Hrev_master Healthcare in Low-resource Settings 2025; volume 13:12723 The effectiveness of risperidone on PANSS score and IL-6 in confirmed COVID-19 schizophrenic patients Sonny Teddy Lisal,1 Hawaidah,1 Dessy Natalia,1 Arifin Seweng,2 Yuyun Widaningsih,3 Erlyn Limoa,1 Saidah Syamsuddin1 1Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar; 2Department of Biostatistics, Faculty of Public Health, Universitas Hasanuddin, Makassar; 3Department of Clinical Pathology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia Abstract The study aimed to determine the efficacy of risperidone on PANSS scores and Interleukin 6 (IL-6) levels in schizophrenia patients with confirmed COVID-19. The study type was analytical observational, with a prospective cohort design. The subjects included inpatient Schizophrenia patients with and without COVID-19, mild-moderate and asymptomatic COVID-19, and schizophrenic patients without COVID-19 who were hospitalized and met the inclusion and exclusion criteria, for a total of 22 sub- jects in each group. The Positive and Negative Syndrome Scale (PANSS) and Elisa Interleukin 6 (IL-6) serum were sampled con- secutively for this study. In the positive covid-19 group, the Mean IL-6 Post was significantly lower than Pre (23.0 vs. 26.1, p<0.001), while in the control group, the Mean IL-6 Post (four weeks) was significantly lower than Pre (baseline), with 19.3 vs. 21.0 (p<0.001). Serum IL-6 levels appeared to be an effective prognostic biomarker in COVID-19 patients. The 35 pg/mL cut- off point could distinguish mild-moderate patients from more severe ones. We discovered that schizophrenia patients with veri- fied positive COVID-19 received COVID-19 therapy in the form of a combination of antipsychotic and antivirals had IL-6 levels lower than 35 pg/mL, indicating the role of antipsychotic (risperi- done) and antiviral in reducing IL-6 levels. Introduction The COVID-19 outbreak caused by the severe acute respira- tory syndrome coronavirus 2 (SARS-Cov-2) was detected for the first time in Wuhan, China, spread throughout the country since late December 2019, and has attracted significant attention from all over the world. The first case of COVID-19 in Indonesia was reported on March 2, 2020, with as many as 2 cases, and until now, the number of cases has been increasing. It was reported that until March 23, 2021, in 34 provinces, there were 1,505,775 pos- itive confirmed cases, 142,695 recovered cases, and 40,754 people died from this disease. South Sulawesi was ranked fifth in the number of positive confirmed cases, with 39,703 (4.5%), recov- ered 33,156 cases (83.5%), and 675 cases died (1.7%).1 The most common clinical manifestations of COVID-19 infection are cough and fever; about 8-19% progress to Acute Respiratory Distress Syndrome (ARDS), especially in the elderly and patients with multiple comorbidities. There have also been reports of lymphopenia, elevated C-Reactive Protein (CRP), proinflammatory cytokines, ferritin, and D-dimer, and histopatho- logical findings show an infiltrate of monocytes, macrophages, lymphocytes, vasculitis, and hypercoagulability in the lung tissue. Diffuse alveolar damage, focal hyperplasia of pneumocytes with infiltration of proinflammatory cells, and intravascular thrombosis lead to impaired pulmonary alveolar gas exchange.2 Coronavirus particles can be found in macrophages, but it is still unknown whether it is due to direct infection by the virus or the phagocytosis process.3 This will activate the NLRP3 inflam- masome receptor on monocytes/macrophages, releasing many proinflammatory cytokines (IL-6, GM-CSF, IL-1B, TNF, CXCL- 8, CCL-3), causing a cytokine storm.4 A study by Gao et al. showed increased levels of cytokines, especially IL-6, which is directly related to the severity of the dis- Correspondence: Dessy Natalia, Department of Psychiatry, Faculty of Medicine, Hasanuddin Universitas, 90245 Makassar, Indonesia. Tel.: +628114615988. E-mail: dessynatalia.psychiatry@gmail.com Key words: COVID-19; risperidone; schizophrenia; positive and nega- tive syndrome scale; Interleukin-6. Conflict of interest: the authors declare no potential conflict of interest, and all authors confirm accuracy. Ethics approval: the research has been granted ethical clearance by the Biomedical Research Ethics Commission of the Faculty of Medicine at Hasanuddin University, under certificate number 492/UN4.6.4.5.31/ PP36/2021. The study is conformed with the Helsinki Declaration of 1964, as revised in 2013, concerning human and animal rights. Informed consent: all patients participating in this study signed a written informed consent form for participating in this study. Patient consent for publication: written informed consent was obtained from a legally authorized representative(s) for anonymized patient infor- mation to be published in this article. Availability of data and materials: all data generated or analyzed during this study are included in this published article. Received: 15 June 2024. Accepted: 10 July 2024. Early access: 22 July 2024. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2025 Licensee PAGEPress, Italy Healthcare in Low-resource Settings 2025; 13:12723 doi:10.4081/hls.2024.12723 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organiza- tions, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its man- ufacturer is not guaranteed or endorsed by the publisher. [Healthcare in Low-resource Settings 2025;13:12723] [page 99] ease.5 Another study showed that IL-6 is an effective biomarker of SARS-CoV-2 and may predict respiratory failure with a high degree of accuracy and help clinicians allocate patients correctly at an early stage. Serum IL-6 levels are a valuable prognostic biomarker in patients diagnosed with COVID-19 disease. The 35 pg/mL cut-off point can differentiate patients with more severe conditions.6 COVID-19 is characterized by complexities, including human- to-human transmission, the transmission of asymptomatic carriers, and high transmission efficiency, leading to a worldwide pandem- ic.7 Patients with severe mental disorders are more susceptible to infection for various reasons, some related to the presence of an underlying disease and some due to environmental factors, includ- ing housing insecurity, smoking, poor access to health facilities, and the effects of medications used to treat the disorder. This increased susceptibility to respiratory tract infections may con- tribute to the risk of COVID-19 in patients with severe mental ill- ness or who are in inpatient care.8 DADI Regional Special Hospital, South Sulawesi Province, reported that 80 patients with Schizophrenia positively exposed to COVID-19 since December 2020 were generally asymptomatic. These patients received typical and atypical antipsychotic thera- pies, including haloperidol, chlorpromazine, risperidone, and clozapine. Schizophrenia is a chronic mental disorder characterized by many symptoms, such as hallucinations, delusions, confused thoughts, and impaired cognitive function.9 The etiology of schizophrenia itself is not well understood. The hypothesis that often arises is that biological mechanisms such as the metabolic system or the immune system are involved in the pathophysiology of schizophrenia. Several processes, such as inflammation, oxida- tive stress, and complex interactions of neurotransmitters, are con- cerned with the pathophysiology of schizophrenia.10 The release of proinflammatory cytokines and free radicals associated with activated microglia is associated with the patho- physiology of schizophrenia. It is also found in postmortem exam- ination of brain tissue.11 An increase in several markers of inflam- mation in serum and CSF, such as Prostaglandin E2 (PGE2), Creative Protein (CRP), and several proinflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and Tumor Necrosis Factor (TNF)α also observed in schizophrenic patients.12 Involvement of the immune system is thought to be related to the pathogenesis of schizophrenia, especially in negative symptoms and cognitive dys- function.13 This immune system dysregulation can be connected to events, risk factors, or responses to therapy in schizophrenic patients.14 Antipsychotic medication is the treatment of choice for schizophrenia. Risperidone is a second-generation antipsychotic drug that is effective for positive and negative symptoms of schizophrenia. Side effects of these drugs are mild and generally do not interfere with cognitive function. There are several mecha- nisms by which risperidone may decrease IL-6 levels. Accumulating evidence has shown that astrocytes can amplify the CNS’s inflammatory response, a phenomenon closely related to the neurobiology and development of neuropsychiatric disorders. Quincozes-Santos et al. observed that risperidone had anti-inflam- matory action on C6 astroglia, decreasing IL-6 release.15 People with schizophrenia and people who have SARS-CoV-2 both have an inflammatory response that includes higher levels of cytokines and inflammatory markers like IL-1β, IL-6, IL-8, and TNF. So, this study aims to explore the relationship between IL-6 levels, the effi- cacy of risperidone therapy, and the PANSS score in schizophrenia patients diagnosed with COVID-19. Materials and Methods Study design This study was an analytical observational study with a prospective cohort approach. A cohort study examines the relation- ship between exposure and disease by selecting two or more study groups based on exposure status and then following them for a cer- tain period to identify and calculate the magnitude of the disease. Population and sample The population in this study were Schizophrenic subjects with and without COVID-19, mild-moderate and asymptomatic COVID-19, and schizophrenic subjects without COVID-19 who were hospitalized and met the inclusion and exclusion criteria. The research sought individuals aged 20-50 diagnosed with both COVID-19 and Schizophrenia, actively taking risperidone at a daily dosage of 2-6 mg for at least four weeks, confirmed with an RT-PCR swab test to have mild to moderate symptoms or be asymptomatic and have a PANSS total score of less than 95, indi- cating significant illness. The control group included individuals with Schizophrenia, negative for COVID-19, also taking Risperidone at a similar dosage for at least four weeks, and a PANSS total score of less than 95. Exclusion criteria involved indi- viduals abusing drugs or alcohol, taking specific medications, or having severe unrelated physical illnesses. Drop-out criteria included individuals leaving the hospital before four weeks or passing away. Research instruments The data collection tools and study instruments utilized in this research included a demographic questionnaire sheet and the Positive and Negative Syndrome Scale (PANSS), a psychometric tool used to evaluate positive and negative symptoms as well as general psychopathology. Each item on the scale is scored from 1 (no symptoms) to 7 (very severe symptoms). In addition, serum Elisa Interleukin 6 (IL-6) was used as a proinflammatory cytokine marker of inflammation with a limit point for serum IL-6 levels set at 35 pg/mL. The normal range of IL-6 concentrations is between 0-7 pg/mL, and the blood plasma IL-6 levels were measured using the ELISA method. Data analysis Data analysis was carried out after the primary data had been collected using the Statistical Package for Social Sciences (SPSS) Program. If the data was normally distributed, an unpaired T-test was applied, and if it was not, Mann-Whitney. Results This study was conducted on schizophrenic patients who con- firmed positive COVID-19 and had been screened; these patients were inpatients at the Dadi Special Hospital from July to August 2021. A total of 41 patients diagnosed with Schizophrenia with COVID-19 were screened and 22 subjects (53.65%) met the inclu- sion criteria. Similarly, 22 subjects with negative COVID-19 were screened for a control group. Data analysis was conducted on 44 subjects aged 18 – 53 years with a mean of 35.9±9.2 years. Table 1 shows the data Normality Testing (n=44), which high- lights the distribution of PANSS (Positive and Negative Syndrome Article [page 100] [Healthcare in Low-resource Settings 2025;13:12723] Scale) scores and IL-6 levels before and after treatment. It reveals that while PANSS scores exhibited a non-normal distribution in both pre-and post-treatment, IL-6 levels were normally distributed after treatment. This table uses the Kolmogorov-Smirnov test to assess data normality. The data in Table 2 presents the demographic statistics of the survey’s 44 respondents, encompassing gender, age, education, employment, and PCR COVID-19 test results. The analysis reveals that 77.3% of the respondents are male, with the most sig- nificant portion falling within the 30-39 age bracket, constituting 43.2% of the sample. Moreover, the majority of participants, total- ing 56.8%, have attained a primary school education, while 79.5% reported being unemployed. Comparison of PANSS and IL-6 Pre-Post demonstrates the significant reduction in both PANSS scores and IL-6 levels follow- ing the treatment, with respective p-values indicating statistical significance. This suggests improvements in the participants’ psy- chiatric symptoms and inflammatory status (Table 3). Table 4 shows that the comparison of PANSS and IL-6 Pre- Post (by gender) shows the impact of treatment on PANSS scores and IL-6 levels, categorized by gender. Both men and women showed significant improvements post-treatment, underscoring risperidone’s effectiveness across genders. In Table 5, the data comparing PANSS and IL-6 Pre-Post by age groups shows that there were significant reductions in PANSS scores and IL-6 levels across all age categories. This suggests that the treatment has broad applicability across different age groups. In Table 6, the comparison of PANSS and IL-6 pre-post (by PCR testing) distinguishes between participants with positive and negative COVID-19 PCR tests. Both groups showed significant decreases in PANSS scores and IL-6 levels, underscoring the potential advantages of risperidone for schizophrenia patients, irre- spective of their COVID-19 status. Article [Healthcare in Low-resource Settings 2025;13:12723] [page 101] Table 1. Data normality testing (n=44). Variables Minimum Maximum Median Mean SD Data Distribution* PANSS Pre 68 81 71.0 72.4 3.4 Not Normal PANSS Post 43 69 58.0 56.9 6.3 Not Normal Difference PANSS 7 34 13.5 15.6 5.9 Not Normal IL-6 Pre (pg/mL) 16.1 31.0 24.1 23.6 4.1 Normal IL-6 Post (pg/mL) 14.3 27.5 21.5 21.1 3.4 Normal Difference IL-6 (pg/mL) 0.2 4.9 2.3 2.5 1.2 Normal *Kolmogorov-Smirnov test. Table 2. Characteristics of respondents (n=44). Category Variables n Percent (%) Gender Men 34 77.3 Women 10 22.7 Age 18-29 years 12 27.3 30-39 years 19 43.2 40-53 years 13 29.5 Education Primary school 25 56.8 Junior high school 6 13.6 Senior High school 11 25.0 College 2 4.5 Employment Employee 2 4.5 Farmer 3 6.8 Entrepreneur 4 9.1 Not work 35 79.5 PCR Positive 22 50.0 Negative 22 50.0 Table 3. Comparison Positive and Negative Syndrome Scale (PANSS) dan IL-6 pre-post. Category n Mean SD Decrease (%) p PANSS Pre 44 72.4 3.4 21.4 0.000* PANSS Post 44 56.9 6.3 IL-6 Pre (pg/mL) 44 23.6 4.1 10.6 0.000** IL-6 Post (pg/mL) 44 21.1 3.4 *Wilcoxon Signed Rank test; **Paired t-test. Discussion This study was conducted to see the effectiveness of risperi- done administration on PANSS scores and Interleukin 6 levels in Schizophrenia patients with confirmed COVID-19 for four weeks, from July to August 2021, with a total sample of 44 people, divided into two groups, namely the COVID-19 POSITIVE group and con- trol groups. Both groups received Risperidone therapy of 2-6 mg per day; the COVID-19 POSITIVE group was the Schizophrenia group with COVID-19, and the control group was the schizophre- nia group without COVID-19. Patients who met the inclusion cri- teria were recorded based on gender, age category, education, occupation, and PCR results. Schizophrenia is a chronic mental disorder characterized by many symptoms, such as hallucinations, delusions, confused thoughts, and impaired cognitive function.9 Several processes, such as inflammation, oxidative stress, and complex interactions of neurotransmitters, are involved with the pathophysiology of schizophrenia.10 The release of proinflammatory cytokines and free radicals associated with activated microglia is associated with the patho- physiology of schizophrenia. It is also found in postmortem exam- ination of brain tissue.11 An increase in several markers of inflam- mation in serum and CSF, such as Prostaglandin E2 (PGE2), C- Reactive Protein (CRP), and several proinflammatory cytokines such as Interleukin (IL)-1β, IL-6, IL-8, and Tumor Necrosis Factor (TNF) α also observed in schizophrenic patients.12 Involvement of the immune system is related to the pathogenesis of schizophrenia, especially negative symptoms and cognitive dysfunction.13 This immune system dysregulation can be connected to events, risk fac- tors, or responses to therapy in schizophrenic patients.14 National patient databases in the UK16 and South Korea17 found that patients with psychotic disorders are at increased risk of severe complications of COVID-19. Patients with severe mental illnesses are more susceptible to infection for various reasons, some related to the presence of an underlying disease and some due to environmental factors, including housing insecurity, smok- ing, poor access to health facilities, and the effects of medications used to treat the disorder. This increased susceptibility to respira- tory tract infections may contribute to the risk of COVID-19 in patients with severe mental illness or who are in inpatient care.8 Schizophrenia subjects in the COVID-19 POSITIVE group and control groups were more male than female; male subjects were 34 subjects (77.3%), and female subjects were 10 subjects (22.7%). Based on the age, 18-29 years was 12 subjects (27.3%), 30-39 years was 19 subjects (43.2%), 40-53 years was 13 subjects (29.5%) (Table 2). Schizophrenia is more common in men than women.10 Men have an earlier onset of schizophrenia than women; the peak age is 25 to 35 years, approximately 15-55 years of age for patients on schizophrenia treatment.9 In this study, the samples were 30-39 years old (43.2%). The education level in this study was 56.8% elementary school. A deficit in social functioning mode made it difficult for subjects with schizophrenia to continue their education to a higher level. This deficit was in the form of social isolation, often indicat- ed by inadequate and inappropriate emotional responses, poor interpersonal relationships, feelings of threat in social situations, difficulty communicating verbally, and reactions to excessive stim- uli.18 The subject’s initial PANSS scores varied between 68–81, with a mean of 72.4±3.4. The distribution of pre-PANSS data was not Normal. Post-subject PANSS scores ranged between 43–69, with a mean of 56.9±6.3. The distribution of PANSS post data was not Normal. The difference scores of PANSS (pre-post) subjects varied between 7–34, with a mean of 15.6±5.9 (Table 1). The difference in PANSS scores showed a decrease in the post-measurement com- pared to pre-measurement. The distribution of PANSS difference data was not normal, possibly due to clinical improvement before and after risperidone antipsychotic therapy. There are several mechanisms by which risperidone may decrease IL-6 levels. The study conducted by De Souza et al. found that risperidone inhibited IL-6-induced S100B secretion, reducing the rate of secretion below the basal level.19 Circulating levels of IL-6 and IL-10 may regulate the expression of the AKT1, DROSHA, NDEL1, DISC1, and MBP genes.20 Thus, risperidone treatment may modulate gene expression during the treatment of schizophrenia. In recent years, scientists have discovered in bio- chemical studies of the central nervous system that IL-6 is pro- duced by neurons, astrocytes, and microglia and acts as a neu- rotrophic factor in the central nervous system. However, recent studies suggest that risperidone can attenuate microglia activation in the brain, reducing IL-6 levels and suggesting risperidone may improve brain disease.21 A meta-analysis study that found a decrease in IL-6 levels after short-term risperidone treatment saw a significant reduction after four weeks of antipsychotic administration.22 In another study that observed a decrease in IL-6 levels within nine days of antipsychot- ic treatment and at eight weeks showed no significant symptoms, there was no difference between patients and control subjects.23 Overall, IL-6 levels were normalized to some extent immediately after risperidone treatment. Evidence that cytokines can be affected by antipsychotic treat- ment, possibly in a dual mode (short-term and long-term), anti- inflammatory in antipsychotics may contribute to the treatment of schizophrenia. Anti-inflammatory effects of antipsychotics may play a role in treating psychotic symptoms.24,25 In a recent meta- analysis of 12 studies (961 patients with schizophrenia and 729 controls) on the effect of antipsychotics on serum production of interleukin-6 (IL-6), a proinflammatory cytokine, they found that antipsychotic treatment was associated with a decrease in IL-6 on the patient. In contrast, trifluoperazine, a conventional antipsy- chotic, has been identified as a potential treatment option for microbial-induced septic shock after it reduced the inflammatory response by suppressing proinflammatory cytokines in mice.26 Recently, Crespo-Facorro et al. suggested that aripiprazole, an atypical antipsychotic, could also be reused as a treatment for COVID-19 after transcriptomic analysis revealed that it could reverse the effects caused by COVID-19 on gene expression in patients.27 In this study, in the COVID-19 POSITIVE group, the Mean of IL-6 Post was significantly lower than Pre, which was 23.0 com- pared to 26.1 (p<0.001). While in the control group, the Mean of IL-6 Post was considerably lower than Pre, which was 19.3 versus 21.0 (p<0.001) (Table 6). The COVID-19-positive group and con- trol groups might had lower IL-6 values below the cut-off (35pg/mL) even before in treatment antiviral. The phenomena could be the effect of risperidone and antivirals made The COVID- 19 positive group asymptomatic and the IL-6 value below the cut- off. Serum IL-6 levels appeared to be a useful prognostic biomark- er in patients with a diagnosis of COVID-19 disease. The 35 pg/mL cut-off point could clearly distinguish the patients with more severe disease. Serum IL-6 levels in patients with COVID- 19: and non-COVID-19, COVID-19: 7.56, Non-COVID: 0.03, Other diseases 9.12.28 A study in Shanghai, China, found that in hospitalized COVID-19 patients, the normal concentration ranges Article [page 102] [Healthcare in Low-resource Settings 2025;13:12723] for IL-1β, IL-8, IL-10, and tumor necrosis factor-alpha (TNFα) were below 5, 62, 9.1, respectively, and 8.1 pg/mL.29 The normal concentration range of IL-6 is between 0-7 pg/mL, and the normal IL-2 receptor (IL-2R) ranges from 223 to 710 U/mL. The lower limit of detection of the kit was 1.5 pg/mL, and the upper limit of detection was 5000 pg/mL without dilution. The upper limit of normal is 7 pg/mL. Baseline IL-6 concentrations are highly predictive of in-hospital mortality for COVID-19 patients. The mean concentration of IL-6 was < 0.001. Serum IL-6 remains high in critically ill patients even after recovery. An IL-6 concen- tration higher than 37.65 pg/mL was predictive of in-hospital mor- tality (AUC 0.97 [95% CI 0.95–0.99], P < 0.001) with a sensitivity of 91.7% and a specificity of 91.7%. 95.7%.30 A study mentions the effect of antipsychotic therapy on disease progression and the cor- relation between cytokine levels and clinical characteristics.31 Later the results of this study showed that the cytokine changes in schizophrenia may differ from the clinical status. In this study, schizophrenic patients with confirmed COVID-19 received COVID-19 therapy with an administration of antivirals. Conclusions The PANSS scores in both the COVID-19 positive group and control groups at the end of the study were significantly lower than at the initial treatment, and the same trend was observed for the IL- 6 scores in both groups. The decreases in PANSS and IL-6 scores were not affected by gender, age, or PCR results. Notably, both the COVID-19 positive group and control groups had a lower value of IL-6 (35pg/mL) at the beginning of the study, suggesting that risperidone may have influenced the IL-6 levels before the COVID-19 diagnosis was confirmed. Additionally, a combination of the antipsychotic risperidone and antivirals was found to lower the IL-6 levels below the cutoff point. Article [Healthcare in Low-resource Settings 2025;13:12723] [page 103] Table 4. Comparison Positive and Negative Syndrome Scale (PANSS) dan IL-6 pre-post (by gender). Category Variables n Mean SD p Man PANSS Pre 34 72.1 3.2 0.000* PANSS Post 34 56.5 5.9 IL-6 Pre (pg/mL) 34 23.6 4.4 0.000** IL-6 Post (pg/mL) 34 21.1 3.6 Women PANSS Pre 10 73.6 4.0 0.000* PANSS Post 10 58.2 7.7 IL-6 Pre (pg/mL) 10 23.4 3.3 0.000** IL-6 Post (pg/mL) 10 21.0 3.0 *Wilcoxon Signed Rank test; **Paired t-test. Table 5. Comparison Positive and Negative Syndrome Scale (PANSS) dan IL-6 pre-post (by age). Category Variables n Mean SD p 18-29 years PANSS Pre 12 72.3 3.6 0.000* PANSS Post 12 56.9 6.2 IL-6 Pre (pg/mL) 12 24.5 3.7 0.000** IL-6 Post (pg/mL) 12 21.9 3.2 30-39 years PANSS Pre 19 71.3 2.6 0.000* PANSS Post 19 56.4 6.4 IL-6 Pre (pg/mL) 19 23.0 4.7 0.000** IL-6 Post (pg/mL) 19 20.8 3.9 40-53 years PANSS Pre 13 74.2 3.9 0.000* PANSS Post 13 57.5 6.8 IL-6 Pre (pg/mL) 13 23.5 3.8 0.000** IL-6 Post (pg/mL) 13 20.9 2.9 *Wilcoxon Signed Rank test; **Paired t-test. Table 6. Comparison Positive and Negative Syndrome Scale (PANSS) dan IL-6 pre-post (by PCR testing). PCR Variables n Mean SD Decrease (%) p Positive PANSS Pre 22 73.5 3.9 22.4 0.000* PANSS Post 22 57.0 6.9 IL-6 Pre (pg/mL) 22 26.1 2.4 11.8 0.000** IL-6 Post (pg/mL) 22 23.0 2.1 Negative PANSS - Beginning 22 71.4 2.6 20.6 0.000* PANSS - End 22 56.7 5.9 IL-6 Pre (pg/mL) 22 21.0 3.9 8.1 0.000** IL-6 Post (pg/mL) 22 19.3 3.4 *Wilcoxon Signed Rank test; **Paired t-test. References 1. Badan Pusat Statistik Provinsi Sulawesi Selatan. Perilaku Masyarakat pada Masa Pandemi COVID-19 Provinsi Sulawesi Selatan. 2022; 1–53 2. Felsenstein S, Herbert JA, McNamara PS, Hedrich CM. COVID-19: Immunology and treatment options. Clin Immunol 2020;215:108448. 3. Diao B, Wang C, Wang R, et al. Human kidney is a target for novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection Running title: SARS-CoV-2 infects human kidney. MedrxivOrg 2020;12:2506. 4. Sokolowska M, Lukasik ZM, Agache I, et al. Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives—A report of the European Academy of Allergy and Clinical Immunology (EAACI). Allergy Eur J Allergy Clin Immunol 2020;75:2445–76. 5. Guo Q, Zheng Y, Shi J, et al. Immediate psychological distress in quarantined patients with COVID-19 and its association with peripheral inflammation: A mixed-method study. Brain Behav Immun 2020;88:17–27. 6. Guirao JJ, Cabrera CM, Jiménez N, et al. High serum IL-6 val- ues increase the risk of mortality and the severity of pneumo- nia in patients diagnosed with COVID-19. Mol Immunol 2020;128:64-8. 7. World Health Organization. Global surveillance for COVID- 19 caused by human infection with COVID-19 virus: interim guidance, 20 March 2020. World Health Organization. 2020. Avaiable from: https://iris.who.int/handle/10665/331506 8. May M, Slitzky M, Rostama B, et al. Antipsychotic-induced immune dysfunction: A consideration for COVID-19 risk. Brain, Behav Immun - Heal 2020;6:100097. 9. Patel KR, Cherian J, Gohil K, et al. Schizophrenia: Overview and treatment options. P T 2014;39:638–645 10. Fitrikasari A, Kartikasari L. Buku Ajar Skizofrenia. UNDIP Press Semarang; 2022. Available from: https://doc- pak.undip.ac.id/id/eprint/18409/1/Buku%20Ajar%20Skizofre nia%20FINAL.pdf 11. Monji A, Kato TA, Mizoguchi Y, et al. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuro-Psychopharmacology Biol Psychiatry 2013;42:115– 121. 12. Müller N, Weidinger E, Leitner B, Schwarz MJ. The role of inflammation in schizophrenia. Front Neurosci 2015;9:372. 13. Meyer U. Developmental neuroinflammation and schizophre- nia. Prog Neuro-Psychopharmacology Biol Psychiatry 2013;42:20–34. 14. Radtke FA, Chapman G, Hall J, et al. Modulating neuroinflam- mation to treat neuropsychiatric disorders. Biomed Res Int 2017;2017:5071786. 15. Quincozes-Santos A, Abib RT, Leite MC, et al. Effect of the atypical neuroleptic risperidone on morphology and S100B secretion in C6 astroglial lineage cells. Mol Cell Biochem 2008;314:59–63. 16. Yang L, Liu S, Liu J, et al. COVID-19: immunopathogenesis and Immunotherapeutics. Signal Transduct Target Ther 2020;5:1–8. 17. Lee SW, Yang JM, Moon SY, et al. Association between men- tal illness and COVID-19 susceptibility and clinical outcomes in South Korea: a nationwide cohort study. Lancet Psychiatry 2020;7:1025–31. 18. Videbeck SL. The eighth edition of Psychiatric–Mental Health Nursing. LWW; 2020. 19. de Souza DF, Wartchow K, Hansen F, et al. Interleukin-6- induced S100B secretion is inhibited by haloperidol and risperidone. Prog Neuro-Psychopharmacology Biol Psychiatry 2013;43:14–22. 20. Noto MN, Maes M, Nunes SOV, et al. Activation of the immune-inflammatory response system and the compensatory immune-regulatory system in antipsychotic naive first episode psychosis. Eur Neuropsychopharmacol 2019;29:416–31. 21. Al-Amin MM, Choudhury MFR, Chowdhury AS, et al. Pretreatment with risperidone ameliorates systemic LPS- induced oxidative stress in the cortex and hippocampus. Front Neurosci 2018;12:1–9. 22. Song X, Fan X, Li X, et al. Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treat- ment in drug naïve, first-episode schizophrenia. Psychopharmacology (Berl) 2014;231:319–25. 23. Frommberger UH, Bauer J, Haselbauer P, et al. Interleukin-6- (IL-6) plasma levels in depression and schizophrenia: Comparison between the acute state and after remission. Eur Arch Psychiatry Clin Neurosci 1997;247:228–33. 24. Zajkowska Z, Mondelli V. First-episode psychosis: An inflam- matory state? Neuroimmunomodulation 2014;21:102–8. 25. Zhou X, Tian B, Han H Bin. Serum interleukin-6 in schizophrenia: A system review and meta-analysis. Cytokine 2021;141:155441. 26. Park JH, Park HJ, Lee SE, et al. Repositioning of the antipsy- chotic drug TFP for sepsis treatment. J Mol Med 2019;97:647- 58. 27. Crespo-Facorro B, Ruiz-Veguilla M, Vázquez-Bourgon J, et al. Aripiprazole as a candidate treatment of COVID-19 identified through genomic analysis. Front Pharmacol 2021;12:1–8. 28. Lu Q, Zhu Z, Tan C, et al. Changes of serum IL-10, IL-1β, IL- 6, MCP-1, TNF-α, IP-10 and IL-4 in COVID-19 patients. Int J Clin Pract 2021;75:1–8. 29. Li J, Rong L, Cui R, et al. Dynamic changes in serum IL-6, IL- 8, and IL-10 predict the outcome of ICU patients with severe COVID-19. Ann Palliat Med 2021;10:3706–14. 30. Zhang J, Hao Y, Ou W, et al. Serum interleukin-6 is an indica- tor for severity in 901 patients with SARS-CoV-2 infection: a cohort study. J Transl Med 2020;18:1–8. 31. Miller BJ, Gassama B, Sebastian D, et al. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects brian. Bone 2008;23:1–7. Article [page 104] [Healthcare in Low-resource Settings 2025;13:12723]