Cerebrospinal Fluid Monoamine Research Articles

Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers

Cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were measured in three groups: 46 healthy volunteers; 9 medication-free patients with DSM III-R major depressive disorder, recurrent; and these same 9 patients following at least 4 weeks of fluoxetine treatment at 20 mg/day. CSF monoamine metabolite levels in medication-free patients did not differ from healthy volunteers; however, CSF 5-HIAA and MHPG decreased significantly from 95.9 ± 24.6 (all values ± SD) to 64.2 ± 26.1 pmol/ml and from 46.7 ± 14.2 to 42.6 ± 11.6 pmol/ml, respectively, following fluoxetine treatment. Fluoxetine also significantly decreased mean Hamilton Depression Rating Scale scores from 23.2 ± 6.5 to 17.4 ± 5.0 and significantly increased the CSF HVA/5-HIAA ratio.

Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18–88 years of age

Concentrations of the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in lumbar cerebrospinal fluid (CSF) of 114 healthy individuals, 18–88 years of age, without histories, symptoms or signs of central nervous system dysfunction. The mean values (± SD) were 253 ± 109 nmol/1 for HVA, 125 ± 54 nmol/1 for 5-HIAA, 47 ± 10 nmol/1 for HMPG, and 2.10 ± 0.52 for the HVA/5-HIAA ratio. Analyses of confounding factors revealed that all metabolites correlated negatively with body height, the values being lower in taller than in shorter individuals. This is probably attributable to a larger surface area for monoamine metabolite transport from the subarachnoid space in taller than in shorter individuals. These correlations make statistical adjustment for body height important in analyses of monoamine metabolite levels. Without considering body height, all monoamine metabolites showed a positive correlation with age, and higher levels of HVA and 5-HIAA were found in women than men. After statistical adjustment for the influence of body height, no differences in CSF monoamine metabolites levels were found between the sexes, and only 5-HIAA showed a positive correlation with age. There were no significant seasonal variations for any of the monoamine metabolites.

Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: Preliminary findings

The syndrome of chronic fatigue, feverishness, diffuse pains, and other constitutional complaints, often precipitated by an acute infectious illness and aggravated by physical and emotional stressors, has a lengthy history in the medical literature. The Centers for Disease Control (CDC) recently formulated a case definition, renaming the illness “chronic fatigue syndrome”. Nevertheless, there remain few biological data that can validate the existence of this syndrome as distinct from a wide variety of other, largely psychiatric disorders, and little understanding of its pathogenesis. In the present study, basal plasma and cerebrospinal fluid levels of the monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were determined in 19 patients meeting CDC research case criteria for chronic fatigue syndrome and in 17 normal individuals. Patients with chronic fatigue syndrome showed a significant reduction in basal plasma levels of MHPG and a significant increase in basal plasma levels of 5-HIAA. Although the functional significance of these findings has not been definitively elucidated, they are compatible with the clinical presentation of a syndrome associated with chronic lethargy and fatigue, and with evidence of persistent immune stimulation, and lend support to the idea that chronic fatigue syndrome represents a clinical entity with potential biological specificity.

Reduction of CSF monoamine metabolites in poststroke depression: a preliminary report.

Monoamine metabolites were measured in the cerebrospinal fluid (CSF) of depressed and nondepressed patients with acute stroke lesions and in nondepressed patients without stroke lesions. Depressed stroke patients had a significantly lower concentration of CSF 5-hydroxyindoleacetic acid (5-HIAA; a serotonin metabolite) than the other two groups. These findings suggest that poststroke depression may be mediated by serotonergic mechanisms.

Cerebrospinal fluid monoamine and adrenal correlates of aggression in free-ranging rhesus monkeys.

Clinical and preclinical studies involving several different mammalian species and research paradigms suggest a negative correlation between aggression and central serotonin activity. To test the generalizability of laboratory findings in rhesus monkeys that show a negative correlation between cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and aggression, we obtained cisternal cerebrospinal fluid and blood plasma samples from monkeys living in naturalistic conditions. During a semiannual trapping, 28 juvenile and adolescent male rhesus monkeys were chosen from a population of 4200 provisioned, free-ranging rhesus monkeys living on Morgan Island, a sea island located off the coast of South Carolina. Based on direct observations of participation or avoidance of aggressive behavior and examinations of apparent fight wounds, 18 monkeys were selected for cerebrospinal fluid taps and blood samples. The remaining 10 monkeys were selected at random. Descriptions of aggressive behavior and the number of old scars and recent wounds were carefully transcribed, and a photograph showing wounds and scars was obtained for each animal. Using the transcriptions and photographs, researchers experienced in rhesus monkey behavior, but blind to the subjects' monoamine and hormone concentrations, were asked to rank the monkeys from the most to the least aggressive. The results showed a significant negative correlation between high rankings for aggression and cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. There was evidence that aggression was associated with stress, in that cerebrospinal fluid, norepinephrine, and plasma corticotropin and cortisol concentrations were positively correlated with high rankings of aggression.

A 2-year prospective follow-up study of children and adolescents with disruptive behavior disorders. Prediction by cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and autonomic measures?

A 2-year prospective follow-up study of 100% (N = 29) of a sample of children and adolescents with disruptive behavior disorders found that the baseline lumbar cerebrospinal fluid monoamine metabolite concentration and autonomic nervous system activity predicted some subsequent outcomes. The 5-hydroxyindoleacetic acid concentration significantly predicted severity of physical aggression during follow-up. The skin conductance level significantly predicted institutionalization. Correlations were in predicted directions with lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and autonomic activity correlated with poor outcome. Moreover, in multivariate analyses, which included nonlaboratory measures as predictors, cerebrospinal fluid and autonomic measures still contributed significantly to the prediction. However, hypothesized predictions of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations for suicide attempts and of low autonomic nervous system activity for arrests were not supported thus far. Patients are still at risk; consequently, these results must be considered preliminary. Nonetheless, the results suggest that further investigation of relationships between biological factors and outcome of children with disruptive behavior disorders is warranted.

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.

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, andHVA 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.

Analysis of cerebrospinal fluid monoamines in schizophrenic patients on and off neuroleptic treatment and compared with healthy controls

Analysis of cerebrospinal fluid monoamines in schizophrenic patients on and off neuroleptic treatment and compared with healthy controls

Personality and Cerebrospinal Fluid Monoamine Metabolites in Alcoholics and Controls

Alcoholics as a group have been consistently reported to show differences from controls on various personality inventories. Moreover, neurobiologic substrates have been postulated to underlie personality dimensions. Therefore, we compared alcoholics with controls on measures of personality and investigated relationships between measures of personality and cerebrospinal fluid monoamine metabolite concentrations. The alcoholics were significantly different from controls on many personality measurements. There were significant, negative correlations between interview-derived lifetime aggression scores and cerebrospinal fluid concentrations of both the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid. However, there were no significant correlations between any cerebrospinal fluid monoamine metabolite concentrations and scores on personality inventories.

CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters.

Monoamine metabolites, cholinesterases and lactic acid in lumbar cerebrospinal fluid (CSF) were investigated on patients with the adult hydrocephalus syndrome (idiopathic normal pressure syndrome; AHS, n = 15), Alzheimer's disease (AD, n = 14), multi-infarct dementia (MID, n = 13) and controls (n = 21). Patients had clinical and CSF hydrodynamic investigations. Monoamine concentrations were determined by reversed-phase liquid chromatography, cholinesterases and lactate were determined photometrically. In the AHS patients, CSF monoamine concentrations were not significantly different compared with controls, AD or MID patients. AHS and AD patients showed a similar reduction of CSF acetylcholinesterase activity compared with controls. Positive correlations were found in concentrations of CSF homovanillic acid, CSF 5-hydroxyindoleacetic acid and CSF lactic acid versus CSF outflow conductance (that is, resistance against CSF outflow) in the AHS patients. A similar pattern was observed in a subgroup of MID patients characterised by dilated ventricles and disturbed CSF hydrodynamics. These data suggest that a low CSF outflow conductance may facilitate the clearance of acidic substances from the arachnoid space at the probenecid sensitive active transport site. Alternative explanations would be that a pathologically low CSF outflow conductance is accompanied by an inverse caudorostral flow of CSF or a compromised trans-ependymal diffusion.

Effects of clomipramine treatment on cerebrospinal fluid monoamine metabolites and platelet 3 H‐imipramine binding and serotonin uptake and concentration in major depressive disorder

In an open study of 12 inpatients who met the DSM-III criteria for a major depressive episode, the effects of clomipramine (CI) on the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured simultaneously with the effects on 3H-imipramine binding, serotonin (5-HT) uptake and 5-HT concentration in platelets after 3 and 6 weeks of treatment. Drug (CI and desmethylclomipramine) plasma concentrations were determined. The concentrations of 5-HIAA and HMPG decreased substantially, and the concentration of HVA remained unchanged. There was also a large and significant reduction of the number of imipramine binding sites (Bmax) and of the platelet 5-HT concentration. The 5-HT uptake was not measurable after 3 weeks of treatment. None of the parameters changed significantly between weeks 3 and 6. There were no significant correlations between antidepressant effect (measured by the Montgomery-Asberg Depression Rating Scale) and plasma drug concentrations, although a tendency to a significant correlation between antidepressant effect and CI was observed at 3 weeks. There were no significant intercorrelations between the different 5-HT parameters and no other significant correlations between the biochemical measures and clinical outcome.

Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the blood-brain barrier function in primary hyperparathyroidism

Psychiatric disturbances are common in primary hyperparathyroidism (HPT), but their pathogenesis is essentially unknown. This study deals with cerebrospinal fluid (CSF) calcium homeostasis and its connection with parathyroid hormone (PTH), blood-brain barrier (BBB) function, and central monoamine and purine metabolites in patients with primary HPT. In 22 patients with primary HPT (serum calcium 2.85±0.21 mmol/l), the CSF concentrations of total and ionized calcium were higher (1.21±0.08 mmol/l, p<0.01, and 1.09±0.05 mol/ll, p< 0.001, respectively) than in 11 normocalcemic reference subjects. The values correlated with serum calcium concentration ( p< 0.001) and CSF/serum albumin ratio, a measure of BBB permeability. The latter ratio was elevated in one-third of the patients with HPT, indicating BBB damage. CSF immunoreactive intact PTH was higher in the HPT patients than in the reference group ( p< 0.05), and serum and CSF PTH were positively correlated ( p< 0.05). The CSF levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were lower, and the level of urate in CSF was higher, in the HPT patients than in the reference subjects, while there were no consistent differences in CSF hypoxanthine or xanthine. CSF 5HIAA correlated inversely with CSF ionized calcium ( r = −0.42, p = 0.02). After parathyroid surgery, CSF calcium and urate decreased significantly and CSF monoamine metabolites increased slightly. The decrease in CSF ionized calcium correlated with the alleviation of psychiatric symptoms. The results indicate the importance of increased CSF calcium concentrations in patients with primary HPT and suggest a relation between central calcium regulation and central turnover of monoamines.

Cerebrospinal Fluid Monoamine Metabolites, Aggression, and Impulsivity in Disruptive Behavior Disorders of Children and Adolescents

Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, were measured in relation to aggression, impulsivity, and social functioning in 29 children and adolescents with disruptive behavior disorders. The cerebrospinal fluid 5-hydroxyindoleacetic acid level was low compared with that of age-, sex-, and race-matched patients with obsessive-compulsive disorder. Within the disruptive group, significant negative correlations with age-corrected 5-hydroxyindoleacetic acid level were seen for the child's report of aggression toward people and the expressed emotionality of the child toward his or her mother; other correlations of age-corrected 5-hydroxyindoleacetic acid level with measures of aggression were in the expected negative direction but did not reach statistical significance. Impulsivity per se and socioenvironmental factors were not significantly related to cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.

Norepinephrine in Acute Exacerbations of Chronic Schizophrenia

In recent years the dopamine hypothesis has failed to explain the complexities of schizophrenia. Because both negative symptoms and noradrenergic activity appear to increase with psychotic relapse, we studied negative symptoms, psychosis, cerebrospinal fluid norepinephrine, and cerebrospinal fluid monoamine metabolites in 32 male patients with a DSM-III diagnosis of schizophrenia while both receiving and not receiving long-term haloperidol treatment. Drug-free cerebrospinal fluid norepinephrine and 3-methoxy-4-hydroxyphenylglycol levels correlated significantly with the severity of negative symptoms and psychosis ratings. When the patients were divided into those who did and did not relapse while not receiving the drug, significant positive correlations between negative symptoms and cerebrospinal fluid norepinephrine and 3-methoxy-4-hydroxyphenylglycol were observed only in the patients who relapsed. Non significant but negative correlations were observed between the same variables in the nonrelapsers. Thus, increased norepinephrine activity in drug-free patients is associated with intensification of schizophrenic symptoms without necessarily causing the symptoms.

Cerebrospinal Fluid Monoamine Metabolites and Neuropeptides in Patients with Panic Disorder

Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG) as well as somatostatin (SRIF) and beta-endorphin (beta-END) were assayed in the cerebrospinal fluid (CSF) of 34 patients with panic disorder and of ten neurological controls. No aberrations of the monoaminergic or peptidergic variables measured were found in the nonpanic state of patients with panic disorder. A modest correlation (P = 0.04) between total anxiety scores and CSF MHPG was observed.

Cerebrospinal fluid monoamine metabolites in alcoholic patients who attempt suicide

Reduced cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid have been reported to be commonly associated with suicidal behaviour. Alcoholics are known to often manifest suicidal behaviour. Therefore, we compared cerebrospinal fluid levels of monoamine metabolites in alcoholics who had (n = 20) and had not (n = 108) attempted suicide and healthy volunteers (n = 30). There were no significant differences among the 3 groups for CSF levels of either 5-hydroxyindoleacetic acid, the dopamine metabolite homovanillic acid, norepinephrine, or the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol.

Lack of seasonal variation in pediatric lumbar cerebrospinal fluid neurotransmitter metabolite concentrations

Seasonal variation of cerebrospinal fluid (CSF) monoamines, particularly 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) has been reported for psychiatrically ill and normal adults. Circannual variability was examined for a group of 72 children (mean age = 159.4 +/- 40.3 (SD), range 77-238 months), with a primary diagnosis of obsessive-compulsive disorder (OCD) or disruptive behavior disorder (DBD) (attention deficit disorder, oppositional disorder and/or conduct disorder), from whom CSF had been obtained systematically. There were no seasonal differences in mean concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), HVA, or 5-HIAA, either for the group as a whole, for the separate diagnostic (OCD vs DBD) categories or for the pre-pubertal subgroup. Log-corrected HVA concentrations for the Tanner IV and V subgroup differed by season with summer concentrations less than those of fall (P = 0.06) and winter (P = 0.005). The results suggest that pubertal changes may play a role in any expression of circannual variability.

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Monoamine Metabolites in Cerebrospinal Fluid and Behavioral Ratings in Patients with Early and Late Onset of Alzheimer Dementia

Patients with Alzheimer disease (AD, onset less than 65 years of age, n = 13) and senile dementia of the Alzheimer type (SDAT, onset greater than or equal to 65 years of age, n = 28) were investigated for cerebrospinal fluid (CSF) content of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) and compared with a group of controls (n = 26). A geriatric rating scale, the Gottfries-Bråne-Steen scale, was used to assess impairment of motor performance, intellectual and emotional functioning, and symptoms common in dementia disorders. The HVA levels in CSF were significantly lower in the AD group than in the SDAT group and controls. MHPG was slightly but significantly increased in the SDAT group when compared with the controls. The HVA and 5-HIAA concentrations were correlated negatively with impairment of motor performance in the SDAT group; 5-HIAA correlated positively with impaired performance in the AD group; and 5-HIAA/HVA ratios were correlated positively with the performance variables. HVA correlated significantly and negatively with "impaired wakefulness" and "inability to increase tempo" in the SDAT group. 5-HIAA and the ratio 5-HIAA/HVA correlated significantly and positively with some items measuring intellectual and emotional impairment. In the AD group, "anxiety" and "fear-panic" correlated positively with 5-HIAA and "restlessness" with MHPG. The data indicate qualitative differences in the CSF monoamine pattern between AD and SDAT.