Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients.

A reduction in 5-hydroxyindoleacetic acid in cerebrospinal fluid was found in depressed and manic patients both while they were symptomatic and also after treatment. The concentration of homovanillic acid was initially reduced and then tended to increase after treatment.

Amine metabolites in human cerebrospinal fluid: effects of cord transection and spinal fluid block.

Patients with spinal cord transection had normal concentrations of 5-hydroxyindoleacetic acid and low concentrations of 3-methoxy-4-hydroxyphenyl glycol in lumbar cerebrospinal fluid. The presence or absence of spinal fluid block in these patients did not affect concentrations of either amine metabolite. However, the concentration of homovanillic acid was lower in patients with spinal fluid block than in those without block. The results suggest that the spinal cord contributes to concentrations of 3-methoxy-4-hydroxyphenyl glycol and possibly 5-hydroxyindoleacetic acid, but contributes little to that of homovanillic acid in the lumbar spinal fluid of man.

Dopamine-beta-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy.

Schizophrenic patients with high ventricle brain ratios and cortical brain atrophy, as shown by computerized tomography, had decreased spinal fluid concentrations of homovanillic acid and dopamine-beta-hydroxylase activity. These decreased cerebral spinal fluid concentrations in patients with brain atrophy support the proposal of disturbed noradrenaline and dopamine neurotransmission in a subgroup of schizophrenic patients.

Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate.

Phenylacetate is a naturally occurring plasma component that suppresses the growth of tumor cells and induces differentiation in vitro. To evaluate the in vivo potential and preventive and therapeutic antitumor efficacy of sodium phenylacetate against malignant brain tumors, Fischer 344 rats (n = 50) bearing cerebral 9L gliosarcomas received phenylacetate by continuous s.c. release starting on the day of tumor inoculation (n = 10) using s.c. osmotic minipumps (550 mg/kg/day for 28 days). Rats with established brain tumors (n = 12) received continuous s.c. phenylacetate supplemented with additional daily i.p. dose (300 mg/kg). Control rats (n = 25) were treated in a similar way with saline. Rats were sacrificed during treatment for electron microscopic studies of their tumors, in vivo proliferation assays, and measurement of phenylacetate levels in the serum and cerebrospinal fluid. Treatment with phenylacetate extended survival when started on the day of tumor inoculation (P < 0.01) or 7 days after inoculation (P < 0.03) without any associated adverse effects. In the latter group, phenylacetate levels in pooled serum and cerebrospinal fluid samples after 7 days of treatment were in the therapeutic range as determined in vitro (2.45 mM in serum and 3.1 mM in cerebrospinal fluid). Electron microscopy of treated tumors demonstrated marked hypertrophy and organization of the rough endoplasmic reticulum, indicating cell differentiation, in contrast to the scant and randomly distributed endoplasmic reticulum in tumors from untreated animals. In addition, in vitro studies demonstrated dose-dependent inhibition of the rate of tumor proliferation and restoration of anchorage dependency, a marker of phenotypic reversion. Phenylacetate, used at clinically achievable concentrations, prolongs survival of rats with malignant brain tumors through induction of tumor differentiation. Its role in the treatment of brain tumors and other cancers should be explored further.

Aberrant monoamine metabolite levels in CSF and family history of schizophrenia. Their relationships in schizophrenic patients.

In 36 drug-free schizophrenic patients, lumbar CSF was analyzed by mass fragmentography for the major monoaminergic transmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). High or deviant concentrations of 5-HIAA were significantly related to a family history of schizophrenia. For patients with deviant 5-HIAA levels, the probability for a family history of schizophrenia was eight times higher than in subjects with normal values. High concentrations of HVA also tended to be significantly related to a family history of schizoprenia. The majority of schizophrenic patients, who lacked family history for the disorder, had normal monoamine metabolite concentrations in CSF. The results suggest a coupling between biochemical variables related to central serotonin and dopamine metabolism and forms of schizophrenia that have a familial disposition.

Reliability of norepinephrine and major monoamine metabolite measurements in CSF of schizophrenic patients.

Concentrations of norepinephrine, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA) were quantified in the CSF of 28 drug-free schizophrenic patients. Fifteen patients provided more than one drug-free sample on separate occasions. Considerable intraindividual variability over time was found in the concentrations of norepinephrine and these major monoamine metabolites in the repeated samples. This was not explained by assay errors or changes in the patient's global psychosis ratings. The variability in the present sample for CSF 5-HIAA concentrations was almost twice as wide as has been reported for patients with affective disorder. Variables that contribute much of the variability of norepinephrine and major monoamine metabolite concentrations in drug-free CSF samples from schizophrenic patients remain unknown and cannot be controlled.

Monoamine metabolites in CSF and suicidal behavior.

Cerebrospinal fluid concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) were measured in 30 psychiatric patients who had attempted suicide and 45 healthy volunteers. The suicide attempters had a significantly lower CSF 5-HIAA level than the controls, especially those who had made more violent attempts. After adjustment for differences in body height and age between controls and patients, the difference in 5-HIAA level became even more marked. Concentrations of 5-HIAA also were lower than normal in suicidal patients who were not diagnosed as depressed at the time of lumbar puncture, while HVA levels were lowered only in the depressives. A follow-up study of these and 89 more patients (depressed and/or suicidal) revealed a 20% mortality by suicide within a year after lumbar puncture in patients with a CSF-HIAA level below the median.

Clomipramine treatment of obsessive-compulsive disorder. II. Biochemical aspects.

Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid, and the noradrenaline metabolite 4-hydroxy-3-methoxyphenyl glycol were measured in CSF before and after three weeks' treatment of severe obsessive-compulsive disorder with clomipramine hydrochloride. Patients who responded to clomipramine treatment had significantly higher CSF levels of 5-HIAA before treatment. The amelioration of obsessive-compulsive symptoms was positively correlated to the reduction of CSF concentrations of 5-HIAA during clomipramine treatment but negatively correlated to plasma concentrations of clomipramine. Reduction of CSF concentrations of 5-HIAA, which probably reflects drug action on central serotonin neurons, was maximal at a plasma clomipramine concentration of about 300 nmole/L. At higher levels, the reduction of CSF levels of 5-HIAA was smaller. The antiobsessive effect of clomipramine may be connected to its capacity to inhibit serotonin uptake.

CSF monoamine metabolites in child and adult psychiatric patients. A developmental perspective.

Concentrations of acid metabolites of dopamine and serotonin were measured in lumbar CSF of a diagnostically heterogeneous group of 154 psychiatric patients following oral probenecid loading. The patients ranged in age from 2 to 67 years old. No patients had received psychoactive medications for at least two weeks prior to the lumbar puncture. Children had higher mean CSF homovenillic acid (HVA) levels, higher mean CSF HVA-probenecid ratios, higher CSF HVA-log probenecid ratios, and lower mean CSF probenecid levels than adults. Age was negatively correlated with CSF HVA level and with CSF HVA-probenecid ratio. These correlations were more pronounced in male patients than in female patients.

Chronic, multiple tics of Gilles de la Tourette's disease. CSF acid monoamine metabolites after probenecid administration.

Central nervous system metabolism in six children and one adult with the syndrome of chronic multiple tics was studied by measuring the accumulation of acid metabolites of dopamine and serotonin (homovanillic acid [HVA] and 5-hydroxyindole-acetic acid [5-HIAA], respectively) in the CSF following probenecid administration. The accumulation of 5-HIAA was reduced in patients with multiple tics in contrast with other pediatric patients (N = 27). The degree of reduction in 5-HIAA relative to HVA appeared to be associated with the severity of the tic disorder. With dextroamphetamine, tic symptoms worsened, CSF HVA level decreased, and CSF 5-HIAA concentration increased. These findings suggest an association in Gilles de la Tourette's disease of reduced functioning of inhibitory serotonergic mechanisms and functional dopaminergic overactivity.

Effects of a dopamine agonist piribedil in depressed patients: relationship of pretreatment homovanillic acid to antidepressant response.

Piribedil, a compound that stimulates dopamine receptors in a relatively specific fashion, was administered to 11 hospitalized depressed patients. The dopamine agonist significantly decreased rapid eye movement (REM) sleep and percent REM sleep and increased REM latency. Piribedil decreased the probenecid-induced accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF. A range of mild to moderate antidepressant effects was noted; one patient worsened and one developed recurrent manic episodes. The degree of improvement in depression was negatively correlated with pretreatment values of HVA in CSF (r = -.66, P less than .05). These data suggest that the heterogeneity of clinical response may be related to biological differences in depressed patients and that those with low initial dopaminergic function respond best to increased dopamine receptor stimulation.

Dopamine and serotonin metabolism in neuropsychiatrically disturbed children. CSF homovanillic acid and 5-hydroxyindoleacetic acid.

Lumbar cerebrospinal fluid homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and probenecid were measured in four subgroups of neuropsychiatrically disturbed children and a contrast group of pediatric patients. With the exception of a serotonin metabolite difference between autistic and nonautistic psychotic children, there were no significant differences in metabolite concentrations among autistic, nonautistic psychotic, aphasic, and cognitively and attentionally impaired groups, or between the developmentally disabled and contrast groups of children. Younger children had higher concentrations of HVA than older children. Girls had significantly lower HVA/probenecid ratios than boys, which did not appear to be related to underlying neuropsychiatric disorder. Significant probenecid-metabolite correlations indicate the importance of measuring probenecid in the cerebrospinal fluid in clinical studies.

CSF acid monoamine metabolites in psychotic syndromes: what might they signify?

Research thus far indicates that CSF 5HIAA and HVA may be correlated with state components of psychotic syndromes. HVA may be positively correlated with a component of arousal or activity. The negative correlation between 5HIAA and state variables of activity or agitation in one study suggests an inhibitory deficit in some acute psychoses or a circulating psychotomimetic substance acting on 5HT receptors. Low CSF HVA values in some psychotic patients could be a manifestation of DA receptor supersensitivity which may antedate and promote the occurrence of acute psychosis. The low CSF HVA is also consistent with a Type B monoamine oxidase deficiency in chronic patients. Such a deficiency could theoretically play a role in either (or both) state or trait behavioral components of psychotic illnesses. Decreased CSF HVA could also be related to trait behaviors in psychoses as a possible reflection of MBD. An increasingly important aspect of biological research in psychotic states in the recognition that biological studies should relate to the component behaviors which make up particular psychotic disorders.

Cerebrospinal fluid gamma-aminobutyric acid and homovanillic acid in depressive disorders.

gamma-Aminobutyric acid (GABA) and homovanillic acid (HVA) levels were determined in the lumbar cerebrospinal fluid (CSF) of hospitalized patients suffering from depression and in a control group. Both mean CSF GABA and HVA levels in the patients with depression were significantly lower than those of the control group (p less than 0.05, p less than 0.01, respectively). No positive correlation was found between the changes in CSF GABA and HVA levels in the patients with depression. The Hamilton Rating score in these depressed patients, age, and sex showed no correlation to CSF GABA levels. It is suggested that decreased activity in the central GABAergic and dopaminergic system may be involved in the pathogenesis of depression.

Cerebrospinal fluid homovanillic acid in male alcoholics: effects of disulfiram.

It is well know that if an individual maintained on disulfiram (Antabuse) ingests alcohol, excess acetaldehyde is formed, resulting in a toxic reaction. In addition to this toxic interaction with alcohol (the basis of its use as a deterrent), there are both behavioral and biochemical observations to suggest that disulfiram alone has a direct effect on the CNS. The possibility that some of disulfiram's effects are related to alterations in biogenic amine metabolism led to the present study of cerebrospinal fluid amine metabolites in a group of male alcoholics. In this group, disulfiram treatment was associated with a significant reduction in homovanillic acid, the major metabolite of dopamine, while no change was noted in 5-hydroxyindoleacetic acid, the major metabolite of serotonin. Prior to disulfiram, patients with withdrawal symptoms had significantly lower homovanillic acid than those without such symptoms.

CSF amine metabolites, clinical symptoms, and body movement in psychiatric patients.

The relationships between CSF monoamine metabolites (HVA and 5HIAA), nurses' ratings of clinical symptoms, and telemetered measures of motor movement of ten schizophrenic and ten depressed patients were investigated. There was a significant negative correlation between CSF 5HIAA and both agitation ratings and motor movement in the schizophrenics. CSF HVA correlated positively to anxiety and anger in the depressives. The schizophrenics had a significantly higher CSF HVA than the depressives which appeared unrelated to motor movement. The effects of serotonin turnover and arousal in schizophrenia and the association between CSF metabolite gradients, stress, motor movement, and biogenic amine levels in depression are discussed.

Probenecid-induced accumulation of cyclic nucleotides, 5-hydroxyindoleacetic acid, and homovanillic acid in cisternal spinal fluid of genetically nervous dogs.

These studies have been conducted on 40 dogs, twenty each of a genetically nervous strain and of a normal strain of short-haired pointers. The nervous strain after about age 3 months displays extreme hypervigilance, timidity, human avoidance, and often shows catatonic-like muscle rigidity when in the presence of humans or novel stimuli. Measurements of probenecid-induced accumulation of acid metabolites in cisternal cerebrospinal fluid (CSF) have been carried out. Among the compounds measured at from 1.5 hr to 6.0 hr after probenecid treatment, homovanillic acid (HVA) was similar for the two strains, 5-hydroxy-indoleacetic acid (5-HIAA) was lower, but cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) were higher for the nervous strain when compared with age- and sex-matched behaviorally normal dogs. Probenecid levels in CSF were similar at all points in time from 1.5 to 6.0 hr after its intravenous administration in a dose of 50 mg/kg body weight. These findings coupled with previously observed differences in the two strains suggest that hyperresponsiveness of the central nervous system (CNS) noradrenergic and cholinergic systems and a hyporesponsiveness of the serotoninergic system are related to the genetically expressed aberrant behavior.

Depression and somatosensory evoked potentials: I. Correlations between SEP and monoamine and purine metabolites in CSF.

In 32 patients with major depressive disorders diagnosed according to Research Diagnostic Criteria (RDC), somatosensory evoked potentials elicited at four levels of tactile fingertip stimulation were recorded. Four peak-to-baseline amplitudes (P100, N140, P200, and P300) and two peak-to-trough amplitudes (P100-N140 and N140-P200) plus their amplitude/stimulus intensity slopes were selected for analysis. All 12 measures were adjusted to same sex, age, height, and weight. Values were linearly and curvilinearly correlated with adjusted levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5HIAA), 3-methoxy-4-hydroxyphenylglycol (MPHG), hypoxanthine, and xanthine in the cerebrospinal fluid (CSF), monoamine and purine metabolites, respectively. Significant negative linear correlations were found between the P300 amplitude and both HVA and hypoxanthine, and between the P200 slope and both 5HIAA and hypoxanthine. A significant positive correlation existed between the N140-P200 slope and 5HIAA. Curvilinear bivariate regressions demonstrated complex topologies of regression surfaces. Neither attention nor benzodiazepine medication were of significant importance in these relationships.

The influence of age, height, and body weight on cerebrospinal fluid amine metabolites and tryptophan in women.

Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5HIAA), homovanillic acid, and tryptophan were measured in 33 depressed, 36 alcoholic, and 32 neurological control female patients selected by strict operational criteria and investigated under controlled circumstances. Plasma total tryptophan was also measured in blood samples taken simultaneously with lumbar punctures. A multivariate regression analysis was done to discover the effect of age, height, and body weight on these four biochemical measures. Only CSF 5HIAA was significantly dependent on the nonspecific patient variables: height, but neither age nor weight, accounted for more than 10% of the variance of 5HIAA. The same analysis was carried out in all three separate patient groups: the relationship between height and CSF 5HIAA was present throughout, and only 2 of 12 correlations proved to be non-homogeneous. To demonstrate the significantly of these clinical parameters a multivariate analysis of covariance was done to eliminate their effect on the four biochemical variables. As a result significant differences emerged in CSF 5HIAA and total plasma tryptophan for some of the patient groups which were not demonstrable without this correction.

Concentration of 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan in the cerebrospinal fluid of depressed patients before and after ECT.

Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5HIAA), tryptophan (TRYP), and homovanillic acid (HVA), were determined prior to electroconvulsive therapy (ECT) and after an average course of 6.7 ECT in six endogenous depressed patients. Depression rating scale (DRS) scores were also obtained by a "blind" research psychiatrist before and after ECT at the time of each lumbar puncture. ECT markedly reduced DRS scores but did not significantly alter CSF levels of 5HIAA, TRYP, or HVA. We found no correlation between ECT-induced DRS score reductions and changes in any of the CSF constituents studied, or between the absolute DRS score and the corresponding CSF concentration of any of the compounds. These data are consistent with those previously reported for ECT and do not suggest that ECT alters cerebral amine metabolism in depressed patients. Neither do they provide any evidence for direct amine mediation of the depression-relieving effects of ECT in man, nor for any relation between severity of depressive illness and CSF concentrations of 5HIAA, TRYP, or HVA.