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We studied 99 hospitalized depressed, 14 manic, and 61 healthy control subjects and evaluated relationships during a drug-free baseline period between behavioral measures (postulated to be associated with brain norepinephrine, dopamine, and serotonin function) and metabolites of these neurotransmitters sampled from lumbar cerebrospinal fluid (CSF): 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid. Depressed subjects with increased anxiety, agitation, somatization, and sleep disturbance were found to have significantly elevated concentrations of CSF MHPG; this relationship was not found in the healthy controls. A correlation between CSF MHPG level and an anxiety/agitation dimension measured in all subjects was statistically significant but explained a modest portion of the total variance. No consistent relationships were found between CSF MHPG and depression/retardation, hostility/interpersonal sensitivity, and global severity, nor did any of these measures correlate significantly with the levels of the other monoamine metabolites, although some trends were found. Other factors did not account for the relationships between CSF MHPG and some behavioral measures, including diagnostic subgroup, motor movement, age, sex, and premenopausal or postmenopausal status in women. Suggested relationships among drug treatment modality, eventual treatment outcome, behavioral and mood state at baseline, and these metabolite levels will require further analyses.

As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function.

The authors examined the quantities of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the urine of 11 schizophrenic female patients, 14 primary affective disorder (depressed type) female patients, and 10 healthy comparison women. The primary affective disorder patients had significantly less MHPG in their urine than did the comparison subjects. The schizophrenic patients when compared with the healthy subjects or the depressed patients did not excrete significantly different amounts of MHPG in urine. The variance in MHPG in schizophrenic patients was quite large; some had very low urinary MHPG. There was a significant positive correlation between agitation and urinary MHPG for schizophrenic but not depressed patients. The authors discuss theoretical and practical implications of these findings.

The available evidence suggests that there is an interaction or linkage between brain adrenergic systems and the functioning of peripheral CA neurons, particularly those in the sympathetic nervous system. Significant correlations between brain, CSF, plasma, and urinary concentrations of NE and MHPG have been observed by several different groups, and these are reviewed and summarized. While these correlations may occur in part because of a direct contribution of brain MHPG to peripheral pools of MHPG, it is also likely that the mechanism underlying these relationships resides in an interactive linkage between central and peripheral adrenergic systems. The use of plasma and urinary MHPG as a probe for central adrenergic function is discussed in relationship to these noted correlations and the central-peripheral interactive paradigm. The question of how well a peripheral adrenergic measure reflects CNS NE neuronal activity is discussed. Finally, it is noted that the existence of interactions between central CA systems and the sympathetic nervous system broadens research strategies, since it can no longer be assumed that measures of plasma or urinary NE, NM, or VMA do not reflect central events because the quantities of these substances entering the periphery from brain are quite small.

Measures of plasma 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) may be useful for investigating noradrenergic function in certain behavioral and physiologic states. Serial plasma and urine samples were obtained from a diagnostically heterogeneous group of ten psychiatric inpatients over a three- to five-day period. The plasma samples were assayed for free and total MHPG and the urine samples for total MPHG. The variance between patients in both plasma free and conjugated MHPG was markedly greater than the variance within patients. The test-retest reliability for free plasma MHPG in both AM vs PM values within and across study days was also significant for both free and conjugated MHPG even though the AM plasma free MHPG values were significantly greater than the PM values. No significant correlations were found between plasma free and conjugated MHPG or between urinary total MHPG and plasma free MHPG.

To test the acute effects of clonidine on plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), the major metabolite of brain norepinephrine (NE), and to examine the relationship between plasma MHPG and concurrently measured blood pressure variables, we performed a series of 31 double blind, placebo controlled, test days in which clonidine (1 and 5 micrograms/kg) or placebo was administered (p.o. at 9:00 a.m.) to six fasting normotensive male subjects. Three h following the 5 micrograms/kg clonidine dose, plasma MHPG reached a nadir significantly below both baseline and placebo levels (P less than 0.05). Mean MHPG concentrations were significantly correlated with diastolic blood pressure (sitting: r = 0.46, df = 88, P less than 0.00001; standing r = 0.49, df = 73, P less than 0.00001). Unexpectedly, this relationship was independent of clonidine dose and sampling time. Under drug-free conditions, the correlation between plasma free MHPG and diastolic blood pressure remained significant (sitting: r = 0.43, df = 40, P = 0.003; standing: r = 0.46, df = 33, P = 0.006). The findings are considered in light of evidence implicating brain NE systems in the regulation of blood pressure.

It has been found that in the brain of the non-human primate (Macaca arctoides) MHPG occurs principally if not exclusively in the free rather than the conjugated form. It has also been found that in all areas of human brain examined MHPG is present in the free form rather than the conjugated form. The quantity of free MHPG present in various structures of human brain ranged from 46.4 to 69.8 microng/gm of tissue.

Urinary 3-methoxy-4-hydroxyphenethylene glycol (MHPG) excretion, which is thought to reflect CNS norepinephrine metabolism, has been shown to be significantly decreased in some depressed patients. Although there is consensus that urinary MHPG excretion varies directly with mood in rapidly cycling bipolar patients, there is little information on longer term state changes, such as those that accompany recovery from depression. Ten female patients with diagnoses of primary affective disorder were studied initially during an inpatient hospitalization and restudied at least ten months after discharge. Five healthy female comparison subjects were also studied over a similar interval of time. During the baseline period, the patient sample excreted less MHPG than did the comparison group. Improvement in clinical state from a seriously depressed baseline was associated with a significant increase in MHPG excretion, while the patients with recurrences of depression showed no change and continued to excrete less MHPG than the comparison subjects. These results suggest that urinary MHPG excretion may represent an index of psychobiological state in depressive patients.

A direct method has been employed to estimate the rate of production by human brain of 3-methoxy-4-hydroxyphenethyleneglycol, the major metabolite of brain norepinephrine, a brain neurotransmitter. Venous specimens were obtained from the internal jugular vein from ten awake human subjects at a puncture site above the common facial vein, the first major source of extracranial inflow. Arterial specimens were simultaneously obtained from the radial artery. Plasma samples were assayed and a highly significant difference was found in the concentration of the metabolite in plasma coming out of the brain (venous blood) as compared to plasma entering the brain (arterial blood). This venous-arterial difference was calculated to be 0.7 +/- 0.1 nanogram per milliliter of blood. Assuming an adult brain weight of 1400 grams and normal cerebral blood flow, it is estimated that the rate of production of 3-methoxy-4-hydroxyphenethyleneglycol by the awake human brain is approximately 597 nanograms per minute or 35.8 micrograms per hour. Urine specimens were also collected from six of these subjects during a period of 1 to 3.5 hours, which bracketed the time the blood samples were obtained. For these six subjects the output of 3-methyoxy-4-hydroxyphenethyleneglycol by whole brain was estimated to be 40.9 micrograms per hour, whereas the rate of its excretion into urine was 64.5 micrograms per hour.

Measurement of urinary 3-methoxy-4-hydroxyphenethylene glycol (MHPG) levels has been suggested as possibly being important in elucidating the role of central noradrenergic function in affective illnesses. The influence on urinary MHPG excretion of the state variables of physical activity and stress has not been clearly defined in previous studies. During a baseline medication-free period, 24 hospitalized depressed female patients underwent a five-day protocol including an eight-hour period of either enhanced or restricted activity. Throughout the protocol, independent measurements of telemetered mobility and stale anxiety were obtained. There were no significant effects of physical activity on urinary MHPG levels. Furthermore, baseline urinary MHPG levels and baseline state anxiety did not covary significantly. However, within-individual analyses yielded a highly significant relationship between changes in urinary MHPG levels and changes in state anxiety. The data suggested that those patients with lower baseline MHPG levels were those more prone to experience increased anxiety under environmentally "activating" circumstances.

To simultaneously measure 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) in human cerebrospinal fluid (CSF), we used an acetonitrile protein precipitation, reversed-phase high-performance liquid chromatography with coulometric detection, and 3-methoxy-4-hydroxyphenyllactic acid (MHPLA) as an internal standard for all three metabolites. MHPG, 5HIAA, HVA, and MHPLA were stable for one month when stored in CSF at -70 degrees C. Three determinations were made in triplicate for each of seven subjects over a 30-day storage period and the coefficients of variation within subject for these determinations ranged from 0.075 to 0.165 for MHPG, 0.045 to 0.148 for 5HIAA and 0.053 to 0.181 for HVA. Means and standard deviations of CSF concentrations were 10.7 +/- 3.0 ng/ml for MHPG, 22.4 +/- 9.9 ng/ml for 5HIAA, and 39.9 +/- 21.4 ng/ml for HVA. This method provides simple sample preparation, sensitivity, and cost advantages, as well as simultaneous extraction and quantitation of MHPG, 5HIAA, and HVA using an internal standard.

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.

A direct method for measuring the rate of production of neurotransmitter metabolites by the brain of awake monkeys is described. The method utilizes a coupling of a measure of cerebral blood flow with the determination of the difference in concentration of the metabolite under study in arterial and internal jugular bulb blood. A consistent veno-arterial difference for 3-methoxy-4-hydroxyphenethylenglycol (MHPG) has been found. The concentration of MHPG in blood obtained from the right and left venous outflows from brain were not significantly different indicating that blood from either the right or left internal jugular bulb may be used with this method. The rate of production of MHPG by the brain of thw awake monkey is estimated to be 24.1 ng/100 g brain/min. The rate of MHPG production by brain is increased by the administration of piperoxan and decreased by clonidine. Using the experimentally determined rate of production of MHPG by brain and extrapolating to the human it is suggested that a substantial fraction of the total body production of MHPG in man occurs in brain.