Endophenotype properties of niacin sensitivity as marker of impaired prostaglandin signalling in schizophrenia

BACKGROUND: Disruption of arachidonic acid pathways and prostaglandin signalling has been implicated in the pathophysiology of schizophrenia. AIMS: We intended to study prostaglandin signalling in groups of young schizophrenia patients, first-degree relatives, and healthy controls in order to assess effects of heritability on this biological marker-one important endophenotype criterion. METHOD: Namely, we assessed intensity of methylnicotinate skin flushing using optical reflection spectroscopy. Tests were applied to 19 adolescent first-episode schizophrenia patients, 21 first-degree relatives, and groups of age and gender matched healthy controls. RESULTS: Compared to healthy controls, attenuation of skin flushing at low niacin concentrations was found only in schizophrenia patients, but not in first-degree relatives. CONCLUSION: While our results indicate niacin hyposensitivity as reliable biological marker in schizophrenia, they do not provide clear evidence for its heritability. Particularly, the results in adolescent schizophrenia patients are suggestive for the perception of attenuated niacin flushing as secondary to the pathophysiology at the onset of schizophrenic illness, namely increased oxidative stress, alterations of unspecific immune-response or inflammation-like processes.     

Niacin skin test response in dyslexia

The niacin skin test reflects a flush and oedema owing to the production of prostaglandin D2 from arachidonic acid. A diminished response may indicate abnormalities in the phospholipid metabolism, which has been shown in schizophrenia. There is evidence that dyslexia might also involve phospholipid abnormalities, therefore we examined the skin response in 51 dyslexics and 45 controls. Four concentrations of aqueous methyl nicotinate were applied topically to the forearm. Flushing was rated using a seven-point scale at 3 min intervals over 21 min. Repeated measures ANOVA for the four concentrations across all seven time-points showed no significant effect of subject group, but when analyses were confined to the first 9 min, flushing was reduced in dyslexics. Significant group differences were also found for the lowest niacin concentration (0.0001M) across six out of seven time-points. The results indicate a slightly reduced and delayed response to niacin in dyslexia.     

Niacin skin-flush response and electrodermal activity in patients with schizophrenia and healthy controls

Patients with schizophrenia have in different studies shown reduced niacin sensitivity and lower electrodermal activity (EDA) after auditory stimulation. Peripheral mediation of prostaglandins may have a physiological role in both responses. This motivates study of both niacin response and electrodermal responding in the same patients with schizophrenia. Thirty patients with schizophrenia and 17 controls were investigated with EDA and thereafter given 200mg niacin orally with continuous assessment of skin temperature. The patients showed a delayed temperature increase after niacin ingestion (P=0.002) and a higher frequency of electrodermal non-responding (P<0.05). Response/non-response for niacin correlated with EDA response/non-response in the patient group (P=0.009). The niacin test revealed a slower vasodilation reaction in the patients. The association between response patterns for the niacin test and EDA suggests that a common aberration in skin physiology may be of importance for both reactions in schizophrenia.     

Niacin Skin Sensitivity Is Increased in Adolescents at Ultra-High Risk for Psychosis

Background

Most studies provide evidence that the skin flush response to nicotinic acid (niacin) stimulation is impaired in schizophrenia. However, only little is known about niacin sensitivity in the ultra-high risk (UHR) phase of psychotic disorders.

Methods

We compared visual ratings of niacin sensitivity between adolescents at UHR for psychosis according to the one year transition outcome (UHR-T n = 11; UHR-NT n = 55) with healthy controls (HC n = 25) and first episode schizophrenia patients (FEP n = 25) treated with atypical antipsychotics.

Results

Contrary to our hypothesis niacin sensitivity of the entire UHR group was not attenuated, but significantly increased compared to the HC group, whereas no difference could be found between the UHR-T and UHR-NT groups. As expected, niacin sensitivity of FEP was attenuated compared to HC group. In UHR individuals niacin sensitivity was inversely correlated with omega-6 and -9 fatty acids (FA), but positively correlated with phospholipase A₂ (inPLA₂) activity, a marker of membrane lipid repair/remodelling.

Conclusions

Increased niacin sensitivity in UHR states likely indicates an impaired balance of eicosanoids and omega-6/-9 FA at a membrane level. Our findings suggest that the emergence of psychosis is associated with an increased mobilisation of eicosanoids prior to the transition to psychosis possibly reflecting a “pro-inflammatory state”, whereas thereafter eicosanoid mobilisation seems to be attenuated. Potential treatment implications for the UHR state should be further investigated.     

The impact of PLA2G4A and PTGS2 gene polymorphisms,and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients

We investigated the etiology of the attenuated niacin skin flush response in schizophrenia patients. Skin response to topical niacin of 0.1 M, 0.01 M, 0.001 M, and 0.0001 M concentrations was rated using method of volumetric niacin response (VNR) and correlated to two functional A/G polymorphisms in genes: phospholipase A2 group IVA (BanI of the PLA2G4A), and rs689466 of the prostaglandin synthase-2 (PTGS2). We further tested the possible correlation between niacin response and fatty acid (FA) content of red blood cells (RBCs). We detected statistically significant but weak impact of both polymorphisms on niacin flush response in schizophrenia patients. The dosage of the G alleles of both polymorphisms was associated with higher VNR values, although each polymorphic variant accounted for only 1% of the overall flush response variability. Regarding FA content, both n?3 and n?6 polyunsaturated FAs (PUFAs) were significantly reduced in the patient group, but an association with niacin sensitivity was not detected.     

Relationship between the niacin skin flush response and essential fatty acids in schizophrenia

The skin flush response to niacin is selectively mediated by the release of vasodilatory prostaglandins from the skin. The normal skin flush response to niacin is attenuated in many individuals with schizophrenia (SCZ). This finding suggests abnormal prostaglandin signaling in SCZ. Since prostaglandins are derived from arachidonic acid (AA), the finding of an abnormal skin flush response is consistent with biochemical data suggesting relative depletion of AA, and other essential fatty acids (EFAs), in a substantial portion of people with SCZ. This paper will describe the mechanism of the skin flush response to niacin, and will review evidence that the response to niacin is abnormal in SCZ, that this abnormality is not related to psychotropic medications, and that it may be a marker of the EFA deficiency which has been documented to be present in many patients with SCZ.     

The topical niacin sensitivity test: an inter- and intra-rater reliability study in healthy controls

Topical application of nicotinic acid results in erythema, and in some cases oedema of the skin, supporting a strong relationship between niacin sensitivity and prostaglandin D2. The aim of this study was to examine the inter-rater and intra-rater reliability of a 12-min niacin sensitivity test in healthy adults. Three raters assessed the skin reaction of 12 volunteers, over 3-min intervals across four niacin concentrations (0.1, 0.01, 0.001, and 0.0001), and over six sessions. Inter-rater reliability estimates ranged from 0.85 to 0.97 for the total niacin sensitivity score. Similar inter-rater reliability estimates were found for niacin sensitivity ratings by concentration and time. Intra-rater reliability estimates ranged from 0.63 to 0.93 for the total niacin sensitivity score. These data indicate that the 12-min topical niacin sensitivity test has excellent reliability.     

Test–retest stability of the oral niacin test and electrodermal activity in patients with schizophrenia

In schizophrenia, well-replicated findings support an attenuated niacin skin-flush response. We have previously reported a delayed skin-flush after niacin ingestion and also an association between niacin non-responding and electrodermal non-responding in schizophrenia. The stability of the niacin and electrodermal tests was now studied in a test–retest design. An additional aim was to assess the association previously found.Twenty-three patients with schizophrenia underwent two sessions 3 months apart during which an oral niacin test was conducted and electrodermal activity was measured. Despite similar values for niacin outcome variables at the group level, there was high intraindividual variation. Test–retest stability for the oral niacin test was thus low, although a trend toward correlation for the dichotomous response criterion was found. Most electrodermal measures correlated between baseline and retest. A significant association between the tests was again found; niacin non-responding implied electrodermal non-responding, providing further support for a common underlying aberration in schizophrenia.     

Regional Abnormality of Grey Matter in Schizophrenia: Effect from the Illness or Treatment?

Both schizophrenia and antipsychotic treatment are known to modulate brain morphology. However, it is difficult to establish whether observed structural brain abnormalities are due to disease or the effects of treatment. The aim of this study was to investigate the effects of illness and antipsychotic treatment on brain structures in antipsychotic-naïve first-episode schizophrenia based on a longitudinal short-term design. Twenty antipsychotic-naïve subjects with first-episode schizophrenia and twenty-four age- and sex-matched healthy controls underwent 3T MRI scans. Voxel-based morphometry (VBM) was used to examine the brain structural abnormality in patients compared to healthy controls. Nine patients were included in the follow-up examination after 8 weeks of treatment. Tensor-based morphometry (TBM) was used to identify longitudinal brain structural changes. We observed significantly reduced grey matter volume in the right superior temporal gyrus in antipsychotic-naïve patients with schizophrenia compared with healthy controls. After 8 weeks of treatment, patients showed significantly increased grey matter volume primarily in the bilateral prefrontal cortex, insula, right thalamus, left superior occipital cortex and the bilateral cerebellum. In addition, a greater enlargement of the prefrontal cortex is associated with the improvement in negative symptoms, and a more enlarged thalamus is associated with greater improvement in positive symptoms. Our results suggest the following: (1) the abnormality in the right superior temporal gyrus is present in the early stages of schizophrenia, possibly representing the core region related to schizophrenia; and (2) atypical antipsychotics could modulate brain morphology involving the thalamus, cortical grey matter and cerebellum. In addition, examination of the prefrontal cortex and thalamus might facilitate an efficient response to atypical antipsychotics in terms of symptom improvement.     

首发未服药精神分裂症患者中线粒体DNA拷贝数及其与血脂指标的相关性分析

精神分裂症是一种重度的精神疾病,伴发严重的能量代谢失衡。其中,脂代谢的异常近年来受到越来越多的关注。多项研究表明,线粒体在精神分裂症患者代谢异常的过程中发挥重要的作用。线粒体DNA拷贝数是线粒体含量及完整性的重要指标,直接参与线粒体的多项重要功能。本研究旨在通过考察首发精神分裂症患者线粒体DNA拷贝数的变化特征及其与相关代谢指标之间的相关性,为阐明精神分裂症代谢异常的机制提供支持。本研究共计纳入82例首发且未服用抗精神病药物的精神分裂症患者和77例健康对照,采用荧光定量PCR技术进行线粒体DNA拷贝数的检测,并进行了临床信息和血脂指标的采集。结果表明,精神分裂症患者组的线粒体DNA拷贝数显著低于健康对照组（P=0.000572,FC=-1.22）。血脂指标中,患者组的HDL-c显著低于健康对照组（P=0.001, FC=-1.12）,LDL-c（P=0.009, FC=1.09）、CHOL/HDL-c（P=0.000019, FC=1.17）、TG/HDL-c（P=0.000656, FC=1.31）和LDL-c/HDL-c（P=0.000004, FC=1.30）均显著高于健康对照组。相关性分析表示,在健康对照组中,mtDNA拷贝数与TG显著负相关（r=-0.232, P=0.0499）,与TG/HDL-c（r=-0.235, P=0.052）呈负相关,但不显著;在精神分裂症患者组,mtDNA拷贝数与各血脂指标的关系都不显著。本研究为精神分裂症患者的线粒体功能障碍、脂代谢异常提供了证据,提示了线粒体在精神分裂症患者并发心血管代谢疾病高风险中可能的重要作用。     

2-D DIGE analysis of liver and red blood cells provides further evidence for oxidative stress in schizophrenia

The molecular disease mechanisms associated with schizophrenia remain largely unknown. Although primarily considered a disorder of the brain, there is evidence of a peripheral component to schizophrenia. In this study, we investigated liver tissue and red blood cells (RBC) from schizophrenia patients and controls using 2-D DIGE proteomic analysis. Fourteen proteins were significantly altered in liver samples from schizophrenia patients (n = 15) compared to healthy controls (n = 15). Analysis of the schizophrenia RBC proteome revealed 8 proteins significantly altered in samples from schizophrenia patients (13 antipsychotic-treated and 7 drug-na?ve) compared to controls (n = 20). Six of the altered proteins in the liver and four of the altered RBC proteins are related to oxidative stress. These results corroborate our earlier findings obtained from post-mortem brain studies and substantiate our hypothesis that metabolic alterations leading to oxidative stress are linked to the schizophrenia disease process. Our results also suggest that at least some of the pathological processes associated with the schizophrenia disease process can be traced in peripheral tissue. If peripheral cells can be used as a disease surrogate, promising new investigative avenues could be explored.     

血清DCN、NRG-1、MIF水平与首发未服药精神分裂症患者临床症状和认知功能的相关性分析

目的:探讨血清核心蛋白多糖(DCN)、神经调节蛋白-1(NRG-1)、巨噬细胞迁移抑制因子(MIF)水平与首发未服药精神分裂症患者临床症状和认知功能的相关性。方法:选择2018年1月~2020年11月期间长江大学附属第一医院收治的首发未服药精神分裂症患者80例作为精神分裂症组,同期于长江大学附属第一医院进行体检的健康志愿者80例作为对照组。应用阳性和阴性症状量表(PANSS)评估患者精神病理症状,应用MATRICS共识认知成套测验(MCCB)评估所有受试者认知功能。根据PANSS评分将精神分裂症组分为PANSS评分高分组和低分组,比较两组血清DCN、NRG-1、MIF水平,并分析以上指标水平与PANSS总分、MCCB各项评分的相关性。结果:精神分裂症组患者PANSS总分为(77.18±13.57)分。精神分裂症组MCCB各项评分均低于对照组(P<0.05)。精神分裂症组血清DCN、NRG-1水平低于对照组,MIF水平高于对照组(P<0.05)。PANSS高分组血清DCN、NRG-1水平低于PANSS低分组,MIF水平高于PANSS低分组(P<0.05)。Pearson相关性分析显示,首发未服药精神分裂症患者血清DCN、NRG-1水平与PANSS总分呈负相关,与MCCB各项评分呈正相关,MIF水平与PANSS总分呈正相关,与MCCB各项评分呈负相关(均P<0.05)。结论:首发未服药精神分裂症患者血清DCN、NRG-1、MIF水平异常,且以上指标水平与患者临床症状和认知功能受损有一定联系,提示检测以上指标水平可能为该病患者认知功能及临床症状的评估提供参考。     

No association of Disrupted-in-Schizophrenia-1 variation with prefrontal function in patients with schizophrenia and bipolar disorder

The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.     

Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results

It has been hypothesised that polyunsaturated fatty acids (PUFA) play an important role in the aetiology of schizophrenia and depression. Evidence supporting this hypothesis for schizophrenia includes abnormal brain phospholipid turnover shown by 31P Magnetic Resonance Spectroscopy, increased levels of phospholipase A2, reduced niacin skin flush response, abnormal electroretinogram, and reduced cell membrane levels of n-3 and n-6 PUFA. In depression, there is strong epidemiological evidence that fish consumption reduces risk of becoming depressed and evidence that cell membrane levels of n-3 PUFA are reduced. Four out of five placebo-controlled double- blind trials of eicosapentaenoic acid (EPA) in the treatment of schizophrenia have given positive findings. In depression, two placebo-controlled trials have shown a strong therapeutic effect of ethyl-EPA added to existing medication. The mode of action of EPA is currently not known, but recent evidence suggests that arachidonic acid (AA) if of particular importance in schizophrenia and that clinical improvement in schizophrenic patients using EPA treatment correlates with changes in AA.     

High throughput lipidomic profiling of schizophrenia and bipolar disorder brain tissue reveals alterations of free fatty acids, phosphatidylcholines, and ceramides

A mass spectrometry based high throughput approach was employed to profile white and gray matter lipid levels in the prefrontal cortex (Brodmann area 9) of 45 subjects including 15 schizophrenia and 15 bipolar disorder patients as well as 15 controls samples. We found statistically significant alterations in levels of free fatty acids and phosphatidylcholine in gray and white matter of both schizophrenia and bipolar disorder samples compared to controls. Also, ceramides were identified to be significantly increased in white matter of both neuropsychiatric disorders as compared to control levels. The patient cohort investigated in this study includes a number of drug naive as well as untreated patients, allowing the assessment of drug effects on lipid levels. Our findings indicate that while gray matter phosphatidylcholine levels were influenced by antipsychotic medication, this was not the case for phosphatidylcholine levels in white matter. Changes in free fatty acids or ceramides in either white or gray matter also did not appear to be influenced by antipsychotic treatment. To assess lipid profiles in the living patient, we also profiled lipids of 40 red blood cell samples, including 7 samples from drug naive first onset patients. We found significant alterations in the concentrations of free fatty acids as well as ceramide. Overall, our findings suggest that lipid abnormalities may be a disease intrinsic feature of both schizophrenia and bipolar disorder reflected by significant changes in the central nervous system as well as peripheral tissues.     

Classification of first-episode schizophrenia patients and healthy subjects by automated MRI measures of regional brain volume and cortical thickness

Background

Although structural magnetic resonance imaging (MRI) studies have repeatedly demonstrated regional brain structural abnormalities in patients with schizophrenia, relatively few MRI-based studies have attempted to distinguish between patients with first-episode schizophrenia and healthy controls.

Method

Three-dimensional MR images were acquired from 52 (29 males, 23 females) first-episode schizophrenia patients and 40 (22 males, 18 females) healthy subjects. Multiple brain measures (regional brain volume and cortical thickness) were calculated by a fully automated procedure and were used for group comparison and classification by linear discriminant function analysis.

Results

Schizophrenia patients showed gray matter volume reductions and cortical thinning in various brain regions predominantly in prefrontal and temporal cortices compared with controls. The classifiers obtained from 66 subjects of the first group successfully assigned 26 subjects of the second group with accuracy above 80%.

Conclusion

Our results showed that combinations of automated brain measures successfully differentiated first-episode schizophrenia patients from healthy controls. Such neuroimaging approaches may provide objective biological information adjunct to clinical diagnosis of early schizophrenia.     

A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes

Despite large-scale genome-wide association studies (GWAS), the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1), is located in, and regulated by the major histocompatibility (MHC) complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes in this network.