1. Introduction
Schizophrenia is a severe mental disorder with high economic burden leading to emotional and social withdrawal with a symptoms such auditory hallucinations, catatonia, and delusions [9, 33]. Early identification of individuals with schizophrenia is important to treat them [12]. A high percentage of patients with schizophrenia have an attenuated or absent flush reaction compared to normal people [32, 34]. Niacin skin flush test has been proposed as a possible simple biochemical test for identification of schizophrenia patients. There is no agreement on the predictive power of niacin skin flush test for identification of schizophrenia patients. Several studies have shown a diminished flush response to applied niacin in most schizophrenia patients, while some studies failed to show any difference [30]. This study aims to investigate niacin sensitivity in schizophrenia patients compared to healthy controls in order to examine the accuracy of niacin skin test results in these patients. 

2. Methods
This diagnostic study was conducted in 2018 on 36 schizophrenia patients aged 20-50 years and 33 healthy controls. Schizophrenia patients who were not in first episode of the disease were recruited from those refereed to psychiatric clinics or hospitals in Zanjan, Iran. Healthy controls were recruited from non-faculty hospital staff through an interview who had no history of major psychiatric disorders. The exclusion criteria were: Comorbid mental disease, acute medical condition, fever, metabolic, rheumatic, allergic, and thyroid diseases, use of mood stabilizer or blood pressure medications, use of haloperidol drugs in the past one year, use of nonsteroidal anti-inflammatory drugs or corticosteroids in the past two weeks, and use of antihistamine or drugs with antihistaminic effect in the past 10 days. Informed written consent was obtained from all participants before collecting data.
We applied niacin patches of three concentrations (0.001 M, 0.01 M, and 0.1 M) of aqueous methyl nicotinate topically to the forearm skin of all subjects for 5 min. Flush responses were rated 10 and 15 min after application. The strength of flush responses was rated as 0= No response and 1= With response according to the literature [32]. Sensitivity, specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of the test were reported for each concentration and evaluation times. Niacin skin flush test was conducted by an expert who was unaware of the study groups. The categorical variables were compared between groups by chi-square test. Statistical analyses were performed in SPSS V. 24 software. 

3. Results
The Mean±SD age of schizophrenic patients was 36.72±8.72 years (55.6% male), and for the healthy control group it was 35.33±7.31 years (54.5% male). There was no significant difference in terms of age and gender between the two groups at baseline, but their education level and employment status were significantly different (higher in controls). Frequency of response and no response in each group at different time points (10 and 15 min) and concentrations (0.1 M, 0.01 M, and 0.001 M) are presented in Table 1.




Accuracy parameters of the niacin skin flush test results in differentiating schizophrenia patients from controls are presented in Table 2.





 4. Discussion and Conclusion
Our findings were consistent with the results of other studies regarding that flush response to niacin patches was significantly impaired in patients with schizophrenia compared to normal healthy population. We found that the use of 0.001 M, 0.01 M, and 0.1 M solutions resulted in different test accuracy results, where better sensitivity and NPV were observed at 0.001 M solution. The increased activity of phospholipase A2 in schizophrenic patients which downregulates the level of arachidonic acid and breakdown membrane phospholipids, may be responsible for reduced responses to niacin [32, 34, 35], but this mechanism does not seem to be a reason in all schizophrenic patients. Previous studies have shown that that only a small group of schizophrenic patients shows impaired flush response to niacin [36, 37]. Therefore, the skin flush response may be an endo-phenotype, rather than a specific marker for schizophrenia. We concluded that the niacin skin flush test is a valuable diagnostic tool for schizophrenia. Better understanding of this biomarker can result in early identification of schizophrenia for conducting interventions.   

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the Ethical Committee of the Zanjan University of Medical Sciences (IR.ZUMS.REC.1397.125). Informed written consent was obtained from all participants before collecting data. All ethical principles are considered in this article. The participants were informed about the purpose of the research and its implementation stages. They were also assured about the confidentiality of their information and were free to leave the study whenever they wished, and if desired, the research results would be available to them.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors contributions
Conceptualization, methodology, validation, analysis data: All authors; Investigation, preparation, writing-review & editing: Mohammad Arzanlou; Project administration: Alireza Armanikian.

Conflicts of interest
The authors declared no conflicts of interest.

Acknowledgements
The authors would like to thank the psychologists and psychiatrists who helped identify schizophrenia patients, the personnel of Shahid Beheshti Hospital in Zanjan for cooperation, and all participants of the study. 

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