Determinations of 5-hydroxyindoleacetic acid and homovanillic acid in human CSF with monitoring of probenecid levels in CSF and plasma

The accumulation of 5-HIAA and HVA in cerebrospinal fluid (CSF) was studied in eight healthy volunteers after oral administration of probenecid. Simulation indicated that a dose of 4.5 g probenecid should be used to achieve probenecid plasma concentrations between 200 and 400 g/ml. Almost complete inhibition of the active transport of the acidic metabolites was assumed to be obtained at these concentrations. Probenecid 4.5 g was administered in two doses (2.5 g and 2 g), separated by 4 h. Plasma samples were drawn at varying intervals over a period of 46 h and lumbar puncture (LP) was performed at either 14 h or 20 h after the first administration of probenecid. The concentration of probenecid, 5-HIAA and HVA in CSF was estimated and the probenecid-induced accumulation of 5-HIAA and HVA was compared with their baseline values. There were no statistically significant differences (P>0.05) in the accumulation of the monoamine metabolites between the two LP (14 h and 20 h), neither were there any differences in CSF concentrations of probenecid at the time of LP. There were only small differences in probenecid plasma concentrations, although statistically significant. Due to maximum blockade of the active transport system no correlation was observed between the CSF concentration of probenecid and the induced accumulation of 5-HIAA and HVA, respectively. The range of probenecid-induced accumulation for 5-HIAA and HVA in these volunteers was 156–429% and 183–600%, respectively. The suggested monitoring of probenecid plasma levels is proposed as a suitable model to investigate central neuronal activity of dopamine and serotonin in the central nervous system.     

Cerebrospinal fluid 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) following probenecid in unipolar depressives treated with amitriptyline

Lumbar cerebrospinal fluid 5-HIAA, HVA, and the ratio 5-HIAA/HVA were measured followed probenecid administration in eleven patints with unipolar depression before and during treatment with amitriptyline (AMI). Control values were obtained from a group of inmate volunteers. Prior to treatment CSF 5HIAA formation in the depressives was not different from controls. During treatment with AMI, CSF 5-HIAA formation decreased. One patient with psychotic symptoms prior to AMI and two patients who developed psychotic reactions on AMI showed relatively low CSF 5HIAA formation prior to antidepressant therapy. Compared to controls CSF HVA values were higher in the depressives prior to AMI therapy.     

Probenecid-induced accumulation of 5-hydroxyindoleacetic acid and homovanillic acid in rat brain

The accumulation of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in rat brain has been examined after probenecid infusion over 8 h. At plasma probenecid concentrations of 200-400 micrograms mL-1 a steady state level in the accumulation of 5-HIAA and HVA was achieved, the increase above the endogenous levels being 135% and 65%, respectively. When the plasma concentration of probenecid rose above 400 micrograms mL-1 there was further accumulation of both 5-HIAA and HVA probably induced by increased neuronal activity or toxicity due to probenecid. The explanation for the plateau of 5-HIAA and HVA obtained over the plasma probenecid concentration interval of 200-400 micrograms mL-1 could be that the levels were reached when there was complete inhibition of active transport, and when the rate of formation of the metabolites equalled the rate of elimination by alternative routes i.e. bulk flow and diffusion. Therefore when probenecid is used to inhibit the active transport of acid monoamine metabolites across the blood-brain barrier, its plasma concentration should be within the range of 200-400 micrograms mL-1.     

5-Hydroxyindole acetic acid and homovanillic acid in cerebrospinal fluid in manic-depressive psychosis and the effect of probenecid treatment

Summary The increased concentrations of 5-hydroxyindole acetic acid and homovanillic acid produced in cerebrospinal fluid by probenecid has been investigated in 15 manic-depressive patients and 21 psychiatric control patients, and has been related to the concentrations of probenecid in the CSF. The pharmacokinetics of probenecid were the same in the manic-depressive patients and the controls, as judged by its concentrations in plasma (bound and free) and CSF after a standard oral dose p.o., and by measurements of half-life and volume of distribution after intravenous injection. — The manic-depressive patients had lower concentrations of 5-HIAA and HVA than controls at similar CSF concentrations of probenecid; this was concluded from results with pairs of patients matched with regard to probenecid in CSF, and from differences between the patients and controls in the slopes of the regression lines for probenecid in CSF against 5-HIAA/HVA. The differences in 5-HIAA/HVA between the diagnostic groups were greater with increasing concentrations of probenecid in CSF; and, with concentrations of probenecid in CSF>1.0 µg/ml, by using the 5HIAA concentrations it was possible to classify the patients correctly into their diagnostic groups in 92% of cases.     

5-hydroxyindoleacetic acid (and homovanillic acid) levels in the cerebrospinal fluid after probenecid application in patiens with manic-depressive psychosis

Summary Probenecid was administered to 17 depressed, 19 manic and 15 control patients and further to 11 healthy volunteers. Before and after the administration the levels of 5-hydroxyindoleacetic acid (5-HIAA) were determined in cerebrospinal fluid (CSF). In six of the depressed, seven of the manic and seven of the patients from the group of controls and volunteers also homovanillic acid (HVA) was determined in CSF. After the application of probenecid there is a significant increase in 5-HIAA and HVA in the control patients and healthy volunteers but not in the depressed and manic patients. No increase in HVA occurred in the depressed patients but in the manic ones the HVA values were almost as high as in the group of controls and healthy volunteers. It is suggested that the lack of increase in 5-HIAA and HVA after probenecid indicates an inhibition of the synthesis of the acids and thus of the corresponding amines (5-hydroxytryptamine and dopamine) in the brain.     

Effect of ECT and imipramine treatment on the concentration of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the cerebrospinal fluid of depressed patients

The influence of probenecid administration on 5HIAA and HVA concentrations in the CSF of depressed patients, was studied before and after treatment with imipramine or ECT.The average increase of the two metabolites in the CSF after probenecid was similar in the untreated depressed patients and in the same patients improved after both imipramine or ECT treatment.The treatment determined a significant increase in the CSF concentration of the acid metabolites also before the probenecid administration.     

Gradients of concentrations of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF).

CSF from neurological and other patients was analyzed for its content of tryptophan, 5-HIAA and homovanilic acid (HVA). The gradients of concentration of these substances from ventricular spaces to lumbar sac indicate that tryptophan and 5-HIAA probably enter the CSF from all levels of the nervous system, but that HVA originates entirely in the brain. A study of CSF tryptophan in patients with hepatic cirrhosis provided no support for theories which implicate abnormal tryptophan metabolism as a cause of hepatic coma.     

Influence of convulsive therapy on 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid in endogenous depression

The cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in 20 patients with endogenous depression before and 2–6 days after a full course of convulsive therapy, the depressive symptoms being simultaneously rated.

1. The level of 5-HIAA was similar to that in previous series of healthy controls while the level of HVA appeared somewhat low.
2. The levels did not change after therapy in spite of considerable clinical improvement.
3. There was no relation between the levels and the severity of the depressive state, nor between changes of the levels and degree of clinical improvement.
4. There was no relation between the levels and the severity of the depressive state, nor between changes of the levels and degree of clinical improvement.

The validity of determination of acid monoamine metabolites in CSF relative to the cerebral turn-over of the amines may be increased, if the elimination of metabolites from CSF is blocked with probenecid.     

5-Hydroxyindoleacetic acid (5 HIAA) and homovanillic acid (HVA) following probenecid in acute psychotic patients treated with phenothiazines

Lumbar CSF 5 HIAA and HVA were measured following probenecid administration in acute psychotic patients before and during treatment with phenothiazines. Patients with more classical schizophrenic symptoms had higher values for 5 HIAA/HVA than other psychotics, depressives, and inmate volunteers. Prior to treatment CSF 5 HIAA, but not HVA, correlated significantly with several clinical items related to psychotic disorganization. Phenothiazine treatment produced significant increases in CSF HVA which could not be correlated with the dose of antipsychotic or antiparkinson drugs.     

Monoamine metabolite levels in rat CSF: kinetic studies

The kinetics of monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (alpha-methyl-p-tyrosine, alpha-MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5-HIAA and HVA, with respective half-lives of 51, 86 and 46 min. alpha-MPT caused a slower decline of MHPG and HVA, while 5-HIAA was unaffected. Results from the MHPG-infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.     

Absence of effect of para-chlorophenylalanine on 5-hydroxyindoleacetic acid in cerebrospinal fluid in man

The effect of para-chlorophenylalanine (PCPA) on the 5-hydroxy-indoleacetic acid (5-HIAA) content in human cerebrospinal fluid (CSF) has been studied. There was no effect on the CSF-content of 5-HIAA 12, 24 or 48 h after a single dose of PCPA 1 g p.o. Neither was there any effect after 1 g/day during 4 days. The increase of 5-HIAA after administration of probenecid was reduced during treatment with PCPA 1 g/day. This reduction, however, is not due to a diminished production of 5-HIAA by PCPA but probably caused by a pharmacological interaction between probenecid and PCPA since the concentrations of probenecid in CSF were lower during administration of PCPA than without that drug.It is concluded that PCPA in the doses used in this study gives no effects on the CSF-concentrations of 5-HIAA.     

马桑内酯对麻醉狗脑脊液中单胺类神经递质代谢物含量影响的初步探讨

作者通过狗口服丙磺舒阻断酸性物质向外周血循环转运的方法来测定肌注马桑内酯1mg/kg,前、后脑脊液中去甲肾上腺素、多巴胺和5-羟色胺的代谢物3-甲氧-4羟苯一乙二醇、高香草酸和5-羟吲哚乙酸的含量改变,以了解三者的更新率。初步结果表明:高香草酸的含量显著下降(P<0.05),5-羟吲哚乙酸的含量有所下降(P>0.05)但无统计学意义,3-甲氧-4羟苯一乙二醇影响不大。     

CSF 5-HIAA,cortisol and DHEAS levels in suicide attempters

The serotonin system and the hypothalamic–pituitary–adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in neuropsychiatric conditions. The aim of this study was to investigate CSF levels of 5-Hydroxyindoleacetic acid (5-HIAA) and CSF and plasma levels of cortisol and DHEAS in 28 medication free suicide attempters and 19 healthy volunteers. Another aim was to investigate the relationship between neuroendocrine measures and childhood trauma in suicide attempters. As the study design includes a longitudinal part, we investigated whether CSF cortisol, 5-HIAA or DHEAS would predict subsequent suicide. We hypothesized higher cortisol levels in suicide attempters and lower CSF 5-HIAA levels and higher cortisol levels in suicide victims. Suicide attempters had higher CSF and plasma cortisol levels compared to healthy volunteers. Male suicide attempters had higher CSF DHEAS levels and female suicide attempters had lower CSF 5-HIAA levels compared to male and female healthy volunteers respectively. Exposure to interpersonal violence as a child showed a negative correlation with CSF cortisol/DHEAS ratio adjusted for age, gender and depression severity in a regression analysis. Suicide victims tended to have low CSF 5-HIAA and high CSF cortisol. Abused suicide victims had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. The results underlie the important role of the serotonergic system and HPA axis in suicidal behaviour and suggest that CSF DHEAS may be elevated in male suicide attempters.     

Stereoselective metabolism of citalopram in plasma and cerebrospinal fluid of depressive patients: relationship with 5-HIAA in CSF and clinical response

Plasma and cerebrospinal fluid (CSF) concentrations of the enantiomers of citalopram (CIT), its N-demethylated metabolite demethylcitalopram (DCIT) and its deaminated metabolite citalopram propionic acid derivative (CIT-PROP) were measured in plasma and CSF in 22 depressed patients after a 4-week treatment with 40 mg/d citalopram, which was preceded by a 1-week washout period. CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured at baseline and after the 4-week CIT medication period. Patients were assessed clinically, using the Hamilton Depression Rating Scale (21-item HAM-D): at baseline and then at weekly intervals. CSF concentrations of S-CIT and R-CIT were 10.6 +/- 4.3 and 20.9 +/- 6 ng/mL, respectively, and their CSF/plasma ratios were 52% +/- 9% and 48% +/- 6%, respectively. The CIT treatment resulted in a significant decrease (28%) of 5-HIAA (P < 0.0001) and a significant increase (41%) of HVA in the CSF. Multiple linear regression analyses were performed to identify the impact of plasma and CSF CIT enantiomers and its metabolites on CSF monoamine metabolites and clinical response. There were 10 responders as defined by a > or =50% decrease of the HAM-D score (DeltaHAM-D) after the 4-week treatment. DeltaHAM-D correlated (Spearman) significantly with CSF S-CIT (r = - 0.483, P < 0.05), CSF S-CIT-PROP (r = -0.543, P = 0.01) (a metabolite formed from CIT by monoamine oxidase [MAO]) and 5-HIAA decrease (Delta5-HIAA) (r = 0.572, P = 0.01). The demonstrated correlations between pharmacokinetic parameters and the clinical outcome as well as 5-HIAA changes indicate that monitoring of plasma S-CIT, CSF S-CIT and CSF S-CIT-PROP may be of clinical relevance.     

Plasma and cerebrospinal fluid probenecid concentrations as related to accumulation of acidic biogenic amine metabolites in man

The oral administration of probenecid (100 mg/kg/18 h) to depressed patients results in marked increases in the acidic metabolites of biogenic amines in the cerebrospinal fluid (CSF). In contrast to previous reports (where lower dose rates of probenecid were employed) the increases in 5-hydroxyindoleacetic acid and homovanillic acid were independent of plasma or CSF probenecid concentrations. Higher plasma and CSF probenecid concentrations were found in this study. The binding of probenecid to plasma proteins for each patient was also determined to examine the pharmacodynamics of probenecid distribution. The ratio of probenecid in CSF to the calculated free probenecid in plasma was higher (0.4) and more constant than previously noted. At these higher dose levels, probenecid successfully competes with the active transport process for biogenic amine acidic metabolites and also appears to block its own removal from CSF.A preliminary report of this work was presented (Fed. Proc. 32, 696 (1973).     

Lower CSF homovanillic acid levels in depressed patients with a history of alcoholism.

Major depression and alcoholism are often comorbid, resulting in more impairment and more suicidal behavior compared with either diagnosis alone. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in depressed subjects with and without a history of alcoholism and healthy volunteers. We hypothesized that depressed subjects with a history of alcoholism would be more aggressive, impulsive, and suicidal than depressed subjects without a history of alcoholism, and would have lower CSF monoamine metabolite levels. We compared 63 subjects with a current major depressive episode (MDE) and a history of alcoholism, 72 subjects with a current MDE but without a history of alcoholism, and 22 healthy volunteers. Participants with a history of alcoholism were in remission for at least 6 months. All subjects were free from prescribed medications known to affect brain serotonin, dopamine, or norepinephrine systems for a minimum of 14 days. Depressive symptoms, lifetime aggression, impulsivity, Axis II disorders, and suicidal behavior were assessed. CSF was sampled and homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-performance lipid chromatography with electrochemical detection. Depressed subjects with a history of alcoholism did not differ from depressed subjects without a history of alcoholism in current severity of depressive symptoms, or in past suicidal behavior. Depressed subjects with a history of alcoholism had lower CSF HVA levels, and higher lifetime aggression and current suicide ideation scale scores and were more likely to be tobacco smokers compared with depressed subjects without a history of alcoholism. Low HVA was present after adjustment for sex, aggression and depression scores, cigarette smoking, antisocial and borderline personality disorders, psychomotor retardation, and delusions. Controls had CSF HVA levels intermediate between the two depressed groups. We found no group difference in CSF 5-HIAA and MHPG levels. In individuals with current MDE, those with a history of comorbid alcoholism had lower CSF HVA levels compared with those without a history of alcoholism. Low CSF HVA suggests that impaired dopaminergic activity is associated with a history of alcoholism in persons with current MDE.     

Increase in the plasma concentration of free tryptophan caused by probenecid in humans

Probenecid was administered orally in a dose of 1 g twice daily for 3 days to eight patients nutriated through a gastric tube with a standarized diet containing a known amount of tryptophan. Probenecid caused an increase by 52% (P<0.01) in the free (non protein-bound) concentration of tryptophan in plasma (from 1.22±0.16 to 1.86±0,28 g/ml; mean±SEM). The total (free + protein-bound) plasma tryptophan concentration was not significantly changed by the present dose of probenecid. There was a positive correlation (Spearmans rank correlation coefficient =0.74; P<0.05) between the increase in percentage free tryptophan and the achieved plasma concentration of probenecid. The cerebrospinal fluid (CSF) concentration of tryptophan was not significantly changed by probenecid (2 g/day during 21/2 days) given to another group of five patients.It is concluded from the present study, that the increase in the CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA) caused by probenecid, in addition to blockade of the 5-HIAA transport out of the CSF, might be explained by an increased rate of synthesis of brain serotonin since the availability of its precursor is increased due to the probenecid-induced increase in the plasma concentration of free tryptophan.     

Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers

The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n = 132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.     

The dopamine-serotonin relationship in clozapine response

The effects of clozapine on the dopamine and serotonin systems may underlie its atypical pharmacologic and clinical profile. To examine this hypothesis, we measured dopamine and serotonin plasma and cerebrospinal (CSF) metabolites and the relationship of these values to treatment response in 19 neuroleptic refractory and intolerant schizophrenic patients. Only a small change in the CSF and plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels was found. However, the pretreatment CSF HVA/5HIAA ratio and, to a lesser extent, the CSF HVA level predicted treatment response. These results suggest that the modest relationship between HVA and 5-HIAA and treatment response supports the involvement of both neurotransmitters in the pathophysiology of schizophrenia.     

CSF monoamine metabolites and lethality of suicide attempts in depressed patients with alcohol dependence.

BACKGROUND: Alcohol dependence (alcoholism) and major depressive disorder are frequently comorbid and are risk factors for suicidal behavior. Monoaminergic abnormalities have been implicated in the pathophysiology of depression, alcohol dependence, and suicidal behavior. Lower cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5-HIAA) levels are associated with higher lethality of suicide attempts in major depression and predict a higher rate of future suicide. We sought to study the relationship of CSF monoamine metabolites to lethality of suicidal acts in depressed subjects with comorbid alcoholism. METHODS: We compared 16 high- and 16 low-lethality drug-free depressed suicide attempters with comorbid alcoholism. Subjects were free from any substance use disorder for at least two months. Demographic and clinical parameters, and CSF 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were examined. RESULTS: The two groups did not differ with regard to the demographic characteristics. CSF 5-HIAA levels were lower in high-lethality attempters compared to low-lethality attempters. There were no group difference in CSF HVA or MHPG levels. CONCLUSION: Higher lethality of suicidal behavior in depressed patients with alcoholism is related to lower serotonergic activity.