Serotonin metabolism is pellagra.

Altered mental status is common in pellagrins. We evaluated the mental status of pellagrins in relation to the neurohormone, serotonin or 5-hydroxytryptamine (5-HT). Levels of 5-hydroxyindoleacetic acid (5-HIAA), an end product of serotonin in the urine and cerebrospinal fluid (CSF), and of platelet 5-HT were determined in a group of pellagrins and in normal subjects. The results indicated that the 5-HT concentration was reduced in platelets and 5-HIAA excretion in urine was below normal levels. The 5-HIAA concentration in CSF was also reduced, suggesting a decrease in 5-HT functional activity in the brain.     

抑郁症患者自杀与脑脊液单胺代谢产物的关系

目的：探讨抑郁症患者自杀与脑脊液单胺代谢产物之间的关系。方法：应用高效液相色谱法，测定24例抑郁症患者(自杀组10例，无自杀组14例)及25例对照组5-羟色胺(5-HT)代谢产物5-羟吲哚乙酸(5-HIAA)，去甲肾上腺素(NE)代谢产物3-甲基-4-羟苯乙二醇(MHPG)及多巴胺(DA)代谢产物高香草酸(HVA)的浓度。结果：抑郁症自杀组5-HIAA浓度显著低于对照组，男性自杀组5-HIAA浓度、HVA浓度和HVA／MHPG比值均显著低于男性对照组，女性则无显著差异：结论：抑郁症患者自杀可能与5-HT和DA功能低下以及DA和NE之间的关系改变有关。     

Depression and parkinson's disease: possible role of serotonergic mechanisms

Summary Depression is frequently encountered in Parkinson's disease and was seen to occur in 14 of 26 patients studied. The levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin (5-HT), in CSF samples of the patients were significantly lower than in those of controls. However, within the group of patients the levels of 5-HIAA in CSF samples were significantly lower in the depressive subgroup compared with the non-depressive patients. Moreover, no correlation was recorded between motor disability and depression. The results indicate that disturbed 5-HT metabolism may possibly play a role in Parkinson's disease as a predisposing factor in the development of depression.     

Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: reciprocal relationships with impulsive aggression in human subjects

While the relationship between cerebrospinal fluid 5-HIAA (CSF 5-HIAA) and aggression is typically reported as inverse, studies of some groups of aggressive individuals demonstrate a positive (or no) relationship, between these two variables. It is possible that simultaneous examination of both CSF 5-HIAA and CSF homovanillic acid (HVA), which co-vary in human subjects may clarify differences in reported findings in different groups of aggressive individuals. CSF 5-HIAA and CSF HVA concentrations were simultaneously examined in 60 healthy human subjects (40 with personality disorder and 20 healthy controls) and were correlated with measures of aggression and impulsivity. CSF 5-HIAA concentrations correlated positively, and CSF HVA concentrations correlated inversely, with a composite measure of impulsive aggression in all subjects as well as in the personality disordered subjects. The CSF 5-HIAA findings are consistent with those demonstrating reduced post-synaptic 5-HT receptor responsiveness to 5-HT agent challenge and suggest differences in the pathophysiology between different groups of subjects with aggressive behavior, particularly with regard to severity of aggressive behavior.     

Maternal absence and stability of individual differences in CSF 5-HIAA concentrations in rhesus monkey infants

OBJECTIVE: Early life events often lead to deficits in CNS serotonin function, which underlie a number of reoccurring psychopathological disorders. Studies using rhesus macaques have demonstrated that early maternal deprivation reduces CNS serotonin turnover, as measured by cisternal CSF 5-HIAA concentrations. In addition, individual differences in CSF 5-HIAA remain stable from the first year of life through adulthood. The purpose of this study was to assess 1) the impact of rearing environment on the early development (<6 months of age) of the serotonin system, and 2) at what stage of early development individual differences in CSF 5-HIAA concentrations stabilize. METHOD: The subjects were 256 infant rhesus macaques reared in three different conditions (mother-reared, peer-reared, and surrogate/peer-reared). Cisternal CSF was obtained at 14, 30, 60, 90, 120, and 150 days of age. RESULTS: No differences in CSF 5-HIAA concentrations were observed between peer only- and surrogate/peer-reared infants, and these groups combined exhibited lower 5-HIAA concentrations than mother-reared infants throughout early development. CSF 5-HIAA concentrations declined with increasing age regardless of rearing condition. Within each rearing condition, individual differences in CSF 5-HIAA concentrations remained stable from 14 to 150 days of age. CONCLUSIONS: Early maternal deprivation reduces CNS serotonin turnover, and individual differences in CSF 5-HIAA concentrations are trait-like and appear to stabilize in infancy.     

Alaproclate a novel antidepressant?

Clinical and biochemical effects of two selective 5-HT uptake inhibitors, zimeldine and alaproclate, were studied in 24 hospitalized patients with endogenous depression. According to a randomized parallel group design 14 patients were treated with zimeldine and 10 with alaproclate. The dosage of both zimeldine and alaproclate was 200 mg daily. For the evaluation of the clinical effect, Montgomery & Asberg Depression Rating Scale (MADRS) was used. Seven of 14 patients treated with zimeldine and seven of 10 treated with alaproclate improved. 5-HT uptake inhibition in patients' platelets and concentration of amine metabolites (5-HIAA, HVA, HMPG) in CSF were studied before and during treatment. After 3 weeks of treatment with zimeldine 5-HIAA and HMPG in CSF decreased significantly while HVA in CSF increased significantly. Zimeldine produced a significant 5-HT uptake inhibition in platelets. During treatment with alaproclate no significant change in amine metabolites concentration in CSF was found and there were no mean changes on 5-HT uptake inhibition in platelets.     

Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients

Plasma levels of ACTH, cortisol and monoamines were examined in 23 depressed patients and 31 healthy subjects. Patients showed increased plasma cortisol levels, but not plasma adrenocorticotropic hormone (ACTH) levels. The plasma levels of a dopamine metabolite, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), were significantly decreased in the patients. In contrast, the plasma levels of a serotonin (5-HT) metabolite, hydroxyindoleacetic acid (5-HIAA), and 5-HT turnover (5-HIAA/5-HT) were increased in the depressed patients. Therefore, plasma levels of HVA and 5-HIAA are proven to be dissociable. Furthermore, plasma levels of 5-HIAA and L-DOPA have positive relationships with severity of depression. On the basis of this and the previous studies, we speculate that an increase in the plasma 5-HIAA levels might be a compensatory mechanism for stress, whereas 5-HT turnover might reflect depressive state. Taken together, plasma levels of HVA and 5-HIAA, and 5-HT turnover (5-HIAA/5-HT) could be good markers for evaluating depression.     

帕金森病外科治疗的综合评价与相关基础研究

目的通过综合研究对帕金森病(PD)外科治疗的价值和疗效进行全面评价。方法采用医学心理学测验(WAISRC)、临床记忆量表(MMPI)、神经生理学检测(听觉P300地形图)、神经电生理学(体感诱发电位SEP)和神经生化检查的脑脊液中多巴胺(DA)、5羟色胺(5HT)、去甲肾上腺素(NE)及其代谢产物)等对手术前后患者进行综合研究,并设对照组。结果手术前后智能和精神症状无显著性差异(P>0.05);手术后SEP的N20波峰潜伏期较术前缩短,统计学处理有差异(P左<0.005,P右<0.05),手术侧较非手术侧峰潜伏期缩短(P<0.05)。伴发抑郁患者组CSF中单胺类神经递质5HT的代谢产物5羟吲哚乙酸(5HIAA)和NE的代谢产物3甲氧基4羟基苯乙二醇(MHPG)低于对照组(P<0.01),患者组DA、高香草酸(HVA),5HT,5HIAA、NE、MPHG低于正常对照组(P<0.001),手术组上述各项均高于手术前组(P<0.001);结论手术不会加重智能和精神障碍;听觉P300地形图可作为诊断和疗效判定的客观指标之一;帕金森病及伴发抑郁症状均具有相应生化病理学基础。     

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.     

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.     

CSF monoamine metabolites in dementia of the Alzheimer type and controls: Evidence for lower levels of homovanillic acid and 5-hydroxyindoleacetic acid in patients

The monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in lumbar cerebrospinal fluid (CSF) were measured in 15 patients with dementia of the Alzheimer type (DAT) and 48 controls by means of a sensitive liquid chromotagraphic method. Relative to a large group of control subjects, the mean CSF 5-HIAA and HVA levels in patients with DAT appeared to be significantly lower. This finding appeared to be sex-related, in that the decrease in CSF monoamine metabolite levels could be attributed predominantly to male patients. A statistically significant relationship was found between 5-HIAA and HVA in both patients and controls. Linear regression analysis revealed a statistically significant positive relationship between age and CSF HVA in female controls only. No relationship was found between 5-HIAA and age either in patients or in controls. It is concluded that CSF 5-HIAA and HVA levels are decreased in male patients with DAT, probably signalling a sex-related change in serotonin and probably dopamine functioning in the central nervous system.     

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.     

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.     

Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice

Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.     

Rorschach ratings in depressed and suicidal patients with low levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid

In order to explore the psychodynamics of a previously observed association between a low concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and an increased tendency to suicidal behavior, blind ratings of Rorschach variables were compared between depressed and/or suicidal patients with low (<80 nanomoles/1) and normal (&#62;80 nanomoles/1) CSF 5-HIAA. In 14 patient pairs matched for sex, age, body height, and interview-based ratings of severity of depression, the low 5-HIAA subjects had significantly more anxiety and more hostility in the Rorschach ratings. Their anxiety tolerance was lower, and they were significantly less efficient in their handling of conflict. The results support the hypothesis that biochemical variables may be of importance for certain psychodynamic mechanisms suggested to be relevant for psychopathology, including suicidal behavior.     

CSF 5-HIAA levels are lower in impulsive as compared to nonimpulsive violent suicide attempters and control subjects.

BACKGROUND: We studied CSF 5-HIAA and HVA concentrations in violent suicide attempters and examined their relationship with depression, anxiety, and impulsivity. METHODS: CSF 5-HIAA and HVA concentrations were determined very shortly after hospital admission and compared to those of a matched control population. Clinical evaluation was performed concomitantly; the level impulsivity was evaluated by the Impulsivity Rating Scale (IRS). RESULTS: Twenty-three patients and 23 control subjects were included. According to the IRS, 14 patients were classified as impulsive, including all patients suffering from personality disorders, and 9 as nonimpulsive, with a main DSM-IIIR diagnosis of melancholia. CSF 5-HIAA concentrations in the suicide group were significantly lower than in control subjects. This difference was entirely due to the impulsive suicide attempters. There was an inverse correlation between the IRS score and CSF 5-HIAA (r = -.47, p = .02) and only a trend for HVA (r = -.41, p = .078) levels in the suicide group. CONCLUSIONS: This study of a group of violent suicide attempters distinguished a subgroup of patients diagnosed with personality disorder with high impulsivity scores and a subgroup of patients with the main diagnosis of severe depression. CSF 5-HIAA was significantly lower in impulsive violent attempters than in nonimpulsive violent attempters, therefore desintangling violence from impulsivity and linking this biologic abnormality to impulsivity.     

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.     

Indole amine deficiency in blood and cerebrospinal fluid from patients with human immunodeficiency virus infection

Twenty-four patients with human immunodeficiency virus (HIV) infection were investigated for possible changes in certain indole amine constituents in blood and cerebrospinal fluid (CSF). Albumin in serum was determined and used as a rough nutritional marker. Six of the 24 patients had acquired immunodeficiency syndrome AIDS, four had other clinical symptoms of HIV infection, and 14 had no apparent symptoms. The HIV-seropositive patients had significantly decreased tryptophan values; their blood concentrations were 28% lower and their CSF concentrations 30% lower than corresponding values in 14 healthy controls. The blood concentrations of 5-hydroxytryptamine (5-HT) were 50% lower, and the platelet content of 5-HT was 36% lower in HIV-infected individuals than in the control group. The most pronounced changes were invariably seen in the six cases with AIDS and in patients with a low number of CD4+ cells. No significant difference between controls and HIV-seropositive patients was detected in the mean CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), although these levels were markedly reduced in four of the HIV patients. Neither was any significant difference seen between patients and controls in the serum concentrations of albumin.     

Neurochemical, hormonal, and behavioral effects of chronic unpredictable stress in the rat

The high comorbidity of anxiety and depression suggests a potential degree of commonality in their etiologies. The chronic unpredictable stress (CUS) model effectively replicates depressive-like phenotypes; however, the ability of CUS to produce anxiety-like behaviors has not been adequately addressed. Using the CUS paradigm (2 stressors per day for 10 days) in adult Sprague-Dawley rats we identified behavioral, hormonal, and neurochemical changes one day after the cessation of treatment. Stress attenuated weight gain throughout the study and increased locomotor activity one day after treatment, but had no effect on anxiety-behavior as measured by the elevated plus maze. In addition, plasma corticosterone levels were positively correlated with hypothalamic serotonin (5-HT) activity one day after stress treatment as determined by the ratio of the metabolite 5-hydroxyindoleacetic acid (5-HIAA) to the parent compound (5-HIAA/5-HT ratio). These data suggest behavioral phenotypes associated with depression, but not comorbid anxiety, emerge in the immediate period after cessation of stress and that stress related physiology is related to 5-HT activity in the hypothalamus.     

Serotonin 5-HT2A receptor binding in platelets from patients with Alzheimer's disease or vascular dementia

It is well known that abnormalities in the brain serotonin system exist in patients with dementia. The present study was performed in order to investigate whether a peripheral serotonin system marker, the platelet 5-HT2A receptor, is affected in dementia. Thirty-eight patients with Alzheimer's disease (AD), 13 patients with vascular dementia, and 40 healthy controls were included in the study. There were no significant differences in receptor density for 5-HT2A receptor binding between the groups. Affinity of the radioligand to the receptor was significantly lower in AD than in vascular dementia and in the controls (p = .006 and p = .003, respectively), whereas there was no significant difference between the vascular dementia group and the control group. In 12 patients, treatment with citalopram was started due to depression or agitation. This treatment significantly reduced the Behavioral Pathology in Alzheimer's Disease Rating Scale scores (p = .001), but did not affect the platelet 5-HT2A receptor status. There was no correlation between 5-HT2A receptor status before treatment and the therapeutic effect of citalopram. The study indicates that platelet 5-HT2A receptor status is of limited value as a peripheral marker in dementia.