Elsevier

Schizophrenia Research

Volume 192, February 2018, Pages 377-384
Schizophrenia Research

State marker properties of niacin skin sensitivity in ultra-high risk groups for psychosis - An optical reflection spectroscopy study

https://doi.org/10.1016/j.schres.2017.06.007Get rights and content

Abstract

Impaired niacin sensitivity (NS) is one of the most replicated findings in untreated schizophrenia, and reflects a disturbance of prostaglandin-mediated pathways in association with deregulated arachidonic acid metabolism, pro-inflammatory activation, and vasomotor function. In ultra-high risk individuals (UHR) increased NS was reported recently, pointing towards dynamic alterations of the underlying pathomechanisms in the period preceding psychosis. However, these characteristics are still unresolved in the diverse UHR groups.

We tested the hypothesis that NS is attenuated in patients who have transitioned to psychosis and in the Brief Limited Intermittent Psychotic Symptoms (BLIPS, UHR-B) and/or the attenuated symptoms (UHR-A) groups, while it is unchanged or increased in the genetic risk group (UHR-G).

Sensitivity to three concentrations (0.1–0.001 M) of aqueous methylnicotinate was tested in 84 UHR patients, 105 first-episode psychosis patients (FEP) and 180 healthy individuals (HC), using optical reflection spectroscopy (ORS).

The UHR subgroup and transition/non-transition outcomes were assessed according to PACE criteria using the CAARMS. Psychopathology was assessed using SANS, SAPS, and BPRS or SCL-90-R self-ratings.

In 0.001 M data, decreased NS was found in the UHR-B (n = 12), UHR-A (n = 45) and the transition groups (n = 13), similar to the result in FEP. NS in the UHR-G (n = 27) and HC groups did not differ. In the UHR-B and FEP groups, NS and positive symptom scores were inversely correlated.

These state marker properties could be used to characterize the intensity of the underlying pathomechanisms during the onset of psychosis or to identify UHR individuals that might benefit from related indicated prevention strategies.

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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    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.

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