Effect of chlorpromazine treatment on monoamine metabolite levels in cerebrospinal fluid of psychotic patients

Levels of HVA, MOPEG and 5-HIAA in cerebrospinal fluid (CSF) from psychotic men and women with a schizophrenic symptomatology were measured by mass fragmentography. Measurements were made before, 2 and 4 weeks after treatment with chlorpromazine (CPZ) which was given randomly in doses of 200, 400 or 600 mg per day. Before treatment there were positive correlations between the levels of HVA and 5-HIAA in both sexes. During CPZ treatment HVA was significantly elevated, whereas MOPEG and 5-HIAA were reduced. There was a tendency towards tolerance to CPZs effect on HVA during treatment but a significant effect persisted after 4 weeks. No indication of tolerance to the effects on MOPEG or 5-HIAA was found. There were the same tendencies for the elevations of the HVA/MOPEG and HVN5-HIAA ratios. The changes in HVA, MOPEG, 5-HIAA, HVA/MOPEG and HVA/5-HIAA were related to dose of CPZ in men but not in women. The bidirectional change of the different metabolites in CSF during CPZ treatment excludes a general and non-specific mechanism for the metabolite changes. The HVA elevations is in accordance with previous results in animals and man, and is pesumably related to blockade of central dopamine receptors. Possible mechanisms for the effects on MOPEG and 5-HIAA are discussed.     

Relationship between platelet MAO activity and concentrations of 5-HIAA and HVA in cerebrospinal fluid in chronic pain patients

Summary Platelet monoamine oxidase (MAO) activity and concentrations of 5-HIAA and HVA in the cerebrospinal fluid (CSF) were estimated in a series of 54 chronic pain patients. Platelet MAO activity was found to correlate, positively to CSF concentrations of 5-HIAA and HVA, which had been adjusted in order to eliminate the influence of age and body height. However, only the correlation with 5-HIAA reached a significant level. When partial correlations were sought, only the positive correlation between platelet MAO activity and CSF 5-HIAA remained. The results support the notion that platelet MAO ia a biological marker for some trait dependent property of the central serotonergic system.Supported in part by grants from the Swedish Medical Research Council (grants No. 166, 4145 and 5740).     

Long-term high frequency transcutaneous electrical nerve stimulation (hi-TNS) in chronic pain. Clinical response and effects on CSF-endorphins, monoamine metabolites, substance P-like immunoreactivity (SPLI) and pain measures

Eighteen patients with chronic pain syndromes of organic origin were treated by means of high frequency transcutaneous nerve stimulation (hi-TNS). The CSF levels of receptorassayable Fraction I and II endorphins, substance P-like immunoreactivity (SPLI), and the monoamine metabolites 5-HIAA, HVA and MOPEG were measured before and after one week of daily treatment. Furthermore, the effects on experimental pain measures were determined. The therapeutic effect was evaluated after 30 days and 3 months of treatment. Patients with low initial concentrations of endorphins in CSF, lower than those observed in healthy volunteers, tended to have the best response to hi-TNS. There were significant increases in Fraction I endorphins and SPLI in CSF, most pronounced in the patients who responded. There were no significant changes in 5-HIAA, HVA or MOPEG in CSF. However, in early responders, the serotonin metabolite 5-HIAA tended to decrease as contrasted to an increase in non-responders. The difference between the groups was statistically significant. Confirming our earlier studies, the therapy induced changes in pain measures showed a significant, positive correlation with increasing Fraction I endorphins in CSF. Our results suggest that hi-TNS induces central changes in the endorphinergic, serotonergic and possibly substance-P-ergic systems.     

Relationships between clinical and biochemical effects of melperone and thiothixene in psychotic women

Summary Clinical and biochemical effects of melperone (100 mg × 3) and thiothixene (10 mg × 3) were studied in women with psychoses of schizophrenic or paranoid type. Psychotic morbidity and side effects were determined by rating scales. Concentrations of the major monoamine metabolites homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl-ethylene glycol (MOPEG), and 5-Hydroxy-3-indoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were measured by mass fragmentography. Concentrations of prolactin in CSF and plasma were determined by radioimmunoassay (RIA). Measurements were performed before and after 2 and 4 weeks of drug treatment.The drugs did not differ in antipsychotic effect, but thiothixene treatment caused greater elevation of HVA and prolactin than melperone. The measures of dopaminergic activity did not correlate significantly with therapeutic outcome in either of the treatment groups. Treatment with melperone, but not thiothixene, reduced MOPEG levels, but only during thiothixene treatment was MOPEG reduction related to clinical improvement. In both treatment groups clinical improvement correlated significantly with an increase in the 5-HIAA/MOPEG ratio. Extrapyramidal side effects correlated negatively with HVA and HVA/MOPEG in the thiothixene, but not in the melperone group.It is concluded that there is no simple relationship between alteration of dopaminergic transmission and therapeutic outcome in drug-treated psychotic patients. In addition to dopamine (DA) receptor blockade, alteration of norepinephrine (NE) mechanisms may play a role in the antipsychotic effect. It is suggested that the balance of activity between central serotonin (5-HT) and NE systems should be considered in the mechanism of action of antipsychotic drugs and the pathophysiology of psychosis.     

Monoamine metabolite levels in cerebrospinal fluid of psychotic women treated with melperone or thiothixene.

Psychotic women with schizophrenic symptoms were treated with melperone 100 mg X 3 (n = 29) or thiothixene 10 mg X 3 (N = 34) USING A DOUBLE-BLIND PROCEDURE. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.     

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

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

CSF monoamine metabolites in patients and controls: support for a bimodal distribution in major affective disorders

The monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) were measured in 38 patients with major affective disorder and 48 age- and sex-matched controls by means of liquid chromatography. Statistical analysis using maximum likelihood normal mixture computations provided evidence for a subgroup of patients characterized by low CSF levels of both 5-HIAA and HVA. In controls, CSF 5-HIAA and HVA levels appeared to be normally distributed when fitted separately, whereas a subgroup of controls characterized by higher values of 5-HIAA and HVA could be discerned when metabolite data were fitted simultaneously. No relationship was found between monoamine levels and suicidal behaviour in patients. A statistically significant relationship was found between CSF 5-HIAA and HVA levels in patients and controls. These data provide supportive evidence for the existence of a subgroup of patients with an abnormal serotonin metabolism as reflected by 5-HIAA, and probably HVA, in CSF.     

Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers

The concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and glutamate were determined in cerebrospinal fluid (CSF) and serum in 10 healthy volunteers. The monoamine metabolites were measured by mass fragmentography and the glutamate by high-performance liquid chromatography. The level of glutamate in CSF was low (0.34 +/- 0.14 nmol/ml) in comparison with previously published values. The concentrations of monoamine metabolites in CSF were in close agreement with earlier findings. There were negative correlations between the concentrations of HVA (r = -0.82, p less than 0.01) and 5-HIAA (r = -0.77, p less than 0.01) and glutamate in CSF, but not in serum. The serum levels of HMPG and glutamate were negatively correlated (r = -0.95, p less than 0.001), but not the CSF levels. The HMPG levels in serum and CSF were positively correlated (r = 0.94, p less than 0.001), but not the HVA and the 5-HIAA levels. The serum and CSF levels of glutamate were positively correlated (r = 0.67, p less than 0.05). The results indicate relationships among the metabolism of dopamine, serotonin, and glutamate in the brain and between the metabolism of noradrenaline and glutamate in peripheral tissue.     

Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid

Background

Monoamine neurotransmitters (serotonin, dopamine, and norepinephrine) are associated with several psychiatric disorders. Limited evidence suggests that monoamine levels are heritable, but no information concerning genetic relationships among monoamines is available. Further genetic analysis can help explain phenotypic correlations among monoamine levels and might eventually help identify genes involved in response to therapy or risk of psychopathology.

Methods

Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-hydroxy-4-methoxyphenylglycol (MHPG) were measured in cerebrospinal fluid from 271 baboons (Papio hamadryas). Variance components methods were used to estimate heritabilities, and multivariate analyses were used to estimate genetic correlations (pleiotropy) and environmental correlations between metabolites.

Results

Each metabolite exhibited significant heritability in baboons (5-HIAA: h² = .30 ± .17; MHPG: h² = .36 ± .16; HVA: h² = .50 ± .19). Multivariate analyses revealed genetic correlations between 5-HIAA and HVA and between HVA and MHPG. Environmental correlations were found between 5-HIAA and HVA and between 5-HIAA and MHPG.

Conclusions

Overlapping, nonidentical sets of genes influence individual variation in 5-HIAA, MHPG, and HVA levels among baboons. The phenotypic correlation between 5-HIAA and HVA observed in nonhuman primates and humans is likely due to both shared genetic and environmental factors. Genetic analyses of monoamine levels in primates can provide novel information concerning the genetics of variation among humans.     

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.     

Aberrant monoamine metabolite levels in CSF and family history of schizophrenia. Their relationships in schizophrenic patients

In 36 drug-free schizophrenic patients, lumbar CSF was analyzed by mass fragmentography for the major monoaminergic transmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). High or deviant concentrations of 5-HIAA were significantly related to a family history of schizophrenia. For patients with deviant 5-HIAA levels, the probability for a family history of schizophrenia was eight times higher than in subjects with normal values. High concentrations of HVA also tended to be significantly related to a family history of schizoprenia. The majority of schizophrenic patients, who lacked family history for the disorder, had normal monoamine metabolite concentrations in CSF. The results suggest a coupling between biochemical variables related to central serotonin and dopamine metabolism and forms of schizophrenia that have a familial disposition.     

Concentration gradients for monoamine metabolites in lumbar cerebrospinal fluid

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

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

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

Monoamine metabolite levels in cerebrospinal fluid of psychotic women treated with melperone or thiothixene

Summary Psychotic women with schizophrenic symptoms were treated with melperone 100 mg×3 (n=29) or thiothixene 10 mg×3 (n=34) using a double-blind procedure. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.A preliminary report of the present study was presented at the VI International Congress of Pharmacology, Helsinki, 1975Financial support was provided by the Swedish Medical Research Council (14X-03560), National Institutes of Mental Health, (MH 27254-01), Bethesda, Maryland, USA, F. Hoffmann-La Roche & Co., Basle, Switzerland, Svenska Sällskapet för Medicinsk Forskning, Karolinska Institutet, AB Ferrosan, Sweden, and Pfizer-Roerig, Sweden.     

Cerebroventricular size and cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy volunteers

Computed tomography (CT) measures and cerebrospinal fluid (CSF) levels of the monoamine metabolites homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in 43 healthy volunteers and in 26 patients with an acute psychosis of the schizophrenic type. There were no differences in the mean CSF levels of monoamine metabolites between the two groups. However, the patients had significantly wider lateral and third ventricles as compared to the volunteers. In the volunteers there were no significant correlations between ventricular sizes and monoamine metabolite levels, whereas in the patients a significant negative correlation was obtained between the size of the lateral ventricles and the levels of HVA and 5-HIAA in the CSF. These results may indicate that the enlargements of the brain ventricles found in a subgroup of schizophrenic patients may be associated with deficiencies in central monoamine transmission mechanisms.     

CSF amine metabolites in depression.

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

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

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

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

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

Monoamine metabolites in the CSF of conscious unrestrained cats

The dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured repeatedly over a period of up to 5 months at different sites of the brain ventricular system in unrestrained, awake cats. Samples of 10 μl CSF were analyzed by high pressure liquid chromatography and subsequent electrochemical detection. Concentrations were in the range of 30–130 ng/ml for DOPAC, 110–340 ng/ml for 5-HIAA and 180–750 ng/ml for HVA. The monoamine metabolites were constant even over a period of several months if measured in he same animal but there was a marked interindividual variation. A marked gradient for monoamine metabolites was found when CSF samples from frontal sites of the lateral ventricle were compared to CSF samples from the dorsal lateral ventricle. The concentrations of DOPAC and HVA were higher at frontal sites.     

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。