranged between 3040 and 68400 mg. ( M = 24586, SD = .19729.63 mg). Cytokines values results All cytokines' panels were successfully assayed and observed values per cytokines (in pg/ml) are reported in Table 1 . Table 1 Mean and (Standard deviation), median and (Interquartile range) for FEP and HC observed cytokines values. FEP HC mean (sd) median (IQR) mean (sd) median (IQR) IL.1 0.6 (0.75) 0.3 (0.2, 0.4) 1.41 (0.89) 1.5 (1.2, 1.6) IL.2 9.16 (4.61) 10.5 (4.8, 13.2) 2.68 (0.93) 2.6 (2.2, 2.9) IL.6 33.1 (60.01) 12.6 (3.5, 23) 7.76 (5.93) 4.6 (3.1, 14.4) IL.8 5.53 (5.12) 3.3 (2.5, 5.8) 10.95 (9.98) 10.4 (5, 12.1) IL.12 1.71 (1.01) 1.6 (1, 2.3) 7.61 (4.2) 7.5 (5.1, 8.9) IL.17 7.18 (10.04) 1.1 (0.7, 13.5) 3.36 (1.95) 2.9 (2.7, 4) TNF.α 7.23 (4.93) 5.2 (3.4, 11.8) 7.49 (4.29) 6.2 (4.3, 10.3) TNF.β 103.33 (37.93) 91.8 (71.2, 147.5) 85.57 (22.7) 85 (68.5, 96) INF.γ 11.52 (13.78) 5 (3.2, 15.6) 7.61 (4.56) 5.1 (4.5, 12.4) GM.CSF 51.4 (23.33) 44.5 (37, 54.9) 41.56 (13.43) 39 (36.5, 49) IL.4 15.29 (34.25) 3.4 (2.8, 9.2) 16.94 (11.61) 15.5 (12.5, 20.3) IL.5 11.06 (19.15) 1.9 (1.4, 16.1) 5.13 (2.75) 4.9 (3.6, 6.1) IL.7 6.52 (5.72) 5.3 (4.4, 6.4) 4.8 (3.24) 3.6 (3.1, 7) IL.10 3.42 (4.69) 0.8 (0.6, 5.8) 4.71 (5.43) 2.7 (1.3, 4.9) IL.13 3.63 (4.42) 1.5 (1, 3.7) 4.36 (3.54) 2.9 (1.9, 7) TGF.β 48.8 (8.75) 45.5 (42, 57.3) 50.75 (5.87) 50.5 (46, 56.3) Table 1 . Descriptive statistics for cytokine concentrations in individuals with first-episode psychosis (FEP) and healthy controls (HC). For each cytokine, the mean and standard deviation (in parentheses), as well as the median and interquartile range (IQR), are reported. Cytokine levels are expressed in pg/mL. This table includes all 16 cytokines measured in the study. Differences between FEP and HC cytokines’ levels All regression models included the variable Diagnosis. Based on lowest AIC value criteria, gender was included in the model for IL-1, IL-2, and IL-6; age was included per IL-4; and BMI for TNF-α. The ANOVA analysis showed significant results for six cytokines (reported in Table 2 ). IRS cytokines IL-2 and IL-6 were significantly higher in those with a FEP compared to the HC group for diagnosis, while IRS cytokines IL-1, IL-8 and IL-12 and CIRS IL-4 were significantly reduced. Differences in IRS, CIRS group and IRS/CIRS ratio in medicated FEP Results of a one-way analysis of variance (ANOVA) did not show any significant difference between FEP and HC in the IRS group [F (1–38) = 9.73 p = 0.15], CIRS group [F (1–38) = 9.73 p = 0.15] and IRS/CIRS ratio [F (1–38) = 9.73 p = 0.15]. That is, in our medicated FEP sample, there is no predominant activation of either IRS or CIRS. Table 2 Results of One-Way Analysis of Variance (ANOVA) (Type II) with p value F) Significance IL-1 Diagnosis 9.96 39.7% 16.24 < 0.001 *** Gender 5.01 8.16 0.01 ** IL-2 Diagnosis 12.01 60.6% 48.05 < 0.001 *** Diagnosis: Gender 1.27 5.07 0.03 * IL-4 Diagnosis 6.52 21% 6.94 0.01 * Age IL-6 Diagnosis 4.65 24.8% 4.25 0.04 * Diagnosis: Gender 7.26 6.63 0.01 * IL-8 Diagnosis 4.32 16.4% 7.46 0.01 ** IL-12 Diagnosis 22.46 54.7% 45.97 < 0.001 *** Table 2 : Type II ANOVA results for the subset of cytokines that showed statistically significant associations (p < 0.05) from a the panel of 16 tested. Best subset univariate multiple regression linear models were used to evaluate the effects of diagnosis, gender, age, BMI and their interaction (where applicable) on cytokine expression levels. For each significant cytokine, the table reports the source of variation, sum of squares, proportion of variance explained (R²), F-statistic, and p-value. Significance codes: *** p < 0.0001, ** p < 0.005, * p < 0.05. Only cytokines with at least one significant predictor are shown. Correlation between Cytokine levels, Severity of symptoms, and Antipsychotic load A Pearson’s correlation coefficient was computed to assess the linear relationship between each Cytokine value and clinical variables. No correlation was found between PANSS total score, negative and positive and the level of cytokines. However, within the 95% confidence interval of our FEP sample there were significant negative correlations between antipsychotic medication load and the cytokines IL-2, IL-5, IL-6, IL-8, IL-10, and IL-17, as shown in Table 3 . This shows that among those cytokines altered in FEP, lower levels of IL-2 and IL-6 and IL-8 correlate with a higher CPZE amount of antipsychotic taken. Table 3 Significant correlations between cytokine values and antipsychotic load Pearson’s Correlation p-values 95%Confidence intervals IL.2 -0.491 0.028 -0.762 -0.049 IL.5 -0.470 0.037 -0.750 -0.022 IL.6 -0.453 0.045 -0.741 -0.002 IL.8 -0.450 0.046 -0.739 0.002 IL.10 -0.445 0.005 -0.736 -0.022 IL.17 -0.49 0.02 -0.761 0.009 Table 3 . Significant Pearson’s correlations between cytokine levels and antipsychotic load in individuals with first-episode psychosis (FEP). For each cytokine, the Pearson correlation coefficient (r), corresponding p-value, and 95% confidence interval for the correlation are reported. Negative correlations indicate that higher antipsychotic load is associated with lower cytokine levels. Only cytokines with statistically significant correlations (p < 0.05) are shown. Discussion This study was designed to examine changes in cytokine levels in people experiencing their FEP and receiving standard treatment from a specialised service, controlling for variables known to have independent effects on cytokines. We found that IL-2 and IL-6 were elevated compared to the age and gender matched healthy control group, while others, IL-1, IL-4, IL-8 and IL-12, were decreased. Some of these results were expected. Although individual cytokine levels differed between the FEP and HC groups, the ratio of pro- to anti-inflammatory cytokines (IRS/CRS) was not different, as expected, in a medicated sample (38). Nevertheless, cytokines previously proposed as state (IL-6) and trait (IL-2) markers for psychosis were changed in our FEP participants, as would be expected in those currently experiencing psychotic symptoms 15 , 17 , 39 , 40 . This study's main finding supports the hypothesis that IL-2 and IL-6 are state (IL-2) and trait (IL-6) markers of psychosis. Both IL-2 and IL-6 are IRS cytokines and promote systemic inflammation. Moreover, both cytokines contribute to the brain changes linked to psychosis 43 , 44 , 45 . While IL-2 is responsible for the differentiation of T-helper cells and the consequent production of IFN-y, IL-4, IL-6 and IL-12 (46). IL-6 increases neuroinflammation, thereby disrupting the integrity of the blood-brain-barrier and activating pro-inflammatory cascades in the brain 47 , 48 . IL-6 also increases neuroinflammation by disrupting the integrity of the blood-brain-barrier and activating pro-inflammatory cascades in the brain 49 . Indeed, it has been hypothesized that inflammatory markers are elevated in a subgroup of patients with FEP 50 , 51 . Some results were unexpected. IRS cytokines (IL-1 IL-12) were strongly reduced below healthy controls, while expected to be elevated in our group 39 , 51 , 52 . Moreover, IRS cytokines (TNF-α and IFN-γ) were only slightly elevated in our group, while being largely reported elevated in psychosis. This might be the result of immunomodulating effects by the antipsychotics 53 , 54 , although we found no correlation between cytokines and antipsychotic medication. Nevertheless, an individual variation in susceptibility to the anti-inflammatory properties of antipsychotics must be considered 55 . Taken together, our findings are suggestive of a dysregulated Th1 response (with high IL-2, elevated IFN-γ and, low IL.12), reporting cytokine mixed features of acuity (elevation of IL-2 and IL-6), and chronic phase (reduction of IL-1 and IL-12) of FEP 17 . Clinically, this could be justified by the presenting clinical status of participants included in the study, that being mod. Indeed, all people with FEP had overcome their acute psychosis and were presenting with persistent symptoms despite treatment, fitting the criteria for the diagnosis of schizophreniform or schizophrenia disorders 55 . Overall, this highlights the dynamic changes in cytokine profiles in medicated people with FEP. Strengths and limitations The main limitations of this study are the small sample size cross-sectional design. Additionally, our recruitment process could be biased, as the treating clinician referred potential participants based on whether they could engage with the assessment process. Strengths of this study include control of environmental and host-related mediators of inflammation known to affect cytokine levels. We screened participants for factors with immunomodulatory effects (medications, fever, smoking, cannabis, alcohol) and included age, gender, and BMI in our analysis 56 , 57 . Moreover, we targeted a well-described population of clients with FEP undergoing antipsychotic treatment, excluding participants with comorbidities such as affective psychosis. A single medically trained investigator (VM) undertook recruitment and data collection and interacted with the clinical team at the specialised psychosis service where recruitment was conducted. Lastly, we applied statistical methodology that aimed to minimise the impact of individual variability of immune markers and increase comparability of the dataset 14 , to increase the reproducibility and generalizability of our findings. Conclusions and Future directions Our study was conducted with a well-controlled, moderately symptomatic group of people with FEP taking antipsychotic treatment. We found that the IRS/CIRS ratio was not altered. IL-2 and IL-6 levels remained elevated despite the immunomodulatory action of antipsychotic agents, confirming that they might act as state (IL-2) and trait (IL-6) markers for FEP. In line with current theories, we conclude that differences in cytokine levels in our FEP group might be indicative of an altered immune response that results in a systemic low-grade inflammation, which contributes to psychotic symptoms. Abbreviations AIC Akaike Information Criterion BMI Body Mass Index CIRS Compensatory Inflammatory Response System CPZE Chlorpromazine Equivalents ELISA Enzyme-Linked Immunosorbent Assay FEP First Episode Psychosis GM-CSF Granulocyte-Macrophage Colony-Stimulating Factor INF Interferon IL(s) Interleukin(s) IRS Inflammatory Response System M Mean NSAIDs non-steroidal anti-inflammatory drugs PANSS The Positive and Negative Syndrome Scale RCC Research Clinical Centre SD Standard Deviation SIPD substance-induced psychotic disorder TNF Tumor Necrosis Factor Declarations Ethics approval and consent to participate This study was approved by the Northern A Health and Disabilities Ethics Committees of New Zealand (reference: 16/NTA/120/AM01). Informed consent to participate in the study was obtained from all participants. Research has been conducted in accordance with the Declaration of Helsinki. Consent for publication Consent for publication was obtained from all participants of this study. Availability of data and materials All data generated or analysed during this study are included in this published article. The dataset supporting this study is available in The University of Auckland repository (DOI: 10.17608/k6.auckland.30239557). Competing interests The authors declare that they have no competing interests for the publication of this article Funding This study was entirely funded by the University of Auckland, through the funds allocated for VM’s PhD programme Authors' contributions " VM gathered study data, participated to data analysis, interpreted result data and wrote up the article. RK and FS supervised all study phases and were major contributors in writing the manuscript. BVdW advised and ran the statistical analysis for the study. BR and IS contributed to the writing of the manuscript. Acknowledgements We would like to thank Te Toka Tumai ‒ Hāpai Ora Early Intervention Psychosis service and its clinicians for supporting and collaborating with VM during the recruitment process. References Ganguli R, Yang Z, Shurin G, Chengappa KN, Brar JS, Gubbi AV, Rabin BS. Serum interleukin-6 concentration in schizophrenia: Elevation associated with duration of illness. Psychiatry Res. 1994;51:1–10. Maes M, Meltzer HY, Bosmans E. Immune-inflammatory markers in schizophrenia: Comparison to normal controls and effects of clozapine. Acta Psychiatr Scand. 1994;89:346–351. Park S, Miller BJ. Meta-analysis of cytokine and C-reactive protein levels in high-risk psychosis. Schizophr Res. 2020;226:5-12. Momtazmanesh S, Zare-Shahabadi A, Rezaei N. Cytokine alterations in schizophrenia: An updated review. Front Psychiatry. 2019;10:892. Frydecka D, Krzystek-Korpacka M, Lubeiro A, Stramecki F, Stanczykiewicz B, Beszłej JA, et al. Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study. Brain Behav Immun. 2018;71:28-36. Marcinowicz P, Więdłocha M, Zborowska N, Dębowska W, Podwalski P, Misiak B, Tyburski E, Szulc A. A meta-analysis of the influence of antipsychotics on cytokine levels in first episode psychosis. J Clin Med. 2021;10(11):2488. Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev. 2014;38:72-93. Patlola SR, Donohoe G, McKernan DP. Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis. J Psychiatr Res. 2023;160:126-136. Cohen L, Keegan A, Melanson SE, Walt DR. Impact of clinical sample handling and processing on ultra-low level measurements of plasma cytokines. Clin Biochem. 2019;65:38-44. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune system abnormalities in schizophrenia: An integrative view and translational perspectives. Front Psychiatry. 2022 Apr 25;13:880568. Tourjman V, Kouassi É, Koué M-È, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, Potvin S. Antipsychotics’ effects on blood levels of cytokines in schizophrenia: A meta-analysis. Schizophr Res. 2013;151:43-47. Kleiner G, Marcuzzi A, Zanin V, Monasta L, Zauli G. Cytokine levels in the serum of healthy subjects. Mediators Inflamm. 2013;2013:434010. Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2017;17(1):49-59. Maes M, Carvalho AF. The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol Neurobiol. 2018;55(12):8885-8903. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry. 2011;70:663-671. Capuzzi E, Bartoli F, Crocamo C, Clerici M, Carrà G. Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: A meta-analysis. Neurosci Biobehav Rev. 2017 Jun;77:122-128. Halstead S, Siskind D, Amft M, Wagner E, Yakimov V, Shih-Jung Liu Z, Walder K, Warren N. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry. 2023 Apr;10(4):260-271. doi: 10.1016/S2215-0366(23)00025-1. Roomruangwong C, Noto C, Kanchanatawan B, Anderson G, Kubera M, Carvalho AF, Maes M. The role of aberrations in the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS) in different phenotypes of schizophrenia: The IRS-CIRS theory of schizophrenia. Mol Neurobiol. 2020;57:778-797. Noto MN, Maes M, Nunes SOV, Ota VK, Rossaneis AC, Verri WA Jr, Cordeiro Q, Belangero SI, Gadelha A, Bressan RA, et al. Activation of the immune-inflammatory response system and the compensatory immune-regulatory system in antipsychotic naive first episode psychosis. Eur Neuropsychopharmacol. 2019;29:416-431. Romeo B, Brunet-Lecomte M, Martelli C, Benyamina A. Kinetics of cytokine levels during antipsychotic treatment in schizophrenia: A meta-analysis. Int J Neuropsychopharmacol. 2018;21(9):828-836. Nakao A. Temporal regulation of cytokines by the circadian clock. J Immunol Res. 2014;2014:614529. Shimba A, Ikuta K. Glucocorticoids regulate circadian rhythm of innate and adaptive immunity. Front Immunol. 2020;11:2143. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-276. WHO ASSIST Working Group. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST): Development, reliability, and feasibility. Addiction. 2002;97(9):1183-1194. Henshaw FR, Dewsbury LS, Lim CK, Steiner GZ. The Effects of Cannabinoids on Pro- and Anti-Inflammatory Cytokines: A Systematic Review of In Vivo Studies. Cannabis Cannabinoid Res. 2021 Jun;6(3):177-195. Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84:2477-2482. Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003;64(6):663-667. Verstraete A. G. (2004). Detection times of drugs of abuse in blood, urine, and oral fluid. Therapeutic drug monitoring, 26(2), 200–205. De Jager, W., Bourcier, K., Rijkers, G. T., Prakken, B. J., & Seyfert-Margolis, V. (2009). Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC Immunology, 10(1), 52. Lombardelli L, Logiodice F, Kullolli O, Piccinni M-P. Evaluation of secreted cytokines by multiplex bead-based assay (X MAP technology, Luminex). In: Methods in Molecular Biology (pp. 121-130). Methods Mol Biol. 2021; Vol. 2359. Sakamoto, S., Putalun, W., Vimolmangkang, S., Phoolcharoen, W., Shoyama, Y., Tanaka, H., & Morimoto, S. (2018). Enzyme-linked immunosorbent assay for the quantitative/qualitative analysis of plant secondary metabolites. Journal of natural medicines, 72(1), 32–42. Genser, B., Cooper, P.J., Yazdanbakhsh, M. et al. A guide to modern statistical analysis of immunological data. BMC Immunol 8, 27 (2007). Davis JM 3rd, Knutson KL, Strausbauch MA, Crowson CS, Therneau TM, Wettstein PJ, Matteson EL, Gabriel SE. Analysis of complex biomarkers for human immune-mediated disorders based on cytokine responsiveness of peripheral blood cells. J Immunol. 2010 Jun 15;184(12):7297-7304. Burnham KP, Anderson DR. Model Selection and Inference - Practical Use of the Information-Theoretic Approach. Springer New York; 1998. Kuznetsova A, Brockhoff PB, Christensen RHB (2017). "lmerTest Package: Tests in Linear Mixed Effects Models." Journal of Statistical Software, 82(13), 1-26. doi:10.18637/jss.v082.i13. Hartig F (2022). DHARMa: Residual Diagnostics for Hierarchical (Multi-Level / Mixed) Regression Models. R package version 0.4.6. Leucht, S., Kane, J. M., Kissling, W., Hamann, J., Etschel, E., & Engel, R. R. (2005). What does the PANSS mean?. Schizophrenia research, 79(2-3), 231-238. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder, and depression. Mol Psychiatry. 2016;21:1696-1709. Capuzzi E, Bartoli F, Crocamo C, Clerici M, Carrà G. Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: A meta-analysis. Neurosci Biobehav Rev. 2017 Jun;77:122-128. Noto C, Ota VK, Gadelha A, Noto MN, Barbosa DS, Bonifácio KL, Nunes SO, Cordeiro Q, Belangero S, Bressan R, et al. Oxidative stress in drug naïve first episode psychosis and antioxidant effects of risperidone. J Psychiatr Res. 2015;68:210-216. Juncal-Ruiz M, Riesco-Dávila L, Ortiz-García de la Foz V, Martínez-Garcia O, Ramírez-Bonilla M, Ocejo-Viñals JG, Leza JC, López-Hoyos M, Crespo-Facorro B. Comparison of the anti-inflammatory effect of aripiprazole and risperidone in 75 drug-naïve first episode psychosis individuals: A 3 months randomized study. Schizophr Res. 2018;202:226-233. Patel S, Keating BA, Dale RC. Anti-inflammatory properties of commonly used psychiatric drugs. Front Neurosci. 2023 Jan 10;16:1039379. Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: A PET study. J Nucl Med. 2009;50:1801-1807. Levitt P, Veenstra-VanderWeele J. Neurodevelopment and the origins of brain disorders. Neuropsychopharmacology. 2015;40(1):1-3. Miller BJ, Lemos H, Schooler NR, Goff DC, Kopelowicz A, Lauriello J, Manschreck T, Mendelowitz A, Miller DD, Severe JB, Wilson DR, Ames D, Bustillo J, Kane JM, Rapaport MH, Buckley PF. Longitudinal study of inflammation and relapse in schizophrenia. Schizophrenia research. 2023;252:88-95. https://doi.org/10.1016/j.schres.2022.12.028 Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180-190. Kummer KK, Zeidler M, Kalpachidou T, Kress M. Role of IL-6 in the regulation of neuronal development, survival and function. Cytokine. 2021;144:155582. https://doi.org/10.1016/j.cyto.2021.155582 Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1-12. Jacomb I, Stanton C, Vasudevan R, Powell H, O'Donnell M, Lenroot R, Bruggemann J, Balzan R, Galletly C, Liu D, Weickert CS, Weickert TW. C-reactive protein: Higher during acute psychotic episodes and related to cortical thickness in schizophrenia and healthy controls. Front Immunol. 2018;9:2230. Lacy, P. (2017). Eosinophil Cytokines in Allergy. In Cytokine Effector Functions in Tissues. https://doi.org/10.1016/B978-0-12-804214-4.00011-7 Bedrossian, N., Haidar, M., Fares, J., Kobeissy, F. H., & Fares, Y. (2016). Inflammation and elevation of interleukin-12p40 in patients with schizophrenia. Frontiers in Molecular Neuroscience, 9(MAR). https://doi.org/10.3389/fnmol.2016.00016 Kaneko, N., Kurata, M., Yamamoto, T., Morikawa, S., & Masumoto, J. (2019). The role of interleukin-1 in general pathology. In Inflammation and Regeneration (Vol. 39, Issue 1). https://doi.org/10.1186/s41232-019-0101-5 Juncal-Ruiz, M., Riesco-Dávila, L., Ortiz-García de la Foz, V., Martínez-Garcia, O., Ramírez-Bonilla, M., Ocejo-Viñals, J. G., Leza, J. C., López-Hoyos, M., & Crespo-Facorro, B. (2018). Comparison of the anti-inflammatory effect of aripiprazole and risperidone in 75 drug-naïve first episode psychosis individuals: A 3 months randomized study. Schizophrenia Research, 202. https://doi.org/10.1016/j.schres.2018.06.039 Patlola, S. R., Donohoe, G., & McKernan, D. P. (2023). Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis. Journal of Psychiatric Research, 160, 126–136. https://doi.org/10.1016/j.jpsychires.2023.01.042 American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). https://doi.org/10.1176/appi.books.9780890425596. Ter Horst R, Jaeger M, Smeekens SP, Oosting M, Swertz MA, Li Y, Kumar V, Diavatopoulos DA, Jansen AFM, Lemmers H, Toenhake-Dijkstra H, Van Herwaarden AE, Janssen M, Van Der Molen RG, Joosten I, Sweep FCGJ, Smit JW, Netea-Maier RT, Koenders MMJF, et al. Host and environmental factors influencing individual human cytokine responses. Cell. 2016;167(4):1111-1124.e13. Comer AL, Carrier M, Tremblay MÈ, Cruz-Martín A. The inflamed brain in schizophrenia: The convergence of genetic and environmental risk factors that lead to uncontrolled neuroinflammation. Front Cell Neurosci. 2020;14:274. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 07 Dec, 2025 Reviewers agreed at journal 28 Nov, 2025 Reviewers invited by journal 12 Nov, 2025 Editor invited by journal 14 Oct, 2025 Editor assigned by journal 13 Oct, 2025 Submission checks completed at journal 13 Oct, 2025 First submitted to journal 29 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7746547","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549170846,"identity":"19ff3426-2647-4529-a08a-a59a598458d1","order_by":0,"name":"Valentina 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14:02:10","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":147241,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7746547/v1/2f077c86ff4e5a39051fc9ac.html"},{"id":96712751,"identity":"004816bf-29d4-486d-8309-a71757878e70","added_by":"auto","created_at":"2025-11-25 10:16:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":903331,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7746547/v1/f1a1a2ed-4e93-405e-87ee-0ba464d2c539.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cytokine levels in symptomatic patients undergoing anti-psychotic treatment for First Episode Psychosis: a cross-sectional study.","fulltext":[{"header":"Background","content":"\u003cp\u003eCytokines, small proteins involved in cell signalling and inflammation, have been reportedly elevated in the peripheral blood of people with psychosis and schizophrenia since the 1990s. \u003csup\u003e1,2\u003c/sup\u003e. Altered cytokine levels have been reported in people at high risk of psychosis \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, during acute psychotic episodes, and in people with chronic schizophrenia \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. While these changes have been reported across the schizophrenia spectrum, there have been a number of contrasting findings \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003edue in part to the inclusion of schizoaffective disorders, the severity and duration of symptoms, the antipsychotic treatment received, and the influence of co-variants that may influence cytokine expression, such as smoking and body mass index (BMI) \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Differences in blood sampling procedures and analytical methodologies, including the fasting status of participants and the time of day at which samples are taken, may also influence cytokine levels \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Further, the interpretation of results may be difficult due to the complexity of immune response mechanisms; there is an intricate functional correlation between cytokines (10), and individual cytokines are reported to have both pro- and anti-inflammatory properties \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTo assist the interpretation of cytokine changes in psychotic disorders, Maes and colleagues proposed grouping cytokines as belonging to either an Inflammatory Response System (IRS) or a Compensatory Inflammatory Response System (CIRS), that exert pro- or anti-inflammatory functions, respectively. They hypothesised that increased IRS activity promotes an incremental compensatory response from the CIRS, establishing a new set-point balancing the activity of the two systems that can be estimated by calculating the IRS/CIRS ratio\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOther research groups have attempted to characterise cytokine changes in psychosis and schizophrenia as either trait markers, altered irrespective of the stage of the disorder, or as state markers, that accompany acute psychotic symptoms\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Recently, Halstead and colleagues presented a comprehensive network-meta-analysis of reported changes in inflammatory proteins in people with schizophrenia spectrum disorders (SSD), including those with FEP\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. They proposed that cytokines that are consistently elevated across both acute and chronic stages of schizophrenia were potential trait markers for the condition, placing IL-1β, IL-1 receptor antagonist (IL-1RA), soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8, IL-10, and tumour necrosis factor (TNF)-α in this category, while IL-2 and interferon-gamma (IFN-γ) that changed only in symptomatic individuals ‒ were potential state markers.\u003c/p\u003e\u003cp\u003eIn the current study, we examined the inflammatory response in the peripheral blood of people experiencing symptoms during their FEP and receiving antipsychotic treatment from a specialised first-episode clinical service, compared to an age and gender-matched healthy control group. Other variables that might influence cytokine levels were controlled for, and blood samples were taken at the same time each day under the same conditions\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. We analysed a large panel of cytokines (n\u0026thinsp;=\u0026thinsp;16), including most of those suggested in the meta-analysis by Halstead and colleagues. Because our patients with FEP were still symptomatic, we anticipated that both state and trait markers would be altered. We also grouped cytokines based on their IRS and CIRS function in FEP\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. As the study group was receiving antipsychotic treatment, we did not anticipate finding significant alterations in the IRS/CIRS ratio, as an earlier study showed this might be normalised by antipsychotic therapy\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. It has also been shown that antipsychotic agents have a non-specific anti-inflammatory effect on most cytokines\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eRecruitment and Study design\u003c/h2\u003e\u003cp\u003eThis was a cross-sectional study comparing cytokine levels in a group of people experiencing their FEP with an age and gender-matched healthy control group. The study was conducted between February 2018 and June 2020 at the Te Toka Tumai ‒ Hāpai Ora Early Intervention Psychosis service in central Auckland. The study was approved by the Northern A Health and Disabilities Ethics Committees of New Zealand (reference: 16/NTA/120/AM01).\u003c/p\u003e\u003cp\u003eTreating clinicians briefed potential FEP participants about the study and referred those interested to the principal investigator, VM, who was embedded in the service, to proceed with preliminary screening against inclusion/exclusion criteria. Eligible people then reviewed participant information sheets and, if they were willing to proceed, written consent was obtained and an assessment date/time with the VM agreed.\u003c/p\u003e\u003cp\u003eThe inclusion criteria for the FEP group were age between 18 and 35 years, a FEP diagnosis and taking antipsychotic medication for no longer than 12 months. A mentally healthy control group recruited by email advertisement at the University of Auckland was matched by age (+/- 5 years) and gender and body mass index (BMI) to FEP participants. This comprised people with no history of any psychiatric condition or treatment with an antipsychotic or any other psychotropic agent. Exclusion criteria for both groups were a history of head injury, neurological disorders or psychiatric comorbidities; current thoughts of self-harm; current suicidal risk; documented cognitive impairment; diagnoses of a substance-induced psychotic disorder (SIPD), a Brief Psychotic Episode, or a psychotic episode with affective features; current use of medication with immunomodulatory effects (e.g., steroids, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, immune-suppressant therapy); the presence of current fever or within the last week before assessment. The last piece of information was gathered later, during the study assessment, and all the others during the eligibility criteria screening.\u003c/p\u003e\u003cp\u003eFor methodological consistency and preserving the circadian rhythm of cytokine production\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, all assessments were conducted in the morning and consisted of a structured clinical interview conducted by a trained interviewer (VM) and blood sampling between 08:30 and 10:00 a.m.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical interview\u003c/h3\u003e\n\u003cp\u003eDuring the clinical interview, VM gathered information about the severity of symptoms using the Positive and Negative Symptom Scale (PANSS)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e and the duration of treatment under the care of the specialized service, from the time admitted to the service till the date of study assessment. This information was supplemented by consulting the participant\u0026rsquo;s treating team and clinical notes. Substance use was recorded using the Alcohol, Smoking and Substance Involvement Screening test-ASSIST\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e and people who used cannabis occasionally (up to once per week) were included in the study although some in-vivo studies have reported immune-modulatory effects of cannabinoids on cytokines\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Cannabinoids are undetectable in the blood in ~\u0026thinsp;31 hours in occasional users\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. For analysis, we computed the antipsychotic load variable in chlorpromazine equivalents (CPZE) by multiplying the daily antipsychotic dosage in CPZE by the number of days the person had been receiving antipsychotics from the initiation of treatment at the clinical service until the date of study clinical assessment. Dosages equivalent to 100 mg/day of CPZE were estimated at 1 mg/day for risperidone, 5 mg/day for olanzapine, 7.5 mg/day for aripiprazole and 75 mg/day for quetiapine\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. This information was retrieved from the participants' clinical notes.\u003c/p\u003e\n\u003ch3\u003eBlood sampling\u003c/h3\u003e\n\u003cp\u003eParticipants refrained from alcohol and tobacco use for 24 hours, and from cannabis use for 48 hours before blood sampling, to ensure sufficient cannabinoid metabolism \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. They also fasted on the morning of the assessment. All blood samples were drawn between 10:00 and 10:30 a.m. by VM, a certified phlebotomist. Within an hour of collecting, the blood sample was centrifuged at 1600 rpm for 10 minutes at room temperature. Following centrifugation, the liquid component (serum) was immediately transferred to a clean polypropylene tube 0.5 mL aliquot using a Pasteur pipette and stored in a minus 80-degree Celsius freezer (29) in the premises of the Research Clinical Centre (RCC) at the University of Auckland. All blood samples were shipped frozen to iPath laboratories in Melbourne in thermal parcels with dry ice packs and kept at minus 80\u0026deg; C until analyzed in two batches within a year of collection. Dispatch to iPath laboratories was organized in collaboration with CompoundLabs, an Auckland-based company (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://compoundlabs.co.nz\u003c/span\u003e\u003cspan address=\"https://compoundlabs.co.nz\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Cytokine analyses were completed using the Luminex XMAP Assay, a multiplex assay technology that permits the simultaneous evaluation of numerous cytokines in several types of biological fluid \u003csup\u003e(30)\u003c/sup\u003e. This technology is derived from the classic Enzyme-linked immunosorbent assay (ELISA) technology (31). A panel of 16 cytokines was analyzed (IL-1, IL-2, IL-6, IL-12, IL-17, IL-8, TNF-α, TNF-β, INF-γ, GM-CSF, IL-4, IL-13, TGF-β, IL-10, IL-5, IL-7).\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics were completed for demographic and clinical variables, and the results of cytokine multi-assay analyses. As the observed cytokine parameters did not meet the assumptions of normality and homogeneity, the values were logarithmically transformed, as recommended for immune parameters such as cytokines \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Once transformed, all cytokine variables met the assumption of linearity. To standardize our scores and facilitate cytokine comparisons, we computed z-scores of all cytokine values \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. We also computed a total score for the IRS and CIRS cytokine groups following Maes and Carvalho\u0026rsquo;s recommendations (14): IRS group value was computed as the sum of the z score of the logarithm of IL.1, IL.2, IL.6, IL.8, IL.12, IL.17, TNF-α, TNF-β, INF-γ, GM-CSF; and CIRS group as the sum of z scores of the logarithm of IL.4, IL.5, IL.7, IL.10, IL.13, TGF- β. To determine the influence of diagnosis (FEP) and demographic variables (age, gender, and BMI) on each cytokine in our sample, the best-suited univariate or multiple regression model based on the minimum Akaike Information Criterion (AIC) value for each cytokine (including all the interaction terms) was estimated using the method of Burnham et al. 1998 \u003csup\u003e34\u003c/sup\u003e. To investigate the IRS/CIRS balance in our FEP sample, as proposed by Maes and colleagues \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, the IRS/CIRS ratio was computed as the z score of the IRS group minus the z scores of the CIRS group value [z (IRS group value) \u0026ndash; z (CIRS group value)]. A univariate regression linear model was then used to investigate the differences between the IRS cytokines the CIRS cytokines, and the IRS/CIRS ratio, in FEP and HC. The Pearson\u0026rsquo;s correlation coefficient was used to study the relationship between each cytokine (logarithmic value) and the clinical variables\u0026rsquo; severity of symptoms (measured by PANSS score) and antipsychotic load. Probability (p) values were calculated based on two-tailed analyses. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered indicative of statistical significance. All statistical analyses were run using R Analysis conducted using R version 4.3. R Core Team (2023), the lmerTest package and package DHARMa \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eRecruitment\u003c/h2\u003e\u003cp\u003eClinicians on the FEP unit referred 46 people for potential inclusion to the study. Of these, 26 were excluded for the following reasons: one had a neurological disorder, two were at current suicidal risk, three had psychiatric co-morbidities, four experienced a worsening of symptoms requiring urgent intervention such as hospital admission and 16 were lost to follow up. Twenty patients with FEP were recruited and completed the assessments. Twenty HCs were matched per age and gender and completed the assessment.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical and demographic variables\u003c/h3\u003e\n\u003cp\u003eEach group (FEP and HC) contained 11 males and 9 females who did not significantly differ in age (FEP range 19\u0026ndash;31 mean\u0026thinsp;=\u0026thinsp;22.6, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.424; HC 19\u0026ndash;30 \u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;22.8, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.94) and BMI (FEP \u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;25.64, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.96; HC \u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24.30, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.46). PANSS total scores ranged between 61 and 89 (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;76.7, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.26), positive subscale scores from 19 to 34 (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24.65, \u003cem\u003eSD\u003c/em\u003e 4.01), and the negative scale from 19 to 34 (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;26.45, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.26), showing that FEP participants were moderately symptomatic (37). All participants had been receiving antipsychotic medication in the range of 1 to 12 months (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.55, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.76). Dosage in CPZ-equivalents ranged between 100 to 250 mg per day, with most participants (n\u0026thinsp;=\u0026thinsp;10) on 100 mg; total amount of antipsychotic load received ranged between 3040 and 68400 mg. (\u003cem\u003eM\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24586, \u003cem\u003eSD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.19729.63 mg).\u003c/p\u003e\n\u003ch3\u003eCytokines values results\u003c/h3\u003e\n\u003cp\u003eAll cytokines' panels were successfully assayed and observed values per cytokines (in pg/ml) are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMean and (Standard deviation), median and (Interquartile range) for FEP and HC observed cytokines values.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eFEP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eHC\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emean (sd)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emedian (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emean (sd)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003emedian (IQR)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.6 (0.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.3 (0.2, 0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.41 (0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.5 (1.2, 1.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.16 (4.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.5 (4.8, 13.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.68 (0.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.6 (2.2, 2.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33.1 (60.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.6 (3.5, 23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.76 (5.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.6 (3.1, 14.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.53 (5.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.3 (2.5, 5.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10.95 (9.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10.4 (5, 12.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.71 (1.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.6 (1, 2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.61 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7.5 (5.1, 8.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.18 (10.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.1 (0.7, 13.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.36 (1.95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.9 (2.7, 4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTNF.α\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.23 (4.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.2 (3.4, 11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.49 (4.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6.2 (4.3, 10.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTNF.β\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e103.33 (37.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.8 (71.2, 147.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e85.57 (22.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e85 (68.5, 96)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINF.γ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.52 (13.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (3.2, 15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.61 (4.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.1 (4.5, 12.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGM.CSF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e51.4 (23.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.5 (37, 54.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e41.56 (13.43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e39 (36.5, 49)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15.29 (34.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.4 (2.8, 9.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16.94 (11.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15.5 (12.5, 20.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.06 (19.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.9 (1.4, 16.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.13 (2.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.9 (3.6, 6.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.52 (5.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.3 (4.4, 6.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.8 (3.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.6 (3.1, 7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.42 (4.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.8 (0.6, 5.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.71 (5.43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.7 (1.3, 4.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.63 (4.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.5 (1, 3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.36 (3.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.9 (1.9, 7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTGF.β\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48.8 (8.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.5 (42, 57.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e50.75 (5.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50.5 (46, 56.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. \u003cem\u003eDescriptive statistics for cytokine concentrations in individuals with first-episode psychosis (FEP) and healthy controls (HC). For each cytokine, the mean and standard deviation (in parentheses), as well as the median and interquartile range (IQR), are reported. Cytokine levels are expressed in pg/mL. This table includes all 16 cytokines measured in the study.\u003c/em\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eDifferences between FEP and HC cytokines\u0026rsquo; levels\u003c/h2\u003e\u003cp\u003eAll regression models included the variable Diagnosis. Based on lowest AIC value criteria, gender was included in the model for IL-1, IL-2, and IL-6; age was included per IL-4; and BMI for TNF-α.\u003c/p\u003e\u003cp\u003eThe ANOVA analysis showed significant results for six cytokines (reported in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). IRS cytokines IL-2 and IL-6 were significantly higher in those with a FEP compared to the HC group for diagnosis, while IRS cytokines IL-1, IL-8 and IL-12 and CIRS IL-4 were significantly reduced.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eDifferences in IRS, CIRS group and IRS/CIRS ratio in medicated FEP\u003c/h2\u003e\u003cp\u003eResults of a one-way analysis of variance (ANOVA) did not show any significant difference between FEP and HC in the IRS group [F (1\u0026ndash;38)\u0026thinsp;=\u0026thinsp;9.73 p\u0026thinsp;=\u0026thinsp;0.15], CIRS group [F (1\u0026ndash;38)\u0026thinsp;=\u0026thinsp;9.73 p\u0026thinsp;=\u0026thinsp;0.15] and IRS/CIRS ratio [F (1\u0026ndash;38)\u0026thinsp;=\u0026thinsp;9.73 p\u0026thinsp;=\u0026thinsp;0.15]. That is, in our medicated FEP sample, there is no predominant activation of either IRS or CIRS.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eResults of One-Way Analysis of Variance (ANOVA) (Type II) with p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMarker\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSource of Variation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSum of Squares\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePr(\u0026gt;\u0026thinsp;F)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSignificance\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39.7%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e16.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60.6%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e48.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis: Gender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24.8%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis: Gender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16.4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e54.7%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e45.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e: \u003cem\u003eType II ANOVA results for the subset of cytokines that showed statistically significant associations (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) from a the panel of 16 tested. Best subset univariate multiple regression linear models were used to evaluate the effects of diagnosis, gender, age, BMI and their interaction (where applicable) on cytokine expression levels. For each significant cytokine, the table reports the source of variation, sum of squares, proportion of variance explained (R\u0026sup2;), F-statistic, and p-value. Significance codes: *** p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, ** p\u0026thinsp;\u0026lt;\u0026thinsp;0.005, * p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Only cytokines with at least one significant predictor are shown.\u003c/em\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eCorrelation between Cytokine levels, Severity of symptoms, and Antipsychotic load\u003c/h2\u003e\u003cp\u003eA Pearson\u0026rsquo;s correlation coefficient was computed to assess the linear relationship between each Cytokine value and clinical variables. No correlation was found between PANSS total score, negative and positive and the level of cytokines. However, within the 95% confidence interval of our FEP sample there were significant negative correlations between antipsychotic medication load and the cytokines IL-2, IL-5, IL-6, IL-8, IL-10, and IL-17, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. This shows that among those cytokines altered in FEP, lower levels of IL-2 and IL-6 and IL-8 correlate with a higher CPZE amount of antipsychotic taken.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSignificant correlations between cytokine values and antipsychotic load\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePearson\u0026rsquo;s Correlation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-values\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e95%Confidence intervals\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.491\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.762\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.049\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.470\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.750\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.022\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.453\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.741\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.450\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.046\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.739\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.445\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.736\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.022\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.761\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. \u003cem\u003eSignificant Pearson\u0026rsquo;s correlations between cytokine levels and antipsychotic load in individuals with first-episode psychosis (FEP). For each cytokine, the Pearson correlation coefficient (r), corresponding p-value, and 95% confidence interval for the correlation are reported. Negative correlations indicate that higher antipsychotic load is associated with lower cytokine levels. Only cytokines with statistically significant correlations (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) are shown.\u003c/em\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study was designed to examine changes in cytokine levels in people experiencing their FEP and receiving standard treatment from a specialised service, controlling for variables known to have independent effects on cytokines. We found that IL-2 and IL-6 were elevated compared to the age and gender matched healthy control group, while others, IL-1, IL-4, IL-8 and IL-12, were decreased. Some of these results were expected. Although individual cytokine levels differed between the FEP and HC groups, the ratio of pro- to anti-inflammatory cytokines (IRS/CRS) was not different, as expected, in a medicated sample (38). Nevertheless, cytokines previously proposed as state (IL-6) and trait (IL-2) markers for psychosis were changed in our FEP participants, as would be expected in those currently experiencing psychotic symptoms \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. This study's main finding supports the hypothesis that IL-2 and IL-6 are state (IL-2) and trait (IL-6) markers of psychosis. Both IL-2 and IL-6 are IRS cytokines and promote systemic inflammation. Moreover, both cytokines contribute to the brain changes linked to psychosis \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. While IL-2 is responsible for the differentiation of T-helper cells and the consequent production of IFN-y, IL-4, IL-6 and IL-12 (46). IL-6 increases neuroinflammation, thereby disrupting the integrity of the blood-brain-barrier and activating pro-inflammatory cascades in the brain \u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. IL-6 also increases neuroinflammation by disrupting the integrity of the blood-brain-barrier and activating pro-inflammatory cascades in the brain\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. Indeed, it has been hypothesized that inflammatory markers are elevated in a subgroup of patients with FEP \u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSome results were unexpected. IRS cytokines (IL-1 IL-12) were strongly reduced below healthy controls, while expected to be elevated in our group \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. Moreover, IRS cytokines (TNF-α and IFN-γ) were only slightly elevated in our group, while being largely reported elevated in psychosis. This might be the result of immunomodulating effects by the antipsychotics \u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e, although we found no correlation between cytokines and antipsychotic medication. Nevertheless, an individual variation in susceptibility to the anti-inflammatory properties of antipsychotics must be considered \u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTaken together, our findings are suggestive of a dysregulated Th1 response (with high IL-2, elevated IFN-γ and, low IL.12), reporting cytokine mixed features of acuity (elevation of IL-2 and IL-6), and chronic phase (reduction of IL-1 and IL-12) of FEP \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Clinically, this could be justified by the presenting clinical status of participants included in the study, that being mod. Indeed, all people with FEP had overcome their acute psychosis and were presenting with persistent symptoms despite treatment, fitting the criteria for the diagnosis of schizophreniform or schizophrenia disorders \u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Overall, this highlights the dynamic changes in cytokine profiles in medicated people with FEP.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and limitations\u003c/h2\u003e\u003cp\u003eThe main limitations of this study are the small sample size cross-sectional design. Additionally, our recruitment process could be biased, as the treating clinician referred potential participants based on whether they could engage with the assessment process.\u003c/p\u003e\u003cp\u003eStrengths of this study include control of environmental and host-related mediators of inflammation known to affect cytokine levels. We screened participants for factors with immunomodulatory effects (medications, fever, smoking, cannabis, alcohol) and included age, gender, and BMI in our analysis \u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. Moreover, we targeted a well-described population of clients with FEP undergoing antipsychotic treatment, excluding participants with comorbidities such as affective psychosis. A single medically trained investigator (VM) undertook recruitment and data collection and interacted with the clinical team at the specialised psychosis service where recruitment was conducted. Lastly, we applied statistical methodology that aimed to minimise the impact of individual variability of immune markers and increase comparability of the dataset \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, to increase the reproducibility and generalizability of our findings.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions and Future directions","content":"\u003cp\u003eOur study was conducted with a well-controlled, moderately symptomatic group of people with FEP taking antipsychotic treatment. We found that the IRS/CIRS ratio was not altered. IL-2 and IL-6 levels remained elevated despite the immunomodulatory action of antipsychotic agents, confirming that they might act as state (IL-2) and trait (IL-6) markers for FEP. In line with current theories, we conclude that differences in cytokine levels in our FEP group might be indicative of an altered immune response that results in a systemic low-grade inflammation, which contributes to psychotic symptoms.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eAIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eAkaike Information Criterion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eBody Mass Index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCIRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eCompensatory Inflammatory Response System\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCPZE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eChlorpromazine Equivalents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eELISA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eEnzyme-Linked Immunosorbent Assay\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eFEP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eFirst Episode Psychosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eGM-CSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eGranulocyte-Macrophage Colony-Stimulating Factor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eINF\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eInterferon\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIL(s)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eInterleukin(s)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eIRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eInflammatory Response System\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eNSAIDs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003enon-steroidal anti-inflammatory drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePANSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eThe Positive and Negative Syndrome Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eRCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eResearch Clinical Centre\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eStandard Deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eSIPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003esubstance-induced psychotic disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eTNF\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 516px;\"\u003e\n \u003cp\u003eTumor Necrosis Factor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Northern A Health and Disabilities Ethics Committees of New Zealand (reference: 16/NTA/120/AM01). Informed consent to participate in the study was obtained from all participants. Research has been conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication was obtained from all participants of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article. The dataset supporting this study is available in The University of Auckland repository (DOI: 10.17608/k6.auckland.30239557).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests for the publication of this article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was entirely funded by the University of Auckland, through the funds allocated for VM\u0026rsquo;s PhD programme\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026quot; VM gathered study data, participated to data analysis, interpreted result data and wrote up the article. RK and FS supervised all study phases and were major contributors in writing the manuscript. BVdW advised and ran the statistical analysis for the study. BR and IS contributed to the writing of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Te Toka Tumai ‒ Hāpai Ora Early Intervention Psychosis service and its clinicians for supporting and collaborating with VM during the recruitment process.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGanguli R, Yang Z, Shurin G, Chengappa KN, Brar JS, Gubbi AV, Rabin BS. Serum interleukin-6 concentration in schizophrenia: Elevation associated with duration of illness. Psychiatry Res. 1994;51:1\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eMaes M, Meltzer HY, Bosmans E. Immune-inflammatory markers in schizophrenia: Comparison to normal controls and effects of clozapine. Acta Psychiatr Scand. 1994;89:346\u0026ndash;351.\u003c/li\u003e\n\u003cli\u003ePark S, Miller BJ. Meta-analysis of cytokine and C-reactive protein levels in high-risk psychosis. Schizophr Res. 2020;226:5-12.\u003c/li\u003e\n\u003cli\u003eMomtazmanesh S, Zare-Shahabadi A, Rezaei N. Cytokine alterations in schizophrenia: An updated review. Front Psychiatry. 2019;10:892.\u003c/li\u003e\n\u003cli\u003eFrydecka D, Krzystek-Korpacka M, Lubeiro A, Stramecki F, Stanczykiewicz B, Beszłej JA, et al. Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study. Brain Behav Immun. 2018;71:28-36.\u003c/li\u003e\n\u003cli\u003eMarcinowicz P, Więdłocha M, Zborowska N, Dębowska W, Podwalski P, Misiak B, Tyburski E, Szulc A. A meta-analysis of the influence of antipsychotics on cytokine levels in first episode psychosis. J Clin Med. 2021;10(11):2488.\u003c/li\u003e\n\u003cli\u003eFeigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev. 2014;38:72-93.\u003c/li\u003e\n\u003cli\u003ePatlola SR, Donohoe G, McKernan DP. Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis. J Psychiatr Res. 2023;160:126-136.\u003c/li\u003e\n\u003cli\u003eCohen L, Keegan A, Melanson SE, Walt DR. Impact of clinical sample handling and processing on ultra-low level measurements of plasma cytokines. Clin Biochem. 2019;65:38-44.\u003c/li\u003e\n\u003cli\u003eErmakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune system abnormalities in schizophrenia: An integrative view and translational perspectives. Front Psychiatry. 2022 Apr 25;13:880568.\u003c/li\u003e\n\u003cli\u003eTourjman V, Kouassi \u0026Eacute;, Kou\u0026eacute; M-\u0026Egrave;, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, Potvin S. Antipsychotics\u0026rsquo; effects on blood levels of cytokines in schizophrenia: A meta-analysis. Schizophr Res. 2013;151:43-47.\u003c/li\u003e\n\u003cli\u003eKleiner G, Marcuzzi A, Zanin V, Monasta L, Zauli G. Cytokine levels in the serum of healthy subjects. Mediators Inflamm. 2013;2013:434010.\u003c/li\u003e\n\u003cli\u003eBecher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2017;17(1):49-59.\u003c/li\u003e\n\u003cli\u003eMaes M, Carvalho AF. The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol Neurobiol. 2018;55(12):8885-8903.\u003c/li\u003e\n\u003cli\u003eMiller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry. 2011;70:663-671.\u003c/li\u003e\n\u003cli\u003eCapuzzi E, Bartoli F, Crocamo C, Clerici M, Carr\u0026agrave; G. Acute variations of cytokine levels after antipsychotic treatment in drug-na\u0026iuml;ve subjects with a first-episode psychosis: A meta-analysis. Neurosci Biobehav Rev. 2017 Jun;77:122-128.\u003c/li\u003e\n\u003cli\u003eHalstead S, Siskind D, Amft M, Wagner E, Yakimov V, Shih-Jung Liu Z, Walder K, Warren N. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry. 2023 Apr;10(4):260-271. doi: 10.1016/S2215-0366(23)00025-1.\u003c/li\u003e\n\u003cli\u003eRoomruangwong C, Noto C, Kanchanatawan B, Anderson G, Kubera M, Carvalho AF, Maes M. The role of aberrations in the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS) in different phenotypes of schizophrenia: The IRS-CIRS theory of schizophrenia. Mol Neurobiol. 2020;57:778-797.\u003c/li\u003e\n\u003cli\u003eNoto MN, Maes M, Nunes SOV, Ota VK, Rossaneis AC, Verri WA Jr, Cordeiro Q, Belangero SI, Gadelha A, Bressan RA, et al. Activation of the immune-inflammatory response system and the compensatory immune-regulatory system in antipsychotic naive first episode psychosis. Eur Neuropsychopharmacol. 2019;29:416-431.\u003c/li\u003e\n\u003cli\u003eRomeo B, Brunet-Lecomte M, Martelli C, Benyamina A. Kinetics of cytokine levels during antipsychotic treatment in schizophrenia: A meta-analysis. Int J Neuropsychopharmacol. 2018;21(9):828-836.\u003c/li\u003e\n\u003cli\u003eNakao A. Temporal regulation of cytokines by the circadian clock. J Immunol Res. 2014;2014:614529.\u003c/li\u003e\n\u003cli\u003eShimba A, Ikuta K. Glucocorticoids regulate circadian rhythm of innate and adaptive immunity. Front Immunol. 2020;11:2143.\u003c/li\u003e\n\u003cli\u003eKay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-276.\u003c/li\u003e\n\u003cli\u003eWHO ASSIST Working Group. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST): Development, reliability, and feasibility. Addiction. 2002;97(9):1183-1194.\u003c/li\u003e\n\u003cli\u003eHenshaw FR, Dewsbury LS, Lim CK, Steiner GZ. The Effects of Cannabinoids on Pro- and Anti-Inflammatory Cytokines: A Systematic Review of In Vivo Studies. Cannabis Cannabinoid Res. 2021 Jun;6(3):177-195.\u003c/li\u003e\n\u003cli\u003eLucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84:2477-2482.\u003c/li\u003e\n\u003cli\u003eWoods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003;64(6):663-667.\u003c/li\u003e\n\u003cli\u003eVerstraete A. G. (2004). Detection times of drugs of abuse in blood, urine, and oral fluid. Therapeutic drug monitoring, 26(2), 200\u0026ndash;205.\u003c/li\u003e\n\u003cli\u003eDe Jager, W., Bourcier, K., Rijkers, G. T., Prakken, B. J., \u0026amp; Seyfert-Margolis, V. (2009). Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC Immunology, 10(1), 52.\u003c/li\u003e\n\u003cli\u003eLombardelli L, Logiodice F, Kullolli O, Piccinni M-P. Evaluation of secreted cytokines by multiplex bead-based assay (X MAP technology, Luminex). In: Methods in Molecular Biology (pp. 121-130). Methods Mol Biol. 2021; Vol. 2359.\u003c/li\u003e\n\u003cli\u003eSakamoto, S., Putalun, W., Vimolmangkang, S., Phoolcharoen, W., Shoyama, Y., Tanaka, H., \u0026amp; Morimoto, S. (2018). Enzyme-linked immunosorbent assay for the quantitative/qualitative analysis of plant secondary metabolites. Journal of natural medicines, 72(1), 32\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eGenser, B., Cooper, P.J., Yazdanbakhsh, M. et al. A guide to modern statistical analysis of immunological data. BMC Immunol 8, 27 (2007).\u003c/li\u003e\n\u003cli\u003eDavis JM 3rd, Knutson KL, Strausbauch MA, Crowson CS, Therneau TM, Wettstein PJ, Matteson EL, Gabriel SE. Analysis of complex biomarkers for human immune-mediated disorders based on cytokine responsiveness of peripheral blood cells. J Immunol. 2010 Jun 15;184(12):7297-7304.\u003c/li\u003e\n\u003cli\u003eBurnham KP, Anderson DR. Model Selection and Inference - Practical Use of the Information-Theoretic Approach. Springer New York; 1998.\u003c/li\u003e\n\u003cli\u003eKuznetsova A, Brockhoff PB, Christensen RHB (2017). \u0026quot;lmerTest Package: Tests in Linear Mixed Effects Models.\u0026quot; Journal of Statistical Software, 82(13), 1-26. doi:10.18637/jss.v082.i13.\u003c/li\u003e\n\u003cli\u003eHartig F (2022). DHARMa: Residual Diagnostics for Hierarchical (Multi-Level / Mixed) Regression Models. R package version 0.4.6.\u003c/li\u003e\n\u003cli\u003eLeucht, S., Kane, J. M., Kissling, W., Hamann, J., Etschel, E., \u0026amp; Engel, R. R. (2005). What does the PANSS mean?. Schizophrenia research, 79(2-3), 231-238.\u003c/li\u003e\n\u003cli\u003eGoldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder, and depression. Mol Psychiatry. 2016;21:1696-1709.\u003c/li\u003e\n\u003cli\u003eCapuzzi E, Bartoli F, Crocamo C, Clerici M, Carr\u0026agrave; G. Acute variations of cytokine levels after antipsychotic treatment in drug-na\u0026iuml;ve subjects with a first-episode psychosis: A meta-analysis. Neurosci Biobehav Rev. 2017 Jun;77:122-128. \u003c/li\u003e\n\u003cli\u003eNoto C, Ota VK, Gadelha A, Noto MN, Barbosa DS, Bonif\u0026aacute;cio KL, Nunes SO, Cordeiro Q, Belangero S, Bressan R, et al. Oxidative stress in drug na\u0026iuml;ve first episode psychosis and antioxidant effects of risperidone. J Psychiatr Res. 2015;68:210-216.\u003c/li\u003e\n\u003cli\u003eJuncal-Ruiz M, Riesco-D\u0026aacute;vila L, Ortiz-Garc\u0026iacute;a de la Foz V, Mart\u0026iacute;nez-Garcia O, Ram\u0026iacute;rez-Bonilla M, Ocejo-Vi\u0026ntilde;als JG, Leza JC, L\u0026oacute;pez-Hoyos M, Crespo-Facorro B. Comparison of the anti-inflammatory effect of aripiprazole and risperidone in 75 drug-na\u0026iuml;ve first episode psychosis individuals: A 3 months randomized study. Schizophr Res. 2018;202:226-233.\u003c/li\u003e\n\u003cli\u003ePatel S, Keating BA, Dale RC. Anti-inflammatory properties of commonly used psychiatric drugs. Front Neurosci. 2023 Jan 10;16:1039379.\u003c/li\u003e\n\u003cli\u003eDoorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: A PET study. J Nucl Med. 2009;50:1801-1807.\u003c/li\u003e\n\u003cli\u003eLevitt P, Veenstra-VanderWeele J. Neurodevelopment and the origins of brain disorders. Neuropsychopharmacology. 2015;40(1):1-3.\u003c/li\u003e\n\u003cli\u003eMiller BJ, Lemos H, Schooler NR, Goff DC, Kopelowicz A, Lauriello J, Manschreck T, Mendelowitz A, Miller DD, Severe JB, Wilson DR, Ames D, Bustillo J, Kane JM, Rapaport MH, Buckley PF. Longitudinal study of inflammation and relapse in schizophrenia. Schizophrenia research. 2023;252:88-95. https://doi.org/10.1016/j.schres.2022.12.028\u003c/li\u003e\n\u003cli\u003eBoyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180-190.\u003c/li\u003e\n\u003cli\u003eKummer KK, Zeidler M, Kalpachidou T, Kress M. Role of IL-6 in the regulation of neuronal development, survival and function. Cytokine. 2021;144:155582. https://doi.org/10.1016/j.cyto.2021.155582\u003c/li\u003e\n\u003cli\u003eVaratharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1-12.\u003c/li\u003e\n\u003cli\u003eJacomb I, Stanton C, Vasudevan R, Powell H, O\u0026apos;Donnell M, Lenroot R, Bruggemann J, Balzan R, Galletly C, Liu D, Weickert CS, Weickert TW. C-reactive protein: Higher during acute psychotic episodes and related to cortical thickness in schizophrenia and healthy controls. Front Immunol. 2018;9:2230.\u003c/li\u003e\n\u003cli\u003eLacy, P. (2017). Eosinophil Cytokines in Allergy. In Cytokine Effector Functions in Tissues. https://doi.org/10.1016/B978-0-12-804214-4.00011-7\u003c/li\u003e\n\u003cli\u003eBedrossian, N., Haidar, M., Fares, J., Kobeissy, F. H., \u0026amp; Fares, Y. (2016). Inflammation and elevation of interleukin-12p40 in patients with schizophrenia. Frontiers in Molecular Neuroscience, 9(MAR). https://doi.org/10.3389/fnmol.2016.00016\u003c/li\u003e\n\u003cli\u003eKaneko, N., Kurata, M., Yamamoto, T., Morikawa, S., \u0026amp; Masumoto, J. (2019). The role of interleukin-1 in general pathology. In Inflammation and Regeneration (Vol. 39, Issue 1). https://doi.org/10.1186/s41232-019-0101-5\u003c/li\u003e\n\u003cli\u003eJuncal-Ruiz, M., Riesco-D\u0026aacute;vila, L., Ortiz-Garc\u0026iacute;a de la Foz, V., Mart\u0026iacute;nez-Garcia, O., Ram\u0026iacute;rez-Bonilla, M., Ocejo-Vi\u0026ntilde;als, J. G., Leza, J. C., L\u0026oacute;pez-Hoyos, M., \u0026amp; Crespo-Facorro, B. (2018). Comparison of the anti-inflammatory effect of aripiprazole and risperidone in 75 drug-na\u0026iuml;ve first episode psychosis individuals: A 3 months randomized study. Schizophrenia Research, 202. https://doi.org/10.1016/j.schres.2018.06.039\u003c/li\u003e\n\u003cli\u003ePatlola, S. R., Donohoe, G., \u0026amp; McKernan, D. P. (2023). Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis. Journal of Psychiatric Research, 160, 126\u0026ndash;136. https://doi.org/10.1016/j.jpsychires.2023.01.042\u003c/li\u003e\n\u003cli\u003eAmerican Psychiatric Association. (2013). \u003cem\u003eDiagnostic and statistical manual of mental disorders\u003c/em\u003e (5th ed.). https://doi.org/10.1176/appi.books.9780890425596.\u003c/li\u003e\n\u003cli\u003eTer Horst R, Jaeger M, Smeekens SP, Oosting M, Swertz MA, Li Y, Kumar V, Diavatopoulos DA, Jansen AFM, Lemmers H, Toenhake-Dijkstra H, Van Herwaarden AE, Janssen M, Van Der Molen RG, Joosten I, Sweep FCGJ, Smit JW, Netea-Maier RT, Koenders MMJF, et al. Host and environmental factors influencing individual human cytokine responses. Cell. 2016;167(4):1111-1124.e13.\u003c/li\u003e\n\u003cli\u003eComer AL, Carrier M, Tremblay M\u0026Egrave;, Cruz-Mart\u0026iacute;n A. The inflamed brain in schizophrenia: The convergence of genetic and environmental risk factors that lead to uncontrolled neuroinflammation. Front Cell Neurosci. 2020;14:274.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"psychosis, first episode psychosis, inflammatory response, cytokines, IRS/CIRS activation","lastPublishedDoi":"10.21203/rs.3.rs-7746547/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7746547/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCytokines in first-episode psychosis (FEP) appear to be activated as part of an Inflammatory Response System (IRS) or a Compensatory Inflammatory Response System (CIRS) and have been proposed as clinical (state and trait) markers of psychosis. Antipsychotic medication normalizes the IRS/CIRS ratio despite a predominant activation of the IRS. The current study examined blood levels of IRS/CIRS cytokines proposed as clinical markers in symptomatic medicated patients with FEP. We screened all co-diagnoses and immunomodulating factors that have been linked to cytokine changes to increase the accuracy of findings.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe compared cytokines (n\u0026thinsp;=\u0026thinsp;16) levels in the blood serum of patients with FEP (n\u0026thinsp;=\u0026thinsp;20) recruited from a specialized FEP clinical service with a matched (age, gender, body mass index) group of healthy control subjects (HC)( n\u0026thinsp;=\u0026thinsp;20). We screened for tobacco smoking, cannabis use, medications, and the absence of fever. Best-fitting regression models were used to identify differences in FEP vs HCs per diagnosis and additional variables of age, gender, and BMI. We correlated cytokine levels to Positive and Negative Symptoms Scale (PANSS) scores and antipsychotic load, recorded as chlorpromazine equivalents.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eWe found elevated levels of IRS (IL-2 and IL-6), and reduced levels of IRS (IL-1, IL-8, IL-12), and CIRS (IL-4) in FEP vs HC. No significant differences in the IRS/CIRS ratio or a correlation between cytokine levels and PANSS scores were found. Lower levels of IL-2, IL-6 and IL-8 correlated to higher amounts of antipsychotics.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eOur study on well-controlled moderately symptomatic patients with FEP taking antipsychotic treatment found that the IRS/CIRS ratio was not altered, while some alterations in cytokine levels were found. IL-2 and IL-6 remain elevated despite the immune-modulatory action of the antipsychotic agents; we suggest they could be used as screening tools for either trait (IL-6) and/or state (IL-2) markers of psychosis, in combination with C-reactive protein, to identify people with FEP that could potentially benefit from an adjuvant anti-inflammatory therapy alongside antipsychotics.\u003c/p\u003e\u003ch2\u003eClinical trial registration number:\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e","manuscriptTitle":"Cytokine levels in symptomatic patients undergoing anti-psychotic treatment for First Episode Psychosis: a cross-sectional study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 14:02:05","doi":"10.21203/rs.3.rs-7746547/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-12-07T10:01:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70572757869415278230561385469520562509","date":"2025-11-28T07:25:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-12T14:34:13+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-14T14:37:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-13T10:05:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-13T10:03:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2025-09-30T03:00:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1c00a897-fa7b-42ff-b810-5b6ce76b18ad","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T14:02:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-24 14:02:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7746547","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7746547","identity":"rs-7746547","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}