Increased endothelin concentration in CSF from patients with subarachnoid hemorrhage

A considerable quantity of endothelin-like immunoreactivity was demonstrated as present in the CSF of patients with subarachnoid hemorrhage. The endothelin levels in the CSF raised from 0.4 +/- 0.2 (Mean +/- SD) pmol/L at Day 0-1 to 2.2 +/- 0.6 pmol/L at Day 6 and the levels decreased gradually. The result suggest that endothelin may contribute the generation of vasospasm often observed in subarachnoid hemorrhage.     

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.     

Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid.

Concentrations of HVA, 5-HIAA, ascorbic acid, and uric acid in the lumbar and cisternal cerebrospinal fluid (CSF) were measured in psychiatric and neurologically impaired patients. The concentration of HVA is 6.1 times and of 5-HIAA 2.7 times higher in cisternal than in lumbar samples, the cisternal level of uric acid is half that of the lumbar region, but no significant differences were found in ascorbic acid concentrations. Correlation between lumbar and cisternal metabolite concentrations is high for 5-HIAA and ascorbic acid, and is less for HVA and uric acid. In cisternal CSF there is a significant correlation between levels of HVA-5-HIAA, 5-HIAA-ascorbic acid, and 5-HIAA-uric acid. These correlations disappear in lumbar CSF. These findings indicate that extrapolations to cisternal neurotransmitter metabolite concentration from lumbar measures are unwarranted for HVA, but not for 5-HIAA.     

Markers of dopamine metabolism in Parkinson's disease. The Parkinson Study Group.

We used two analytic methods (a multichannel coulometric electrode array with high-performance liquid chromatography, and gas chromatography-mass spectrophotometry) to measure CSF dopamine (DA) and its metabolites in mildly affected, unmedicated subjects with Parkinson's disease (PD). The mean (+/- SD) concentration of homovanillic acid (HVA), the most abundant product of DA turnover, was 164.57 +/- 95.05 nM. As sequential aliquots of CSF were collected from the first to 23rd ml, CSF HVA concentration almost doubled. After HVA, 3-O-methyldopa (3-O-MD) was the next most abundant compound. The summed concentrations of 3-O-MD, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, DA, DA-3-sulfate, homovanillol, and levodopa (LD) amounted to 12.6% of HVA. Concentrations of the DA metabolites did not correlate to a variety of indices of PD severity. The presence of LD and 3-O-MD may be indicators of DA synthesis and possibly could reflect compensatory processes among surviving dopaminergic neurons of the PD brain.     

Cerebrospinal fluid and behavioral changes after methyltestosterone administration: preliminary findings

BACKGROUND: Anabolic androgen steroid abuse is associated with multiple psychiatric symptoms and is a significant public health problem. The biological mechanisms underlying behavioral symptom development are poorly understood. SUBJECTS AND METHODS: We examined levels of monoamine metabolites, neurohormones, and neuropeptides in the cerebrospinal fluid (CSF) of 17 healthy men, at baseline and following 6 days of methyltestosterone (MT) administration (3 days of 40 mg/d, then 3 days of 240 mg/d). Subjects received MT or placebo in a fixed sequence, with neither subjects nor raters aware of the order. Potential relationships were examined between CSF measures, CSF MT levels, and behavioral changes measured on a visual analog scale. RESULTS: Following MT administration, levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly lower (mean +/- SD, 103.8 +/- 47 vs 122.0 +/- 50.7 pmol/mL; P<.01), and 5-hydroxyindoleacetic acid (5-HIAA) levels were significantly higher (mean +/- SD, 104.7 +/- 31.3 vs 86.9 +/- 23.6 pmol/mL; P<.01). No significant MT-related changes were observed in CSF levels of corticotropin, norepinephrine, cortisol, arginine vasopressin, prolactin, corticotropin-releasing hormone, beta-endorphin, and somatotropin release-inhibiting factor. Changes in CSF 5-HIAA significantly correlated with increases in "activation" symptoms (energy, sexual arousal, and diminished sleep) (r = 0.55; P =.02). No significant correlation was observed between changes in CSF and plasma MT, CSF MHPG, and behavioral symptoms. CONCLUSIONS: Short-term anabolic androgenic steroid use affects brain neurochemistry, increasing CSF 5-HIAA and decreasing MHPG. Changes in 5-HIAA levels caused by anabolic androgenic steroids are related to the behavioral changes we observed. In this small sample, we did not observe a significant relationship between behavioral measures and either dose of MT or CSF and plasma levels of MT.     

Glutamic acid decarboxylase in cerebrospinal fluid in infancy and childhood. Part I. Glutamic acid decarboxylase activity in cerebrospinal fluid of normal infants and children

Glutamic acid decarboxylase (GAD) activity in the cerebrospinal fluid (CSF) of normal infants (n:14) and children (n:28) was determined by measuring the amount of 14CO2 released from L-[1-14C]-glutamic acid. The mean GAD activity in CSF of infants and children was 5.2 +/- 2.5 pmol CO2 formed/hr/ml. Dividing these subjects into 4 groups according to age, GAD activities in CSF were 5.4 +/- 1.6 pmol CO2 formed/hr/ml in neonates (0-1 m), 3.6 +/- 1.6 pmol CO2 formed/hr/ml in infants (2-12 m), 3.9 +/- 1.1 pmol CO2 formed/hr/ml in young children (2-6 yr) and 7.1 +/- 2.3 pmol CO2 formed/hr/ml in school children (7-16 yr), respectively. In neonates and school children, GAD activities were significantly higher (p less than 0.001) than those in the other age groups. In infants under 6 months of age, a significantly negative correlation between GAD activity in CSF and their ages was recognized (r = -0.52, p less than 0.001). In infants and children ranging from 6 months to 16 years of age, a significantly positive correlation between GAD activity in CSF and their ages was found (r = 0.67, p less than 0.001). These data suggest that high GAD activity in neonates may be due to hypoxia at birth and the activity gradually increases from 6 months to 15 years of age.     

Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations.

The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12+/-2 microg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22+/-4 microg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.     

Homovanillic acid concentrations in brain,CSF and plasma as indicators of central dopamine function in primates

Summary In a large number (91) of vervet monkeys, correlation coefficients were determined between homovanillic acid (HVA) concentrations in four brain areas. Significant correlations existed between dorsal frontal cortex and orbital frontal cortex and between putamen and caudate nucleus. However, no significant correlations existed between either cortical area and the basal ganglia areas.Correlations were tested between CSF and plasma HVA and between these fluids and brain regions. The only significant relationship found was between CSF and dorsal frontal cortex, after possible treatment effects were statistically removed. The assumption that primate CSF HVA concentration necessarily reflects basal ganglia HVA concentration is questioned and furthermore, the results suggest that HVA from cortex contributes significantly to that in cisternal CSF. Raw plasma HVA measurements (even when uninfluenced by diet or anesthetic) appear to be of limited value in gauging central dopamine metabolism and turnover.Presented in part at 5th Catecholamine Symposium, Göteborg, Sweden (June 1983).     

Concentrations of monoamines and monoamine metabolites in cerebrospinal fluid determined by high-performance liquid chromatography with electrochemical detection

Using reversed-phase high-performance liquid chromatography with an electrochemical detection, I have developed a sensitive technique to measure monoamines and their metabolites in cerebrospinal fluid (CSF). The present method has been shown to offer simplicity and high sensitivity for the determination of dopamine (DA) and norepinephrine (NE), as well as monoamine metabolites, in small amounts of human CSF. The first 2 ml of CSF was obtained from 61 patients (27 males and 34 females), aged from 15 to 88 years, with a variety of non-neurological diseases by lumbar puncture performed between 8:45 a.m. and 4:20 p.m. CSF was collected in the lateral decubitus position before lumbar anesthesia for surgical treatment. Samples were immediately frozen at -80 degrees C until assayed. None had any history of neurological or psychiatric illness. Concentrations in lumbar CSF were 10.9 +/- 6.0 pg/ml (mean +/- SD, n = 22) for DA, 105.8 +/- 63.6 pg/ml (n = 60) for NE, 30.5 +/- 1.6 ng/ml (n = 61) for homovanillic acid (HVA), 1.8 +/- 1.2 ng/ml (n = 46) for 3,4-dihydroxyphenylacetic acid (DOPAC), 7.7 +/- 2.1 ng/ml (n = 46) for 3-methoxy-4-hydroxyphenylglycol (MHPG) and 18.8 +/- 10.9 ng/ml (n = 61) for 5-hydroxyindoleacetic acid (5 HIAA), respectively. While 5 HIAA concentrations in lumbar CSF taken in the afternoon tended to be lower than those in the morning, MHPG in the afternoon was significantly higher than that in the morning. There were no sex differences in the concentrations of monoamines and their metabolites examined. There was a tendency for the concentrations of HVA and DOPAC to be lower in older subjects. A significant correlation was found among HVA, 5 HIAA and MHPG concentrations in lumbar CSF. The present study suggests that a standardized condition for collecting CSF should be employed to compare the concentrations of monoamines and their metabolites across central nervous system disorders. Furthermore, in addition to the measurement of individual monoamine or monoamine metabolite level in CSF, future studies should be extended to include comparisons of a mutual relationship among several monoamine metabolites.     

CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome.

PURPOSE: To evaluate the role of CNS dopaminergic systems in Restless Legs Syndrome (RLS), homovanillic acid (HVA), tetrahydrobiopterin (BH4), and neopterin (NEOP), were assayed in CSF from RLS patients. The serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was also measured. METHODS: CSF was taken from 16 RLS patients after 2 weeks off medication and from 14 control subjects. The CSF metabolites were determined using HPLC techniques. RESULTS: There was no significant difference in HVA or 5-HIAA, but NEOP and BH4 were higher in RLS patients. The RLS group was significantly older than the control group (64.2 +/- 9.2 years vs. 51.4 +/- 6.3 years; P < 0.001). A multiple regression analysis showed a strong correlation between age and 5-HIAA (r = 0.46, P = 0.04) and between age and NEOP (r = 0.61, P < 0.01). To eliminate the potential error created by the age difference between groups, an age-adjusted subgroup of RLS and control subjects were compared. There was still no difference found for HVA; however, 5-HIAA was now significantly lower (P < 0.01) in the RLS subgroup. Age-adjustment eliminated the differences previously found for NEOP, (P = 0.12), but BH4 continued to remain higher in the RLS group (P < 0.01). CONCLUSION: Differences in CSF HVA concentrations were not found. The changes in 5-HIAA and BH4 are of unclear clinical significance and require further assessment with appropriate age-matched controls.     

Neurophysiological correlates of age-related changes in human motor function

BACKGROUND: There are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. OBJECTIVE: To delineate age-related changes in the physiology of brain systems subserving simple motor behavior. METHODS: Ten strongly right-handed young (<35 years of age) and 12 strongly right-handed elderly (>50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced "button-press" motor task with their dominant right hand alternating with a rest state. RESULTS: Although the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score plus minus SD, young subjects = 547 +/- 97 ms, elderly subjects = 794 +/- 280 ms, p < 0.03). There was a greater extent of activation in the contralateral sensorimotor cortex, lateral premotor area, supplementary motor area, and ipsilateral cerebellum in the elderly subjects relative to the young subjects (p < 0.001). Additional areas of activation, absent in the young subjects, were seen in the ipsilateral sensorimotor cortex, putamen (left > right), and contralateral cerebellum of the elderly subjects. CONCLUSIONS: The results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes.     

Cerebrospinal fluid monoaminergic metabolites are elevated in adults with Down's syndrome

Under conditions of rest and a low monoamine diet, brain monoamine activity was examined in young (less than 35 years) and old (greater than 35 years) adults with Down's syndrome and in control subjects by measuring the cerebrospinal fluid (CSF) and plasma concentrations of the neurotransmitter norepinephrine, and of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy 4-hydroxyphenylglycol (MHPG), the respective metabolites of the neurotransmitters serotonin, dopamine, and norepinephrine. There were no age-related differences in metabolite concentrations in either the Down's syndrome or control subjects. CSF concentrations of 5-HIAA, HVA, and norepinephrine were significantly higher in young subjects with Down's syndrome as compared with young controls, and CSF concentrations of 5-HIAA and norepinephrine were significantly higher, by twofold or more, in old subjects with Down's syndrome as compared with older controls. The results suggest that monoamine turnover and brain functional activity involving monoamines is elevated in Down's syndrome, and that the early neuropathological changes in the disorder are not associated with a monoamine deficit.     

The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type.

OBJECTIVE: To evaluate the production rate of CSF in patients with differing disease states. METHODS: The authors measured the production rate of CSF in three groups of patients: five patients with PD below age 60 (aged 51 +/- 4 years, mean +/- SD), nine with PD over age 60 (aged 69 +/- 6 years, mean +/- SD), and seven with dementia of the Alzheimer's type (AD) (aged 72 +/- 9 years, mean +/- SD). This method, based on the Masserman technique, employs ventricular rather than a lumbar access to the CSF space. Furthermore, the volume of CSF removed during the procedure is only 3 mL rather than 10 mL. RESULTS: These measurements indicate that the mean rate of CSF production in patients with PD under age 60 was 0.47 +/- 0.13 mL/minute, in patients with PD aged 60 or older the mean rate was 0.40 +/- 0.12 mL/minute, and in patients with AD the mean rate was 0.20 +/- 0.06 mL/minute. CONCLUSION: These results indicate that the rate of CSF production in patients with PD is normal, and that the rate of CSF production in patients with AD is markedly reduced.     

CONCENTRATIONS OF MONOAMINE METABOLITES IN HUMAN LUMBAR AND CISTERNAL CEREBROSPINAL FLUID

5HIAA and HVA were determined in successive samples of CSF withdrawn at the lumbar and cisternal levels in connection with gas myelographic examinations in 16 patients. The mean of 5-HIAA in the first cisternal samples were 83 ng/ml (n equal to 8) and of HVA 143 NG/ML (N equal to 7). A sharp increase in the concentration of both metabolites, but particulary of HVA, was seen in successive lumbar samples. The ratio of cisternal/lumbar 5-HIAA was 3/1, and of HVA 10/1 in one patient in whom lumbar and cisternal CSF were obtained with 2 weeks' interval. The concentrations of monoamine metabolites in CSF obtained at lumbar puncture are thus highly dependent on the amount of fluid withdrawn. This fact should be taken into consideration when different materials are compared.     

A study on cisternal CSF levels of arachidonic acid metabolites after aneurysmal subarachnoid hemorrhage

Arachidonic acid (AA) metabolites may play an important role in the pathogenesis of cerebral vasospasm which complicate subarachnoid hemorrhage. Authors have studied levels of 4 major AA metabolites in lumbar CSF samples and in CSF collected from perianeurismatic cisterns of 40 patients admitted with diagnosis of subarachnoid hemorrhage. Lumbar levels of AA metabolites are significantly higher in SAH patients than in control cases; moreover, cisternal CSF levels of PGD2, TxB2 and LTC4 are significantly higher than lumbar levels. Cisternal CSF levels (expressed in pg/ml +/- SEM) are in the "spasm" group: PGD2: 1129.62 +/- 146.33; 6-keto-PGF1 alpha: 214.2 +/- 19.96; TxB2: 4350.25 +/- 656.87; LTC4: 2582.19 +/- 381.83. In the "no spasm" group: PGD2 460.1 +/- 55.89; 6-keto-PGF1 alpha: 306.37 +/- 88.74; TxB2: 5752.5 +/- 899.25; LTC4: 812.92 +/- 142.06. Statistical analysis (paired t-test) shows values significantly higher for cisternal levels of PGD2 (P less than 0.005) and LTC4 (P less than 0.005) in patients presenting vasospasm. This suggests the importance of the subarachnoidal clot as a source of vasoactive compounds. Higher levels of leukotriene C4 in patients presenting vasospasm suggest a role for the compound in the genesis of local inflammatory processes and morphological changes of the arterial wall.     

L-dopa pharmacokinetics in plasma and cisternal and lumbar cerebrospinal fluid of monkeys

The pharmacokinetics of levodopa (L-dopa) in plasma and in cisternal and lumbar cerebrospinal fluid (CSF) were studied in Rhesus monkeys that were given 2- to 3-hour intravenous infusions of L-dopa. Steady-state L-dopa concentrations in cisternal CSF correlated well with plasma levels, and yielded a CSF:plasma ratio of 0.17. The disappearance of L-dopa from plasma and cisternal CSF compartments fits an open, two-compartment pharmacokinetic model. Although slower, the distribution and elimination half-lives for L-dopa from cisternal CSF (8.9 and 49.2 minutes, respectively) were of a similar magnitude to those from plasma (4.9 and 33.2 minutes, respectively). If cisternal CSF reflects brain extracellular fluid, then plasma pharmacokinetics of L-dopa are a reasonable approximation of those in the brain. In contrast to cisternal CSF, the disappearance of L-dopa from lumbar CSF fits an open, one-compartment model with an elimination half-life of 100 minutes. This indicates that the lumbar CSF compartment is unsuitable for investigation of the pharmacokinetics of L-dopa in the brain.     

Cerebrospinal fluid 5-hydroxyindoleacetic acid as an index of central serotonergic processes

Faulty transmission in the central serotonin and catecholamine systems may be involved in some psychiatric and neurological conditions. Central monoamine metabolism can be studied by measuring amine metabolites in the lumbar cerebrospinal fluid (CSF), but results to date have been inconsistent. Since most studies have analyzed lumbar CSF, one reason for the inconsistencies may be that lumbar fluid does not reflect brain amine metabolism. We measured 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in serial CSF samples obtained in connection with pneumoencephalographic (PEG) examinations: through seven samples of equal volume, a gradual increase was found for both metabolites in 14 neurological patients, and the first and last fractions were statistically significantly correlated. In addition, a small series of cisternal CSF samples from psychiatric (depressed and alcoholic) and neurological patients were analyzed for 5HIAA. Frequency distribution in cisternal CSF was similar to that of lumbar values, although the levels were about twice as high, close to those found in the last PEG fractions. There were no significant differences between patient groups either in cisternal or lumbar CSF 5HIAA. These findings suggest that while there is an ascending gradient, lumbar CSF samples do reflect amine metabolite concentrations of the more central fluid. No disease-specific differences in cisternal CSF were found which were absent in the lumbar fluid.     

Lactate and Lactate Dehydrogenase in Cistern as Biomarkers of Early Brain Injury and Delayed Cerebral Ischemia of Subarachnoid Hemorrhage

Objective: The pathophysiology of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) has not been fully evaluated. The aim of this study was to evaluate the dynamics of lactate and lactate dehydrogenase (LDH) in carotid cisternal cerebrospinal fluid (CSF), and to discuss their effectiveness as markers of early brain injury (EBI) and DCI following aSAH. Patients and Methods: Among 91 consecutive aSAH patients treated between January 2012 and March 2019 at National Hospital Organization Beppu Medical Center, 19 patients (20.9%) were eligible for this retrospective study. Concentrations of lactate and LDH in carotid cisternal CSF within 14 days after onset of aSAH were evaluated. Results: Six of the 19 patients (31.6%) had a history of DCI. Both lactate and LDH levels in carotid cisternal CSF were significantly higher in the DCI group than in the non-DCI group on postbleeding day (PBD) 1-2, 3-4, and 5-6. Interestingly, neither lactate nor LDH levels in blood differed significantly between DCI and non-DCI groups on PBD 1-2. Conclusions: Lactate and LDH concentrations in carotid cisternal CSF may vividly reflect the EBI and may thus represent predictive biomarkers of DCI following aSAH.     

Homovanillic acid and 5-hydroxyindole-acetic acid in the csf of patients after a severe head injury. I. Lumbar csf concentration in chronic brain post-traumatic syndromes.

Lumbar CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5HIAA) have been determined in ten patients suffering from chronic brain post-traumatic syndromes, at various length of time after the brain trauma. Lower concentrations of HVA (mean 21 +/- 14 mug/ml) compared to controls (mean 46 +/- 10 mug/ml) was observed in 7 cases; 5HIAA levels were within normal values. The 5HIAA/HVA ratio (1.59 +/- 0.66) was significantly higher (p less than 0.001) than the one recorded in controls (0.66 +/- 0.10). Monitoring of lumbar HVA and 5HIAA over time, before, during and after L-dopa treatment, revealed interesting correlations between modification of clinical picture and the levels of monoamines acid metabolites. The data indicate a profound alteration of brain monoamines in chronic syndromes following a severe head injury and suggest that measurements of lumbar HVA and 5HIAA in these patients may be of euristic and diagnostic value.     

Risperidone and 9-hydroxyrisperidone concentrations are not dependent on age or creatinine clearance among elderly subjects

Risperidone is extensively metabolized to an active metabolite, 9-hydroxyrisperidone (9-OH), which is dependent on renal clearance. Risperidone and 9-OH clearances are reduced in the elderly when compared to young subjects. The objective of this study was to determine whether among elderly subjects, risperidone and 9-OH clearance would further decline with increasing age and decreasing creatinine clearance (CrCl). Twenty geriatric inpatients were evaluated in a naturalistic setting with regard to total daily risperidone dose and dosing interval. Creatinine clearance was determined using an 8-hour urine collection. Risperidone and 9-OH concentrations were determined by radioimmunoassay. Spearman's correlation coefficients were used to examine the impact of age and CrCl on concentrations of risperidone, 9-OH, their sum, and the quotient of 9-OH/risperidone. Mean age was 76.4 +/- 9 years (range 56-91). Mean CrCl was 55.4 +/- 32.8 mL/min/1.73 m2 (range 17-142 mL/min/1.73 m2). Mean risperidone daily dose was 1.3 +/- 0.7 mg. Steady-state risperidone and 9-OH concentrations were 4.1 +/- 5.3 ng/mL and 9.1 +/- 6.2 ng/mL, respectively. Mean 9-OH/risperidone was 6.2 +/- 6.1. Concentrations of risperidone, 9-OH, their sum, and 9-OH/risperidone were not significantly correlated with age or CrCl. These results were unchanged when concentrations were corrected for total daily risperidone dose. Among elderly subjects, risperidone and 9-OH clearance do not decline with increasing age or declining CrCl.