Urine metabolic phenotyping in children with nocturnal enuresis and comorbid neurobehavioral disorders.

Nocturnal enuresis (NE) is a common problem among 10% school-aged children. The etiologies underlying childhood NE is complex and not fully understood nowadays. Nevertheless, increasing evidence suggests a potential link between neurobehavioral disorders and enuresis in children. In this study, we aimed to explore novel metabolomic insights into the pathophysiology of NE and also, its association with pediatric psychiatric problems. Urine collected from 41 bedwetting children and 27 healthy control children was analyzed by using 1H-nuclear magnetic resonance spectroscopy from August 2017 to December 2018. At regular follow-up, there were 14 children with refractory NE having a diagnosis of attention deficient hyperactivity disorder (ADHD) or anxiety. Eventually, we identified eight significantly differential urinary metabolites and particularly increased urinary excretion of betaine, creatine and guanidinoacetate linked to glycine, serine and threonine metabolism were associated with a comorbidity of neurobehavioral disorders in refractory bedwetting children. Notably, based on physiological functions of betaine acting as a renal osmolyte and methyl group donor, we speculated its potential role in modulation of renal and/or central circadian clock systems, becoming a useful urinary metabolic marker in diagnosis of treatment-resistant NE in children affected by these two disorders.

Urinary biomarker panel for diagnosing patients with depression and anxiety disorders.

Available data indicate that patients with depression and anxiety disorders are likely to be at greater risk for suicide. Therefore, it is important to correctly diagnose patients with depression and anxiety disorders. However, there are still no empirical laboratory methods to objectively diagnose these patients. In this study, the multiple metabolomics platforms were used to profile the urine samples from 32 healthy controls and 32 patients with depression and anxiety disorders for identifying differential metabolites and potential biomarkers. Then, 16 healthy controls and 16 patients with depression and anxiety disorders were used to independently validate the diagnostic performance of the identified biomarkers. Finally, a panel consisting of four biomarkers-N-methylnicotinamide, aminomalonic acid, azelaic acid and hippuric acid-was identified. This panel was capable of distinguishing patients with depression and anxiety disorders from healthy controls with an area under the receiver operating characteristic curve of 0.977 in the training set and 0.934 in the testing set. Meanwhile, we found that these identified differential metabolites were mainly involved in three metabolic pathways and five molecular and cellular functions. Our results could lay the groundwork for future developing a urine-based diagnostic method for patients with depression and anxiety disorders.

Uric acid in major depressive and anxiety disorders.

BACKGROUND: Uric acid has neuroprotective effects, owing to its antioxidant properties. Lowered antioxidant capacity, causing increased oxidative stress, may be involved in affective disorders and might be altered by antidepressants. This study investigated the association of plasma uric acid, the greatest contributor to blood antioxidant capacity, with major depressive disorder (MDD) and anxiety disorders. METHODS: Data were from the Netherlands Study of Depression and Anxiety including patients with current (N = 1648), remitted (N = 609) MDD and/or anxiety disorders (of which N = 710 antidepressant users) and 618 controls. Diagnoses were established with the Composite International Diagnostic Interview. Symptom severity was assessed with the Inventory of Depressive Symptoms-Self Report, Beck Anxiety Inventory and Fear Questionnaire. Uric acid was measured in plasma. Analyses were adjusted for sociodemographic, health and lifestyle variables. RESULTS: Plasma uric acid adjusted mean levels were lower in current MDD and/or anxiety disorder(s) (289µmol/l) compared to remitted disorders (298µmol/l, p < .001) and controls (299µmol/l, p < .001; Cohen's d .10). This finding was independent of antidepressant use. Depressive (ß-.05, p = .0012), anxiety (ß-.04, p = .009) and phobic (ß-.03, p = .036) symptom severity, and symptom duration (ß-.04, p = .009) were negatively associated with uric acid. LIMITATIONS: Limitations include the lack of data on dietary intake which could be a potential confounding factor. From these cross-sectional findings, the association between uric acid and psychopathology cannot be inferred to be causal. CONCLUSION: This large scale study finds plasma uric acid levels are lower in current, but not remitted, MDD and/or anxiety disorders, according to a dose-response gradient. This suggests the involvement of decreased antioxidant status in affective disorders, and points to their potential as an avenue for treatment.

Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors.

Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation.

Sleep symptoms during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

STUDY OBJECTIVES: Describe the severity of getting to sleep, nighttime awakening, and early morning awakening across the menopausal transition (MT) and early postmenopause (PM) and their relationship to age, menopausal transition factors, symptoms, stress-related factors, and health related factors. DESIGN: Cohort. SETTING: community. PARTICIPANTS: 286 women from the Seattle Midlife Women's Health Study cohort. MEASUREMENTS: Participants completed annual menstrual calendars for MT staging, diaries in which they rated their symptoms, stress levels, and perceived health multiple times per year from 1990-2007 and provided first morning urine samples assayed for E1G, FSH, cortisol, and catecholamines. Multilevel modeling (R program) was used for data analysis. RESULTS: Severity of self-reported problems going to sleep was associated with all symptoms, perceived stress, history of sexual abuse, perceived health (-), alcohol use (-) (all P < 0.001), and lower cortisol (P = 0.009), but not E1G or FSH. Severity of nighttime awakening was significantly associated with age, late MT stage, and early PM, FSH, E1G (-), hot flashes, depressed mood, anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-), and alcohol use (-) (all P < 0.001, except E1G for which P = 0.030). Severity of early morning awakening was significantly associated with age, hot flashes, depressed mood anxiety, joint pain, backache, perceived stress, history of sexual abuse, perceived health (-) (all P < or = 0.001, except E1G for which P = 0.02 and epinephrine (P = 0.038), but not MT stages or FSH. Multivariate models for each symptom included hot flashes, depressed mood, and perceived health. CONCLUSION: Sleep symptoms during the MT may be amenable to symptom management strategies that take into account the symptom clusters and promote women's general health rather than focusing only on the MT.

Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities.

OBJECTIVE: To assess urinary 6-sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. BACKGROUND: Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders. METHODS: Urine samples were collected into a single plastic container over a 12-hour period from 8:00 pm to 8:00 am of the next day, and 6-sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory. RESULTS: A total of 220 subjects were evaluated - 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6-sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6-sulphatoxymelatonin levels and depression, anxiety, and fatigue. CONCLUSIONS: To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.

Extreme anxiety/panic disorder.

A 45 year old man is referred to a specialist psychiatric centre. For 3 years he has been experiencing worsening impending fear of death and anxiety which he describes as 'panic attacks'. During these episodes he often experiences palpitations and becomes sweaty. These episodes have not been relieved despite several courses of electroconvulsive therapy. On examination, the man is alert and orientated. He has a normal blood pressure of 125/75 mmHg and electrocardiogram reveals a pulse rate of 102 beats per minute. A psychiatrist orders a number of routine tests to rule out organic disease.

[The action of high-intensity light on catecholamine excretion in depressive patients]. / Deistvie sveta povyshennoi intensivnosti na ékskretsiiu katekholaminov u bol'nykh depressiei.

The action of bright light (2600-2800 lux) on the catecholamine (CA) excretion was analyzed in patients with anxious (11) and melancholic (12) depressions resultant from manic-depressive psychosis and schizophrenia. The melancholic depressed patients were characterized by decreased noradrenaline (NA) and increased adrenaline (A) levels; in anxious depression NA and A were increased. The light therapy resulted in decrease of A level but NA level remained invariable in melancholic depression. Meanwhile the tendency to normalization of excretion of both CA was observed in anxious patients after light therapy. The contrary alterations in A/NA ratio as well as its considerable individual fluctuations were observed after light therapy. The A/NA ratio after light therapy depended mainly upon the initial A/NA ratio (the higher or lower ratio compared to control value).

The association of the serotonin metabolite, 5-HIAA, to the lysosomal enzyme N-acetyl-beta-glucosaminidase.

Twenty-one medication-free patients with generalized anxiety disorder (GAD) collected urine samples for 5-hydroxyindoleacetic acid (5-HIAA) and N-acetyl-beta-glucosaminidase (NAG). Nine patients with no comorbid psychiatric diagnosis showed a significant association between 5-HIAA and NAG, r = -0.683, p = 0.04. The possibility that NAG could be a marker for serotonin metabolism is discussed.

The association of urinary 5-hydroxyindoleacetic acid and vanillylmandelic acid in patients with generalized anxiety.

There is evidence that serotonin and norepinephrine are in some way involved in the pathophysiology of anxiety disorders. Urinary levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the norepinephrine metabolite vanillylmandelic acid (VMA) were measured in 46 patients with generalized anxiety disorder. There was a significant association between urinary levels of 5-HIAA and VMA: r = 0.79; p = 0.0001. Possible implications of this finding are discussed.

Urinary catecholamines in attention-deficit hyperactivity disorder with and without comorbid anxiety.

OBJECTIVE: To determine whether there are differences in noradrenergic or adrenergic functioning in children with attention-deficit hyperactivity disorder (ADHD) with and without anxiety. METHOD: ADHD children with and without a comorbid overanxious (ANX) disorder were compared to each other and to normal controls in terms of 2-hour urinary excretion of norepinephrine (NE), epinephrine (EPI), and their metabolites. All subjects performed a fixed series of mentally stressful tasks during the collection period. RESULTS: Children with ADHD, regardless of comorbid anxiety, excreted more normetanephrine (NMN), the chief extracellular metabolite of NE, than controls, as well as more vanillylmandelic acid. Children with ADHD alone had lower NE/NMN and EPI/metanephrine ratios compared to controls. Children with ADHD/ANX excreted more EPI than ADHD children without anxiety. CONCLUSIONS: Children with ADHD may have a higher tonic activity of the noradrenergic system than controls, while children with comorbid ADHD/ANX may be differentiated from those with ADHD alone by higher adrenergic activity.

The reliability of urinary 5-HIAA levels.

Examination of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the urine of psychiatry patients has generally not been used because the reliability of urinary 5-HIAA levels has been questioned. Thirty-seven generalized anxiety disordered patients collected two consecutive urines for measurement of 5-HIAA. The correlation of the 5-HIAA collections was r = 0.82, p = 0.0001.

Urinary phenylacetic acid in panic disorder with and without depression.

Phenylacetic acid (PAA) excretion was measured in 39 patients who met criteria for panic disorder; 9 of these also had major depression, and 30 did not. Patients with panic and depression excreted 66 +/- 23 mg/day of PAA, an amount significantly lower than in normal controls; patients with panic disorder but without depression excreted 104 +/- 23 mg/day of PAA (not significantly lower than controls). The results support previous studies indicating that PAA excretion is a marker for depressive disorder.

Differential rates of urinary noradrenalin excretion in affective disorders: utility of a short time sampling procedure.

Levels of morning urinary noradrenalin (NA) excretion were compared in 61 patients with unipolar major depression (MDE), 25 patients with minor depression (mDE), 39 patients with anxiety disorder (AD), and 21 healthy control subjects (C). The following differences in the level of urinary NA excretion rate were found: MDE greater than mDE = AD greater than C. In addition, a significant positive correlation was found in the MDE group between severity of illness, expressed as total Hamilton depression score, in diagnostic subclasses from the Research Diagnostic Criteria, and urinary NA excretion rates (first episode, MDE total group, recurrent, with psychotic features). These data support the utility of a short time urine sampling procedure to measure NA excretion as a peripheral marker monitoring sympathetic activity in inpatient as well as outpatient conditions.

The relationship of panic disorder and its treatment outcome to 24-hour urinary MHPG levels.

Levels of 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) were not markedly elevated in a group of 35 panic disorder patients when compared to healthy controls (mean = 2,430 micrograms/day vs. 2,130 micrograms/day). There was a weak association between elevated pretreatment levels of MHPG and a positive treatment response to alprazolam or diazepam. Alprazolam and diazepam may differ in their effects on MHPG.

Urinary catecholamine metabolite and tribulin output during lactate infusion.

Urinary output of homovanillic acid and 4-hydroxy-3-methoxymandelic acid was decreased both in patients with panic attacks and in normal controls during lactate infusion, whereas that of tribulin (an endogenous monoamine oxidase inhibitor and benzodiazepine receptor binding inhibitor) was increased. There was no change in urinary excretion of any of these compounds during saline infusion. These findings provide further evidence of a link between tribulin output and stress and anxiety in man and point to its possible in vivo action as a monoamine oxidase inhibitor.

Urinary free catecholamines--diagnostic application of an HPLC technique to the investigation of neural crest tumours.

Experience in the use of an in-house urinary free catecholamine assay for the investigation of possible neural crest tumours in a District General Hospital laboratory is described. Elevated excretion of catecholamines and vanillylmandelic acid was found in a number of cases including phaeochromocytoma and neuroblastoma. These as well as several other situations in which elevated catecholamine and vanillylmandelic acid values were found are discussed.