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Anxiety may be associated with increased norepinephrine activity. Urinary levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were examined in depressed patients with and without panic attacks. Depressed patients with panic attacks had significant elevations of MHPG.

In this improved method for quantifying 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in urine, after a multistep extraction of MHPG and internal standard (iso-MHPG) from 3.0 mL of urine, the compounds are separated on a C18 reversed-phase column and quantified by use of an electro-chemical detector. The isocratic chromatographic separation takes about 16 min. The mobile phase is phosphate buffer/acetonitrile (88/12 by vol), the flow rate 0.7 mL/min. Recycling the mobile phase and automating the sample injection make possible the unattended assay of more than 70 samples per day. The within-run precision of the method is excellent (CV 1.8%) at a mean concentration of 1.1 mg/L.

The relationships between neuropsychological performance and urinary amine metabolite levels (HVA, 5-HIAA, MHPG) were examined in a sample of 27 medication-free patients with Tourette's Syndrome. Correlations with specific metabolites indicated neuropsychological deficit associated with higher levels of HVA and lower levels of 5-HIAA. Variables computed to express the interaction of the various neurotransmitter systems provided strong and consistent support for such interactions in the underlying mechanism of the neurobehavioral deficits observed in these patients. The implications of these findings and directions for future research were discussed.

Data on 24-hour urinary levels of catecholamines and metabolites were determined in 114 depressed patients. For each patient, a D-type score was calculated, using a discriminant function equation that was previously derived using data from an independent group of depressed patients. Of all measures, D-type scores provided the highest sensitivity and specificity for separating bipolar/schizoaffective-depressed patients from all remaining patients or from those patients with unipolar nonendogenous depressions. Using Research Diagnostic Criteria (RDC), bipolar I patients demonstrated significantly lower D-type scores than did all other RDC depressive subtypes, including bipolar II disorders. Similar findings were observed using the Clinical Inventory for the Diagnosis and Classification of Affective Disorders (CIDCAD) system: bipolar/schizoaffective patients demonstrated significantly lower D-type scores than all remaining subtypes, including diagnostically unclassifiable, probable bipolar patients (a category somewhat akin to RDC bipolar II disorder). Data pointed to the heterogeneity of bipolar disorders. Catecholamine and metabolite data in this study were compared with recent studies of others.

Deuterium-labelled 4-hydroxy-3-methoxyphenylglycol (MHPG), when administered intravenously, is rapidly converted to 4-hydroxy-3-methoxymandelic acid (or vanillylmandelic acid [VMA]) or conjugates of MHPG. Since over half of either racemic D,L-MHPG or the natural D-MHPG is converted to VMA and since about half of urinary VMA is derived from MHPG, estimates of the proportion of urinary MHPG derived from the brain must be revised. The results indicate that only about one fifth of urinary MHPG is derived from the brain, and clearly urinary MHPG cannot be used as a valid index of brain norepinephrine metabolism. While these observations do not alter the value of urinary MHPG as a predictor of therapeutic response or in subclassifying affective disorders, it is clear that new research questions must be formulated and appropriate investigations completed before the relationship of urinary MHPG to affective disorders is understood.

The urinary excretion of 3-methoxy, 4-hydroxyphenyl-glycol, (3-MHPG) was measured in 20 unipolar depressed patients before treatment with imipramine and electroconvulsive therapy (ECT) to investigate the relationship between pretreatment urinary excretion of 3-MHPG and clinical response. There was no difference in 3-MHPG excretion for depressed patients and controls. There was no significant difference between the mean percentage reduction of Hamilton Depression Rating Scale Scores in "low" and "high" excretors of 3-MHPG in the imipramine and ECT group of patients after four weeks of treatment.

The authors compared a group of boys with childhood autism and a group of normal boys of similar age and found a decrease in urinary 3-methoxy-4-hydroxyphenethylene glycol (MHPG) in the autistic group. They hypothesize that autistic children might have an alteration in central and peripheral noradrenergic function, which might be related to impaired regulation of attention, arousal, and anxiety.

In this paper we summarize the results of our recent and present research focused on analyzing the correlations between neurochemical, pharmacological and clinical parameters in patients with Major Depression. There is evidence that: a) pretreatment urinary MHPG is a useful predictor for clinical response to tricyclic antidepressants and to long-term lithium treatment; b) urinary MHPG is positively correlated to the age at onset of the disease; c) previous responses to tricyclics and age at onset of affective illness are supplementary tools for predicting the effectiveness of lithium and antidepressant drugs; d) platelet alpha-2-adrenoceptor density is inversely correlated with both urinary MHPG and age at onset; e) cerebral ventricular size is positively correlated with urinary MHPG and age at onset and may discriminate between patients with different outcomes on lithium prophylaxis; f) low MHPG excretors are more likely to have suffered from stressful life events in early childhood than normal-to-high excretors. Taken together, these results lend strong support to the hypothesis that Major Affective Disorder is a heterogeneous illness and that inherently different subgroups of affective patients can be recognized.

3-Methoxy-4-hydroxyphenylglycol (MHPG), the urinary metabolite thought best to reflect brain norepinephrine metabolism, was studied in a large group of hospitalized depressed patients with primary affective disorder and in normal controls, as part of an ongoing effort to evaluate the role of central amine dysfunction in affective illness. Overall there was no difference in MHPG between the depressed patients and controls. Hosever, within the depressed population the bipolar patients excreted significantly less MHPG than the unipolars and, as a group, the male bipolar patients had significantly lower MHPG than male controls. MHPG correlated positively with age, age of onset, rating of anxiety and psychosis and, most importantly, with systolic blood pressure. These data support the concept of biological heterogeneity among individuals with major depressive disorders. However, the relationship between MHPG excretion and various psychological and physiological parameters is both intriguing and complex and warrants careful interpretation.

The authors studied the effect of a catecholamine-controlled diet on the urinary level of 3-methoxy-4-hydroxyphenylglycol (MHPG) of 6 depressed patients and 6 normal volunteers. The normal subjects showed no change in MHPG levels on or off the diet; the depressed patients showed a significant increase in MHPG while off the diet.

A sensitive and convenient electron-capture gas chromatographic procedure for analysis of MHPG in small volumes of urine is described. The method involves acetylation under aqueous conditions, extraction with an organic solvent and reaction with trifluoroacetic anhydride under anhydrous conditions. The resultant derivative is separated and quantitated on a gas chromatograph equipped with a fused silica capillary column and an electron-capture detector.

Urinary MHPG concentrations and platelet 3H-imipramine binding (Bmax, Kd) were measured in 20 psychiatric inpatients with diagnoses of major depressive disorder. Clinical assessments were performed using the Present State Examination (PSE) interview, and several dimensions of symptomatology were constructed on the basis of the PSE items. There was a significant positive relationship between Bmax and items reflecting both psychomotor retardation and anxiety. Urinary MHPG bore a comparatively complex nonlinear relationship to Bmax and to the psychomotor retardation symptom dimension. Urinary MHPG also showed an inverse, curvilinear correlation with certain neurotic symptoms. The implications of these findings are briefly discussed in the light of the "dysregulation" hypothesis of affective disorder.

Measurement of urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) is being tested in a number of psychiatric problems, most notably affective disorders. These measurements have certain problems. First, the collection of 24-hour urine specimens continues to be somewhat difficult, and no suitable solution has been found for using collections that might be incomplete. Second, the range of excretion of MHPG is rather similar in normal persons, depressed patients, and geriatric patients. One can think of no situation in all of medicine where diagnostic or prognostic distinctions can be made on the basis of variations within the normal limits of a laboratory test. Third, the variability of MHPG excretion may be high in some patients, even over the short term, clouding the significance of mean values of repeated determinations.

Twelve acute depressed patients were studied in the course of antidepressant treatment. Three-day-24-hour urine samples for 3-methoxy-4-hydroxy-phenylglycol (MHPG) were collected both before and after a five week treatment schedule. MHPG were estimated by spectrophotometry. Initial MHPG excretion did not reflect the severity of pretreatment depression and final MHPG showed no specific correlation with post-treatment improvement. No specific or uniform influence of different anti-depressant treatments or changes in MHPG was evident. Depressed patients with bipolar affective disorder tend to have initially lower MHPG levels than patients with unipolar depression. Urinary MHPG excretion measurements may prove not to be a useful index in the diagnosis and choice of treatment in patients suffering from primary depression.

Urine samples from patients with propionic acidemia and from a patient with methylmalonic acidemia contained unknown non-acidic metabolites by gas chromatography/mass spectrometry after ethyl acetate extraction. It could be demonstrated by mass spectrometric studies and by synthesis of reference compounds that the major metabolite was 2-methyl-2,3-butanediol, while smaller amounts of 2,3-pentanediol were also present. These diols were present in abnormal amounts in these patients during attacks of metabolic decompensation.

Abnormalities of noradrenaline metabolism and of the activity of hypothalamic-pituitary adrenal axis (HPA) have been reported in depression. To study the possible relationship between these 2 parameters, urinary excretion of 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG) and Dexamethasone Suppression Test (DST) were analyzed in 58 depressed patients. A positive correlation was found between the age of depressed patients and 24-h urinary excretion of MHPG. Twenty-two patients (38%) were DST non suppressors. Pre-DST plasma cortisol levels were significantly higher in non suppressors than suppressors. No difference was found however between urinary MHPG levels in suppressors and non suppressors. There was no correlation between pre-DST plasma cortisol and levels of urinary excretion of MHPG. These results do not support the hypothesis of a relationship between these 2 parameters. However, when depressed patients were separated into two groups according to urinary excretion of MHPG ("high MHPG" and "low MHPG"), the "high MHPG" group included significantly more non suppressors then the "low MHPG" one. This result is not sufficient to demonstrate of link between HPA system activity and central noradrenaline metabolism.

A reverse phase high performance liquid chromatographic method for determining levels of 4-hydroxy-3- methoxyphenylethylene glycol (MHPG) in human urine that is virtually free of all interfering peaks has been developed. After addition of a homologous internal standard, enzymatic hydrolysis is performed. Samples are then placed onto columns containing AG1-X8, and the MHPG is collected in a phosphate buffer wash of the column. After ethyl acetate extraction and evaporation of the organic solvent, the dry residue is redissolved in mobile phase, and injected onto a reverse phase column. Results obtained with this assay were almost identical (101+/-5.6%, mean+/-SD, n=6) with those obtained using a gas chromatography - mass spectrometry (GCMS) assay.

Following the removal of a pheochromocytoma in three female patients the daily excretion of catecholamines and their metabolites was still considerably elevated for about one week. The excretion rates declined during this period with half-lives of 1.8 to 10.9 days for catecholamines and 2.1 to 4.7 days for metanephrines, vanilmandelic acid, and vanilglycol. The cumulative urinary excretion of catecholamines and their metabolites following surgical removal of the tumour was nearly as high as the catecholamine content of the pheochromocytomas. This large amount of catecholamines must have been located outside the tumour, most probably within the sympathetic nerve, where it is subject to release following physiological stimuli. Furthermore, this fact may provide an explanation for hypertensive crises in pheochromocytoma patients.

A modified method is described for determination of 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine by gas chromatography with electron capture detection. The method is reproducible and mean (+/- SD) recoveries of MHPG from urine were 78.5 +/- 12.7% and 76.5 +/- 15.0% in two separate series of analyses. Mean 24-hour MHPG excretion was 1884 +/- 591 microgram in 11 normal subjects and 1688 +/- 593 microgram in 20 patients with various types of depression. Males excreted more MHPG than females but this difference could be eliminated by expressing the values relative to the creatinine in urine. Variations in diet did not appear to influence urinary MHPG excretion.

We have investigated hypotheses that link the stiff-man syndrome to an imbalance of neurotransmitter systems. No evidence was found to support the concept of defective synaptic transmission at either cholinergic input to Renshaw inhibitory elements or at glycinergic inhibitory input to motoneurons from spinal interneurons, since neither physostigmine nor glycine altered symptomatology. Urinary excretion of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenyl glycol showed a high correlation with clinical status. This suggests the involvement in the stiff-man syndrome of a central norepinephrine neuronal system that has net excitatory effects upon motoneurons, a system whose activity can be increased slightly by levodopa and decreased markedly by diazepam, with corresponding changes in stiffness.

To investigate the interrelationships between the noradrenergic and serotonergic systems and the hypothalamic-pituitary-adrenal (HPA) axis, we measured the excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and free cortisol (UFC) in 24-h urine both before and after loading with 2 g L-tryptophan (L-TRP) orally in 24 healthy controls and 33 depressed patients categorized according to DSM-III. Loading with L-TRP reduced MHPG excretion significantly by 56% in major depressives, whereas in healthy controls and in minor depressives no significant effects were observed. Although basal MHPG did not differ among these study groups, loading with L-TRP resulted in MHPG excretion in major depressives being significantly lower than in healthy controls and minor depressives. Loading with L-TRP increased UFC significantly by 49% only in major depressives with associated features. After L-TRP those patients exhibited significantly increased UFC as compared with all other depressives and controls, whereas basal UFC values did not differ among the study groups. In baseline conditions there were no significant correlations between MHPG and UFC excretion.

Eight cocaine-dependent subjects had significantly lower urinary 3-methoxy-4-hydroxyphenylglycol excretion than did eight normal control subjects. Cocaine-dependent subjects also had lower plasma tyrosine levels but not to a statistically significant degree.

The authors studied growth hormone (GH) release after insulin-induced hypoglycemia (HI) in relation to urinary MHPG, the major metabolite of central norepinephrine. There was a significant linear correlation of urinary MHPG levels and GH peaks after HI in unipolar depressed patients and in manic patients; however, GH peaks in manic patients shifted downward on the GH axis in comparison to the unipolar depressive patients. The authors suggest that such shifts in the GH response may occur as a result of abnormalities of other neurotransmitter systems also known to facilitate GH release.

We describe the conjoint measurement in urine of the alcoholic catecholamine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The method involves extraction with ethyl acetate and back-extraction into acetic acid (MHPG), followed by adsorption onto alumina (DHPG). The separation is performed by reversed-phase liquid chromatography with column switching and amperometric detection. Total (free plus conjugated) compounds are determined after a 24-h enzymatic hydrolysis. Twelve-hour excretion values for normal and hypertensive subjects are given, together with results obtained for patients with pheochromocytoma, chemodectoma, and congenital dopamine-beta-hydroxylase deficiency. The assay is sensitive, reproducible, and free of interferences, and may lead to a better understanding of overall catecholamine metabolism in health and disease.

A short term course (8-11 days) of diethylpropion 50 mg a day was administered to 12 obese children of both sexes fed a mixed low calorie diet containing about 1000 calories/day. A group of 10 obese children received the same diet and no medication. The sex-distribution was similar in both groups as well as the degree of overweight (appreciated by the Quettelet index). The urinary excretion of some noradrenergic derivative (adrenaline-A, noradrenaline-NA, vanillyl-mandelic acid VMA, metanephrines NM and methoxy hydroxyphenyl glycol-MHPG) and of homovanillic acid (HVA) was measured in both groups before and after drug therapy or diet, respectively. After the diethylpropion course, the urinary mean value of MHPG decreased (2.17 +/- 0.30, mean +/- SE vs 1.47 +/- 0.21) but the significance was borderline. The mean level excretion of NA, VMA, MN and HVA were significantly lower following diethylpropion. No significant change was observed in the diet-only group of patients as regards the same determinations. These observations are not entirely explained by the previous pharmacologic knowledge on diethylpropion and other sympathomimetic amines.

A reversed-phase liquid chromatographic method with amperometric detection has been developed for the determination of urinary 3-methoxy-4-hydroxyphenylglycol. Before and after enzymatic deconjugation, it was purified by an extraction procedure and rapidly quantified under isocratic conditions. The 24-h excretion profile in normal human subjects (eight males and seven females) was determined; our results are consistent with those arrived at in a number of other studies. The present method is highly sensitive and selective; in addition, a good degree of precision is assured by use of 4-methoxy-3-hydroxyphenylglycol as internal standard.

The urinary excretion of 4-hydroxy-3-methoxyphenylglycol was compared in a group of 23 depressive patients and 27 control subjects of similar age. There was no difference between patients and controls although female controls excreted less than males. After 6 weeks' treatment with 150 mg daily of amitriptyline there was no correlation between therapeutic response and pretreatment urinary excretion value.

MHPG excretion of 14 endogenously depressive patients and 5 healthy controls was investigated before, during and after a night of sleep deprivation (SD). Patients having a minimum improvement of 40% in the Cronholm-Ottoson rating scale had shown a significantly higher MHPG excretion in the night before SD ( p less than 0.02) as compared to the non-improved group. The MHPG excretion of the night before SD shows a significant negative correlation, both with the depression score according to Cronholm-Ottoson (p less than 0.05) and with the self-rating score according to von Zerssen (p less than 0.005), on the day after SD. No correlation was found between the motor activity measured by pedometer and MHPG excretion. The results are discussed in connection with values found in controls.

Procedures are described for the determination of methylpentynol carbamate in serum, either by injection into the chromatograph of diluted serum or extraction of the drug into chloroform and injection of an aliquot of the concentrated organic phase; a 4% CDMS column is used. Similar assays for measuring the metabolite 3-methylpentyne-3,4-diol in urine are reported. The methods have been used for measuring methylpentynol carbamate and its metabolite in samples from rats and dogs.

Determinations of noradrenaline (NA), adrenaline (A), vanillylmandelic acid (VMA), metanephrines (MN), homovanillic acid (HVA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) were performed in 24 h urine samples of three groups of children: 26 normal children, 7 cases of congenital myxedema (not treated for at least one month) and 8 obese children to whom a short (9-14 days) course of thyroid extract was administered. No sex difference was noted in any group. The results in the control group (mean +/- SE) were as follows: NA 23.8 +/- 2.18 micrograms, A 6.2 +/- 0.35 micrograms, VMA 1.58 +/- 0.22 mg, NM 0.526 +/- 0.079 mg, HVA 1.24 +/- 0.142 mg, MHPG, 1.60 +/- 0.232 mg. The excretion of MHPG was significantly (cor)related to NA (p less than .05) and completely unrelated to the other derivatives. Significant equations and curves were obtained from linear regression analysis of MHPG excretion to age (p less than .025), weight (p less than .025), body surface (p less than .05), and creatinine excretion (p less than .05) but not to height and Quetelet index. No significant change was encountered in both myxedema or thyroid extract-treated obese group in any urinary metabolite determined. It was concluded that in children the urinary MHPG excretion is closely correlated to NA excretion and is linearly dependent on age, weight and creatinine extraction. Thyroid activity seems to have no evident effect on urinary excretion of various catechol metabolites. Suggestion is made that the MHPG (cor)relation(s) found originate(s) in corresponding change(s) of noradrenergic receptor sensitivity within the brain.

Urinary 3-methoxy-4-hydroxyphenylglycol has been reliably assayed on a routine basis using an electron-capture detector method. Modifications of previous procedures include simplifcation of extraction and derivatization of urine, inclusion of an internal standard, prevention of losses during concentration, use of each urine as its own standard, and better chromatographic resolution by lengthening of columns and programming temperature. The assay shows a coefficient of variation of 3.1%.

Urinary MHPG excretion in patients with acute schizophrenia was studied before and during a trial of the isomers of flupenthixol and placebo. Pretrial MHPG excretion was not related to severity of illness before the trial or to other pretrial clinical variables. In male subjects higher pretrial MHPG excretion was associated with a better outcome 1 year post-trial. However in females no relationship between MHPG excretion and outcome was established. During the trial there was a reduction in MHPG excretion in patients treated with beta-flupenthixol but no decrease in the group treated with alpha-flupenthixol or chlorpromazine. In patients on placebo there was a reduction in MHPG excretion in those who did well clinically, but not in those who did poorly. Thus low MHPG excretion may be a predictor of poor outcome in schizophrenia, but MHPG excretion also changes both as a function of clinical state and of neuroleptic drug administration.

The 24-h pattern of urinary 3-methoxy-4-hydroxy-phenylglycol (MHPG) was studied in 15 depressives and 15 healthy controls. MHPG was measured at 3-h intervals over two consecutive 24-h periods. The shape of the MHPG excretion pattern of the depressed group was different from that of the control group. However, both the consistency and shape of the individual 24-h MHPG patterns exhibited a high interindividual variability. Therefore it is difficult to speculate on a circadian phase difference between depressives and healthy controls. Major factors that may have influenced our results are discussed.