CSF Monoamine Metabolism in Patients with Tardive Dyskinesia: Effect of Oxypertine and Hydroxyzine Pamoate

Abstract: Cerebrospinal fluid (CSF) HVA, MHPG, 5-HIAA, cAMP and cGMP concentrations were measured in schizophrenic patients with tardive dyskinesia before and after a three-week administration of oxypertine (n = 4), hydroxyzine pamoate (n = 4) or placebo (n = 4). The oxypertine administration resulted in a reduction of the CSF HVA concentration and an elevation of the MHPG and cAMP concentrations, associated with a clinical improvement in tardive dyskinesia. The hydroxyzine administration reduced the CSF 5-HIAA concentration in all the patients and the CSF HVA concentration in two of four patients with a clinical improvement. A reduction in the CSF HVA concentration associated with possible therapeutic effects of oxypertine or hydroxyzine may suggest the normalization of a hyperdopaminergic state. Discussions were held that functional disorders of not only the dopaminergic system but the norepinephrinergic and serotoninergic systems may relate to the pathogenesis of tardive dyskinesia.     

CSF studies on the relationship between dopamine and 5-hydroxytryptamine in Parkinsonism and other movement disorders.

In Parkinson's disease, the concentration of homovanillic acid (HVA) was reduced in lumbar CSF from patients with idiopathic Parkinsonism (n = 54, P less than 0.05) and post-encephalitic Parkinsonism (n = 19, P less than 0.01). The reduction in the concentrations of 5-hydroxyindolylacetic acid (5-HIAA) was not significant, and there was no alteration in the levels of 4-hydroxy-3-methoxyphenylethylene glycol (MHPG). Treatment with L-dopa increased the concentration of HVA in the CSF (P less than 0.05) but had no effect on the levels of 5-HIAA and MHPG. Carbidopa given in combinations with L-dopa produced similar CSF concentrations of dopa as did L-dopa alone but caused less than half the rise in HVA. Fourteen patients who became functionally independent on treatment with L-dopa had higher 5-HIAA levels than 23 patients who showed no such improvement (P less than 0.001), suggesting that intact 5-hydroxyltryptamine neurones may be important in the therapeutic response to L-dopa. In a variety of movement disorders, the levels of HVA, 5-HIAA, and MHPG were not significantly different from age-matched controls. Treatment with tetrabenazine did not significantly alter the metabolite levels in patients in whom it produced either improvement, or side effects.     

Cerebrospinal fluid monoamine metabolites and cyclic nucleotides in chronic schizophrenic patients with tardive dyskinesia or drug-induced tremor.

Lumbar CSF HVA, MHPG, 5HIAA, cAMP, and cGMP were measured in 12 chronic schizophrenics with tardive dyskinesia before and 3 weeks after sodium valproate (VPA) or cyproheptadine treatment. HVA levels significantly decreased and cAMP and cGMP levels significantly increased during the administration of VPA or cyproheptadine. There were no significant correlations between the degree of improvement in tardive dyskinesia and the changes of amine metabolities or cyclic nucleotides. None of the pretreatment values for CSF amine metabolites or cyclic nucleotides were different from those of 15 chronic schizophrenics without tardive dyskinesia as controls. Decrease of HVA and increase of cGMP during the treatment might indicate the normalization of dopaminergic-cholinergic imbalance in the brain. Furthermore, significantly low levels of 5HIAA were observed in the patients with drug-induced tremor. It is suggested that neuroleptic-induced tremor may be attributed to serotonergic dysfunction in the brain.     

CSF neurochemical study of tardive dyskinesia

Twenty-three inpatients who met DSM-III criteria for schizophrenia were selected for cerebrospinal fluid (CSF) neurochemical study of tardive dyskinesia (TD). Ten inpatients had tardive dyskinesia, and the remaining 13 patients without TD served as controls. There were no intergroup differences in sex, age, duration of neuroleptic treatment, or in total amount of neuroleptics received between the TD and the control groups. Cerebrospinal fluid was collected by lumbar puncture, and concentrations of homovanillic acid (HVA), MHPG, 5-hydroxyindoleacetic acid (5-HIAA), and acetylcholinesterase (AChE) activity were measured. The concentrations of MHPG (TD 11.56 +/- 3.48 ng/ml versus control 14.20 +/- 3.86 ng/ml), 5-HIAA (45.27 +/- 9.77 ng/ml versus 40.34 +/- 13.77 ng/ml), and HVA (38.26 +/- 18.31 ng/ml versus 31.40 +/- 7.83 ng/ml), and the activity of AChE (TD 7.95 +/- 5.21 mmol/g.hr versus control 12.89 +/- 8.04 mmol/g.hr) showed no significant differences between the two groups, but the ratios of HVA/AChE (t = 2.21, p = 0.05), 5-HIAA/AChE (t = 2.62, p = 0.02), MHPG/HVA (t = -2.16, p = 0.04), and MHPG/5-HIAA (t = -2.48, p = 0.02) were statistically different. The results indicated that TD might involve an imbalance of dopamine-acetylcholine, noradrenalin-dopamine, noradrenalin-serotonin, and serotonin-acetylcholine.     

Cerebrospinal fluid levels of monoamine metabolites in panic disorder.

The cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), and the dopamine metabolite homovanillic acid (HVA) did not differ significantly in a group of patients with panic disorder (n = 17) as compared to age- and sex-matched normal controls (n = 17). While CSF concentrations of HVA and 5HIAA were significantly correlated in both patients and controls, CSF MHPG levels were significantly correlated with the concentrations of CSF 5HIAA and HVA only in patients. In a small number of subjects (n = 5), successful reduction of anxiety attacks by administration of clomipramine or imipramine (50-150 mg/day) for at least 2 months was associated with a significant decrease in CSF concentrations of 5HIAA and MHPG, but not HVA.     

Biogenic amine metabolites in human CSF after hypoxia due to cardiac arrest

The concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) were determined in CSF of patients with hypoxia due to circulatory arrest. Patients were divided into neurologically disabled and recovered according to the Glasgow Coma Scale. CSF was collected 4, 28, 76 and 172 h after commencement of resuscitation and once from control patients subjected to spinal anaesthesia. The initial concentrations of MHPG, 5-HIAA and HVA were significantly higher in a subgroup of neurologically disabled patients who died within 76 h. In recovered patients the concentration of MHPG declined with time to the value of the control group, whereas it increased in neurologically disabled patients. In the latter group the concentration of 5-HIAA also showed an increase with time, whereas in recovered patients it declined after an initial rise. It is concluded that high concentrations of MHPG, 5-HIAA and HVA in CSF may be prognostic for hypoxic brain injury after cardiac arrest.     

Monoamine metabolites in the CSF of epileptic patients.

To assess the possible role of amine neurotransmitters in human epilepsy, we measured metabolites of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), dopamine (homovanillic acid [HVA]), and norepinephrine (3-methoxy-4-hydroxyphenylethylene glycol [MHPG]) in the lumbar cerebrospinal fluid (CSF) of patients with partial complex seizures and in neurologic controls. Untreated epileptic patients had lower concentrations of 5-HIAA and HVA in the lumbar CSF than the controls, but the differences were not statistically significant. Among epileptic patients receiving effective antiepileptic drug treatment, the HVA concentration was within the control range. Mean MHPG concentrations were similar in patients and controls. From the epileptic patients whose CSF was obtained at pneumoencephalography we obtained a second sample of CSF that was originally in the basal cisterns. No significant differences between treated and untreated patients were found for any of the three metabolites. The concentrations of HVA and 5-HIAA were higher in cisternal than in lumbar CSF, but there was no such gradient for MHPG.     

CSF-amine metabolites in depression, dementia and in controls

Lumbar CSF concentration of 5-HIAA, MHPG, and HVA were measured in patients with depression, dementia due to normal pressure hydrocephalus (NPH) and in controls. Moreover, ventricular concentrations of the metabolites were measured in patients with NPH. It was aimed to match patients and controls for age, sex, and body height. Non-parametric statistics were used throughout the study. No differences in lumbar concentrations of CSF 5-HIAA, MHPG and HVA were found between the different diagnostic groups. A ventriculo-lumbar gradient of 5-HIAA and HVA being 4:1 and 5:1, respectively, was found in patients with NPH. No correlation between the difference in ventricular and lumbar concentrations and body height was found, suggesting that body height may be an inaccurate measure for the rostro-caudal gradient. Moreover, no correlation between ventricular and lumbar levels of 5-HIAA and HVA was seen.     

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 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.     

Neurochemical findings in the cerebrospinal fluid of schizophrenic patients with tardive dyskinesia and neuroleptic-induced parkinsonism

Monoamine and their acid metabolites were determined in the CSF of 18 drug-treated chronic schizophrenic patients with the symptoms of tardive dyskinesia and neuroleptic-induced Parkinsonism (Parkinsonism). Six healthy volunteers were used as the control group. The norepinephrine (NE) levels were found to be significantly higher in the patients with tardive dyskinesia than in the controls. Furthermore, elevated CSF NE levels were also observed in the patients with Parkinsonism. Epinephrine (E) and Dopamine (DA) were not present in the CSF of the control group, whereas measurable levels of DA could be detected in 4 out of 9 and E was found in 8 out of 9 patients with tardive dyskinesia. The mean concentration of HVA was slightly but not significantly elevated in the patients with tardive dyskinesia and Parkinsonism. The mean values of CSF 5-HIAA were all within the normal range in both patient groups. From the above results, it was suggested that abnormal adrenergic activity rather than abnormal dopaminergic activity may play an important role as a mechanism in the etiopathogenesis of extra-pyramidal disorders. Furthermore, in the patients with Parkinsonism, CSF neurochemical observations were similar to those of the patients with tardive dyskinesia in this study. It may help to explain the clinical coexistence of tardive dyskinesia and neuroleptic-induced Parkinsonism.     

Spinal reflexes and the concentrations of 5-HIAA, MHPG, and HVA in lumbar cereborspinal fluid after spinal lesions in man.

Descending bulbospinal pathways that employ specific neurotransmitter substances are known to be capable of modulating segmental reflex activity in the experimental animal. To determine whether this might also occur in man correlations have been sought between the activity in spinal reflex pathways and the lumbar cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA), 3 methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) in 12 patients with complete or virtually complete spinal lesions. The concentrations of 5-HIAA and MHPG in lumbar CSF ARE REDUCED AFTER COMPLETE OR VIRTUALLY COMPLETE SPINAL LESIONS IN MAN. This may occur within 18 days of the lesion. MHPG concentrations appear to be inversely related to the level of the lesion. The HVA concentration in lumbar CSF is reduced when there is obstruction of the CSF pathways. No relationship could be demonstrated between the concentrations of 5-HIAA or MHPG in lumbar CSF and the activity in the spinal monosynaptic pathway (estimated from the proportion of the motoneurone pool activated by the Achilles tendon reflex or H reflex) or the activity of a spinal inhibitory mechanism (estimated by the degree of vibratory inhibition of the monosynaptic reflex). Patients with a tonic vibration reflex (TVR) tended to have higher MHPG levels. There appeared to be an association between low CSF HVA and enhanced vibratory inhibition of the monosynaptic reflex in the nine patients whose spinal lesions were complete.     

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-Br?ne-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.     

Neurochemical Findings in the Cerebrospinal Fluid of Schizophrenic Patients with Tardive Dyskinesia and Neuroleptic-Induced Parkinsonism

Abstract: Monoamine and their acid metabolites were determined in the CSF of 18 drug-treated chronic schizophrenic patients with the symptoms of tardive dyskinesia and neuroleptic-induced Parkinsonism (Parkinsonism). Six healthy volunteers were used as the control group.
The norepinephrine (NE) levels were found to be significantly higher in the patients with tardive dyskinesia than in the controls. Furthermore, elevated CSF NE levels were also observed in the patients with Parkinsonism. Epinephrine (E) and Dopamine (DA) were not present in the CSF of the control group, whereas measurable levels of DA could be detected in 4 out of 9 and E was found in 8 out of 9 patients with tardive dyskinesia. The mean concentration of HVA was slightly but not significantly elevated in the patients with tardive dyskinesia and Parkinsonism. The mean values of CSF 5-HIAA were all within the normal range in both patient groups. From the above results, it was suggested that abnormal adrenergic activity rather than abnormal dopaminergic activity may play an important role as a mechanism in the etiopathogenesis of extrapyramidal disorders. Furthermore, in the patients with Parkinsonism, CSF neurochemical observations were similar to those of the patients with tardive dyskinesia in this study. It may help to explain the clinical coexistence of tardive dyskinesia and neuroleptic-induced Parkinsonism.     

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.     

Amine metabolites in ventricular cerebrospinal fluid in coma.

The concentrations of homovanillic acid (HVA), 3-methoxy, 4-hydroxyphenylglycol (MHPG), and 5-hydroxyindolylacetic acid (5-HIAA) were measured in samples of ventricular cerebrospinal fluid (CSF) taken from 15 patients who were comatose as a result of an acute head injury, a tumour, or a cerebrovascular accident. The metabolite levels were not related to the ventricular fluid pressure. In the eight patients who recovered and from whom serial samples of CSF were obtained, the metabolite levels did not change, except for two patients in whom HVA increased as coma progressed. The concentration of MHPG, but not of HVA or 5-HIAA, was greater (P less than 0.02) in the five patients who died without regaining consciousness than in the 10 patients who recovered.     

Tryptophan and biogenic amine metabolites in post-mortem human cisternal fluid: effects of post-mortem interval and agonal time.

Cisternal fluid (CF) tryptophan (TRP), 5-hydroxyindole-3-acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were measured from 40 adult cadavers. They were divided into 4 groups (n = 10 in each group), with samples taken 2, 4, 10 and 24 h after death. The CF concentrations of TRP and all determined biogenic amine metabolites were distinctly higher than in lumbar CSF during life, and concentrations of 5-HIAA were also higher in post-mortem samples than in cisternal or ventricular CSF in living humans. The means of the samples of 5-HIAA, DOPAC, HVA and MHPG were not statistically significantly different over time, but some trends were evident. TRP concentrations in CF increased linearly with time (from 4.6 to 23.6 mumol/l, P less than 0.001). CF DOPAC and HVA concentrations were dependent on agonal time and dopamine infusions. Our results imply that both ante-mortem and post-mortem conditions may influence monoamine metabolite and TRP concentrations in CF. These conditions should be accounted for in studies using post-mortem samples to study differences between patient groups in CNS neurochemistry.     

Concentration of monoamines and their metabolites in the cerebrospinal fluid from patients with senile dementia of the Alzheimer type and vascular dementia of the Binswanger type

Summary We measured the concentrations of total (conjugated and unconjugated) monoamines (dopamine, DA; norepinephrine, NE) and monoamine metabolites (homovanillic acid, HVA; 3-methoxy-4-hydroxyphenyleneglycol, MHPG; 5-hydroxyindoleacetic acid, 5-HIAA) in the cerebrospinal fluid (CSF), using HPLC-ECD in 11 patients with Alzheimer's disease (AD) or senile dementia of the Alzheimer type (SDAT), 17 patients with vascular dementia of the Binswanger type (VDBT), and 15 controls. In AD/SDAT, there was a significant decrease in the DA concentration and a significant increase in the MHPG concentration. The average NE concentration was not altered, but significantly increased with the progression of intellectual disability. There were no significant changes in HVA and 5-HIAA concentrations. Patients with VDBT showed a significant increase in the DA concentration and a significant decrease in HVA and 5-HIAA concentrations. The DA concentrations increased significantly with the progression of dementia and ventricular enlargement. These results indicate that the noradrenergic and dopaminergic system in particular are altered in AD/SDAT, while the dopaminergic and serotonergic systems are mainly involved in VDBT.     

Biogenic amine metabolites in cerebrospinal fluid of patients with affective disorders

Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 33 patients with affective illnes and from 23 neurological controls. The group of patients with affective illness comprised 29 depressed and four manic patients. During illness, the concentration of HVA was higher in the depressed patients (P >0.001) than in the controls. Both unipolar and bipolar depressed patients had increased HVA levels (P >0.001 and P >0.05, respectively). The concentration of MHPG was greater than control values in the unipolar (P < 0.001) and bipolar (P < 0.002) subgroups but did not differ from control values in the depressed group as a whole. The concentration of 5-HIAA in the depressed patients as a whole and in the unipolar and bipolar subgroups did not differ from control concentrations. During illness the manic patients had increased levels of HVA (P >0.01) and normal levels of 5-HIAA and MHPG. Sixteen of the 29 depressed patients had a second lumbar puncture after they had recovered. Compared with the pre-recovery values, the concentration of HVA was reduced in the unipolar depressives (P < 0.01) and the concentration of 5-HIAA lowered in the depressed group as a whole (P >0.02). The present findings suggest involvement of catecholamines in affective disorders.