Lack of correlation between plasma DOPEG and urinary MOPEG levels in depressed patients

Twenty-four-hour urinary excretion of 3-methoxy,4-hydroxyphenylethyleneglycol (MOPEG) and levels of free and conjugated plasma 3,4-dihydroxyphenylethyleneglycol (DOPEG) were measured in 56 depressed patients to find a possible correlation between these two peripheral indices of cerebral noradrenergic activity. Plasma DOPEG was measured at 9:00 AM on the same day that urine was collected for the measurement of MOPEG. All depressed patients were diagnosed as having affective disorders according to DSM-III. No correlation was found between plasma free or conjugated DOPEG levels and urinary MOPEG output. This lack of correlation was found in the total sample of depressed patients (56), in 45 patients diagnosed as having major depressive episodes, and in 24 depressed patients diagnosed as major depressive with melancholia. The authors discuss the significance of this lack of correlation between two peripheral indices of central noradrenergic metabolism.     

Relationships in healthy volunteers between secretion of monoamine metabolites in urine, and family history of psychiatric morbidity

In 66 physically and mentally healthy human subjects the total concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and dihydroxyphenyl acetic acid (DOPAC) in urine collected between midnight and 8 AM were analyzed by mass fragmentography. In the volunteers reporting the occurrence of psychiatric morbidity among relatives an increased variance in their MOPEG levels was found as compared to the volunteers without such a family history. In the male subjects with no family history of psychiatric disease there was a positive correlation between urine and cerebrospinal fluid levels of MOPEG. The urine levels of 5-HIAA, HVA, and DOPAC did not demonstrate any changes that could be related to psychopathology within the family. Changes in urine secretion of MOPEG indicate an altered metabolism of norepinephrine/MOPEG in some subjects with the occurrence of severe psychiatric disease within the family. MOPEG levels in urine may be a predictor of a family vulnerability for psychiatric morbidity in healthy subjects.     

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.     

Biogenic amine metabolites in delusional (psychotic) depression and melancholia subtypes of major depression

1. 1. The levels of the urinary main metabolites of norepinephrine 3-methoxy-4-hydroxyphenylglycol (MHPG), of dopamine homovanillic acid (HVA) and of serotonin 5-hydroxyindoleacetic acid (5-HIAA) were measured in 84 patients with major depressive disorder, 34 delusional and 50 nondelusional. Melancholia subtype was also defined (N=62).

2. 2. MHPG was significantly higher in the delusional depressed group (p=0.023). Female patients with delusional major depression also had significantly higher HVA excretion than female patients with non delusional major depression (p=0.036). 5-HIAA excretion was similar in the two patient subgroups.

3. 3. No significant differences in the three monoamine metabolites were found between the melancholic and nonmelancholic depressed patients.

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.     

Urinary excretion of 5-hydroxyindoleacetic acid--no relationship to the level in cerebrospinal fluid

Concentrations of 5-hydroxyindoleacetic acid (5-HIAA) were determined in urine and cerebrospinal fluid (CSF) by mass fragmentography. A pronounced day-to-day variation in the urinary excretion of 5-HIAA was found both in psychiatric patients and a healthy control. Lumbar punctures performed twice 3-12 weeks apart in 11 healthy controls resulted in reproducible levels of 5-HIAA in CSF (r = 0.89; P less than 0.001). The mean of three periods of daily 5-HIAA excretion was not correlated to the CSF level measured in 18 psychiatric patients (r = 0.09). Three weeks of chlorimipramine treatment significantly decreased CSF 5-HIAA levels (P less than 0.05), but not the urinary excretion of 5-HIAA. It might be concluded that measurement of urinary 5-HIAA excretion is of little value compared to CSF levels in studies of serotonin in the central nervous system.     

Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals--a genetic study

The concentrations of the major monoamine metabolites, homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), of platelet monoamine oxidase (MAO) and of dopamine beta-hydroxylase (DBH)-activity in serum and CSF were determined in pairs of healthy mono- and dizygotic twins, brothers and unrelated individuals. Intraclass correlations were calculated for each category of pairs. Of the monoamine metabolites, only MOPEG was found to be under any major genetic influence. Genetic heritability for MOPEG was 0.74 with no evidence of cultural heritability or environment common to twins. For HVA and 5-HIAA, a familial influence was found, where the cultural heritability was higher than the genetic. As in previous studies of MAO in blood platelets and of DBH activity in serum, there was strong evidence for a genetic component. The genetic heritability for MAO was 0.78. For DBH in serum the genetic component was 0.98, and for DBH in CSF, 0.83. The demonstration of a familial influence on 5-HIAA and HVA in CSF requires a more detailed analysis of the character of such environmental and genetic influences, using more direct techniques.     

Plasma aldosterone and magnesium in serum and urine during lithium treatment.

Serum magnesium, urinary magnesium excretion and plasma aldosterone were determined in 8 manic-depressive before and at intervals during 3 months of lithium treatment (longitudinal study), and in 27 manic-depressive patients who had been treated with lithium for 3 months to 20 years (transversal study). In the longitudinal study urinary magnesium excretion and urine flow increased slightly after 1-3 months of therapy; serum magnesium and plasma aldosterone were unchanged. In the transversal study urinary magnesium excretion, serum magnesium and plasma aldosterone were within normal limits, and they did not differ significantly from levels in the longitudinal study. No correlation was found between serum magnesium or urinary magnesium excretion and plasma aldosterone in either study. The results indicate that changes in urinary magnesium excretion during lithium therapy are not mediated via changes in plasma aldosterone, but may be secondary to diminished renal water reabsorption induced by lithium.     

Biogenic Amine Metabolites During Electroconvulsive Therapy of Melancholic Patients

We assayed the urinary neurotransmitter metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxy-indoleacetic acid (5-HIAA) in unipolar depressed patients before and after a simulated electroconvulsive therapy ECT (SECT), and during course of 10 ECT sessions. A repeated measures analysis of variance (ANOVA) showed no significant changes in the three-metabolite excretion during the course of ECT. Planned comparisons performed after ANOVA revealed a trend for HVA and 5-HIAA levels to increase after SECT and a significantly higher MHPG excretion after the 10th ECT session. Seven depressed patients who responded favorably to ECT (reduction in Hamilton Rating Scale for Depression score of 50% or more) but not the seven nonresponders had significantly higher MHPG excretion after the final ECT compared to baseline levels. A significant relationship was found between low pretreatment MHPG excretion and therapeutic response.     

Pemoline and urinary excretion of catecholamines and indoleamines in children with attention deficit disorder

To test the hypothesis that any change in urinary noradrenergic excretion accompanies drug-induced improvement in attention deficit disorder with hyperactivity, the authors gave pemoline (mean dose, 2.9 mg/kg of body weight) to 11 boys with this disorder in a 4-week open trial. Pemoline administration improved behavior but did not significantly change urinary catecholamine excretion. Serotonin excretion was unchanged, but phenylethylamine (PEA) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased. Clinical responders and nonresponders did not differ with respect to baseline urinary monoamine excretion or change in PEA and 5-HIAA excretion.     

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.     

THE EXCRETION PATTERNS OF URINARY GLUCOSAMINOGLYCANS IN A FAMILY WITH PROGRESSIVE FAMILIAL MYOCLONUS EPILEPSY

The urinary excretion of uronic acid and the electrophoretic composition of urinary glucosaminoglycans were studied in 10 members of a family, of which 3 had progressive familial myoclonus epilepsy. This seems to be the first detailed investigation of the excretion of urinary glucosaminoglycans in patients suffering from this neurologic disease. The uronic acid excretion was found to be increased in the affected family members exclusively, whereas the excretion of the unaffected members were found within the normal limits characterized in this investigation. The urinary glucosaminoglycans could be separated into 5 fractions by electrophoresis. One or two of these fractions were increased in the urines of the three affected family members, the clinically most affected member showing the most abnormal electrophoretic results. An abnormal electrophoretic distribution of fractions was also found in the urines of 5 other members, clinically not affected. Only the maternal part of the family (mother and maternal grandmother) was shown to have a normal electrophoretic distribution of urinary glucosaminoglycans. The implication of these electrophoretic differences in the paternal and maternal family on the conditions for the development of the disease is discussed. The two fractions in question (designated fraction-0.65 and fraction-0.71) have until now been regarded as glycoproteins, but the present results show that they are true glucosaminoglycans (acid mucopolysaccharides), probably of low sulphate content.     

Urinary monoamine metabolite excretion in disorders of movement: Effects of amantadine and levodopa

We have studied the urinary excretion of 1,4-methylhistamine (1,4-MeHm), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in patients with Parkinson's disease, choreiform movements and essential tremor. The effect of amantadine on urinary excretion has been measured in each group of patients as well as the effect of levodopa in patients with Parkinson's disease.In patients with Parkinson's disease, excretion of 1,4-MeHm and HVA was significantly lower than in controls. Patients with choreiform movements had a reduced excretion of HVA but trends toward low levels of 1,4-MeHm and, in patients with Huntington's chorea, elevated excretion of 5-HIAA, were not significant. In patients with essential tremor, urinary excretion of the amine metabolites studied did not differ significantly from controls.Administration of amantadine to patients with Parkinson's disease was not followed by increased excretion of monoamine metabolites except in those patients who were already receiving anticholinergic drugs. This increase is not significant and there was no effect in other groups of patients. These findings lend no support to the view that amantadine has a general amine-releasing action although there is limited evidence for such an effect in Parkinson's disease.In addition to the expected increase in HVA excretion, administration of levodopa to Parkinsonian patients was followed by significantly reduced excretion of 1,4-MeHm and 5-HIAA. However, if amantadine and levodopa were given together, excretion of 5-HIAA was still reduced, but that of 1,4-MeHm was normal. Levodopa may thus modify the turnover of histamine, which appears to be reduced in Parkinson's disease, and this effect may be modified by amantadine.     

The evaluation of 4-hydroxy-3-methoxyphenylglycol sulfate as a possible marker of central norepinephrine turnover. Studies in healthy volunteers and depressed patients

Much evidence indicates that urinary 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG) is an insensitive measure of central norepinephrine metabolism. This conclusion, however, seems to apply mainly to total urinary MHPG, since previous findings point to the possibility that the major proportion of urinary MHPG sulfate originates in the CNS, while most urinary MHPG glucuronide originates in peripheral organs. To examine this hypothesis, experiments were performed by which we altered MHPG turnover in man at two different stages: firstly, strong physical exercise (ergometer) increased the urinary excretion rate of MHPG glucuronide and not that of MHPG-sulfate; secondly, ethanol (l g/kg), which is known to block the metabolism of MHPG to vanilmandelic acid in the liver, increases the urinary excretion rate of the glucuronide and not that of sulfate. Both experiments indicate that alteration of peripheral norepinephrine turnover changes the urinary excretion of MHPG glucuronide only and not that of sulfate, thus providing strong, albeit indirect, evidence for a primarily central origin of MHPG sulfate. Preliminary experiments in 32 depressed patients showed little difference in both MHPG fractions compared with healthy controls, apart from a slightly reduced excretion rate of glucuronide. These findings fail to provide any evidence of central, and only small changes in peripheral norepinephrine metabolism in depression.     

Stimulants, urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate and dextroamphetamine

Children with attention deficit disorder with hyperactivity were given either methylphenidate hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's effects were distinctly different from those of dextroamphetamine. After methylphenidate administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites was unchanged by either drug. Urinary PEA excretion was not significantly changed after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine. Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic acid excretion. Effects of dextroamphetamine were not tested.     

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.     

Effect of amantadine on the urinary excretion of some monoamines and metabolites in normal and Parkinsonian subjects

The urinary excretion of several monoamines and metabolites was determined in Parkinsonian patients immediately prior to, and during the first 4 days of amantadine (200 mg daily) therapy. Amantadine produced a statistically-significant increase in the excretion of 1,4-methylhistamine and 5-hydroxyindole-3-acetic acid. There was also a tendency towards a higher dopamine and homovanillic acid excretion. These findings suggest that amantadine increases the release of monoamines and this may be the basis of its beneficial effect in Parkinson's disease.     

Psychogenic polydipsia and water intoxication—Concepts that have failed

Ten patients (8 men, 2 women; mean age 38.7 ± 8.1 years), 7 of whom had schizophrenic disorders and 3 of whom had bipolar disorder (manic-depressive illness), manifested psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome). The relationship between serum sodium and urinary water excretion among the 10 PIP patients is described in detail. The success of lithium in improving serum sodium levels and in decreasing urinary water excretion among the three PIP patients with bipolar disorder and the failure of changes in urinary water excretion to explain changes in serum sodium levels among the 10 PIP patients argue against “psychogenesis” as the explanation for the polydipsia and excessive water intake as the sole explanation for hyponatremia or complications ascribed to water intoxication.     

Differential changes of blood and urinary indoleamines following intravenous ethanol administration in alcoholic and non-drinker women

Summary Total blood serotonin (5-HT) and the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL) were measured before and after intravenous administration of 0.65 g/kg ethanol to nine chronic alcoholic female patients. Changes were compared to those obtained in twelve age-matched non-drinker neurotic or hysteric women. The two groups showed different pattern of indoleamine response to ethanol: alcoholics reacted by a reduction of 5-HIAA output in the urine, while controls showed no change in the 5-HIAA excretion but a marked fall of blood serotonin. Urinary 5-HTOL excretion increased equally in both groups. Despite these biochemical variations, behavioral responses to ethanol were indistinguishable in the two groups. The results indicate that chronic alcoholism leads to permanent changes of the biogenic amine metabolism.     

Urinary excretion of catecholamines and their metabolites in relation to circulating catecholamines. Six-hour infusion of epinephrine and norepinephrine in healthy volunteers.

Some depressed patients have been shown to excrete abnormal amounts of catecholamines and their metabolites in urine. Some studies suggest that hypersecretion of epinephrine by the adrenals and of norepinephrine by the peripheral sympathetic system cause increased excretion of urinary catecholamines and their metabolites in a subgroup of patients. To evaluate the effect of increased catecholamine levels in the peripheral circulation on urinary catecholamine and metabolite levels, we infused healthy volunteers during 6 hours with epinephrine, norepinephrine, or placebo, respectively, in a three-period, double-blind, crossover design. The results indicate that (1) urinary epinephrine and norepinephrine levels were the most sensitive indicators of increased circulating epinephrine and norepinephrine levels, respectively; (2) changes in circulating epinephrine or norepinephrine levels were not readily reflected in changes in urinary vanillylmandelic acid or 3-methoxy-4-hydroxyphenylglycol levels; and (3) increased normetanephrine excretion was not only induced by infusion of norepinephrine but also by epinephrine. This last finding may be due to activation of the sympathetic nervous system by circulating epinephrine. These results may help to explain the mechanism of adrenal epinephrine and sympathetic nervous system norepinephrine hypersecretion observed in subgroups of depressed patients.