Niacin Skin Sensitivity Is Increased In Adolescents At Ultra-High Risk For Psychosis

High_Prob

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Niacin Skin Sensitivity Is Increased in Adolescents at Ultra-High Risk for Psychosis (2016)

Abstract
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.

Introduction

The observation that human kind responds with a red flush reaction of the upper body after intake of large doses of nicotinic acid (niacin, vitamin B3) goes back to the early fifties of the last century [1] a time when nicotinic acid was introduced as possible treatment of schizophrenia [2] While controlled studies failed to demonstrate a sustained clinical benefit of niacin in schizophrenia treatment [3] the clinical observation of an attenuated or even absent niacin flush reaction of the upper body in patients with schizophrenia compared to healthy controls caught the attention of some researchers [4,5]. The latter observation combined with other clinical observations such as that patients with schizophrenia are less sensitive to pain [6], have a lower temperature sensitivity [7] and a markedly decreased risk of rheumatoid arthritis [8], led to the proposal that schizophrenia might be associated with a deficiency or dysfunction of prostaglandin metabolism [9]. Prostaglandins are metabolites of arachidonic acid (AA), a key modulator of signal transduction [10]. The latter in conjunction with the observation that in particular AA levels are reduced in post mortem and peripheral red blood cell membranes in schizophrenia [11] lead to the formulation of the membrane and phospholipid hypothesis of schizophrenia [12,13].

The pathway underlying the niacin skin reaction includes the activation of G protein-coupled nicotinic acid receptors on skin macrophages and epidermal Langerhans cells that release AA from membrane phospholipids. As a next step a sequential oxidation of AA, and (to smaller quantities) also of dihomogamma-linolenic (DGLA) or eicosapentaenoic acid (EPA) by cyclooxygenases (COX-1 and COX-2) follows. Finally, prostaglandin synthases are responsible for the formation of a range of prostaglandins (e.g. D2, E2) that stimulate the production of cyclic AMP, which in turn triggers capillary vasodilatation and increase regional blood flow, observable as regional skin flushing [14,15].

A recent systematic review identified over 30 niacin sensitivity studies in schizophrenia and related disorders [16]. The majority of studies using the topical variant of the niacin skin test [17] reported that 23% up to 90% of patients with schizophrenia have an attenuated or absent flush reaction compared to less than 0–25% of the normal population [1722]. Niacin sensitivity seemed to be more attenuated in first-episode than in multi-episode schizophrenia patients [23], raising the question if altered niacin sensitivity, as well as altered PUFAs and eicosanoid metabolism may be more relevant for the onset of psychosis than for chronic illness stages.

The identification of young people with a high risk for schizophrenia and other psychotic disorders has become a worldwide focus of attention [24]. Different clinical approaches have been applied to identify young people with an at risk mental state for psychosis, such as the Melbourne ultra-high risk (UHR) criteria [2527] and the basic symptom concept [28,29]. To our knowledge at the current state of research only clinically defined approaches found their way into clinical daily routine and are able to identify help-seeking young people with an about 20% risk (with a range between 10–50%) to progress to a full-blown psychotic disorder within one year [30]. Most clinicians would agree that clinically defined help-seeking UHR individuals already need some kind of treatment, or at least intensive monitoring. However, there is also a clear need to further optimize the so far available UHR criteria. Following this demand, a range of biological markers, such as structural [3133] and functional [34] imaging, neuropsychological [35], metacognitive [26,36,37] and electrophysiological [38] risk markers have been proposed. To our knowledge, alterations of niacin sensitivity in UHR populations have never been systematically investigated in this context. The few niacin sensitivity studies in first-degree relatives of patients with schizophrenia (with no drop in functioning in contrast to the UHR genetic liability subgroup) are inconclusive [14,39].

Therefore, our first aim in this study was to investigate niacin sensitivity in adolescents meeting the Melbourne UHR criteria compared to first episode psychosis patients (FEP), who meet criteria for schizophrenia or schizophreniform disorder, as well as to healthy controls (HC). Our second aim was to investigate if baseline niacin sensitivity differed between those who progressed towards psychosis (converters) versus those who did not (non-converters). Our third aim was to address the relationship of niacin sensitivity with other markers of phospholipid and fatty acid (FA) metabolism established in schizophrenia research, such as intracellular phospholipase A2 (inPLA2) activity and membrane mono- and polyunsaturated fatty acid (MUFA, PUFA) profile, within the UHR sample.

16,40], increased inPLA2 activity in blood plasma and post mortem brain tissue [41,42] and decreased PUFA levels [4346], we postulated the following a priori hypotheses that: I) niacin sensitivity of our UHR sample will be attenuated, however to a lower extend than in FEP (in-between HCs and FEP), II) in the UHR sample niacin sensitivity will be positively correlated with membrane omega-6 fatty acid levels, in particular with arachidonic acid (AA), i.e. the lower the AA level, the weaker the niacin skin response, and III) niacin sensitivity will be negatively correlated with inPLA2 activity, i.e. the lower the niacin sensitivity, the higher the inPLA2 activity. IV) based on our recent findings of a dynamic interrelation between inPLA2 activity and PUFA levels between UHR non-transition (UHR-NT) and UHR transition (UHR-T) patients [47] we expected that niacin sensitivity will be more attenuated in the UHR-T group than in the UHR-NT group.
Discussion

In summary, there were three main findings. First, in contrast to the results in established schizophrenia and also to our initially formulated hypotheses, niacin sensitivity is not attenuated, but significantly increased in our UHR compared to HC and FEP groups (see Fig 1). Second, also contradictory to our hypotheses, within our UHR sample an inverse correlations between niacin sensitivity and levels of single omega-6 and 9 fatty acids are present. Finally, in line with our hypothesis lower niacin sensitivity is associated with a higher inPLA2 activity.

We believe that the finding of increased niacin sensitivity in conjunction with decreased omega-6 and omega-9 FA in UHR individuals may be a signifier of a range of interrelated pathomechanisms (e.g. oxidative stress) resulting in an increased demand of bioactive lipids or an adaptive function associated with the emergence of psychosis. Having not investigated cerebral processes in this study, we speculate i) that an increased release/demand or an adaptive down regulation of AA and (to a smaller extend) also DGLA could relate to an unspecific “proinflammatory” process due to the excessive synaptic elimination and the associated pruning {Feinberg, 1982 #1895;Feinberg, 1990 #1894;Keshavan, 1994 #1232;Farooqui, 2007 #9895;[51] or ii) to excessive production of reactive oxygen species in the context of a weakened antioxidative defense mechanisms, e.g. through a dysfunctional glutathione cycle [5257].

Indeed, outside the central nervous system, AA and their bioactive lipids play a crucial role for inflammatory processes. However, in the brain they are key players for the regulation of neurodevelopment, long-term potentiation, synaptic plasticity and excitatory neurotransmission [5860]. Having in mind the preliminary character of our findings, the inverse correlations between niacin sensitivity (that occurs as a result of a prostaglandin mediated pathway) and omega-6 or -9 FA could be interpreted as follows: Increased niacin sensitivity in UHR individuals could signify an increased demand for omega-6 FA (in particular for AA and its metabolites) and in the due course also for omega-9 FA resources, since monounsaturated omega-9 FA serve as compensatory replacements once omega-6 FA are exhausted [47]. Although providing some explanation for the increased niacin sensitivity in UHR individuals, this pathology seems not yet very pronounced in our UHR sample, as inverse correlations were observed only in single FA, but not in sum values of omega-6 FA, PUFA or MUFA. Thus, while bioactive lipids and fatty acids seem to be still in balance in our UHR population due to effects of compensation, the attenuated niacin sensitivity observed in FEP may then be the result of manifest exhaustion of omega-6 FA resources and the incapacity to compensate the PUFA deficiency. This interpretation is also supported by our observation of an inverse correlation between niacin sensitivity and inPLA2 activity, and by the positive correlations between single omega-6 and omega-9 FA and inPLA2 activity respectively, as increasing inPLA2 activity is counted as marker of up-regulated membrane lipid repair/remodeling processes [61] and was repeatedly found in patients suffering schizophrenia [42].

Another line of research suggests that regulatory deficits in immune function are present in schizophrenia and related disorders [62]. As mentioned earlier, niacin sensitivity is regulated by prostaglandins (PGD2, PGE1), mainly metabolites of AA that is released by inPLA2 and further metabolized mainly by COX-1 and COX-2. Considering this pathway, it is also possible that increased niacin sensitivity may signify altered immunomodulatory activity in UHR individuals, i.e. prior to the onset of psychosis. Such an idea may also provide explanation for our findings, and may support the idea that progression to acute psychosis is accompanied by increased need of AA and its derivatives (such as eicosanoids) [63,64].

65] omega-3 fatty acids induced the in vivo brain glutathione levels by 30%, a strong intracellular antioxidants often induced during inflammation [55,66]. Furthermore T2 relaxation time [67], a very sensitive albeit unspecific marker of active potentially proinflammatory processes, was increased in UHR individuals [65,67]. Second, nervonic acid, a monounsaturated omega-9 FA crucially involved in myelination and a signifier of an exhaustion of proinflammatory metabolites, was decreased in UHR individuals, in particular in those suffering transition to acute psychosis within one year [68]. Finally, early prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infections, nutritional deficiencies as well as obstetric complications were found associated with increased demands of PUFAs [51].

50]. This was also found in this study. In particular in females, age significantly influenced group effects. Another potential confounder could be substance abuse that was overexpressed in our UHR group. Our group was able to demonstrate an inverse association between niacin sensitivity and cannabis abuse (niacin sensitivity decreased in consuming healthy controls) [69]. Furthermore, pharmacological treatment could have affected niacin sensitivity. The use of antidepressants and benzodiazepines was higher in the treated UHR group and therefore could have affected PUFA/oxylipin metabolism and the HPA-axis. As effects of these agents on niacin sensitivity have not been shown or systematically investigated as yet, a potential contribution to our results cannot be excluded at this stage of knowledge.

16,70]. In depression, this pathology is linked to hypothalamic-pituitary-adrenal (HPA) axis dysfunction, showing ongoing (nocturnal) ACTH and cortisol secretion (as caused by HPA axis hyperactivity) to disturb the balance between omega-6 and omega-3 PUFA [71,72], which may in turn causes down-stream effects on prostaglandin-mediated pathways. In the context of this study, the findings that niacin flush response was positively correlated with severity of melancholic features, anxiety, feelings of guilt and somatic concerns is interesting [70,73], depression is quite common in UHR [7476]. Therefore, niacin sensitivity in UHR individuals may be influenced by the composition of the UHR population and the spectrum/severity of symptomatology. In our particular UHR cohort from Vienna, most converters developed schizophrenia (see consort diagram of the clinical trial publication by [48]), however this may not be the case in other UHR populations. We were not able to show associations between niacin sensitivity and psychopathology, presumably due to the limited range in symptom severity in this UHR sample. For future niacin test studies, it could be important to stratify the study population according to UHR subgroups, spectrum/severity of symptoms as well as according to the long-term diagnosis.

23]. The presented (weak) associations with omega-6- and omega-9 FA metabolism and with PLA2 activity suggest niacin sensitivity may indicate that the UHR state may be associated with a “pro-inflammatory state”. Future research should address the question if the UHR state is associated with an incipient neurovulnerability that is associated with bioactive lipid abnormalities and an activation of neuro-inflammatory processes. Potential implications for neuroprotective treatments should be addressed. [67,77].
 
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Tarmander

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Pretty fascinating...so those at high risk for schitzo are more sensitive to flushes then those who are either healthy or already have schitzo
 
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sensitivity was inversely correlated with omega-6 and -9 fatty acids (FA),

Probably flush could be used as a not very accurate test for PUFA status. Stronger flush - more PUFA in the system.
 

DonLore

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Probably flush could be used as a not very accurate test for PUFA status. Stronger flush - more PUFA in the system.
It said inversely correlated, so shouldnt it mean that the more PUFA, the less flush?
Can someone chime in about how to interprete this study?
 

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