Serotonin and monoamine metabolites in cerebrospinal fluid in children: interrelationships and the influence of age, sex and precursor]

Cerebrospinal fluid and blood were taken from 15 non-neurologic children. Tryptophan(Trp), 5-HTP, 5-HT, 5-HIAA, HVA, MHPG in CSF, and 5-HT, free and total Trp(F-Trp and T-Trp) in serum were determined by HPLC method. Results showed that Trp, 5-HTP, 5-HT, 5-HIAA in CSF were positively correlated significantly. Good correlations were also found between F-Trp in serum and Trp in CSF (C-Trp), 5-HIAA and HVA, 5-HTP and MHPG. C-Trp, 5-HTP, 5-HT, 5-HIAA and HVA declined significantly with increasing age. MHPG was higher in male than in female children.     

Clinical, biochemical, and pharmacological observation in a patient with postasphyxic myoclonus: association to serotonin hyperactivity

Posthypoxic action myoclonus is usually associated with impaired serotonin (5-HT) neurotransmission but in some patients 5-HT precursors aggravate and 5-HT blockers improve action myoclonus. We studied a 65-year-old man who presented with action myoclonus following a prolonged episode of moderate hypoxia and severe hypercarbia. The myoclonus increased with 5-hydroxytryptophan (5-HTP) 1,200 mg/day plus carbidopa 300 mg/day and sodium salt of valproic acid (SVA) 800 mg/day, and improved with 1 mg of clonazepam (CNZ) in an intravenous bolus. Biochemical analysis of the cerebrospinal fluid (CSF) prior to any drug therapy did not reveal abnormalities in the levels of homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) but 5-hydroxyindoleacetic acid (5-HIAA) levels were elevated in comparison with controls (33 versus 21 ng/ml). SVA therapy produced a moderate increase and 5-HTP plus carbidopa a threefold elevation of 5-HIAA in CSF and marked aggravation of action myoclonus. Methysergide (3 mg/day) totally suppressed myoclonus and decreased CSF 5-HIAA to undetectable levels. Methysergide also reduced CSF tryptophan to 40% of baseline levels. Discontinuation of methysergide and substitution by placebo was followed by reappearance of myoclonus. A partial and incomplete spontaneous remission of symptoms took place 7 months after the asphyxic episode. Action myoclonus and enhanced 5-HT neurotransmission may be present in patients in which acidosis reverses the effects of hypoxia on 5-HT neurotransmission.     

Indole levels in human lumbar and ventricular cerebrospinal fluid and the effect of L-tryptophan administration

Levels of tryptophan (TRP), 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in human lumbar and ventricular cerebrospinal fluid (CSF) were measured by reversed phase liquid chromatography (HPLC) with electrochemical detection. The levels of TRP ranged from 1593 to 4865 nmol/l in ventricular (VF) and from 1257 to 2557 nmol/l in lumbar CSF. The level of 5-HTP varied from 1.1 to 68.9 nmol/l in VF and from 5.3 to 10.8 nmol/l in lumbar CSF; no previous reports of 5-HTP levels in CSF exist. The serotonin level was 1.9-27.3 nmol/l in VF and 5.7-12.0 nmol/l in lumbar CSF. The levels of 5-HIAA were considerably higher in VF than in lumbar fluid with respective means of 498 +/- 52.4 nmol/l and 112 +/- 15.6 nmol/l (P less than 0.001). An oral dose of 2 g L-tryptophan significantly increased all indole levels except that of 5-HT, both in patients with progressive myoclonus epilepsy and in controls.     

Altered monoamine metabolism in children with epilepsy

Tryptophan (Trp), 5-HTP, 5-HT, 5-HIAA, HVA, and MHPG in CSF and total Trp(T-Trp), free Trp(F-Trp) and serotonin in serum were determined in 80 children with epilepsy and also in a control group. It was found that Trp, 5-HT, 5-HIAA in CSF and F-Trp in blood decreased in children with epilepsy. But the decrease of F-Trp was not the main cause of decreased 5-HT metabolism, because the no positive correlations among the four substances were found. Each of them returned to normal levels after the treatment with phenytoin or valproate. 5-HT concentration was negatively correlated with the frequency of the epilepsy episodes. 5-HIAA and HVA levels were relatively higher in the epileptics with brain damage as with compared with those who had no brain damage. The MHPG level was higher in the patients simple partial seizures. Complex partial epileptics and those patients receiving antiepileptic drugs had a lower serum T-Trp level. T-Trp was negatively correlated with the serum valproate concentration. Both T-Trp and F-Trp levels decreased in the patients treated with phenytoin.     

The effect of L-tryptophan and some psychotropic drugs on the formation of 5-hydroxytryptophan in the mouse brain in vivo

Summary L-Tryptophan and various agents known to interfere with the brain monoamines were injected intraperitoneally to mice. Subsequently, the accumulation of 5-hydroxytryptophan (5-HTP) in the brain induced by the intraperitoneal injection of the decarboxylase inhibitor Ro 4-4602 was investigated. Also the tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the brain were measured.L-Tryptophan approximately doubled the 5-HTP accumulation induced by Ro 4-4602, indicating that tryptophan hydroxylase is about halfsaturated in the normal mouse brain. Inhibitors of tryptophan hydroxylase as well as nialamide, N,N-dimethyltryptamine and LSD-25 retarded the 5-HTP accumulation, whereas reserpine had no significant effect.The data appear to support the view that the synthesis and turnover of 5-HT is regulated by a feed-back mechanism operating via changes in the intraneuronal 5-HT levels and/or in the activity of postsynaptic 5-HT receptors.     

Serotoninergic development in the postnatal rat brain

Summary Various characteristics of the developing serotoninergic system in the brain of rats aged 1 to 28 days were studied biochemically.The levels of the precursor amino acid tryptophan showed a maximal increase in the blood, brain and cerebrospinal fluid (CSF) during the 7th and 10th postnatal days. The development of tryptophan hydroxylase activity measuredin vivo by means of 5-hydroxytryptophan (5-HTP) accumulation after NSD 1015 was closely related to the 5-hydroxytryptamine (5-HT) levels at the various ages. 5-HTP accumulation and 5-HT levels increased most markedly after the second postnatal week. 5-Hydroxyindoleacetic acid (5-HIAA) levels were found to increase rapidly in the brain but somewhat more slowly in the CSF during the second week of postnatal development. Regional studies of 5-HTP accumulation after NSD 1015, 5-HT and 5-HIAA levels indicated a caudal to rostral way of maturation.The disappearance of 5-HT was measured after inhibition of tryptophan hydroxylase with H 22/54. The half-life generally decreased in the various brain parts with advancing age, and in the younger animals the shortest half-life was found in the most caudal brain parts. At 28 days of age the half-life was similar in all brain parts studied. These results indicate the existence of an adult like nerve impulse flow in the 5-HT neurons in the brain stem region of the newborn rats. The results from this investigation clearly indicate that the maturation of the different biochemical parameters of the 5-HT pathways develop in a caudal to rostral direction.The study also supports the view that tryptophan hydroxylase may be the limiting step in the development of the serotoninergic system.     

Homovanillic acid and 5-hydroxyindoleacetic acid in lumbar cerebrospinal fluid after total and REM sleep deprivation in humans.

Lumbar CSF HVA and 5-HIAA levels were assayed in 3 groups each of 10 subjects, which were respectively deprived of sleep for 30 h, deprived of REM sleep and disturbed with several awakenings during SW sleep for two consecutive nights. HVA levels after total sleep (39 +/- 20 ng/ml) or REM (35 +/- 11 ng/ml) deprivation as well as after SW sleep awakenings (32 +/- 26 ng/ml) were not different from controls (42 +/- 14 ng/ml). 5-HIAA levels after REM deprivation (32 +/- 15 ng/ml) appeared increased when compared with controls (21 +/- 7 ng/ml), total sleep-deprived subjects (21 +/- 10 ng/ml) or subjects with SW sleep awakenings (27 +/- 13 ng/ml). Possible increase in 5-HT turnover after REM deprivation and possible 5-HT role in REM sleep regulation in humans are discussed.     

Study of tryptophan metabolism via serotonin in cerebrospinal fluid of patients with noncommunicating hydrocephalus using a new endoscopic technique

By a recent minimally invasive neuroendoscopic technique, the cerebral ventricles have been reached in a quick, reliable, and harmless way, making possible the study of cerebrospinal fluid (CSF) of the lateral ventricles and, above all, the CSF adjacent to the walls of the third ventricle. Tryptophan, 5-hydroxytryptophan, serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in CSF by HPLC equipment. Twenty-six patients affected with noncommunicating hydrocephalus were enrolled in the study and, as controls, 28 subjects not suffering from any neurological disease. The concentrations of tryptophan were higher in right ventricular CSF than in lumbar CSF (P < 0.01). 5-HT was detectable in the CSF of the right ventricle of hydrocephalic patients. 5-HIAA was higher in right ventricular CSF than in cisternal and lumbar CSF (P < 0.01), both in controls and in hydrocephalic patients. However, there was a higher concentration of 5-HIAA in right ventricular (P < 0.05) and cisternal (P < 0.01) CSF in hydrocephalic patients in comparison with controls. In the CSF samples withdrawn during neuroendoscopy, 5-HT presented the highest concentrations in the pineal recess. The highest amounts of 5-HIAA were found in the choroid plexus, third and right ventricles, pituitary recess, and aqueduct, and the lowest in pineal recess, subarachnoid space, infundibulum, and interpeduncolar cistern. These results provide new insight into the fate of tryptophan and its metabolites via serotonin in the CSF and suggest the feasibility of the new neuroendoscopic technique for brain metabolic studies.     

Serotoninergic system in dementia of the Alzheimer type. Abnormal forms of 5-hydroxytryptophan and serotonin in cerebrospinal fluid

Serotonin (5-HT), its precursor 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in the cerebrospinal fluid (CSF) of 14 patients with dementia of the Alzheimer type (DAT) and in nine controls by high-performance liquid chromatography with a novel multisensor coulometric detection system. Concentrations of both 5-HT and 5-HIAA detected by this system were lower than the concentrations obtained using conventional amperometric detection. This difference was caused by coelution of compounds that could be resolved from 5-HT and 5-HIAA by the multisensor coulometric system. One of the coelution compounds, observed in DAT but not in control CSF, behaved like a partially oxidized 5-HT. A compound behaving like partially oxidized 5-HTP was also observed in DAT CSF. Concentrations of 5-HTP, 5-HT, and 5-HIAA were lower in DAT CSF than in a corresponding fraction of control CSF. These results indicate involvement of the serotoninergic system in DAT and might lead to development of a diagnostic test for DAT.     

LCEC monitoring of 5-hydroxyindolic compounds in the cerebrospinal fluid of the rat related to sleep and feeding

A new technique which allows for both the chronic withdrawal of CSF and continuous recording of EEG sleep patterns and food intake in the freely moving rat is described. Liquid chromatography with electrochemical detection (LCEC) was used for the direct assay of tryptophan metabolities in the CSF. Both 5-hydroxyindolacetic acid (5-HIAA) and 5-hydroxytryptophan (5-HTP) were easily detectable. However, serotonin (5-HT) levels were relatively low and 5-hydroxytryptophol (5-HTPhol) and N-methylserotonin (N-Me-5HT) were undetectable in several cases. The continuous monitoring of 5-HIAA and 5-HTP indicated stable values throughout the 3-hr experiments during which no food or small meals were consumed. In the rat which consumed a large meal, both 5-HIAA and 5-HTP significantly increased following that meal. This increase in metabolites may be the result of an increased availability of tryptophan to the brain as a result of the meal. Although this study is preliminary, the described technique can provide further information about the possible relationship between behavioral (sleep and/or feeding) changes and the concomitant neurochemical fluctuations.     

Functional meaning of tryptophan-induced increase of 5-HT metabolism as clarified by in vivo voltammetry

Differential pulse voltammetry with carbon fiber electrodes was used to study serotonin (5-HT) metabolism in freely moving rats. The electrodes implanted in the striatum recorded the extracellular 5-hydroxyindoleacetic acid (5-HIAA) oxidation peak after oral tryptophan (150 mg/kg). This 5-HT precursor did not modify the 5-HIAA peak in any rat tested, but it raised 5-HIAA levels determined in total tissue by a classical biochemical method (HPLC). The administration of 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.) induced an increase of 5-HIAA detectable both in the extracellular medium by voltammetry and in tissue samples. As previously shown, dorsal raphe electrical stimulation raises extracellular 5-HIAA in the striatum and this effect is enhanced by pretreatment with tryptophan. The results suggest that tryptophan in 'normal' conditions enhances 5-HT metabolism without affecting 5-HT release unless such release is stimulated. 5-HTP increases 5-HT metabolism and release.     

Neuropharmacology of Progressive Myoclonus Epilepsy: Response to 5-Hydroxy-L-Tryptophan

Summary: Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lundborg disease (U-L), mitochondria1 encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L- 5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (<20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondria1 encephalomyopathy developed status epilepticus during treatment with L-5-HTP.As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.     

Pulsatile growth hormone,prolactin, and thyrotropin secretion in rats with hypothalamic deafferentation

Rats submitted to regular 12 h cycles of light and darkness for three weeks were sacrificed at various times of the day. 5-HT, 5-HIAA and tryptophan levels were estimated in the fronto-parietal cerebral cortex. Tyrosine and free and total tryptophan levels in serm were estimated in parallel. Significant circadian variations in 5-HT and 5-HIAA levels were found in cerebral tissues. The peaks of 5-HT and 5-HIAA levels were detected during the light and dark periods respectively, the maximal fluctuations being seen between 17.00 h and 21.00 h, two times separating the light off. Important significant circadian variations in free and total serum tryptophan levels were also observed. In both cases, the maximal levels were found during the middle of the dark phase after the peak of 5-HIAA levels. The circadian rhythm of tyrosine levels in serum was in opposite phase with that of tryptophan (free or total). The diurnal changes in tryptophan content in cerebral tissues seemed thus related to those found in serum. Taking in consideration results obtained in previous studies^16,17 carried out in similar experimental conditions, it was concluded that the parallel increase in serum free tryptophan and in tissues 5-HIAA levels seen during the night were not related to a stimulation of 5-HT turnover. Indeed 5-HT synthesis is minimal at this time¹⁶.     

Serotonin metabolism in human epiepsy: The influence of anticonvulsant drugs

Cerebrospinal fluid levels of tryptophan, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were measured in 26 untreated and 46 treated epileptic patients and 32 neurological controls. Levels of these substances were normal in the untreated epileptic patiens, but elevated CSF tryptophan and a trend toward elevation of 5-HIAA were found in the treated group. The rise in CSF tryptophan and 5-HIAA appeared related to the number of anticonvulsants administered and the serum levels of phenobarbital and diphenylhydantoin. Particularly high values were seen in anticonvulsant-intoxicated patients. There was no significant correlation between CSF levels of tryptophan and 5-HIAA in control and untreated patients, but a positive correlation was found in the treated group. The slight rise in CSF levels of HVA in treated epileptic patients was not significant, but a positive correlation was found between CSF levels of 5-HIAA and HVA.     

Changes in brain and spinal tryptophan and 5-hydroxyindoleacetic acid levels following acute morphine administration in normal and arthritic rats.

The effects of morphine (10 mg/kg/s.c.) on tryptophan (TRP), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were studied in normal and arthritic rats. (1) In normal rats morphine induced a discrete but significant increase of 5-HIAA levels in the forebrain and the spinal cord. (2) By contrast, in rats suffering from experimentally induced arthritis large modifications were apparent. The basal levels of TRP, 5-HT and 5-HIAA were significantly higher than in normal rats. Morphine induced clear increases of 5-HIAA and TRP in the forebrain, the brain stem and the spinal cord, without any modification of 5-HT. The effects were dose-dependent and suppressed by naloxone (1 mg/kg/i.m.). Statistical analysis clearly revealed that arthritic rats were much more sensitive to morphine. The results support the hypothesis of an activation of a 5-HT descending pathway by morphine which parallels the activation of the ascending pathway previously demonstrated by several authors and confirmed here.     

CSF monoamine patterns in pathological gamblers and healthy controls

Previous reports on compounds in the cerebrospinal fluid (CSF) of pathological gamblers have focused on disturbed NA, DA and 5-HT function in the central nervous system. We have analysed precursors, transmitters and transmitter metabolites in 3 x 6 ml of CSF obtained from one female and 11 male pathological gamblers and 11 healthy male controls lumbar punctured at the L4-5 level after 8 h of fasting without preceding strict bedrest. Pathological gamblers displayed lower CSF levels of tryptophan and 5-HT while the opposite was the case for 5-HIAA, tyrosine, DA, HVA, DOPAC and HMPG. In contrast to previous studies, the NA level did not differ between pathological gamblers and healthy controls. A disrupted CSF gradient was noted for tryptophan, 5-HT, DA, HVA, DOPAC, NA and HMPG, but only in pathological gamblers. A disrupted gradient was found for 5-HIAA in both pathological gamblers and healthy controls. The results are in line with the presence of altered indoleamine and catecholamine function in pathological gamblers as well as an altered CSF transport from the brain to the lumbar compartment in such gamblers.     

Changes in brain and spinal tryptophan and 5-hydroxy-indoleacetic acid levels follwing acute morphine administration in normal and arthritic rats

The effects of morphine (10 mg/kg/s.c.) on tryptophan (TRP), 5-hydroxy-tryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were studied in normal and arthritic rats.

(1) In normal rats morphine induced a discrete but significant increase of 5-HIAA levels in the forebrain and the spinal cord.

(2) By contrast, in rats suffering from experimentally induced arthritis large modifications were apparent. The basal levels of TRP, 5-HT and 5-HIAA were significantly higher than in normal rats. Morphine induced clear increases of 5-HIAA and TRP in the forebrain, the brain stem and the spinal cord, without any modification of 5-HT. The effects were dose-dependent and suppressed by naloxone (1 mg/kg/ i.m.). Statistical analysis clearly revealed that arthritic rats were much more sensitive to morphine.

The results support the hypothesis of an activation of a 5-HT descending pathway by morphine which parallels the activationn of theascending pathway previously demonstrated by several authors and confirmed here.     

Measurement of 5-hydroxyindole compounds during L-5-HTP treatment in depressed patients.

L-5-hydroxytryptophan (L-5-HTP), an immediate serotonin precursor, was given to the hospitalized depressed patients in an open clinical trial of the Phase 2 study for antidepressive effects of the agent. A relatively small dose, 150mg orally for seven days, was employed, and seven of 14 patients responded to the treatment with mild or moderate emelioration of their depressive symptoms. Urinary excretion levels and plasma concentrations of three 5-hydroxyindole compounds, 5-HTP, 5-HT and 5-HIAA, were measured during the drug treatment. Approximately 70% of the orally administered dose of L-5-HTP was recovered from the urine of depressed patients. Major part of urinary indoleamine metabolites was free and conjugate 5-HIAA. Excretion levels of these compounds in urine were not consistenly altered in the depressed patients as compared to those in normal subjects. Clinical response to L-5-HTP treatment appeared to have some correlation with the biochemical measures in the depressed patients, that is, non-responders exhibited significantly lower excretion levels of 5-HT and 5-HIAA in urine, and lower plasma levels of 5-HT than responders. Administered L-5-HTP may not be fully utilized in the depressed patients who did not react to the agent.     

Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals

Summary The aim of the present study was to investigate the effects of physical exercise (running) on serotonin (5-hydroxytryptamine, 5-HT) synthesis and metabolism in midbrain on the one hand, and in striatum and hippocampus on the other hand. To address such a question, tryptophan (TRP) and 5-hydroxytryptophan (5-HTP) were measured in running rats pretreated with an inhibitor of aromatic amino acid decarboxylase, namely NSD 1015. In another series of experiments, the consequences of a TRP load on TRP, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were compared in resting and running rats.Although running triggered a 30% increase in TRP levels in the three brain regions examined, inhibition of 5-HT synthesis by NSD 1015 was found to promote increased (midbrain), unchanged (striatum) or decreased (hippocampus) 5-HTP accumulation in the running situation, respectively compared to that measured in the resting situation. Inasmuch as running-induced elevation in TRP was not associated with an increased 5-HTP accumulation in the striatum and the hippocampus, the consequences of running on regional TRP, 5-HT and 5-HIAA levels were analyzed in saline- and TRP-injected rats. Indeed, running, per se, was found to increase central TRP, 5-HT and 5-HIAA levels. On the other hand, a TRP load that promoted identical increases in central TRP levels in running and resting rats revealed that running, according to the region examined, differentially affected TRP utilization in the 5-HT synthesis pathway. Thus, in the midbrains of the resting and running rats, respective 210–250% increases in TRP led to identical 25% increases in 5-HT and 90% increases in 5-HIAA levels. Conversely, in hippocampus, TRP loads triggered marked increases in TRP levels that were similar in the controls and the runners, but the rise in 5-HIAA promoted by such a precursor load was found to be significantly minored in the runners, compared to the resting rats. Moreover, such a running-induced impairment in 5-HT synthesis and metabolism was even more observable in the striatum; thus, TRP loads which promoted identical increases in striatal TRP levels in the resting and the running rats respectively triggered a 50% and a 32% increase in 5-HT levels and a 76% and a 47% increase in 5-HIAA levels.The results presented herein indicate that under certain pharmacological conditions, TRP utilization into the 5-HT synthesis pathway is altered in serotonergic nerve terminals, but not in the cell bodies of the running rat.     

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.