Phenylethylamine and phenylacetic acid in CSF of schizophrenics and healthy controls

Summary Phenylethylamine (PEA) is an endogenous substance with amphetamine-like stimulant properties. On the basis of this ability an abnormal brain PEA metabolism has been proposed as an etiological factor in some forms of schizophrenia.In the present study 28 schizophrenic patients and 15 healthy controls were investigated. No significant difference from control values was found in PEA concentration in cerebrospinal fluid (CSF) of either untreated or neuroleptic-treated schizophrenics. However, 2 schizophrenics with highest BPRS scores had extremely high PEA concentrations. Free phenylacetic acid (PAA), the major metabolite of PEA, was significantly decreased in ummedicated but not in drug-treated schizophrenics.Because of the assumed neuromodulatory properties of PEA, it is suggested that lowered PAA concentrations and the tendency for PEA to be elevated may imply that altered central neurotransmission occurs in certain forms of schizophrenia.     

Phenylethylamine and phenylacetic acid in CSF of schizophrenics and healthy controls

Phenylethylamine (PEA) is an endogenous substance with amphetamine-like stimulant properties. On the basis of this ability an abnormal brain PEA metabolism has been proposed as an etiological factor in some forms of schizophrenia. In the present study 28 schizophrenic patients and 15 healthy controls were investigated. No significant difference from control values was found in PEA concentration in cerebrospinal fluid (CSF) of either untreated of neuroleptic-treated schizophrenics. However, 2 schizophrenics with highest BPRS scores had extremely high PES concentrations. Free phenylacetic acid (PAA), the major metabolite of PEA, was significantly decreased in ummedicated but not in drug-treated schizophrenics. Because of the assumed neuromodulatory properties of PEA, it is suggested that lowered PAA concentrations and the tendency for PEA to be elevated may imply that altered central neurotransmission occurs in certain forms of schizophrenia.     

CSF monoamine metabolites in mania

As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function.     

CSF monoamine metabolites in melancholia

The neurotransmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured by mass fragmentography in 83 patients with melancholia (diagnosed by the Newcastle Inventory and the Research Diagnostic Criteria), and 66 healthy volunteer controls. After adjustment by analysis of covariance for differences between the subject groups in body height, age and sex distribution, significantly (P less than 0.001) lower concentrations of 5-HIAA and HVA were found in the melancholia patients than in the controls. HMPG did not differ between the groups. The differences could not be accounted for by differences in timing or examination techniques, and not by previously administered drugs (all patients were drug-free at the examination, but a minority had taken small amounts of psychotropic drugs prior to the wash-out period). The differences persisted after excluding the suicidal patients. There were no clear-cut differences between unipolar and bipolar patients. It is suggested that the reduced concentrations of 5-HIAA and HVA in the melancholic patients may be due to altered serotonin and/or dopamine functions in the central nervous system, which may be connected with an increased vulnerability to certain types of affective illness.     

CSF monoamine metabolites in schizophrenic patients

The monoamine metabolites 3-methoxy-4-hydroxyphenyglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the cerebrospinal fluid (CSF) of 16 psychiatrically health controls and in 28 schizophrenic patients. There was no difference in CSF MHPG and HVA levels between the group of patients and the controls. CSF levels of 5-HIAA were significantly lower in schizophrenic patients than in controls. Differential analysis of patients with and without neuroleptics revealed that these findings were not due to drug treatment. Positive correlations were found between the level of 5-HIAA and the items: hallucinatory behaviour, grandiosity, and tension as rated on the Brief Psychiatric Rating Scale. As 5-HIAA CSF data are controversial for nosological entities, the search for correlations between 5-HIAA and individual psychopathological variables could provide more specific indices for psychiatric diagnosis, treatment or prophylaxis.     

CSF monoamine metabolites in old age dementias

Cerebrospinal Fluid (CSF) levels of the main metabolites of monoamines (HMPG, 5-HIAA, and HVA) were measured in patients with early onset (AD) and late-onset (SDAT) Alzheimer’s disease, vascular dementia (VD), and elderly controls. Psychobehavioral assessment was carried out by means of MMSE and GBS. Mean HMPG levels did not differ from controls; 5-HIAA was lower in VD when compared to both controls and SDAT. HVA was decreased in AD, SDAT, and VD with respect to controls. Significant correlations between HVA and psychobehavioral parameters were observed in SDAT and VD groups, whereas no relationship was documented in AD. The SDAT group was divided in SDAT-A (age at onset: >65≤80 yr) and SDAT-B (age at onset: >80 yr). SDAT-A had significantly lower CSF HVA values than SDAT-B (165±64 vs 235.7±85). SDAT-B HVA levels were similar to those observed in controls. Correlation analysis between HVA and neuropsychological variables was significant in SDAT-A, but not in SDAT-B. These results might support the evidence of SDAT heterogeneity.     

Monoamines and monoamine metabolites in brains from demented schizophrenics.

The brains from 12 schizophrenic patients were investigated post-mortem for their content of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5-HIAA). Six of the schizophrenics had been lobotomized 25--30 years prior to death. A control group matched for age was collected in the autopsy room. The concentrations of NA, DA, and HVA in different parts of the brain from the schizophrenic group did not differ from those of the controls. 5-HT was determined in 11 nuclei or areas of the brain. The schizophrenic group had lower mean values compared with the controls, and in the hypothalamus, medulla oblongata, and hippocampus the difference was at a significant level. 5-HIAA was determined in six areas of the brain but only in a few cases. There was a trend towards lower means of 5-HIAA in the schizophrenics. Cause of death, medication, food intake, age, time between death and autopsy, time the corpses have lain in room temperature, and dissection technique are discussed in relation to these findings. These variables have to be kept under careful control before changes can be claimed as having pathogenetic importance for schizophrenia or for the progressing dementia in this disease.     

Concentration gradient of CSF monoamine metabolites in children and adolescents

Whether the lumbar cerebrospinal fluid (CSF) concentration gradient of monoamine metabolites found in adults is influenced by age or pubertal status was studied in 26 children ranging from 6.5 to 17.3 years of age. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-power liquid chromatography (HPLC) with electrochemical detection. Eight patients were prepubertal (Tanner stage I). The slopes in units of picomoles/milliliter/milliliter for regression lines for CSF monoamine metabolite concentrations versus milliliter of CSF collected were 5.07 +/- 0.65, 10.13 +/- 2.0, and 0.67 +/- 0.22 for 5-HIAA, HVA, and MHPG, respectively, for the group as a whole. Significant correlations with age, height, weight, or Tanner stage were not found for the HVA or MHPG concentration gradients. Tanner stage and 5-HIAA slope were significantly correlated. Three of eight prepubertal patients had nonsignificant 5-HIAA gradients. CSF studies in pediatric populations must control for aliquot collected, as the size of the gradient could produce differences sufficient to mimic a "positive" clinical study if the aliquots collected are not the same.     

CSF monoamine metabolites and MRI brain volumes in alcohol dependence

Correlations between cerebrospinal fluid (CSF) concentrations of monoamine metabolites (MAM) and brain structure have been described in schizophrenia, but not in alcoholism. To investigate the relationship between monoaminergic transmission and brain structure in alcoholism, the metabolites of dopamine (homovanillic acid, HVA), norepinephrenine (3-methoxy-4-hydroxyphenylethyleneglycol, MHPG) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) were measured in lumbar CSF in 54 alcohol-dependent patients and 20 healthy subjects. The volumes of the cerebrum, total grey and white matter, total and ventricular CSF, left and right hippocampus, and corpus callosum area were measured with MRI. MHPG and age were positively correlated in alcoholic women. The MAM concentrations were not significantly correlated with the MRI volumes in the subject categories. There were no differences in MAM across subjects defined by diagnosis and gender, age of onset of alcoholism or comorbidity of psychiatric disorders. Total CSF, cerebrum, and white and grey matter tissue volumes differed between patients and healthy subjects. The greatest difference was the white matter reduction in alcoholic women. In alcoholic women and men, monoaminergic neurotransmission measured by the CSF MAM HVA, MHPG, and 5-HIAA is not significantly correlated with the size of different brain structures.     

Memory effects of clomipramine treatment: relationship to CSF monoamine metabolites and drug concentrations in plasma.

Performance on tasks tapping automatic and voluntary aspects of memory, attention, and motor speed was examined in 14 patients with major depressive disorder, before and after 3 weeks of treatment with clomipramine (150 mg/day), a potent serotonin and noradrenaline uptake blocker with anticholinergic side effects. Performance on tasks requiring frontal functions improved or did not change, whereas verbal learning and retention, where hippocampal functioning is critical, were impaired. The latter tasks were negatively related to cerebrospinal fluid (CSF) 5-HIAA levels and plasma concentration of clomipramine. The results provide further support for the regulatory role of monoaminergic systems in cognition. Furthermore, we found the automatic-voluntary capacity distinction less heuristically useful. Physiological mechanisms regulating different aspects of cognition and memory appeared to be more closely related to the type of task used than to its capacity-demanding properties.     

Natural killer cell activity and CSF monoamine metabolites in suicide attempters

The aim of this study was to investigate markers of serotonin and immune function in suicidal patients. Cytotoxic activity of natural killer cells (NK) and CD16 lymphocytes were studied in 28 suicide attempters and 26 healthy controls, and related in patients to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF). Patients with CSF 5-HIAA below the median had significantly lower NK cell activity than other patients. CD16 cell frequency was significantly lower in patients than in controls, and patients also tended to have lower NK cell cytotoxicity than healthy controls. There were no statistically significant correlations between 4-hydroxy-3methoxyphenyl glycol (HMPG), homovanillic acid (HVA), CSF cortisol and NK cell activity. The results support the hypothesis of compromised immune function in suicidal patients with evidence of disordered serotonin function.     

CSF monoamine metabolites in patients with progressive supranuclear palsy]

Neurochemical abnormalities in the patients with progressive supranuclear palsy (PSP) are not well understood. We investigated CSF levels of the monoamine metabolites HVA, 5HIAA and MHPG in 5 patients with PSP in order to investigate, especially dopaminergic, serotonergic and noradrenergic metabolism. Results were as follows (value; mena +/- S.D.). [table: see text] The levels of HVA were significantly lower than those in controls. These findings suggest that there is a hypofunction of dopaminergic neurons in PSP patients.     

Effects of monoamine oxidase inhibition by selegiline on concentrations of noradrenaline and monoamine metabolites in CSF of patients with Alzheimer's disease

Summary A double-blind, cross-over trial with 12 patients with Alzheimer's disease (AD) was carried out primarily to test the suitability of this design in the investigation of the clinical, effects of selegiline (10 mg/day) in AD. Cerebrospinal fluid (CSF) samples for the determination of concentrations of noradrenaline (NA) and several monoamine metabolites were collected at baseline and at the end of both four-week treatment periods (placebo and selegiline). The severity of dementia was assessed using Ferm's and Gottfries-Bråne-Steen (GBS) dementia scales. The concentrations of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the NA metabolites, 3,4-dihydroxyphenylglycol (DHPG), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) decreased significantly during selegiline treatment. There was a clear trend of reduction in concentrations of homovanillic acid (HVA) during selegiline treatment, whereas the concentrations of NA, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan did not differ significantly. The study design was not suitable for the analysis of the clinical results as there was a significant carry-over effect in both scales. As only the first period data could be used in the analysis, there were no significant differences in the scores of Ferm's or GBS scales, but clear positive trends could be detected in favour of selegiline.     

Variations in CSF monoamine metabolites according to the season of birth

The cerebrospinal fluid (CSF) concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) as well as their ratios and correlations were analyzed in relation to the season of birth. The sample consisted of 241 drug-free patients participating in psychobiological programs and comprising the DSM-III-R diagnoses of mood, anxiety and adjustment disorders. Significant season-of-birth variations were found even after adjusting for sex, age, height, the diagnostic category and the month of lumbar puncture. Those born during February to April had significantly lower values of 5-HIAA. Values of HVA and of the ratios HVA/5-HIAA and HVA/MHPG were significantly higher for those born during October to January. Correlation coefficients also showed season-of-birth variations. These results may provide an important link for the season-of-birth variations reported for several neuropsychiatric disorders.     

CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression.

Decreased cerebrospinal fluid (CSF), somatostatinlike immunoreactivity (SLI) and alterations in the CSF monamine metabolites 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) have been reported in patients with probable Alzheimer's disease (AD) and in patients with major depression. In this study, we found CSF SLI to be significantly lower in a large group of AD patients (n = 60) and in a group of age-matched patients with major depression (n = 18) as compared with normal controls (n = 12). Mean CSF, MHPG, 5-HIAA, and HVA levels were not significantly different among diagnostic groups. Within a group of "depressed" AD patients, CSF levels of 5-HIAA showed a significant positive correlation (p = 0.03) with CSF SLI; a similar relationship was found within the group of patients with major depression. Further exploration of the relationship between the somatostatin and serotonin systems may provide clues as to how neuropeptides interact with monoamine neurotransmitters and what role they have in depression.     

CSF concentration gradients of monoamine metabolites in patients with hydrocephalus.

Concentration gradients of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed in 762 successive CSF fractions (2 ml lumbar CSF) from 15 patients with the adult hydrocephalus syndrome (AHS) and 11 patients with hydrocephalus of other causes (mixed group). A mean volume of 49.6 (SD 11.8) ml CSF was removed in the AHS group and 56.4 (10.2) ml in the mixed group. The CSF was collected with a specially designed carousel fraction collector and the corresponding CSF dynamics were continuously registered by a constant pressure CSF infusion method. Pronounced gradients in CSF HVA and CSF 5-HIAA were seen in both patient groups in the first 25 ml of CSF removed. The concentration curves levelled off, despite the removal of larger amounts of CSF and stabilised at about twice the initial concentrations. This phenomenon has not been described before. Concentrations of HVA and 5-HIAA in the first CSF fraction correlated strongly with concentrations in fractions up to about 40 ml. A positive correlation between the first fraction of CSF HVA and CSF 5-HIAA concentrations and CSF outflow conductance was found in the AHS group. There was no gradient in MHPG. It is suggested that the rostrocaudal gradients in CSF HVA and 5-HIAA may be explained by a downward flow of CSF along the spinal cord with absorption of metabolites occurring during passage. Mixing of CSF from different CSF compartments, extraventricular production sites of CSF, clearance of metabolites to venous blood or extracellular fluid, and CSF outflow conductance are probably important determinants of the plateau phase in patients with hydrocephalus. It is concluded that lumbar CSF does not exclusively reflect the concentrations of HVA, 5-HIAA, or MHPG in the ventricles. It should be noted that these results obtained in patients with hydrocephalus may not be applicable to other groups of patients or normal subjects.     

CSF monoamine metabolites of depressed patients during illness and after recovery

Repeated lumbar punctures in 16 healthy volunteers showed reproducible concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). In seven depressed patients, studied during two or three illness periods, the metabolite concentrations were also fairly stable. In 11 patients CSF concentrations of 5-HIAA, but not of HVA, were higher after recovery than during depression. This increase of 5-HIAA after recovery was confined to patients whose initial serotonin metabolite levels were low. The finding constitutes further evidence of a biochemical heterogeneity within the depressive disorders, and suggests that patients whose CSF 5-HIAA is low during a depressive episode may have a less stable serotonin system than other patients with depressive illness.