Non-termination of sickness behavior as precipitating factor for mental disorders

The term niacin is the generic name for the two compounds nicotinic acid and nicotinamide, the major dietary precursors for two important coenzymes, nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. Niacin is important for the maintenance of cellular integrity and energy production and is involved in more than 500 intracellular reactions. Deficiencies of niacin may contribute to neuropsychiatric and neurodegenerative disorders. Patients who develop nutritional deficiencies as a result of poor dietary intake, could potentially suffer from niacin deficiency and NAD depletion.However, de novo synthesis of niacin and NAD in the kynurenine pathway of tryptophan metabolism may compensate for impaired dietary intake. The rate of synthesis of NAD and niacin from tryptophan oxidation depends on the induction of the enzyme indoleamine 2,3-dioxygenase (IDO) by pro-inflammatory cytokines such as interferon-gamma. Niacin 2 synthesis is not limited by a decrease in tryptophan and excessive IDO activity may therefore lead to a decline in tryptophan levels. Antidepressants have an anti-inflammatory effect, including reduction of interferon-gamma and therefore inhibition of IDO, the ratelimiting enzyme of the kynurenine pathway. In theory, this could account for increased serotonin as more tryptophan becomes available for serotonin synthesis. However, the downside may be that less NAD and niacin are synthesised downstream, which could exacerbate common psychiatric problems. It is our hypothesis that patients with poor dietary intake, who are treated with antidepressants, are at risk of developing niacin/NAD deficiency with possible development of associated neuropsychiatric symptoms.We therefore propose that niacin supplementation be considered in patients with inadequate diets who are treated with antidepressants. We believe that if this does not happen, a subclinical niacin deficiency may result, which would be difficult to detect as it would cause the same symptoms of the original illness (e.g. depression). Niacin deficiency should be considered and ruled out in all patients with treatment-resistant depression, who have a poor response to antidepressants. This is potentially a cost-effective and easy intervention, which could be examined in a randomized controlled trial.

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“…Above normal levels of proinflammatory cytokines have also been reported for many psychiatric conditions [35].…”

Section: Conditions Associated With Increased Activity In the Kynurenmentioning

confidence: 87%

“…In contrast to eating disorders, the link between many other psychiatric disorders, especially depression, and pro-inflammatory activity is well-known. [35,37].…”

Section: Conditions Associated With Increased Activity In the Kynurenmentioning

confidence: 99%

Antidepressants may lead to a decrease in niacin and NAD in patients with poor dietary intake

2015

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“…Although several possible mechanisms for the pathogenesis of CD/FND are under consideration, its specific origin is unknown ( Ratcliff and van der Feltz-Cornelis, 2020 ). Mechanisms that have been proposed are systemic low-grade inflammation (SLI) ( Del Grande da Silva et al., 2016 ; Kovacs et al., 2016a , Kovacs et al., 2016b ; Tiyekli et al., 2013 ; Viljoen and Panzer, 2005 ; Vogelzangs et al., 2016 ). Elevated CRP was found in some, but not all, children with CD/FND ( Kozlowska et al., 2019 ); this may indicate that the relationship is not straightforward.…”

Section: Introductionmentioning

confidence: 99%

Assessment of cytokines, microRNA and patient related outcome measures in conversion disorder/functional neurological disorder (CD/FND): The CANDO clinical feasibility study

Feltz-Cornelis¹,

Brabyn²,

Ratcliff³

et al. 2021

Brain, Behavior, & Immunity - Health

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Background Conversion disorder/functional neurological disorder (CD/FND) occurs often in neurological settings and can lead to long-term distress, disability and demand on health care services. Systemic low-grade inflammation might play a role, however, the pathogenic mechanism is still unknown. Aim 1) To explore the feasibility to establish and assess a cohort of CD/FND with motor symptoms, involving persons with lived experience (PPI). 2) To generate proof of concept regarding a possible role for cytokines, microRNA, cortisol levels and neurocognitive symptoms in patients with motor CD/FND. Method Feasibility study. Results The study showed active involvement of patients despite high clinical illness burden and disability, neurocognitive symptoms, childhood adverse experiences (ACE) and current life events. The study provided valuable knowledge regarding the feasibility of conducting a study in these patients that will inform future study phases. In the sample there were elevated levels of IL6, IL12, IL17A, IFNg, TNFa and VEGF-a, suggesting systemic low-grade inflammation. Also, microRNAs involved in inflammation and vascular inflammation were correlated with TNFa and VEGFa respectively, suggesting proof of concept for an epigenetic mechanism. Owing to the COVID-19 outbreak, the patient sample was limited to 15 patients. Conclusion It is a novelty that this study is conducted in the clinical setting. This innovative, translational study explores stress-related SLI in CD/FND patients and the feasibility of a larger project aiming to develop new treatments for this vulnerable population. Given the positive findings, there is scope to conduct further research into the mechanism of disease in CD/FND.

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“…Peripheral IL-1b communicates with the brain via neural and humoral pathways to induce brain expression of IL-1b, the activity of which subsequently elicits changes in behavior [Johnson, 2002;Dantzer, 2006]. Importantly, IL-1b activity in the brain is subject to tight regulation, so as to control the intensity and duration of the response, and to guard against responses occurring out of context [Dantzer, 2004].There is a striking degree of overlap between symptoms of sickness behavior and clinical symptoms of depression, the recognition of which has led to the view that depression could, in some part, be a manifestation of inappropriate (and maladaptive) sickness behavior [Smith, 1991;Charlton, 2000;Viljoen and Panzer, 2005;Dantzer, 2006]. Given the pivotal role of IL-1b in mediating sickness behavior, the further implication of this is that dysregulation of IL-1b activity could be a causal factor in depressive disorders.…”

mentioning

confidence: 99%

Tagging SNP association study of the IL‐1β gene (IL1B) and childhood‐onset mood disorders

Misener

Gomez

Wigg

et al. 2009

American J of Med Genetics Pt B

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Given substantial evidence for IL-1beta involvement in the etiology of depression, the IL1B gene is a strong candidate for involvement in susceptibility to depressive disorders. However, association studies investigating this, to date, have been limited to just two polymorphisms (rs1143627[-31T/C] and rs16944[-511C/T]) that constitute only a fraction of the genetic variation that is actually present across this gene in the population. Here, in a family-based association study of childhood-onset mood disorders (COMD), characterized by onset of depression before the age of 15, we have used a gene-wide approach, employing a panel of five tagging SNPs spanning the entire gene. Based on TDT analyses of both individual alleles and haplotypes, in a study sample of 646 families (with 782 affected children), none of the SNPs, including those implicated in transcriptional regulation of the gene, showed evidence for association with COMD. This is the largest and most comprehensive study of IL1B in relation to mood disorders that has been carried out, to date. The results do not support the involvement of IL1B as a major factor in genetic risk for early-onset mood disorders.

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Non-termination of sickness behavior as precipitating factor for mental disorders

Cited by 10 publications

References 63 publications

Antidepressants may lead to a decrease in niacin and NAD in patients with poor dietary intake

Antidepressants may lead to a decrease in niacin and NAD in patients with poor dietary intake

Assessment of cytokines, microRNA and patient related outcome measures in conversion disorder/functional neurological disorder (CD/FND): The CANDO clinical feasibility study

Tagging SNP association study of the IL‐1β gene (IL1B) and childhood‐onset mood disorders

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