State marker properties of niacin skin sensitivity in ultra-high risk groups for psychosis - An optical reflection spectroscopy study☆
Introduction
Impaired flush response to niacin (vitamin B3) stimulation (niacin sensitivity, NS) was first reported in schizophrenia by Hoffer (Hoffer and Osmond, 1962), and can be assessed by standardized semi-quantitative visual rating scales (Kerr et al., 2008, Ward et al., 1998) and several objective measurement techniques, including laser Doppler flowmetry (Messamore et al., 2010, Yao et al., 2016), photoplethysmography (Wilson and Douglass, 1986) or malar temperature (Fiedler et al., 1986). A combined method study was performed by Rybakowski and Weterle using an oral challenge dose of 200 mg niacin and two different techniques (thermometric recordings and visual ratings) (Rybakowski and Weterle, 1991).
Attenuated NS is one of the well-replicated biological findings in schizophrenia (Messamore, 2003, Nadalin et al., 2010, Smesny et al., 2003, Smesny et al., 2005, Yao et al., 2016). Following the discovery of the underlying pathomechanisms, impairment of NS has been integrated in the prostaglandin deficiency hypothesis (Horrobin, 1977), and later the membrane lipid hypothesis (Horrobin, 1998, Horrobin et al., 1994) of schizophrenia. The prostaglandin-mediated pathway involves G protein-coupled nicotinic acid receptor stimulation at epidermal Langerhans cells, Ca2 + dependent expression of prostaglandin synthases, and the formation of vasodilatory prostaglandins (PGD2) (Benyo et al., 2006, Maciejewski-Lenoir et al., 2006, Offermanns, 2006). In animals, dietary polyunsaturated fatty acid (PUFA) deprivation is associated with altered expression of the enzymes in the arachidonic acid (20:4n-6, ARA) cascade (cytosolic phospholipase A2 - cPLA2, respectively) and the docosahexaenoic acid (22:6n-3, DHA) cascade (calcium-independent phospholipase A2 - iPLA2, respectively) (Rao et al., 2007). Furthermore, administration of acetylsalicylic acid reduced skin flushing by 30% (Papaliodis et al., 2008). Similarly, in humans attenuated NS has been directly correlated with decreased PUFA precursors of prostaglandins (Berger et al., 2016, Glen et al., 1996) and is almost completely abolished by acetylsalicylic acid (Smesny et al., 2003). Additional findings in first-episode schizophrenia patients (FEP) further support the association of NS with pro-inflammatory activation (Milleit et al., 2010), while studies in medicated patients relate NS to vasomotor function (Messamore et al., 2010). Taken together, this evidence supports the notion of NS as a marker of deprivation of PUFA, and possibly also of a non-specific pro-inflammatory activation, alterations that are specified within both the membrane lipids (Horrobin et al., 1994) and neuroinflammatory concepts of schizophrenia (Bechter, 2013, Fillman et al., 2015, Goldsmith et al., 2016, Upthegrove et al., 2014).
In research on psychosis prevention and early intervention, the investigation of biological markers, such as NS, has increasingly gained attention in order to define risk groups according to biological (instead of psychometric) criteria (Fusar-Poli et al., 2016a, Fusar-Poli et al., 2016b) to enable the prediction of transition/non-transition, functional outcomes (Emanuele et al., 2012, Gifford et al., 2016) and treatment response (Rapaport et al., 2016). So far, the available research on NS in this field has revealed inconclusive results. In the entire group of ultra-high risk (UHR) individuals the most recent study has shown increased (instead of decreased) NS (Berger et al., 2016), while previous smaller studies in genetic risk groups revealed attenuated (Lin et al., 2007, Shah et al., 1999, Waldo, 1999) or unchanged (Nikolov et al., 2002, Smesny et al., 2007a) skin responses. These findings suggest dynamic changes of NS around the time of the first acute psychotic episode (Smesny et al., 2005). However, having not stratified their UHR individuals according to the PACE (Personal Assessment and Crisis Evaluation) subgroups (Yung et al., 2012, Yung et al., 2008) and psychopathology, Berger and colleagues were not able to further explore their unexpected finding (Berger et al., 2016).
By investigating a completely different (i.e. non-overlapping) population, and using an objective assessment technique of skin flush response (optical reflection spectroscopy, ORS), the present study aimed to further resolve the state marker properties of NS; namely, differential response in UHR subgroups (according to PACE criteria), associations with symptomatology, and predictive validity in terms of transition outcome. Therefore, our hypotheses are:
- I)
that alterations of NS vary across the different UHR subgroups according to PACE criteria (BLIPS group, UHR-B; attenuated symptoms group, UHR-A; genetic risk group, UHR-G).
- II)
that NS differs between transition (UHR-T) and non-transition (UHR-NT) individuals, where transition individuals show similar NS alterations as FEP, and
- III)
that NS in UHR individuals is associated with psychopathology, as previously shown in schizophrenia patients by our (Smesny et al., 2007b) and other (Glen et al., 1996) groups.
Section snippets
Description of study population
Niacin skin tests were performed on 84 UHR individuals (54 male, 30 female; detailed demographic information is provided in Table 1), 105 FEP (69 male, 36 female), and 180 healthy controls (HC; 88 male, 92 female). The group of UHR individuals included 45 assigned to the UHR-A group (30 male, 15 female), 12 assigned to the UHR-B group (11 male, 1 female) and 27 assigned to the UHR-G group (13 male, 14 female). One individual belonged to the UHR-A as well as the UHR-G subgroup, and was assigned
Investigation of potential confounders
Due to significant differences in mean age (p < 0.001), gender distribution (Chi2, p < 0.010), and the use of cannabis (Chi2, p < 0.001) and nicotine (Chi2, p < 0.001) between groups, initial repeated measure ANOVA included these potential confounders as additional between-subject variables or co-variable (age). These tests did not reveal significant confounding effects (age p = 0.937, gender p = 0.746, nicotine p = 0.559, cannabis p = 0.871). Therefore, these covariates were not included in further analyses.
Discussion
In this study we have investigated alterations of an established and easy-to-apply bedside biological marker in different risk groups for psychosis as compared to the manifest psychotic state and in HC. The alterations in FEP, with decreased NS compared to HC shown in the current study, are in line with previous studies, which have been consistently replicated (Messamore, 2003, Nadalin et al., 2010, Smesny et al., 2003, Smesny et al., 2005, Yao et al., 2016). Our main novel finding is that NS
Conclusions
Our results indicate that NS is attenuated in UHR individuals of the UHR-A and UHR-B subgroups, similarly to the previously reported impairment of NS in FEP. Attenuation of NS is associated with specific symptom characteristics, severity of symptoms and transition to psychosis. These findings strongly support the notion of NS being a state marker property throughout the phase proximal to transition to psychotic illness. Our findings also suggest a disturbance of the prostaglandin-mediated
Contributors
Study conception and design: Kerstin Langbein PhD, Stefan Smesny MD PhD, G. Paul Amminger MD PhD, and Heinrich Sauer MD PhD.
Acquisition of data was performed by: Ulrike Schmidt MD, Maria Rudzok MD, Stephan Schack MD, and Natalie J. Biesel MD.
Analysis and interpretation of data: Kerstin Langbein PhD, Stefan Smesny MD PhD, Ulrike Schmidt MD, Maria Rudzok MD, Stephan Schack MD, and Natalie J. Biesel MD.
Drafting of manuscript: Kerstin Langbein PhD, Stefan Smesny MD PhD, G. Paul Amminger MD PhD, and
Role of the funding source
Dr. Stefan Smesny was supported by the German Research Foundation (DFG) (Sm 68/3–1).
Conflict of interest
None of the authors have any actual or potential conflicts of interest, including any financial, personal or other relationships with other people or organizations.
Acknowledgements
Dr. Stefan Smesny was supported by the German Research Foundation (DFG) (Sm 68/3-1). We thank all participants and their families for their engagement in this study.
Dr. Kerstin Langbein and Dr. Stefan Smesny had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis.
None of the authors have any actual or potential conflicts of interest, including any financial, personal or other relationships with other people or
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Plasma metabolic alterations and potential biomarkers in individuals at clinical high risk for psychosis
2022, Schizophrenia ResearchCitation Excerpt :The impaired niacin sensitivity (NS) is a notable feature in treated or untreated schizophrenia, and even affective disorders, which is caused by a disturbance of prostaglandin-mediated pathways in association with in vivo unbalanced oxidative stress and deregulated arachidonic acid metabolism (Langbein et al., 2018; Sun et al., 2018; Wang et al., 2021). However, the NS of CHR-P population are diverse, and the manifestations are not consistent in different studies (Berger et al., 2016; Langbein et al., 2018). In present study, we detected elevated dissociative arachidonic acid in plasma of CHR-P subjects.
Relationship between allostatic load and clinical outcomes in youth at ultra-high risk for psychosis in the NEURAPRO study
2020, Schizophrenia ResearchCitation Excerpt :Identifying biomarkers and endophenotypes can assist in determining who will benefit most from treatment, and to better estimate the risk for psychosis transition and other adverse outcomes (Davis et al., 2015; McGorry et al., 2014). To date, several studies have examined candidate biomarkers in UHR groups including markers of oxidative defence (Lavoie et al., 2017), membrane fatty acids (Amminger et al., 2015; Berger et al., 2017), cortisol (Labad et al., 2015; Walker et al., 2013), niacin skin sensitivity (Langbein et al., 2017) and multi-analyte indices (Perkins et al., 2015). Allostatic load (AL), the cumulative adverse effects of chronic stress and maladaptation, has been linked to somatic comorbidity in psychiatric populations and may be implicated in the pathophysiology of psychotic disorders (Bizik et al., 2013).
An association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia
2020, Prostaglandins Leukotrienes and Essential Fatty AcidsCitation Excerpt :Individuals with schizophrenia frequently exhibit abnormal signaling of dopamine and other neurotransmitters, disturbances of lipid and glucose metabolism and attenuated niacin-induced skin flushing [1,4,5,7-9]. Reported findings indicate that a reduced niacin sensitivity is associated with greater severity of schizophrenia symptoms (evaluated via Brief Psychiatric Rating Scale); worse global functioning; cognitive impairment; and illness progression among individuals experiencing their first psychotic episode [10-13]. One study also demonstrated that a subgroup of patients with schizophrenia who underwent antipsychotic therapy exhibited conversion of absent niacin skin flushing to a positive niacin-induced skin flush response [14].
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None of the authors have any actual or potential conflicts of interest, including any financial, personal or other relationships with other relevant people or organizations.