Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours.

5-hydroxyindole acetic acid, a metabolite of serotonin, is used in the diagnosis and monitoring of patients with neuroendocrine tumours, in particular patients with small intestinal neuroendocrine tumours associated with the carcinoid syndrome. Analysis of 5-hydroxyindole acetic acid was commonly performed in urine, but blood-based assays are now becoming available. The objective of this study was to assess how 5-hydroxyindole acetic acid compares in plasma and serum as a biochemical marker of neuroendocrine tumours. Twenty-four-hour urine, plasma and serum samples were obtained from 80 patients with neuroendocrine tumours and 30 healthy volunteers. We developed a liquid chromatography tandem mass spectrometry assay for plasma and serum 5-hydroxyindole acetic acid. Comparison was made between them, and their cut-off was determined using a receiver-operating characteristic curve. A close correlation was shown between plasma and serum 5-hydroxyindole acetic acid. At a cut-off of 135 nmol/l, a sensitivity of 91.2% with a specificity of 61.9% was obtained for both compared to the urinary assay. A statistically significant agreement was shown when plasma and serum 5-hydroxyindole acetic acid were compared with the currently used urine assay in patients with neuroendocrine tumours; κ = 0.675 (95% CI 0.49 to 0.86), p < 0.001 and healthy volunteers; 0.967 (95% CI 0.828 to 0.999), p = <0.001. In conclusion, 5-hydroxyindole acetic acid in plasma and serum were comparable, hence either sample type can be used interchangeably.

G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans.

G protein-coupled receptors (GPCRs) regulate many animal behaviors. GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. To further elucidate the role of GRKs in regulating GPCR-mediated behaviors, we utilized the genetic model system Caenorhabditis elegans Our studies demonstrate that grk-2 loss-of-function strains are egg laying-defective and contain low levels of serotonin (5-HT) and high levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA). The egg laying defect could be rescued by the expression of wild type but not by catalytically inactive grk-2 or by the selective expression of grk-2 in hermaphrodite-specific neurons. The addition of 5-HT or inhibition of 5-HT metabolism also rescued the egg laying defect. Furthermore, we demonstrate that AMX-2 is the primary monoamine oxidase that metabolizes 5-HT in C. elegans, and we also found that grk-2 loss-of-function strains have abnormally high levels of AMX-2 compared with wild-type nematodes. Interestingly, GRK-2 was also found to interact with and promote the phosphorylation of AMX-2. Additional studies reveal that 5-HIAA functions to inhibit egg laying in a manner dependent on the 5-HT receptor SER-1 and the G protein GOA-1. These results demonstrate that GRK-2 modulates 5-HT metabolism by regulating AMX-2 function and that 5-HIAA may function in the SER-1 signaling pathway.

Clinical and biochemical assessment of depressive symptoms in patients with Alkaptonuria before and after two years of treatment with nitisinone.

OBJECTIVE: Concerns exist over hypertyrosinaemia that is observed following treatment with nitisinone. It has been suggested that tyrosine may compete with tryptophan for uptake into the central nervous system, and or inhibit tryptophan hydroxylase activity reducing serotonin production. At the National Alkaptonuria (AKU) Centre nitisinone is being used off-licence to treat AKU, and there is uncertainty over whether hypertyrosinaemia may alter mood. Herein results from clinical and biochemical assessments of depression in patients with AKU before and after treatment with nitisinone are presented. PATIENTS AND METHODS: 63 patients were included pre-nitisinone treatment, of these 39 and 32 patients were followed up 12 and 24 months after treatment. All patients had Becks Depression Inventory-II (BDI-II) assessments (scores can range from 0 to 63, the higher the score the more severe the category of depression), and where possible urinary monoamine neurotransmitter metabolites and serum aromatic amino acids were measured as biochemical markers of depression. RESULTS: Mean (±standard deviation) BDI-II scores pre-nitisinone, and after 12 and 24 months were 10.1(9.6); 9.8(10.0) and 10.5(9.9) (p ≥ 0.05, all visits). Paired scores (n = 32), showed a significant increase at 24 months compared to baseline 10.5(9.9) vs. 8.6 (7.8) (p = 0.03). Serum tyrosine increased at least 6-fold following nitisinone (p ≤ 0.0001, all visits), and urinary 3-methoxytyramine (3-MT) increased at 12 and 24 months (p ≤ 0.0001), and 5-hydroxyindole acetic acid (5-HIAA) decreased at 12 months (p = 0.03). CONCLUSIONS: BDI-II scores were significantly higher following 24 months of nitisinone therapy in patients that were followed up, however the majority of these patients remained in the minimal category of depression. Serum tyrosine and urinary 3-MT increased significantly following treatment with nitisinone. In contrast urinary 5-HIAA did not decrease consistently over the same period studied. Together these findings suggest nitisinone does not cause depression despite some observed effects on monoamine neurotransmitter metabolism.

Associations of cerebrospinal fluid monoamine metabolites with striatal dopamine transporter binding and 123I-meta-iodobenzylguanidine cardiac scintigraphy in Parkinson's disease: Multivariate analyses.

Cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA), dopamine and serotonin metabolites, are decreased in Parkinson's disease (PD). Although some reported associations between HVA and striatal dopamine transporter (DAT) or 5-HIAA and cardiac 123I-meta-iodobenzylguanidine (MIBG) findings, respectively, whether these are direct associations remained unknown. We retrospectively reviewed 57 drug-naïve patients with PD who underwent CSF analyses and DAT and cardiac MIBG imaging. Z-score of striatal DAT specific binding ratio (Z-SBR) was measured, and the positivity of MIBG abnormalities were judged by an expert. The mean age was 75.5 ± 8.7 years. Thirty-three were MIBG-positive and 24 were MIBG-negative. 5-HIAA levels were significantly lower in the MIBG-positive group. Logistic regression analysis showed that MIBG positivity was associated with 5-HIAA level (odds ratio = 0.751, p = 0.006) but not with age, sex, and HVA. DAT Z-SBR correlated with both HVA and 5-HIAA. Multiple regression analysis showed that HVA was the only significant variable associated with Z-SBR (t = 3.510, p < 0.001). We confirmed direct associations between 5-HIAA and cardiac MIBG, and between HVA and striatal DAT binding.

A three-pronged analysis confirms the association of the serotoninergic system with attention deficit hyperactivity disorder.

BACKGROUND: The serotonin transporter (SERT), encoded by the solute carrier family 6 number 4 (SLC6A4) gene, controls serotonin (5-HT) availability and is essential for the regulation of behavioral traits. Two SLC6A4 genetic variants, 5-HTTLPR and STin2, were widely investigated in patients with various neurobehavioral disorders, including attention deficit hyperactivity disorder (ADHD). METHODS: We analyzed the association of the 5-HTTLPR (L/S) and STin2 (10/12) variants, plasma 5-HT, and 5-hydroxyindole acetic acid (5-HIAA), as well as SERT messenger RNA (mRNA) with ADHD in the eastern Indian subjects. Nuclear families with ADHD probands (n = 274) and ethnically matched controls (n = 367) were recruited following the Diagnostic and Statistical Manual of Mental Disorders. Behavioral traits, executive function, and intelligence quotient (IQ) of the probands were assessed using the Conner's Parent Rating Scale - Revised, Parental Account of Children's Symptoms (PACS), Barkley Deficit in Executive Functioning-Child and Adolescent Scale, and Wechsler Intelligence Scale for Children-III, respectively. After obtaining informed written consent, peripheral blood was collected to analyze genetic variants, plasma 5-HT, 5-HIAA, and SERT mRNA expression. RESULTS: ADHD probands showed a higher frequency of the 5-HTTLPR "L" allele and "L/L" genotype (P < 0.05), lower 5-HIAA level, and higher SERT mRNA expression. Scores for behavioral problems and hyperactivity were higher in the presence of the "S" allele and "S/S" genotype, while executive deficit was higher in the presence of the "L" allele. IQ score was lower in the presence of the STin2 "12" allele and L-12 haplotype. CONCLUSION: Data obtained indicate a significant association of the serotoninergic system with ADHD, warranting further in-depth investigation.

5-HIAA as a Potential Biological Marker for Neurological and Psychiatric Disorders.

Neurological and psychiatric disorders occur in about 6 percent of the global population indicating a significant amount of people suffering from neurological disorder on a varying range in day to day life. On an extensive view, there is a critical requirement for the development of an alternative biomarker for these conditions. The thwart found in developing a biomarker is the difficulty in identifying a serum biomarker as these are mostly limited to the central nervous system (CNS). Serotonin being a neurotransmitter synthesized in the raphe nuclei of the brain could serve as an alternative biomarker. Here, the limitation is that it's quickly metabolized by the mitochondrial enzyme MAO to 5-hydroxy indole acetic acid (5HIAA). This subsequent metabolite can be used for the analysis of serotonin levels in brain by analysing its concentration in the cerebrospinal fluid (CSF). Many theories suggest that the variations in serotonin level could lead to the development of many neurological and psychiatric disorders like Alzheimer's disease (AD), schizophrenia, depression and so on. A decreased level is noticed in these patients but this could either be due to decreased production or increased reuptake of serotonin from the neuronal synapses. For instance, we know that a patient with depression shows a significant reduction in the levels of 5HIAA, due to the location of the raphe nuclei within regions of memory and cognition. Similarly, it does shows variation in AD and mild cognitive disorder. Evolving of 5HIAA as a biomarker, could be more delicate and enhanced strategy for monitoring these disorders.

Assessment of the Effect of Once Daily Nitisinone Therapy on 24-h Urinary Metadrenalines and 5-Hydroxyindole Acetic Acid Excretion in Patients with Alkaptonuria After 4 Weeks of Treatment.

BACKGROUND: One of the major metabolic consequences of using nitisinone to treat patients with alkaptonuria is that circulating tyrosine concentrations increase. As tyrosine is required for the biosynthesis of catecholamine neurotransmitters, it is possible that their metabolism is altered as a consequence. Herein we report the 24-h urinary excretion of normetadrenaline (NMA), metadrenaline (MA), 3-methoxytyramine (3-MT) (catecholamine metabolites) and 5-hydroxyindole acetic acid (5-HIAA, metabolite of serotonin) in a cohort of AKU patients before and after a 4-week treatment trial with nitisinone. MATERIALS AND METHODS: 24 h urinary excretions of NMA, MA, 3-MT and 5-HIAA were determined by liquid chromatography tandem mass spectrometry. Interassay coefficient of variation was <10% for all analytes measured, at all concentrations tested. RESULTS: Urine samples were assayed at baseline (pre-nitisinone, n = 36) and 4 weeks later; 7 received no nitisinone (4 male, mean age (±SD) 46.3 (16.4) years), and 29 received a daily dose of nitisinone [1 mg (n = 7, 6 male, mean age 45.9 (10.9) years), 2 mg (n = 8, 5 male, mean age 43.9 (13.7) years), 4 mg (n = 8, 5 male, mean age 47.3 (10.7) years) and 8 mg (n = 6, 4 male, mean age 53.8 (8.3) years)]. 3-MT concentrations increase significantly (p < 0.01, at all doses) following nitisinone therapy but not in a dose-dependent manner. NMA concentrations decreased (p < 0.05, at all doses) following nitisinone therapy at all doses. 5-HIAA concentrations decreased following nitisinone therapy and were significantly lower at a daily dose of 8 mg only (p < 0.05). CONCLUSIONS: This study shows that catecholamine and serotonin metabolism is altered by treatment with nitisinone.

Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Carcinoid Heart Disease: A Contraindication or a Promising Treatment Approach Bettering Chances for Corrective Surgery?

We report the gratifying response of functioning metastatic neuroendocrine tumor with carcinoid heart disease (uncontrolled by long-acting octreotide) to treatment with 177Lu-DOTATATE. This response favorably altered the clinical course of the patient, enabling corrective valvular surgery, enhancing health-related quality of life, improving symptoms (from New York Heart Association grade III at baseline to grade I after 6 cycles), stabilizing the disease, and substantially reducing the level of 5-hydroxyindole acetic acid. Avoiding concerns about volume overload by administering amino acids over a relatively prolonged period of 7.5-8 h during peptide receptor radionuclide therapy could be particularly helpful and could be conveniently adopted in this clinical setting. Considering the significantly shortened overall survival of patients with carcinoid heart disease, the relative paucity of available treatment options, and the risk of complications during corrective surgery on poorly controlled functioning disease, 177Lu-DOTATATE can emerge as a potent option in this group of patients.

Trace level determination of 5-hydroxytryptamine and its related indoles in amniotic fluid by gas chromatography-mass spectrometry.

5-hydroxytryptamine (5-HT) and its derivatives are endogenously active substances involved in multiple physiological and pathological processes. A novel method of detetermining 5-hydroxyindole ethanol (5-HTOL), 5-hydroxyindole acetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP) and 5-HT in amniotic fluid by gas chromatography-mass spectrometry (GC-MS) was established based on a modified method of derivatization by silanization, in combination with solid-phase extraction pretreatment. Good linearity was achieved in the tested calibration range. The limits of detection (LOD) were 0.05, 0.08, 0.56, 0.43µg/L for 5-HTOL, 5-HIAA, 5-HTP and 5-HT, respectively. Accuracy (92.4-103.3) and precision (RSD <5.4%) for all analytes was also determined. Then the method was used to analyze samples of amniotic fluid from 12 patients carrying foetuses with trisomy 21 and 12 healthy controls. Compared with normal fetuses, the levels of 5-HTOL, 5-HTP and 5-HT in the amniotic fluid were significantly altered in the fetuses with trisomy 21 (P<0.01); the level of 5-HIAA showed no significant difference between the two groups (P>0.05). This is a rapid, sensitive and reliable method for the determination of 5-HTOL, 5-HIAA, 5-HTP and 5-HT, and the study provide both potential trisomy 21 markers and elucidation of the physiological and pathological roles of 5-HT.

Low-dose acute vanillin is beneficial against harmaline-induced tremors in rats.

OBJECTIVE: To study the effect of pretreatment with low doses of vanillin, a flavoring agent used as a food additive, on harmaline-induced tremor in rats. METHODS: Sprague Dawley rats (110 ± 5 g) were divided into groups of six animals each. Vanillin (6.25 mg, 12.5 mg, and 25 mg/kg) was administered by gavage to different groups of rats, 30 minutes before the induction of tremor. Harmaline (10 mg/kg, i.p.) was used for the induction of tremor. The latency of onset, duration, tremor intensity, tremor index, and spontaneous locomotor activity were recorded. A separate batch of animals was used for the determination of serotonin (5HT) and 5 hydroxyindole acetic acid (5HIAA) levels in the brain. RESULTS: Harmaline treatment resulted in characteristic tremor that lasted for more than 2 hours and decreased the locomotor activity of rats. Pre-treatment with vanillin significantly reduced the duration, intensity, and tremor index of harmaline-treated animals. Vanillin treatment also significantly attenuated harmaline-induced decrease in the locomotor activity. An increase in 5HT levels and the changes in 5HIAA/5HT ratio observed in harmaline treated rats were significantly corrected in vanillin pretreated animals. DISCUSSION: Vanillin in low doses reduces harmaline-induced tremor in rats, probably through its modulating effect on serotonin levels in the brain. These findings suggest a beneficial effect of vanillin in essential tremor.

Improving therapeutics in anorexia nervosa with tryptophan.

A growing body of evidence suggests that our diet is an important contributing factor in the development, management and prevention of a number of psychiatric illnesses. Tryptophan, an essential amino acid, is the sole precursor of neurotransmitter 5-hydroxytryptamine (5-HT; serotonin). Administration of tryptophan can boost serotonin neurotransmission to produce therapeutically important effects in serotonin deficiency disorders. Anorexia nervosa (AN) an eating disorder associated with high levels of psychiatric comorbidity including psychosis, hyperactivity, depression and anxiety has highest lethality of all psychiatric illnesses. Evidence suggests that excessive dieting and food restriction can decrease brain tryptophan and serotonin in AN patients to precipitate depression, psychosis and hyperactivity. There are currently no FDA approved pharmacological treatments available for AN patients; antidepressants and antipsychotics, largely used to treat associated psychiatric comorbidities are also not very effective. The aim of this non-systematic review article is to evaluate and document a potential importance of tryptophan supplementation in improving therapeutics in AN patients.

Paraquat and psychological stressor interactions as pertains to Parkinsonian co-morbidity.

A number of epidemiological and experimental studies have implicated the non-selective herbicide, paraquat, in the development of sporadic Parkinson's disease (PD). While preclinical research has focused mainly on elucidating the nigrostriatal effects of paraquat, relatively little data are available concerning non-motor brain systems and inflammatory immune processes (which have been implicated in PD). Hence, in the present study, we sought to take a multi-system approach to characterize the influence of paraquat upon extra-nigrostriatal brain regions, as well ascertain whether the impact of the pesticide might be enhanced in the context of chronic intermittent stressor exposure. Our findings support the contention that paraquat itself acted as a systemic stressor, with the pesticide increasing plasma corticosterone, as well as altering neurochemical activity in the locus coeruleus, paraventricular nucleus of the hypothalamus, nucleus accumbens, dorsal striatum, and central amygdala. However, with the important exception striatal dopamine turnover, the stressor treatment did not further augment these effects. Additionally, paraquat altered inter-cytokine correlations and, to a lesser extent, circulating cytokine levels, and concomitant stress exposure modulated some of these effects. Finally, paraquat provoked significant (albeit modest) reductions of sucrose preference and weight gain, hinting at possible anhendonic-like or sickness responses. These data suggest that, in addition to being a well known oxidative stress generator, paraquat can act as a systemic stressor affecting hormonal and neurochemical activity, but largely not interacting with a concomitant stressor regimen.

Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis.

The involvement of immune system activation in the pathophysiology of certain psychiatric disorders is well documented. Inflammatory molecules such as pro-inflammatory cytokines could enhance the activity of the indoleamine 2,3-dioxygenase (IDO) enzyme which is the first rate-limiting enzyme of the tryptophan degradation pathway, the kynurenine pathway. The increased tryptophan degradation could induce serotonin depletion and depressive mood. On the other hand, the downstream metabolites from this pathway, such as 3-hydroxykynurenine, quinolinic acid and kynurenic acid, are neuroactive metabolites which can modulate several neurotransmissions, such as glutamatergic, GABAergic, dopaminergic and noradrenergic neurotransmissions, which in turn induce changes in neuronal-glial network and neuropsychiatric consequences. In this issue, we have revised the previous 'neurodegeneration hypothesis,' which explained the involvement of cytokines and IDO pathway interaction in depression, with a further extended view related to the network beyond IDO, the network between immune molecules, tryptophan metabolites and different neurotransmitters, in depression and other major psychiatric disorders such as schizophrenia, bipolar disorder and childhood psychiatric disorders.