A niacin skin-flushing test may help identify patients with schizophrenia, new research shows.
The study included 163 patients with schizophrenia (SZ), 63 patients with a mood disorder (depression, mania, or bipolar disorder), and 63 healthy control participants (HCs). Participants underwent a niacin skin-flushing test consisting of applications of niacin at four different concentrations on the forearm.
Investigators led by Chunling Wan, PhD, of Shanghai Jiao Tong University in China, found that patients with schizophrenia displayed a blunted response to niacin, compared to those with a mood disorder (MD) and HCs.
The subgroup that displayed a blunted response accounted for close to a third of all SZ patients. The specificity of the test was more than 80% in both male and female patients.
“In this study, we used niacin skin test in a relatively large sample set and successfully identified a subgroup of niacin-blunted SZ patients out from MD patients and HCs with impressive specificity,” the authors write.
“Our result provides extra clues for etiological research of SZ and helps to optimize clinical strategies and facilitate precise diagnosis and personalized medicine for patients with SZ.”
The study was published online October 25 in Schizophrenia Bulletin.
Lack of Diagnostic Markers
The authors state that the “lack of diagnostic markers has long been a challenge in the clinical management of SZ.”
Previous research has demonstrated that patients with SZ require much higher doses of niacin to produce skin flushing in the niacin-flushing test than normal control persons do. The finding led to further investigation of the potential connection between niacin and SZ.
The authors explain that niacin-induced skin flushing is mediated by a hydroxyl-carboxylic acid receptor 2, which is a G-protein-coupled receptor widely expressed on keratinocytes and epidermal immune cells.
The binding of niacin to HCA2 activates phospholipase A 2 and hydrolyzes membrane phospholipids, resulting in the release of arachidonic acid (AA). The free AA is then transformed into prostaglandin D2 and prostaglandin E2 by cyclooxygenase enzymes. These relax the vascular smooth muscle, inducing vasodilation and skin redness.
The authors describe the niacin skin-flushing test for SZ as “intuitional and biochemically based” and note that it has been “successfully replicated in various cohorts.” However, previous studies have employed different procedures and different criteria, making comparisons of findings difficult.
The authors explain that they chose MDs as a comparator for the niacin skin-flushing response in patients with SZ because MDs share common symptoms with SZ, as well as common biochemical and genetic traits.
Some previous studies have suggested that diminished responses to niacin also occur in patients with bipolar disorder. However, previous studies of the niacin skin-flush response in SZ did not include MD as a comparator, and when they did, only patients with bipolar disorder and depression but not mania were included.
Moreover, most studies were conducted only in white patients, and the sample sizes were small. The researchers therefore decided to study the Chinese Han population. They included patients with mania, depression, and bipolar disorder as MD comparators, as well as HCs.
They used a 4-point scale to measure the niacin flush responses in these groups, “with the aim of identifying indicators that can properly diagnose and discriminate a niacin-blunted subgroup of patients with SZ from subjects with MD and HCs.”
Effective Indicator
The researchers recruited SZ and MD patients from among inpatients in a hospital. Age-matched HCs were recruited from staff at the same hospital and included physicians and nurses.
To be considered “healthy,” participants had to have no current or past symptoms of psychiatric illness. HCs were aged 15 to 75 years.
Exclusion criteria included the presence of a neurologic disease or substance dependence, treatment with nonsteroidal or steroidal anti-inflammatory drugs within the past 14 days, the presene of severe skin diseases or disease that could induce significant immune response, and pregnancy.
Niacin was applied to the skin via aqueous methylnicotinate (AMN, C7H7NO2, 99) in four concentrations: 0.1, 0.01, 0.001, and 0.0001 M. The responses were photographed and rated on a 4-point scale in which 0 indicated no erythema, 1 indicated incomplete erythema, 2 indicated complete erythema within the area covered by the patch, and 3 indicated erythema beyond the definite area of the patch.
Most patients in the SZ and MD groups were appropriately matched, but the HC group included more females, and the members of that group were also thinner, shorter, more educated, and were nonsmokers. The researchers adjusted their findings using multivariate analysis to account for these confounders.
Of those in the SZ group, <3% (n = 4) patients were undergoing their first episode; for the remainder of the SZ patients, episodes were recurrent. In the MD group, 23 patients were diagnosed with mania, 32 with bipolar disorder, and five with depressive disorder. Of the MD group, more than 90% were experiencing recurrent episodes.
Compared with the HC group, those with SZ exhibited lower mean flush scores under all conditions, “indicating a delayed and weakened niacin flush response in patients with SZ,” the authors report.
Although the flush responses in the MD group were similar to those in the SZ group at the lowest concentration (0.0001 M) or at the shortest time point (5 min), the responses were comparable with the HC group at 20 minutes or at a higher concentration (0.01 M).
The MD group’s skin flush was even more intensive than the HC group at 0.1 M AMN at 20 min, “indicating that the niacin flush response was rather delayed but not diminished,” the authors write.
Flush Response
On further statistical evaluation conducted via MANOVA analysis, patients’ sex and disease type were shown to have significant effects on overall scores (P = .004 and P < .0001, respectively).
By contrast, body mass index, education, and smoking status were not found to be related to the flush responses. No interaction effect was observed between patients’ sex and disease type.
On a univariate analysis with simple contrasts, in the test on the score variable at 0.1 M AMN at 15 min, both the HC and MD groups had significantly higher scores than the SZ group (MD vs SZ: P = .0001; HC vs SZ: P = .001). Males had significantly higher scores than females (P = .004).
In the test of the total score, the HC group showed significantly higher scores than the SZ group (P < .0001); however, sex and education (P = .037 and P = .004, respectively) did affect the score.
The researchers identified niacin-blunted SZ patients by using discriminative scores. They found that the niacin-blunted SZ subgroup accounted for 30.67% of all SZ patients.
The disease specificity of the subgroup was high: 88.89% in males and 82.35% in females in participants with SZ or HC, 88.24% in males and 86.21% in females in patients with SZ or MD, and 88.37% in males and 83.75% in females among all three groups.
“We confirmed that the SZ group showed delayed and attenuated skin flush reactions after niacin stimulation, while the MD group exhibited delayed but not attenuated or even accentuated reactions in response to the niacin treatment. This property of MD group was more evident when AMN concentration is high (such as 0.1 M AMN),” the researchers note.
They add that the “total score valuable was identified as the most effective indictor for differentiating SZ patients from HC group and the score variable at 0.1 M at 15 minute as the most discriminant score for SZ versus MD comparison.”
Meaningful Conclusions
Commenting on the study for Medscape Medical News, Erik Messamore, MD, PhD, associate professor of psychiatry at Northeast Ohio Medical University and medical director of the Best Practices in Schizophrenia Treatment Center, Rootstown, Ohio, said the study was “well-designed in that the sample size was large enough to derive meaningful conclusions.”
He noted that the researchers “used an objective measure to quantify the flush response, had the flush response rated by two independent raters, and verified that there was high agreement between the two sets of ratings, so their methodology was sound.”
The study makes an important contribution to the field, he said. “It soundly validates earlier research showing that the abnormal niacin response biomarker has extremely high specificity for schizophrenia.”
He continued, “If someone with psychiatric symptoms tests positive for this biomarker, the likelihood of schizophrenia is present with about 90% likelihood.”
The findings “further confirm that ability of this type of testing to separate schizophrenia from bipolar disorder, even in the setting of active mania where associated symptoms of psychosis can make the diagnosis more challenging using standard clinical criteria for diagnosis.”
He called the study “interesting” and “surprising” in that it identified two components of the niacin flush response: not only the overall intensity of the redness but also the pace at which the red response developed.
He pointed out that this is in keeping with an emerging recognition in the studies of the niacin response that the rate of response vs the magnitude of response may be “indicators of two different phenomena – both apparently having some association with severe mental illness.”
Recent data show that patients with mood disorders have a “significantly more sluggish rate of response – even though they ultimately develop a flush intensity equivalent to those with no mental illness,” said Dr Messamore.
But in those with schizophrenia, the redness from niacin proceeds at a normal pace. Instead, the “ultimate magnitude of the flush will be lower than in comparison groups of mood disordered patients or non-ill controls.”
Potential Implications
This has important potential implications, he said. Patients with mood disorders might differ from healthy populations in their rate or response, and those with schizophrenia might differ in the magnitude of response.
This has several important clinical applications.
“Sometimes, symptoms of bipolar disorder can be confused with symptoms of schizophrenia, and vice versa, so being able to use a biomarker like the niacin skin test might help to guide clinical decision making in cases where diagnosis is not clear, based on symptom expression.”
Moreover, he continued, “the fact that some patients with schizophrenia had a decidedly impaired blood flow response to niacin while others had a normal response” further supports the notion that there are different underlying physiologies within what is called “schizophrenia” – ie, “a syndrome composed of distinct physiological subtypes, rather than being a unitary diagnosis.”
A second contribution of the study, said Dr Messamore, is that it provides a basis for “categorizing persistent psychotic illness along physiological lines, rather than purely symptom-descriptive lines,” because “the research data are now extremely clear that schizophrenia exists in ‘niacin-flush-normal’ and ‘niacin-flush-impaired’ subtypes.”
From prior research, it seems that those who are niacin-impaired have poorer cognitive and functional outcomes, he observed. This line of research allowed for personalized medicine or improved drug development, he said.
In addition, the findings may pave the way for preventive approaches. “If it can be shown that the niacin response biomarker is present before the onset of psychosis, it may become possible to detect individuals with merely prodromal symptoms who would ultimately progress to full schizophrenia.”
Showing that the biomarker is specific to a subtype of schizophrenia may “ultimately lead to discovery of novel schizophrenia risk genes,” he added.
The authors conclude that studying the abnormalities in the membrane phospholipid-AA-prostaglandin pathway in fatty acid metabolism or in the endogenous concentration would open the door to understanding the etiologic implications for SZ and provide new perspectives for exploring the disease and would facilitate the design of “efficient drugs for treatment of these niacin-blunted SZ patients in the future.”
The study was supported by the Natural Science Foundation of China, the Ministry of Science and Technology of China, the Shanghai Brain-Intelligence Project from STCSM, the Science and Technology Commission of Shanghai Municipality, and the Science and Technology Plan Project of Wuhu, Anhui Province, China. The authors have disclosed no relevant financial relationships.
Schizophr Bull . Published online October 25, 2017. Full text
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