Introduction

Many mechanisms of the pathogenesis of mental and somatic disorders share common points of contact, related to the increase in markers of oxidative stress and inflammation. Oxidative stress and decreased antioxidant activity play important roles in the development of these disorders. Violations of mitochondrial functions, depletion of NAD+ (Nicotinamide adenine dinucleotide oxidized form), NAD+ -induced signaling cascades, and increases in levels of reactive oxygen and nitrogen species are the basis of this process [1]. Zapata-Pérez R. et al. (2021) describe the relationship between the oxidized (NAD+) and reduced (NADH) forms of nicotinamide adenine dinucleotide, the redox balance, and the biosynthesis of fatty acids and nucleic acid [2]. The balance between the synthesis and breakdown of NAD+ is required to maintain cellular homeostasis and physiological functioning. It is known that NAD+ deficiency, which can be genetically determined and also due to low levels of its precursors as a result of dietary deficiencies and synthesis issues, leads to serious somatic and mental disorders. For example, niacin deficiency is associated with pellagra symptoms such as diarrhea, dermatitis, and dementia [3]. Sitarz R. et al. (2023), describe the mechanisms underlying metabolic imbalances due to fatty acid and vitamin B3 deficiency. The authors reported the effectiveness of omega-3 fatty acids in the onset of mental disorders, even when there are no clear indications for the initiation of psychotropic therapy [4]. The nicotinate phosphoribosyl transferase gene (NAPRT1) encodes a key enzyme for niacin metabolism. According to Periyasami S. et al. (2019), niacin deficiency is associated with schizophrenia-like symptoms [5]. Therefore, the antioxidant and anti-inflammatory properties of some food additives, such as omega-3 fatty acids, vitamin B3, and NAD (Nicotinamide adenine dinucleotide), can be used as alternative or adjuvant therapies for mental diseases and comorbid somatic pathology caused by inflammatory reactions and oxidative stress. Such therapies may include the use of NAD+ precursors like nicotinamide mononucleotide and nicotinamide ribose, which quickly increase NAD+ levels in the brain and periphery [1, 6]. TThe disturbances of neurotransmission constitute one of the pathogenetic elements of the membrane phospholipid hypothesis in schizophrenia [7]. Impaired prostaglandin signaling in schizophrenia is established, with several pathways explaining this mechanism: reduced levels of arachidonic acid, a precursor of prostaglandins; increased activity of the enzyme phospholipase A2, and abnormal expression of niacin receptors in cutaneous capillary walls. Skin flushing in response to niacin administration is also considered to be influenced by prostaglandins [8]. David F. Horrobin, the proponent of the prostaglandin signaling imbalance hypothesis in schizophrenia, stated in 1977 that it “does not necessarily contradict modern theories of the transmitters of schizophrenia, since prostaglandins alter the secretion and action of mediators.” He supported his hypothesis with clinical observations, noting that the increased pain threshold and decreased inflammation in patients with schizophrenia could be attributed to prostaglandins. Additionally, he noted that the increase in prolactin due to antipsychotic treatment might be associated with prostaglandin synthesis. However, it remains unclear why “all effective antischizophrenic drugs stimulate prolactin secretion” but “high doses of drugs recently shown to be prostaglandin antagonists cause schizophrenia-like syndromes [9]. Clinical practice shows that high doses of antipsychotics are less associated with symptom exacerbation. Another important metabolic criterion and risk factor is the omega-3 index, which represents the percentage of red blood cells with omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) in erythrocytes [10, 11]. According to David F. Horrobin et al. (1994), “in schizophrenia, the metabolism of phospholipids may be impaired both in the brain and in red blood cells” [12]. The authors note that the patients with negative symptoms have had “the concentrations of arachidonic acid (AA) and DHA in erythrocyte membrane phospholipids deviated sharply from the norm”[12]. Ya-Hui Yu et al. (2022) also report the membrane hypothesis of schizophrenia, according to which low levels of polyunsaturated fatty acids, including omega-3 arachidonic acid (AA), lead to dysfunctional signaling, changes in the structure, rigidity, and conformation of cell membranes, and pathology of receptor activity, proteins, prostaglandins, cyclooxygenases, and ion channels in these patients [13]. Reporting an abnormal response to niacin in patients, Ranpiao Gan et al. (2022) conclude that this response occurs in the “early stage of psychosis” and during “disease progression,” linking it to PUFAs (polyunsaturated fatty acids) [14]. Zhang T. et al. (2023) stated a significant correlation between attenuated niacin response and core negative symptoms in patients with first-episode psychosis. According to the authors, this indicates that an attenuated niacin response (ANR) may be a potential biomarker for certain subtypes characterized by negative symptoms and poor symptomatic remission [15]. 

The aim of the research

The aim of this paper was to study the mechanisms of pathogenesis and the evidence supporting the use of niacin skin and oral tests in patients with schizophrenia, first-episode psychosis, and those at clinical high risk for psychosis (CHR-P). Additionally, the research aimed to examine the rationale for the use of vitamin B3 as an additional or preventive therapy in these groups of patients.

Material and methods

A literature review was conducted on the occurrence of specific reactions to the niacin skin or oral test in patients with schizophrenia, first-episode psychosis, and those at clinical high risk for psychosis (CHR-P). Information was sourced from the PubMed, MEDLINE, Medscape, Scopus, Cochrane Library, and research4life.org databases up to and including 2024, from which 48 sources were selected. The inclusion criteria were studies published in English and human studies only. The literature was analyzed concerning mechanisms of action, risk factors, and evidence supporting the utility of the niacin skin or oral test in high-risk psychosis states and schizophrenia.

Results and discussions

,,Niacin is a general term used to define vitamin B3 and derivatives, including nicotinic acid, nicotinamide, and related compounds, such as nicotinamide riboside” [2]. Pathological processes at the level of membrane phospholipids are considered an essential factor in the pathophysiology of schizophrenia. These processes are believed to have a direct influence on the imbalance of neurotransmitters within the central nervous system [16]. It is known that niacin and its amide, nicotinamide, are considered precursors of vital coenzymes that participate in metabolic reactions. They play a key role in the Krebs cycle and the recovery of nicotinamide adenine dinucleotides (NAD, NADH, NAD+, and NADP+). These coenzymes are involved in DNA repair, detoxification, and the synthesis of steroid hormones [16]. Abram Hoffer (1998) recommends the use of vitamin B3, specifically niacin, in doses ranging from 1 to 12 grams per day for treating psychotic states, including schizophrenia. If adverse reactions occur with niacin, niacinamide can be administered as an alternative, as it generally produces a more moderate effect [17]. The recommended dose for niacin is 2 to 4 mg for infants, 6 to 8 mg for children, 12 mg for teenagers, 16 mg for men, 14 mg for women, and 17 and 18 mg for lactating and pregnant women [18, 19]. In a randomized clinical trial involving patients with schizophrenia who had negative symptoms, the patients failed to flush and had significantly reduced levels of arachidonic and docosahexaenoic acids. Over a period of six months, supplementation led to a conversion from non-flushing to flushing. This conversion was predicted by an increase in arachidonic acid levels in red blood cell membranes, regardless of the nature of the supplementation [20]. Niacin enters the body through food and can also be synthesized from the amino acid tryptophan with the help of vitamin B6. Studies have shown that 1 mg of nicotinamide is produced from 67 mg of tryptophan [21]

In Table 1, the results of several niacin or methylnicotinate skin flush test studies in patients with schizophrenia can be seen. 

Hoffer A. and Osmond H. (1966) proposed the NAD-deficiency hypothesis of schizophrenia, concluding that „schizophrenia is an NAD-deficiency disease”. They explained this position by stating that „large doses of nicotinic acid and nicotinamide are effective in schizophrenia”, quickly improving the clinical condition of patients. The authors drew a parallel between schizophrenia and pellagra, suggesting that patients with schizophrenia „are not able to synthesize NAD as effectively” as the control group [29]. Sang-Young Kim et al. (2017) provide evidence of “redox disturbances” in schizophrenia and mood disorders. The authors identify elements of pathogenesis in schizophrenia, which, in their opinion, include the “immune-oxidative” pathway, oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell-mediated immune response [30]. Ramachandran P. et al. (2012) propose a hypothesis for the therapeutic treatment of schizophrenia using vitamin B3 (niacin), based on the adrenochrome theory of schizophrenia by Hoffer (1981). According to this theory, a pathological product of oxidative metabolism, an adrenaline derivative called adrenochrome, is involved in the productive symptoms of schizophrenia, which have hallucinogenic properties. Vitamin B3, by limiting the production of adrenaline, reduces the synthesis of adrenochrome [31, 32]. In schizophrenia, a high level of adrenochrome accumulates in the central nervous system. Vitamin B3, as a precursor of nicotinamide adenine dinucleotide (NAD) and its reduced form (NADH), participates in these transformations under normal conditions and in schizophrenia. With sufficient levels of NAD and NADH, coenzyme B3 enables adrenochrome to convert back into adrenaline. Hoffer (1981) discussed the influence of stress on changes in the neurotransmitter system: „Stress is harmful for two reasons. The increase in the production of noradrenaline and adrenaline will lead to an increase in adrenochrome,” and genetically predisposed individuals might experience an ,,increase in adrenolutin”, a toxic metabolite of adrenochrome [32]. Many authors have studied the hypothesis that early life stress is associated with the development of schizophrenia later in life. This is linked to changes in the hippocampus during stressful situations, leading to neuroinflammation, microglial activation, the expression of proinflammatory mediators (IL-1β, TNF-α, IL-6), the loss of hippocampal neurons, and schizophrenia-like behavior. NAD therapy reverses these changes. It is believed that NAD has neuroprotective activity and could be used during puberty to prevent neuronal loss and improve hippocampal function in people exposed to early life stress [30-33]. The biological importance of NAD metabolites extends beyond participation in carbohydrate metabolism. They also play a role in oxidative stress processes and are involved in many metabolic pathways. NAD+ supports various processes, including the conversion of glucose and other nutrients into energy, energy metabolism and modulation, repair of damaged DNA and gene expression, support of cell defense systems and immunological functions, calcium homeostasis, regulation of the sleep-wake cycle, and antioxidant activity. Additionally, it participates in apoptosis, the aging process, and carcinogenesis [30]. Taking the tablet form of NADH helps increase wakefulness, attention, daily performance, and vitality [31]. Indications for prescribing NADH include the prevention of fatigue and maladjustment when changing time zones, as well as improving memory, attention, and other aspects of cognitive functioning of various causes. These causes include stress-related maladjustment, aging, and metabolic syndrome. Improvement is observed in cases of asthenia of any origin, chronic fatigue syndrome, Parkinson's and Alzheimer's diseases, depression, and the normalization of mood swings [31]. 

The Redox Ratio as an index for oxidative stress

According to Ryszard Sitarz et al. (2023), the niacin skin test is a simple and inexpensive method “used to assess the fatty acid content of cell membranes” and is “a possible indicator in the diagnosis of mental disorders” [4]. The niacin skin patch test is characterized by a decrease in skin hyperemia in patients with schizophrenia, manifesting as an abnormal response to niacin (niacin response abnormality - NRA). This serves as an endophenotype for schizophrenia, compared with the control group, where redness is pronounced [7, 34, 35]. The practical significance of this test involves the rapid screening of patients at risk for schizophrenia at the onset of the disease, even before clinical symptoms appear, allowing for timely intervention [7]. The NAD+/NADH ratio plays a crucial role in maintaining redox homeostasis. Sang-Young Kim et al. (2017) describe redox balance as the ratio of NAD+ to NADH concentrations, expressed as the Redox Ratio (RR) = [NAD+]/[NADH]. According to authors, the Redox Ratio serves as an index for determining oxidative stress levels in the brains of individuals with schizophrenia, as measured by magnetic resonance spectroscopy [30].

Interaction of the GPR109A receptor and phospholipase A2 in individuals with schizophrenia

Oxenkrug G. and Forester B. (2024) report the interaction between the GPR109A receptor and phospholipase A2 in individuals with schizophrenia. The GPR109A receptor exhibits anti-inflammatory and neuroprotective activities. In the brains of individuals with schizophrenia and those at high risk of developing psychosis, phospholipase A2 levels are elevated. Phospholipase A2 regulates the conversion of arachidonic acid to prostaglandins, contributing to pathological activity in schizophrenia by producing excess prostaglandins and depleting arachidonic acid levels. This enzyme can destroy the myelin layer of axons, thereby reducing neuroprotective functions and disrupting nerve conduction. The authors found correlations between the upregulation of the GPR109A receptor and the inhibition of phospholipase A2. One of the mechanisms influencing the niacin test result, as noted by the authors, is attributed to a genetic mutation in GPR109A. This mutation leads to a decreased blood flow response to niacin exposure, which is a characteristic of individuals with schizophrenia [34]. Tavares et al. (2003) conducted a study involving 38 individuals with schizophrenia and 28 individuals in a control group. They found that phospholipase A2 levels were significantly increased in the schizophrenia group compared to the control group (344±115 pmol/ml/min vs. 290±71 pmol/ml/min; p=0.03). Over 8 weeks of antipsychotic treatment, phospholipase A2 levels were reduced to approximately 267±39 pmol/ml/min (p=0.001). Additionally, 4 out of 13 individuals who previously showed no response to the niacin test exhibited a positive response after treatment [36].

Inflammatory imbalance, phospholipid dysregulation, and the „Two hit hypothesis of schizophrenia”

In schizophrenia, there is an imbalance between pro-inflammatory and anti-inflammatory metabolites. Levels of polyunsaturated fatty acids, anti-inflammatory prostaglandins PGE1 and 15d-PGJ2 are reduced, while the level of the pro-inflammatory prostaglandin PGE2 is increased. According to the “two-hit hypothesis,” changes in membrane phospholipids can contribute to the pro-inflammatory pathogenesis of schizophrenia and act as a vulnerability factor [37]. Jeffrey K. Yao (2016) discussed mechanisms underlying the abnormal niacin response in individuals with schizophrenia, focusing on signaling pathways involving cell membrane phospholipids, arachidonic acid, and eicosanoids. G protein-coupled receptors, such as GPR109A or HM74A, located on dermal macrophages and adipocytes, activate phospholipase A2, releasing arachidonic acid from cell membranes. This arachidonic acid is then converted into prostaglandins PGD2 and PGE2, which have vasodilatory effects [35]. Proinflammatory responses in patients with schizophrenia activate microglia, leading to neuronal apoptosis. According to Fillman, S.G., et al. (2014), “excessive activation leads to increased synthesis of cyclooxygenases, causing inflammatory reactions”. Microglia synthesize various cytokines and respond to stimuli, which also occurs in patients with schizophrenia, but with a shift towards pro-inflammatory activity [38]. Keith A. Feigenson also reports the “Two-Hit Hypothesis of Schizophrenia,” which posits that “early immune activation of microglia may sensitize them to later activation.” This hypothesis suggests that prenatal risk factors, stress, and early infections lead to the formation of pathological microglia that are easily “activated” in the long term, for example, at puberty in response to a new trigger [37]. 

The Niacin Test and High Risk for Psychosis. Correlation between PUFA and Phospholipase A2

An important component in the pathophysiology of schizophrenia is the kynurenine pathway. Tryptophan, an essential amino acid, is vital for the development of the serotonin and kynurenine pathways. The World Health Organization recommends a daily intake of tryptophan of about 3.5–6.0 mg/kg of body weight [44]. In the serotonin pathway, metabolism ends with the production of serotonin and melatonin. In the kynurenine pathway, the production of nicotinic acid occurs, followed by nicotinamide, and finally NAD+[45]. Plitman et al. (2017) attribute about 90% of tryptophan metabolism to the kynurenine pathway [46].  Increased levels of kynurenic acid and cytokines in the brain have been reported post-mortem in patients with schizophrenia [47]. The kynurenine pathway influences behavior, the immune system, energy metabolism, and serotonin balance. Dysregulation of this pathway is also associated with gut and brain inflammation [45].

Kynurenine pathway in schizophrenia

An important component in the pathophysiology of schizophrenia is the kynurenine pathway. Tryptophan, an essential amino acid, is vital for the development of the serotonin and kynurenine pathways. The World Health Organization recommends a daily intake of tryptophan of about 3.5–6.0 mg/kg of body weight [44]. In the serotonin pathway, metabolism ends with the production of serotonin and melatonin. In the kynurenine pathway, the production of nicotinic acid occurs, followed by nicotinamide, and finally NAD+[45]. Plitman et al. (2017) attribute about 90% of tryptophan metabolism to the kynurenine pathway [46].  Increased levels of kynurenic acid and cytokines in the brain have been reported post-mortem in patients with schizophrenia [47]. The kynurenine pathway influences behavior, the immune system, energy metabolism, and serotonin balance. Dysregulation of this pathway is also associated with gut and brain inflammation [45]. 

In Table 2, the most common mechanisms underlying the abnormal response to the niacin test in schizophrenia are highlighted:

Table 2. Mechanisms of abnormal niacin response in patients with schizophrenia

There are publications describing oral niacin reactions in schizophrenia. Francisco Carena et al. (2023) state that even with this route of niacin administration, patients with schizophrenia have an abnormal response to niacin compared to controls and individuals with other mental illnesses. The prevalence of abnormal niacin response is higher in patients with schizophrenia. According to the authors' studies, the prevalence of this abnormal response in patients with schizophrenia is 90.5%, while in the control group it is 0%. Additionally, the abnormal response to oral niacin in these patients is dose-dependent [27].

A genome linkage scan of niacin skin flush response

A study conducted by Yin-Ju Lien et al. (2011) on 115 families, including 226 affected individuals, 137 unaffected individuals, and 94 healthy controls (HCs), established that both affected and unaffected individuals had lower niacin flush scores compared to HCs for moderate (0.01 M) and high (0.1 M) concentrations of niacin in skin patches. The authors revealed a linkage region with a significant signal (3.39 at 14q32.12). They identified two genes located in the 14q32.12 region that could be related to schizophrenia: ataxin 3 (AT3) and chromogranin A (CGA). Both genes are not related to phospholipase A2, which is encoded by the PLA2G6 gene located in the 22q13.1 region. The authors concluded that the 14q32.12 region could be responsible for the response to niacin in schizophrenia [48].

Conclusions 

1. The abnormal niacin response in schizophrenia is linked to metabolic disturbances such as imbalances in the omega-3/omega-6 and NAD+/NADH ratios, along with low levels of vitamin B3. These imbalances contribute to a pro-inflammatory state, oxidative stress, and phospholipid dysregulation.

2. Vitamin B3 (niacin) and its derivatives, along with omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), show potential as adjunctive therapies for schizophrenia by reducing oxidative stress, inflammatory responses, and improving membrane fluidity.

3. Genetic factors, including mutations in the GPR109A receptor and dysregulation of the kynurenine pathway, play a significant role in the pathophysiology of schizophrenia. These genetic influences contribute to the observed metabolic imbalances and inflammatory responses.

4. The niacin test has a high degree of sensitivity and specificity, making it an easy and cost-effective screening tool for identifying clinical high-risk (CHR) individuals, patients with schizophrenia, or those at risk for developing schizophrenia. Assessing additional parameters could enhance preventive or adjunctive interventions.

Competing interests

None declared.

Authors’ contribution

LB conceived the original draft preparation and was responsible for the conception and design of the review. LB and IN were responsible for the data acquisition, collection and assembly of the articles/published data, as well as their inclusion and interpretation in this review. Both authors reviewed the manuscript and approved the final version. 

Informed consent for publication

Not needed for this article.

Ethics approval 

No approval was required for this study.

Funding

None.

Authors’ ORCID IDs

Igor Nastas – https://orcid.org/0000-0001-8751-9101

Larisa Boronin – https://orcid.org/0000-0001-8180-8711

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