CSF amine metabolites in depression.

The amine metabolites, namely homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) were measured in cerebrospinal fluid (CSF) of depressives (n = 30) and controls (n = 30). Depressed patients had significantly lower HVA levels than controls. No significant differences were noted between the two groups in 5-HIAA levels. However, the differences between the groups for the CSF HVA/5-HIAA ratio were larger than those for the CSF HVA alone (p less than 0.01 versus p less than 0.025, respectively). HVA levels correlated positively with monoamine oxidase activity and adenosine deaminase activity.     

Cerebrospinal fluid monoamine precursor and metabolite levels in children treated for leukemia: age and sex effects and individual variability

Lumbar cerebrospinal fluid (CSF) was obtained from children during and following treatment for acute lymphoblastic leukemia (ALL). One hundred ninety-two CSF samples from 50 subjects, which were selected to minimize the effects of the disease and its treatment (i.e., to approach "normality" as closely as possible), were analyzed for the monoamine precursors tyrosine (Tyr) and tryptophan (Trp) and the metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). Levels of HVA (p less than 0.0001), 5-HIAA (p less than 0.002), and Tyr (p less than 0.05) decreased with age from 3 to 17 years. Significant correlations were observed between the acid metabolites HVA and 5-HIAA (r = 0.79) and between the amino acid precursors Tyr and Trp (r = 0.71). Within individuals, levels of all four compounds were relatively stable over time, with total mean coefficient of variation ranging from 20% to 25%. No significant sex differences for CSF levels of HVA, 5-HIAA, Tyr, or Trp were found. Assessment of CSF monoamine precursors and metabolites in children treated for ALL may provide a method for understanding the chronic effect of CNS trauma on the ontogeny of monoamine systems.     

Relapse in violent crime in relation to cerebrospinal fluid monoamine metabolites (5-HIAA,HVA and HMPG) in male forensic psychiatric patients convicted of murder: a 16-year follow-up

OBJECTIVE: Our purpose was to investigate if low levels of cerebrospinal fluid (CSF) monoamine metabolites of 5-HIAA, HVA and HMPG predict relapse in violent crimes. METHOD: Relapse in crime and level of CSF monoamine metabolites (5-HIAA, HVA and HMPG) was studied in a group of 29 murderers. The follow-up was 16 years. RESULTS: Fourteen of the 29 murderers were convicted of crime; nine of them committed violent crimes; one was convicted of a new murder. The differences in mean CSF monoamine metabolites were lower in subjects who relapsed into any type of crime, but only the difference in mean CSF HVA was statistically significant. CONCLUSION: The risk to commit new murder is very small in males who earlier have been convicted of murder. Low levels of CSF HVA is associated with an increased risk for relapse in any type of crime.     

Cerebrospinal fluid kynurenic acid in male and female controls - correlation with monoamine metabolites and influences of confounding factors

The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91nM+/-0.20) compared to healthy male controls (1.06nM+/-0.07) and lower CSF levels of HMPG (39.2nM+/-2.0 and 43.4+/-1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3nM+/-21.9 and 93.7nM+/-11.4, respectively) and males (138.9nM+/-12.6 and 74.8nM+/-5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover.     

CSF levels of dopamine and serotonin, but not norepinephrine, metabolites are influenced by the ketogenic diet in children with epilepsy

The ketogenic diet (KD) is a non-pharmacological treatment of medically refractory epilepsy in children. Its mechanisms of action are still unclear but monoamine neurotransmitters have been proposed to be involved. Norepinephrine, dopamine, and serotonin are known to modulate seizure susceptibility in many animal models. We examined whether the concentrations of norepinephrine, dopamine, and serotonin metabolites were affected by the KD in children with pharmacoresistant epilepsy. The metabolites of norepinephrine, HMPG, of dopamine, HVA, and of serotonin, 5-HIAA, were analyzed in cerebrospinal fluid (CSF) before and 3 months after starting the KD. Twenty-six children (mean age 5.9 years) participated. Twenty-one children had generalized epilepsy and five partial. CSF was sampled by lumbar puncture. Seizure frequency before and during the diet was determined. Highly significant changes were found for HVA (p=0.0002) and 5-HIAA (p=0.004), which were both decreased during the KD compared to before diet. The levels of HMPG were unchanged. However, no differences were found between response groups. Valproate medication affected the levels of HMPG during diet with decreased levels in children on valproate and increased in those not on valproate (p=0.04). Our study indicates that the KD significantly alters the levels of metabolites of dopamine and serotonin but with a stable ratio HVA/5-HIAA in the CSF of children with refractory epilepsy, which finding may be of importance for the mechanism of action.     

A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous depression. II. Biochemical findings

In a comparative evaluation of zimelidine, a potent serotonin (5-HT) uptake inhibitor, and desipramine, a potent noradrenaline (NA) uptake inhibitor, 65 hospitalized patients with endogenous depression were evaluated for the following biochemical variables: 5-HT uptake in platelets, 5-HT concentration in whole blood, inhibition of the 5-HT and NA accumulation in rat hypothalamic synaptosomes incubated in the patients' plasma, the excretion of 4-hydroxy-3-methoxyphenyl glycol (HMPG) in urine and the pretreatment levels of the amine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and HMPG in cerebrospinal fluid (CSF). results of the biochemical studies confirmed that zimelidine and desipramine have different profiles with respect to monoamine uptake. Thus zimelidine caused more marked inhibition of 5-HT uptake than desipramine, especially in rat brain synaptosomes incubated in the patient's plasma. Desipramine plasma was much more effective than zimelidine plasma in inhibiting NA uptake in the same preparation. The urinary excretion of HMPG decreased significantly during desipramine treatment but remained unchanged during zimelidine treatment. The combined clinical and biochemical results indicated that patients with low pretreatment levels of 5-HIAA and HVA in CSF responded significantly better to zimelidine than patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of HMPG in CSF tended to respond better to desipramine than those with low levels of this NA metabolite.     

Concentration gradients for monoamine metabolites in lumbar cerebrospinal fluid

Summary Concentration gradients in lumbar cerebrospinal fluid (CSF) for the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were studied in 9 healthy controls and 47 neuropsychiatric patients without diseases causing disturbed CSF circulation. In a serial sampling of the first 24 ml of CSF, steep concentration gradients between the first (0–4 th ml) and last (21th–24th ml) portions of CSF were found for HVA (99±59% increase; p<0.001) and 5-HIAA (88±54% increase; p<0.001), while the concentration gradient was slight for HMPG (11±7% increase; p<0.001). The existence of marked concentration gradients for the monoamine metabolites HVA and 5-HIAA gives further evidence for an active transport system for these metabolites and indicates that the lumbar CSF-HVA and 5-HIAA levels reflect the dopamine and serotonin metabolism in the brain. Moreover, the existence of pronounced concentration gradients for HVA and 5-HIAA levels reflect the dopamine and serotonin metabolism in the brain. Moreover, the existence of pronounced concentration gradients for HVA and 5-HIAA stresses the importance of making analyses on a standardized volume of CSF.     

Relationships between clinical symptoms and monoamine metabolite concentrations in biochemically defined subgroups of depressed patients

In 28 patients with primary depression, relationships were sought between rating scores on the Montgomery-Åsberg Depression Rating Scale and the concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). Among the single items in the rating scale, reported sadness correlated negatively with HMPG. No other significant relationships were found in the total group of patients. However, in subgroups with low or high concentrations of monoamine metabolites, several significant relationships were found, such as a negative correlation between inner tension and concentration difficulties, respectively, and 5-HIAA in the low-HMPG subgroup. Curvilinear relationships were found between pessimistic thoughts and 5-HIAA in the high-5-HIAA subgroup and between apparent sadness and 5-HIAA in the low-HMPG subgroup. Suicidal thoughts tended to correlate in a curvilinear way with the ratio of HMPG/5-HIAA in the low-HVA and the high-HMPG subgroups, but the curves were mirrored. The results indicate that relationships between clinical symptoms and monoamine metabolite homeostasis in CSF are qualitatively and quantitatively different in defined high-and low-monoamine subgroups of depressed patients.     

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 less than 0.01, and 1.09 +/- 0.05 mmol/l, p less than 0.001, respectively) than in 11 normocalcemic reference subjects. The values correlated with serum calcium concentration (p less than 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 less than 0.05), and serum and CSF PTH were positively correlated (p less than 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.     

Concentration gradients of monoamine metabolites in human cerebrospinal fluid.

The monamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), vanillylmandelic acid (VMA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were analysed in CSF from different regions of the CSF system to study the caudocranial concentration gradient of the metabolites. Four consecutive 10 ml fractions of CSF were withdrawn in 17 patients during the course of four minutes. The CSF pressure was monitored through a lumbar cannula because of suspected adult hydrocephalus. A pronounced gradient of the HVA concentration was found with a ratio between the last and the first fraction of 1,7. 5-HIAA showed a slight increase while HMPG and VMA showed no increase at higher levels of the CSF system. The results suggest that lumbar HVA reflects dopaminergic activity in the brain, whereas lumbar 5-HIAA and HMPG/VMA reflect the activity of 5-hydroxytryptamine and noradrenaline secreting neurones in both the brain and the spinal cord.     

Fluoxetine treatment of depression. Clinical effects, drug concentrations and monoamine metabolites and N-terminally extended substance P in cerebrospinal fluid

In an open study of depressed inpatients, the effects of the selective serotonin uptake blocker fluoxetine on 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) and N-terminally extended substance P (SP) in cerebrospinal fluid (CSF) were measured. Thirteen unmedicated patients who met the DSM-III criteria for major depressive episode were included, and 9 completed the study. During treatment the 5-HIAA concentration decreased by 46%. The HVA and HMPG concentrations also decreased significantly, but to a lesser degree. The mean level of N-terminally extended SP was unaffected by fluoxetine treatment, but the pretreatment level correlated significantly with the pretreatment level of HMPG. The pretreatment level of HVA was the only biochemically variable that appeared to predict therapeutic outcome. The plasma concentrations of both fluoxetine and its metabolite norfluoxetine increased significantly between 3 and 6 weeks. Plasma and CSF levels of both the parent drug and its active metabolite were correlated.     

Phenylethylamine and monoamine metabolites in CSF of schizophrenics: Effects of neuroleptic treatment

Phenylethylamine (PEA) and the monoamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been measured in the cerebrospinal fluid (CSF) of nine paranoid schizophrenics before and after three weeks of neuroleptic treatment. Patients were classified according to the Research Diagnostic Criteria and rated by means of the Brief Psychiatric Rating Scale. A significant increase was seen in HVA CSF concentrations during neuroleptic treatment (p less than 0.01). No influence was found on levels of PEA, 5-HIAA, and MHPG. Concentrations of both MHPG and 5-HIAA correlated positively with those of HVA. These results in combination with previous findings do not support the contention that PEA and NA metabolisms are grossly disturbed in paranoid schizophrenics whereas involvement of other neurotransmitters i.e. dopamine, seems more probable.     

Influence of tapping-time and atmospheric pressure on concentrations of monoamine metabolites in the cerebrospinal fluid: A prospective study in female volunteers

Lumbar puncture was performed on 12 healthy female volunteers at the L4-5 level. CSF concentrations of 5-HIAA, HVA and HMPG were included in turn as dependent variables in repeated analyses of covariance with age, height, tapping-time, atmospheric pressure and the distance on the spine in the lying position as regressors. Use or non-use of oral contraceptives was included as a nominal variable. Results obtained were confirmed by nonparametric statistics. We found significant relationships between 5-HIAA and HVA, respectively, and height when the concentrations per minute of tapping-time (nM/min) were used as dependent variables. Hypothetically, the tapping-time mirrors the transport of concentrated CSF from the cranial to the caudal region when sitting up. We also found significant influences of atmospheric pressure and the use or non-use of oral contraceptives on HMPG. The role of atmospheric pressure is not clear but it might contribute to the transport of HMPG from the periphery to the CSF or affect the outflow of HMPG from the lumbar CSF compartment. The contribution of oral contraceptives might reflect interactions in the cerebral catecholamine metabolism.     

New evidence for an association between the CSF HVA:5-HIAA ratio and psychopathic traits

OBJECTIVES: To replicate the relation between the CSF HVA:5-HIAA ratio and psychopathic traits previously reported in a pilot group of 22 perpetrators of violent crimes. METHODS: CSF monoamine metabolite concentrations in another 28 violent and sexual offenders, aged 45 or below, referred to pretrial forensic psychiatric investigation, were compared to features of psychopathy according to the Psychopathy Checklist-Revised (PCL-R). RESULTS: Our previous finding was repeated in the new study group, where the HVA:5-HIAA ratio was strongly associated with psychopathic traits (r = 0.50, p = 0.010), particularly its behavioural aspects (r = 0.523, p = 0.004). In subsamples of individuals from both study groups who had no medication (n = 25) or no current axis I disorder, including a history of mood disorder or substance dependence (n = 21), the HVA:5-HIAA ratio remained strongly associated with all psychopathy factors but most closely with the behavioural features. Retrospective assessments of childhood disruptive symptomatology, such as attention deficit hyperactivity disorder or conduct disorder, analysed in relation to the monoamine metabolites, showed the same association with the HVA:5-HIAA ratio. CONCLUSIONS: Violent and aggressive behavioural traits with childhood onset and adult expression as psychopathic features are associated with changed activity in the brain dopaminergic system, possibly as a result of serotonergic dysregulation.     

Effects of environmental stimulation on biochemical and psychological variables in dementia

The nursing care of a group of moderately demented patients (n = 11) in a nursing home was improved as a result of an education of the staff. Thus the patients were subjected to an increased emotional and intellectual stimulation during the ordinary daily care and participated in group sessions twice a week. In order to evaluate the effects of the treatment, psychological parameters and cerebrospinal fluid (CSF) HVA (homovanillic acid), 5-HIAA (5-hydroxyindole acetic acid) and HMPG (4-hydroxy, 3-metoxyphenylglucol) were quantified before and after a 2-month treatment period. A group of similar patients (n = 13) in another nursing home constituted a control group. The ratings of concentration, absent mindedness and recent memory showed a more favorable development in the treatment group than in the control group where an intellectual deterioration was evident. Restlessness was rated higher in the treatment group after the treatment period, while the psychological testings showed no significant changes between the groups. CSF HVA concentrations increased in the treatment group and decreased in the control group (P less than 0.05). No change was evident in 5-HIAA or HMPG concentrations in either group. The results suggest that environmental factors influence biochemical markers of transmitter activity which thus possibly may be of etiological importance in dementia.     

Susceptibility to neuroleptic malignant syndrome in Parkinson's disease

OBJECTIVE: To determine susceptibility to neuroleptic malignant syndrome (NMS) in patients with PD in relation to central monoamine metabolism. METHODS: CSF levels of homovanillic acid (HVA), 3-methoxy-4-hydroxy phenyletilene glycol (MHPG), and 5-hydroxyindole acetic acid (5-HIAA) were assayed in 98 PD patients (mean age, 77.2 years), including 11 patients with a prior NMS-like episode, by high-performance liquid chromatography with electrochemical detection. RESULTS: Patients with a previous NMS-like episode had worse parkinsonian disability as measured by Hoehn & Yahr scale (3.7 +/- 0.8 versus 3.0 +/- 1.1; p = 0.038) and lower CSF HVA levels (20.9 +/- 17.3 versus 44.7 +/- 22.2 ng/mL; p = 0.001) compared to those without, despite similar age, disease duration, and daily dosages of antiparkinsonian drugs between groups. Logistic regression analysis showed that the CSF HVA level (p = 0.008), but not 5-HIAA level (p = 0.621), was significantly and independently related to NMS, and that the MHPG level (p = 0.070) was tendentially associated with the disorder. Odds ratios (95% confidence intervals) corresponding to 10 ng/mL increment in CSF HVA, MHPG, and 5-HIAA levels were 0.30 (0.13 to 0.73), 4.03 (0.89 to 18.2) and 1.29 (0.47 to 3.58), respectively. CONCLUSIONS: Central dopaminergic and possible noradrenergic activity contributes to NMS development in an elderly population of PD patients. Measuring CSF levels of monoamine metabolites may provide a means for identifying NMS susceptibility in PD patients.     

Influence of parenting style on the offspring's behaviour and CSF monoamine metabolite levels in crossfostered and noncrossfostered female rhesus macaques

We investigated the association between variation in parenting style and the offspring's behaviour and CSF monoamine metabolite (5-HIAA, HVA, and MHPG) levels in rhesus monkeys. Study subjects were 25 two-year-old females reared by their biological mothers and 15 same-aged females that were crossfostered at birth and reared by unrelated mothers. Subjects that were rejected more by their mothers in the first 6 months of life engaged in more solitary play and had lower CSF concentrations of 5-HIAA than subjects that were rejected less. The relation between these variables was generally similar in crossfostered and noncrossfostered females. CSF levels of 5-HIAA were negatively correlated with rates of scratching, a behavioural indicator of anxiety. These results suggest that that early exposure to high rates of maternal rejection can result in higher anxiety later in life, and that this effect may be mediated by serotonergic mechanisms. Variation in maternal protectiveness did not affect offspring behaviour and neither protectiveness nor rejection affected CSF levels of HVA and MHPG. CSF levels of MHPG, however, were negatively correlated with solitary play behaviour and avoidance of other individuals, suggesting that individuals with lower CSF MHPG were more fearful and socially phobic than those with higher CSF MHPG. Taken together, these findings suggest that individual differences in anxiety and fearfulness in young rhesus monkeys are accounted for, at least in part, by variation in CSF levels of monoamine metabolites, and that the development of brain monoamine systems, particularly serotonin, can be affected by early exposure to variable maternal behaviour.     

Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers

Concentrations of monoamine metabolites (MM) in lumbar cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. We investigated possible relationships between DNA polymorphisms in the tryptophan hydroxylase (TPH) and catechol-O-methyltransferase (COMT) genes and CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 66). Lower CSF 5-HIAA levels were found in men with the TPH U allele (p = 0.005), but not in women. A similar but less significant pattern was observed for CSF HVA. No relationship was found between the TPH polymorphism and CSF MHPG. COMT genotypes did not relate significantly to MM concentrations. The results suggest that TPH genotypes participate differentially in the regulation of serotonin turnover rate under presumed steady state in the central nervous system of men. Due to the uncertain functional relevance of the DNA polymorphism investigated and the many calculations performed, the results should be interpreted with caution until replicated.     

Monoamine metabolites in cerebrospinal fluid during and after acute cerebral ischemia

In order to understand the role of monoamines in cerebral ischemia, 3-methyoxy-4-hydroxyphenylglycol(MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid(HVA), the three major unconjugated monoamine metabolites in cerebrospinal fluid (CSF), of 33 patients and 18 controls were measured with high performance liquid chromatography. Results showed all three metabolites were raised in patients with severe ischemia, but only MHPG and 5-HIAA were elevated significantly, MHPG changes more quickly and regularly as a consequence of cerebral ischemia than the two others. A positive correlation between any pair of metabolites was found in controls and in patients in the first week after stroke, but not at the end of the second week. Computer assisted multivariate analysis indicated 5-HIAA and MHPG correlated more closely with the state of illness in the acute stage, whereas HVA correlated the least. Possible explanations for the changes of CSF levels of amine metabolites are discussed.     

Cerebrospinal fluid monoamine markers are decreased in dementia of the Alzheimer type with extrapyramidal features

We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Alzheimer type (DAT), with or without extrapyramidal signs, and in 14 age-matched healthy controls. Compared with concentrations in DAT and controls, the concentrations of homovanillic acid (HVA) and biopterin were significantly decreased in DAT with extrapyramidal signs (EDAT). CSF 3-methoxy-4-hydroxy-phenethyleneglycol and 5-hydroxyindoleacetic acid did not differ significantly among these groups. Age at onset of dementia was positively correlated with CSF HVA (r = 0.49, p less than 0.05). The two dementia groups did not differ significantly in the extent of ventricular dilation as measured by quantitative CT, but EDAT patients had lower Mini-Mental State Examination scores than did DAT patients. When patients were matched for age and dementia severity, CSF HVA and biopterin concentrations remained significantly lower in EDAT than in DAT patients. These results indicate that EDAT patients form a distinct subgroup of DAT with evidence of central monoamine dysfunction.