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The National Institute of Mental Health-Clinical Research Branch Collaborative Study investigated 132 drug-free, severely depressed patients and 80 healthy controls. Forty-five percent of the depressed patients excreted markedly elevated levels of urinary epinephrine (E) and metanephrine (MET), while only 5% of healthy controls did so. Using gaussian mixture distributions, we identified two subgroups of depressed patients: one excreting normal levels and the other excreting high levels of urinary E, MET, norepinephrine, and normetanephrine. Cerebrospinal fluid homovanillic acid levels were low in a subgroup of depressed patients. When analyzed by subgroup, the elevated E + MET group had markedly lower cerebrospinal fluid homovanillic acid levels than controls, whereas depressed patients with normal catecholamine levels did not. Since it has been postulated that there are two subgroups of depressed patients, those with low 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and normal 5-hydroxyindoleacetic acid (5-HIAA) levels and those with normal MHPG levels and low 5-HIAA levels, several analyses were performed to see if such a group could be identified. Our analysis failed to find evidence of a subgroup of depressives with low MHPG and normal 5-HIAA levels or normal MHPG and low 5-HIAA levels.

We have previously reported high correlations between norepinephrine and its metabolite outputs in depressed patients. In this article, we expand this finding to healthy volunteers and alcoholic patients. Furthermore, we find similar high correlations between urinary outputs of dopamine, norepinephrine, and their major metabolites. The same is true, to a lesser degree, for epinephrine and metanephrine outputs. There are implications of these findings for psychobiological research on the monoamine systems.

The urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and other catecholamine metabolites was measured in a series of 63 patients with various clinically defined subtypes of depressive disorders. MHPG excretion was significantly lower in patients with bipolar manic-depressive depressions and schizo-affective depressions than in patients with unipolar nonendogenous depressions. Patients with schizophrenia-related depressions also excreted reduced levels of MHPG when compared with patients with unipolar nonendogenous depressions. Moreover, levels of urinary epinephrine and metanephrine were significantly lower in patients with schizophrenia-related depressions. These data, coupled with our recent finding that patients with schizophrenia-related depressions had significantly higher levels of platelet monoamine oxidase activity than control subjects of patients with unipolar endogenous depressions, suggest that we can discriminate three biochemically discrete subgroups of depressive disorders corresponding to the following clinically defined subtypes: (1) the bipolar manic-depressive depressions plus the schizo-affective depressions; (2) the unipolar nonendogenous depressions; and (3) the schizophrenia-related depressions.

The previous article in this series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with various clinically defined subtypes of depressive disorders. We now report that further biochemical discrimination among depressive subtypes is provided by the following equation, derived empirically by applying multivariate discriminant function analysis to data on urinary catecholamine metabolits: Depression-type (D-type) score = C1(MHPG) + C2(VMA) + C3(NE) +C4(NMN + MN)/VMA + C0. In the original derivation of this equation, low scores were related to bipolar manic-depressive depressions, and high scores were related to unipolar nonendogenous (chronic characterological) depressions. Findings from a series of depressed patients whose biochemical data had not been used to derive this equation confirmed these differences in D-type scores among subtypes of depressions. The findings presented in this report further suggest that we can discriminate three biochemically discrete subgroups of depressive disorders.

Urinary catecholamine levels were measured in 25 anorexia nervosa patients at the time when they were acutely ill with secondary depressive symptoms and again after treatment and weight gain to see whether changes in weight, activity levels, and symptoms of depression occurring during treatment might be associated with changes in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations. The latter was significantly lower in the acutely ill anorectics than in the control group. An increase in urinary MHPG concentration after treatment was significantly correlated with a decrease in depressive symptomatology. The increase in urinary MHPG level during treatment did not correlate significantly with change in patient's activity level. There seems to be a relationship between MHPG and the symptom of depression in a group of patients who do not carry a primary diagnosis of depression.

Catecholamine metabolites excreted by long-term methadone hydrochloride-dependent subjects were studied in a protocol involving a two-study design. After a two-week methadone maintenance period, 15 subjects underwent abrupt methadone withdrawal and 12 subjects, gradual methadone withdrawal. The first study compared levels of catecholamine metabolites excreted during the stable methadone period with those excreted during the abrupt withdrawal period, as well as with those eliminated by healthy nonaddicted controls. No changes in the excretion of 3-methoxy-4-hydroxyphenylglycol and normetanephrine were noted between the methadone maintenance period and the time of abrupt methadone withdrawal. These values did not differ from those obtained for controls. However, higher levels of metanephreine were excreted during the stable methadone period than those in controls. During withdrawal, levels of metanephrine dropped a statistically significant amount in comparison with levels observed during the stable methadone period. The gradual withdrawal study confirmed these findings.

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.