Cerebrospinal Fluid Monoamine Metabolites Research Articles

Altered brain dopamine metabolism is a trait marker for bipolar disorder

Pharmacological treatment, imaging, and neurochemistry studies identify altered dopamine signaling in bipolar disorder. Our previous work has shown higher concentration of homovanillic acid (HVA), the end metabolite of dopamine, in cerebrospinal fluid (CSF) from individuals with bipolar disorder compared to healthy controls. Here, we analyzed HVA concentrations from a follow-up visit in 103 adults with bipolar disorder and 57 controls from our first cohort. Further, we analyzed CSF monoamine metabolite concentrations in a second cohort of 152 adults with bipolar disorder and 55 controls. At the follow-up visit for the first cohort, HVA was higher in individuals with bipolar disorder (278 ± 102 nmol/L, p = 0.003) compared with controls (232 ± 83 nmol/L). In the second cohort, individuals with bipolar disorder had higher HVA (272 ± 97 nmol/L, p = 0.001) and lower 3-methoxy-4-hydroxyphenylglycol (MHPG, 40 ± 9 nmol/L, p = 0.002) concentrations than controls (HVA, 231 ± 71 nmol/L and MHPG, 45 ± 9 nmol/L). Baseline and follow-up measures of monoamine metabolites showed medium to high correlation to each other but did not predict course of illness. We failed to replicate the association of HVA concentration and psychotic symptoms but confirmed lower 5-hydroxyindoleacetic acid (5-HIAA) concentration in individuals treated with antidepressants. In conclusion, we confirmed high HVA concentration in CSF in patients with bipolar disorder compared to a control group. Previous work suggest that this is a feature shared with ADHD but distinct from schizophrenia and major depressive disorder. The role of increased HVA concentration in the course of illness in bipolar disorder remains unclear.

Central nervous system monoaminergic activity in hip osteoarthritis patients with disabling pain: associations with pain severity and central sensitization.

Monoaminergic activity modulates nociceptive transmission in the central nervous system (CNS). Although pain is the most disabling symptom of osteoarthritis (OA), limited knowledge exists regarding the CNS mechanisms that amplify pain and drive sensitization processes in humans. The main objective of this study was to evaluate associations between cerebrospinal fluid (CSF) monoamine metabolites, pain severity, and central sensitization in patients with OA undergoing total hip arthroplasty (THA). Patients with OA (n = 52) and pain-free controls (n = 30) provided CSF samples for measurement of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), noradrenaline (3-methoxy-4-hydroxyphenylglycol [HMPG]), and dopamine (homovanillic acid [HVA]) monoamine metabolites. Patients with OA completed longitudinal evaluation of pain using clinical measures and quantitative sensory testing. Patients with OA had higher HMPG levels when compared with controls (P = 0.036). Within patients with OA undergoing THA, higher 5-HIAA and HVA levels were consistently associated with higher preoperative pain severity. Higher concentrations of 5-HIAA and HVA were also associated with lower conditioned pain modulation levels, whereas higher HMPG levels were linked to more efficient conditioned pain modulation. Patients with higher levels of CSF HVA exhibited increased pressure pain sensitivity (arm pressure pain detection threshold < 250 kPa vs ≥ 250 kPa, P = 0.042). Higher preoperative levels of CSF 5-HIAA predicted poorer pain control 6 months postoperatively (brief pain inventory pain severity; adjusted β = 0.010, 95% CI 0.001-0.019). In OA patients with disabling pain, higher CSF levels of serotonin and dopamine metabolites are associated with increased pain severity and central sensitization. Increased noradrenergic activity may be associated with more efficient pain inhibitory capacity.

A New Look on an Old Issue: Comprehensive Review of Neurotransmitter Studies in Cerebrospinal Fluid of Patients with Schizophrenia and Antipsychotic Effect on Monoamine's Metabolism.

Neurotransmitters metabolism has a key role in the physiopathology of schizophrenia as demonstrated by studies measuring monoamine metabolites in patient’s cerebrospinal fluid (CSF) since the beginning of the antipsychotic use. This comprehensive review aims to understand the anomalies of CSF monoamines in schizophrenia and their correlation with clinical and paraclinical features. We also review the influence of antipsychotic treatment on CSF monoamines and discuss the connection with metabolic and inflammatory processes. Studies comparing CSF homovanillic acid (HVA) levels between patients and controls are miscellaneous, due to the heterogeneity of samples studies. However, low HVA is associated with more positive symptoms and a poorer outcome and negatively correlated with brain ventricle size. Based on humans and animals’ studies, antipsychotic treatments increase HVA during the first week of administration and decrease progressively over the time with a fall-off after withdrawal. 5‐hydroxyindolacetic acetic acid levels do not seem to be different in the patient’s CSF compared to controls. Considering metabolic co-factors of neurotrans-mitters synthesis, there is evidence supporting an increase of kynurenic acid in the CSF of patients with schizophrenia. Few studies explore folate metabolism in CSF. Literature also emphasizes the relationship between folate metabolism, inflammation and monoamine’s metabolism. Those results suggest that the CSF monoamines could be correlated with schizophrenia symptoms and treatment outcome. However, further studies, exploring the role of CSF monoamines as biomarkers of disease severity and response to treatment are needed. They should assess the antipsychotic prescription, inflammatory markers and folate metabolism as potential confounding factors.

Intracerebroventricular Administration of Interferon-Alpha Induced Depressive-Like Behaviors and Neurotransmitter Changes in Rhesus Monkeys.

Interferon-alpha (IFN-α) is a cytokine widely used in the treatment of brain cancers and virus infections with side effects including causing depression. Monoamine neurotransmitter systems have been found playing important roles in peripheral IFN-α-induced depression, but how peripheral IFN-α accesses the central nervous system and contributes to the development of depression is poorly known. This study aimed to develop a non-human primate model using long-term intracerebroventricular (i.c.v.) administration of IFN-α (5 days/week for 6 weeks), to observe the induced depressive-like behaviors and to explore the contributions of monoamine neurotransmitter systems in the development of depression. In monkeys receiving i.c.v. IFN-α administration, anhedonia was observed as decreases of sucrose consumption, along with depressive-like symptoms including increased huddling behavior, decreases of spontaneous and reactive locomotion in home cage, as well as reduced exploration and increased motionless in the open field. Chronic central IFN-α infusion significantly increased the cerebrospinal fluid (CSF) concentrations of noradrenaline (NA), and 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). These CSF monoamine metabolites showed associations with some specific depression-related behaviors. In conclusion, central IFN-α administration induced anhedonia and depression-related behaviors comparable to the results with peripheral administration, and the development of depression was associated with the dysfunction of monoamine neurotransmitters.

Cerebrospinal fluid monoamine metabolite concentrations in depressive disorder: A meta-analysis of historic evidence

Altered monoaminergic functions have been implicated in the pathophysiology of depressive disorder. However, previously reported cerebrospinal fluid (CSF) monoamine metabolite concentrations in major depression have been inconsistent. We performed a meta-analysis of historic evidence to determine whether CSF monoamine metabolite levels were different between patients with depression and normal controls, and could be used as depression biomarkers. Relevant studies that investigated CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with depression and normal controls were identified in PubMed, Web of Science, PsycINFO, and Embase databases through September 5, 2017, using a synonymous search for depression, CSF, normal, control, and each monoamine metabolite name, and in the reference lists of the acquired articles. Obtained records were individually scrutinized for eligibility. Our search strategy identified 26 studies, including our own. We employed random effects modeling and adopted “Hedges's g” as an index of effect size. In the meta-analyses, no significant difference was observed in CSF 5-HIAA or MHPG levels between patients with depressive disorder and controls. In contrast, CSF HVA was significantly decreased in patients with depression (Hedges's g = −0.30, P = 0.0000025), and these results remained significant after patients with bipolar disorder were excluded (Hedges's g = −0.37, P = 0.000061). In the meta-regression, sex was significantly associated with the Hedges's g of CSF HVA (Q = 4.41, P = 0.036). This meta-analysis revealed that only CSF HVA, and not 5-HIAA or MHPG, levels were decreased in depressive disorder. The reduction in the CSF HVA concentration in patients with depression may guide future studies on depression and serve as a useful biomarker of depressive disorder.

No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals

Metabolism of the monoamines dopamine, serotonin and noradrenaline, is altered in the central nervous system of people with schizophrenia, and their major metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively, have been intensively studied as indirect measures of these neurotransmitters in cerebrospinal fluid (CSF). Regular tobacco smoking has been shown to alter neurotransmitter metabolism in the brain and studies have found CSF monoamine metabolite concentrations to be substantially lower in smokers. However, few studies investigating these monoamines in CSF have controlled for regular tobacco smoking. We investigated if regular tobacco smoking influences CSF HVA, 5-HIAA and MHPG concentrations in patients treated for psychotic disorders (n = 69) and healthy non-psychotic human volunteers (n = 200). After lumbar puncture CSF samples were analyzed with mass fragmentography. CSF HVA, 5-HIAA and MHPG concentrations did not significantly differ between smokers and non-smokers neither in patients, nor in healthy subjects, whereas back-length predicted HVA and 5-HIAA and antipsychotic medication MHPG concentrations. The results indicate that regular tobacco smoking has no significant effect on monoamine metabolite concentrations in CSF. This suggests that lack of controlling for regular tobacco smoking should not substantially violate the results in studies of the major monoamine metabolites in CSF.

Seasonality of cerebrospinal fluid monoamine metabolite concentrations and their associations with meteorological variables in humans

Seasonal variations in neurotransmitter parameters have been previously reported in humans. However, these studies have involved small sample sizes and have not examined possible relationships with meteorological variables. We compared cerebrospinal fluid (CSF) concentrations of the major monoamine neurotransmitter metabolites (5-HIAA, HVA, and MHPG) in 188 healthy controls (80 men, 108 women) in relationship to age, sex, BMI, and available meteorological variables. All subjects had a lumbar puncture (LP) performed at 9 a.m. after overnight stay. Meteorological data for the day prior to LP were obtained from the National Climatic Association and included the photoperiod, percent sunshine, temperature (max, min, mean), barometric pressure, relative humidity, amount of precipitation and sky cover. Results revealed differences across seasons and cross-seasons for CSF 5-HIAA (p ≤ .05), with post-hoc differences emerging between spring versus summer and fall and between x-spring and x-summer (p ≤ .05). Differences were also found across seasons for CSF HVA (p ≤ .05) with post-hoc differences between spring versus fall. CSF 5-HIAA was significantly inversely correlated with maximum (r = −.28, p ≤ .02), minimum (r = −.24, p ≤ .04), and mean temperature (r = −.28, p ≤ .02) in men. In women, 5-HIAA (r = −.22, p ≤ .02) and HVA (r = −.28, p ≤ .003) were significantly correlated with relative humidity. These data confirm previous findings of variations in serotonin and dopamine metabolites across the year and highlight possible underlying mechanisms involving meteorological changes, which may result in alterations in neurophysiology and behavior.

Relationships of Cerebrospinal Fluid Monoamine Metabolite Levels With Clinical Variables in Major Depressive Disorder.

Many studies have investigated cerebrospinal fluid (CSF) monoamine metabolite levels in depressive disorders. However, their clinical significance is still unclear. We tried to determine whether CSF monoamine metabolite levels could be a state-dependent marker for major depressive disorder (MDD) based on analyses stratified by clinical variables in a relatively large sample. Subjects were 75 patients with MDD according to DSM-IV criteria and 87 healthy controls, matched for age, sex, and ethnicity (Japanese). They were recruited between May 2010 and November 2013. We measured homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in CSF samples by high-performance liquid chromatography. We analyzed the relationships of the metabolite levels with age, sex, diagnosis, psychotropic medication use, and depression severity. There was a weak positive correlation between age and 5-HIAA levels in controls (ρ = 0.26, P < .016) and a similar trend in patients, while sex was unrelated to any metabolite. All monoamine metabolites in moderately to severely depressed patients (17-item Hamilton Depression Rating Scale score > 12) were significantly lower than those in controls (P < .0005 for all 3 metabolites). We found that antidepressants decreased the levels of 5-HIAA (ρ = -0.39, P < .001) and MHPG (ρ = -0.49, P < .0001) and that antipsychotics increased levels of HVA (ρ = 0.24, P < .05). There was a strong correlation between HVA and 5-HIAA levels (controls: ρ = 0.79, P = .000001; MDD: ρ = 0.66, P = .000001). HVA levels (ρ = -0.43, P < .001) and 5-HIAA levels (ρ = -0.23, P < .05), but not MHPG levels (ρ = -0.18, P > .1), were related to depression severity. CSF 5-HIAA and HVA levels could be state-dependent markers in MDD patients. Since 5-HIAA levels greatly decrease with the use of antidepressants, HVA levels might be more useful in the clinical setting.

Cerebrospinal fluid monoamine metabolite profiles in bipolar disorder, ADHD, and controls

Alterations in monoaminergic signaling are suggested as key aspects of the pathophysiology in bipolar disorder and ADHD, but it is not known if the monoamine metabolic profile differs between these disorders. One method to study monoaminergic systems in humans is to measure monoamine end-point metabolite concentrations in cerebrospinal fluid (CSF). Here, we analyzed CSF monoamine metabolite concentrations in 103 adults with bipolar disorder, 72 adults with ADHD, and 113 controls. Individuals with bipolar disorder had significantly higher homovanillic acid (HVA, 264 ± 112 nmol/L, p < 0.001) and 5-hydroxyindoleacetic acid (5-HIAA, 116 ± 42 nmol/L, p = 0.001) concentration, but lower 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG, 38 ± 8 nmol/L, p < 0.001) concentrations than controls (HVA, 206 ± 70 nmol/L; 5-HIAA, 98 ± 31 nmol/L; and MHPG, 42 ± 7 nmol/L). Higher HVA concentrations were associated with a history of psychosis in the bipolar disorder sample. Subjects with ADHD had higher HVA (240 ± 94 nmol/L, p < 0.001) concentrations compared with controls. In addition, SSRI treatment was associated with lower 5-HIAA concentrations in both patient groups. A power analysis indicated that for within-group comparisons, only large effects would be reliably detectable. Thus, there may be moderate-to-small effects caused by medication that were not detected due to the limited size of the sub-groups in these analyses. In conclusion, the present study suggests disorder-specific alterations of CSF monoamine metabolite concentrations in patients with bipolar disorder and ADHD compared with controls; these differences were independent of acute symptoms and medication effects.

Simultaneous measurement of monoamine metabolites and 5-methyltetrahydrofolate in the cerebrospinal fluid of children

BackgroundWe describe a new method for simultaneous measurement of monoamine metabolites (3-O-methyldopa [3-OMD], 3-methoxy-4-hydroxyphenylethyleneglycol [MHPG], 5-hydroxyindoleacetic acid [5-HIAA], and homovanillic acid [HVA]) and 5-methyltetrahydrofolate (5-MTHF) and its use on cerebrospinal fluid (CSF) samples from pediatric patients. MethodsMonoamine metabolites and 5-MTHF were measured by high-performance liquid chromatography with fluorescence detection. CSF samples were prospectively collected from children according to a standardized collection protocol in which the first 1-ml fraction was used for analysis. ResultsMonoamine metabolites and 5-MTHF were separated within 10min. They showed linearity from the limit of detection to 1024nmol/l. The limit of quantification of each metabolite was sufficiently low for the CSF sample assay. In 42 CSF samples after excluding cases with possibly altered neurotransmitter profiles, the concentrations of 3-OMD, MHPG, 5-HIAA, HVA, and 5-MTHF showed significant age dependence and their ranges were comparable with the reference values in the literature. The metabolite profiles of aromatic l-amino acid decarboxylase deficiency, Segawa disease, and folate receptor α defect by this method were compatible with those in the literature. ConclusionsThis method is a simple means of measuring CSF monoamine metabolites and 5-MTHF, and is especially useful for laboratories not equipped with electrochemical detectors.

Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid.

The blood–brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10−8, β=0.08) and DDX6 (P=2.9 × 10−7, β=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10−52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.

Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity

BackgroundTo examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum.MethodsIn this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post-operative day 1–5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre-operatively and CSF immediately before spinal anesthesia.ResultsFifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor.ConclusionHigher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group.

PS238. Altered balance between monoamine metabolites in human cerebrospinal fluid with major depressive disorder.

PS238. Altered balance between monoamine metabolites in human cerebrospinal fluid with major depressive disorder.

Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis

Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.

Cerebrospinal Fluid Levels of Monoamine Metabolites in the Epileptic Baboon.

The baboon represents a natural model for genetic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). In this retrospective study, cerebrospinal fluid (CSF) monoamine metabolites and scalp electroencephalography (EEG) were evaluated in 263 baboons of a pedigreed colony. CSF monoamine abnormalities have been linked to reduced seizure thresholds, behavioral abnormalities and SUDEP in various animal models of epilepsy. The levels of 3-hydroxy-4-methoxyphenylglycol, 5-hydroxyindolacetic acid and homovanillic acid in CSF samples drawn from the cisterna magna were analyzed using high-performance liquid chromatography. These levels were compared between baboons with seizures (SZ), craniofacial trauma (CFT) and asymptomatic, control (CTL) baboons, between baboons with abnormal and normal EEG studies. We hypothesized that the CSF levels of major monoaminergic metabolites (i.e., dopamine, serotonin and norepinephrine) associate with the baboons' electroclinical status and thus can be used as clinical biomarkers applicable to seizures/epilepsy. However, despite apparent differences in metabolite levels between the groups, usually lower in SZ and CFT baboons and in baboons with abnormal EEG studies, we did not find any statistically significant differences using a logistic regression analysis. Significant correlations between the metabolite levels, especially between 5-HIAA and HVA, were preserved in all electroclinical groups. While we were not able to demonstrate significant differences in monoamine metabolites in relation to seizures or EEG markers of epilepsy, we cannot exclude the monoaminergic system as a potential source of pathogenesis in epilepsy and SUDEP. A prospective study evaluating serial CSF monoamine levels in baboons with recently witnessed seizures, and evaluation of abnormal expression and function of monoaminergic receptors and transporters within epilepsy-related brain regions, may impact the electroclinical status.

EPA-0868 – Genetic determinants of monoamine turnover in human cerebrospinal fluid: associations with 5-HT seasonality and mood symptoms

Although monoamines are thought to be involved in seasonal mood disorders, it is unknown how such concentrations may impact seasonal variation in mood symptoms. Studies of monoaminergic seasonality and a possible influence of the serotonin transporter gene, SLC6A4, on serotonin seasonality have yielded conflicting results. To study this comprehensively, we first performed a genome-wide association study (GWAS) of monoamine metabolites in human cerebrospinal fluid (CSF). We then examined whether the S/L promoter polymorphism of the serotonin transporter gene (5-HTTLPR) affects seasonal changes in CSF serotonin metabolite levels. To translate our findings to the behavioral level, we tested for correlations of 5-HT seasonality values with mood symptoms. The GWAS yielded a locus significantly associated with monoamine metabolite levels 20kb from SSTR1 (P = 4.92 x 10−8), a locus that was shown to control expression of PDE9A, a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. We additionally show evidence for involvement of the S allele with 5-HT seasonality (standardized β = 0.12, P = 0.020). Moreover, 5-HT seasonality correlated positively with depressive symptoms (Spearman's rho = 0.13, P = 0.018). We demonstrate how genetic variation in a range of genes involved with neuronal activity influences monoamine metabolite levels in human CSF. We furthermore highlight a dose-dependent association of the 5-HTTLPR with 5-HT seasonality and a positive correlation between 5-HT seasonality and depressive symptomatology. The presented data provide new insights into the genetic determinants of 5-HT seasonality and its role in affective disorders.

Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis.

BackgroundHomovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis.MethodsWe have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder.ResultsThere were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls.ConclusionsThe present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.

Early death and CSF monoamine metabolites in schizophrenia spectrum psychosis

Introduction: Patients with schizophrenia have higher rates of mortality than the general population. Lower concentrations of the cerebrospinal fluid (CSF) monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been associated with suicidal, aggressive and impulsive behavior. Mortality has been suggested as a measure of impulsivity and a relationship between early death and lower concentrations of CSF monoamine metabolites has been reported but the studies are few with short periods of follow-up and small numbers. Aim: The objective of this study was to investigate a relationship between early death and concentrations of CSF 5-HIAA and HVA. Methods: Three hundred and eighty-five inpatients with schizophrenia spectrum psychosis were lumbar punctured in a standardized manner and followed for a median of 26 years. Patients were searched to identify those who had died. Causes of death were obtained from the Causes of Death Register. Results: During the time of follow-up, 97 patients died. Schizophrenia spectrum psychosis patients died at an earlier age from both natural and unnatural causes of death. No significant associations were found between CSF 5-HIAA and HVA concentrations and non-suicidal death. Attempted suicide was not a risk factor for non-suicidal death at younger age. Conclusion: Patients with schizophrenia spectrum psychosis die at an earlier age from both natural and unnatural causes of death. Attempted suicide is not a risk factor for non-suicidal death at younger age. Low concentrations of CSF HVA and 5-HIAA were not a risk factor for non-suicidal death at younger age in schizophrenia spectrum psychosis.

Associations between the angiotensin-converting enzyme insertion/deletion polymorphism and monoamine metabolite concentrations in cerebrospinal fluid

Angiotensin II has been suggested to influence central dopamine and serotonin turnover. Since the angiotensin-converting enzyme (ACE) plays a key role in angiotensin regulation by converting inactive angiotensin I to active angiotensin II, we hypothesised that the functional insertion/deletion (I/D) polymorphism in the ACE gene, which has previously been suggested to be associated with, depression and panic disorder, may influence monoamine activity. A well-established technique for assessing brain monoamine turnover in humans is to measure concentrations of monoamine metabolites in the cerebrospinal fluid (CSF). We thus investigated possible associations between the ACE I/D polymorphism and CSF monoamine metabolite concentrations in a population of healthy male subjects. After having found such an association between the ACE I/D polymorphism and CSF levels of the dopamine metabolite homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid in this sample, I carriers displaying lower levels, we tried to replicate this observation in a population of violent male offenders from which also both CSF and DNA were available. Also in this sample, the same associations were found. Our results suggest that the ACE I/D polymorphism may play a role in the modulation of serotonergic and dopaminergic turnover in men.

Relationship between dopamine D 2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine

Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naïve patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trail with 600 mg/day quetiapine. CSF monoamine metabolites levels were compared with dopamine D 2 receptor occupancy (DA-D 2) using [ 18F]fallypride and positron emission tomography (PET). Quetiapine produced preferential occupancy of parietal cortex vs. putamenal DA-D 2, 41.4% ( p < 0.05, corrected for multiple comparisons). DA-D 2 receptor occupancies in the occipital and parietal cortex were correlated with CSF quetiapine and norquetiapine levels ( p < 0.01 and p < 0.05, respectively). CSF monoamine metabolites were significantly increased after treatment and correlated with regional receptor occupancies in the putamen [DOPAC: ( p < 0.01) and HVA: ( p < 0.05)], caudate nucleus [HVA: ( p < 0.01)], thalamus [MHPG: ( p < 0.05)] and in the temporal cortex [HVA: ( p < 0.05) and 5-HIAA: ( p < 0.05)]. This suggests that CSF monoamine metabolites levels reflect the effects of quetiapine treatment on neurotransmitters in vivo and indicates that monitoring plasma and CSF quetiapine and norquetiapine levels may be of clinical relevance.