Increased stress response and beta-phenylethylamine in MAOB-deficient mice.

MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-II alcoholism and in cigarette smokers. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

m-Hydroxyphenylacetic acid formation from L-dopa in man: suppression by neomycin.

The increased excretion of m-hydroxyphenylacetic acid in the urine of patients with parkinsonism being treated with L-dopa was reduced by gut sterilization with neomycin. The p-de-hydroxylation step is thus brought about solely by the action of gut flora; the pathway is unlikely to be involved in the events within the brain leading to the therapeutic benefit effected by L-dopa.

Phenylethylamine in paranoid chronic schizophrenia.

Phenylethylamine (PEA) is an endogenous amine that is structurally and pharmacologically related to amphetamine. Urinary PEA excretion is significantly higher in paranoid chronic schizophrenics than in nonparanoid chronic schizophrenics and normal controls. Diet, hospitalization, and medication do not account for differences in PEA concentrations. These findings offer some indication that PEA may be an endogenous amphetamine.

Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.

Marked reduction in indexes of dopamine metabolism among patients with depression who attempt suicide.

Cerebrospinal fluid studies have reported that low concentrations of the dopamine metabolite homovanillic acid are associated with suicidal behavior in depression. Although only a small proportion of homovanillic acid in the urine derives from the brain, we decided to examine 24-hour urinary outputs of homovanillic acid in relation to suicidal behavior in depression. Patients with depression who had attempted suicide had significantly smaller urinary outputs of homovanillic acid, dihydroxyphenylacetic acid, and total body output of dopamine (sum dopamine) than did patients with depression who had not attempted suicide. Patients with depression who reattempted suicide during 5-year follow-up had significantly smaller urinary outputs of homovanillic acid and sum dopamine than did patients who did not reattempt suicide, patients who never attempted suicide, and normal control subjects, and had significantly smaller outputs of dihydroxyphenylacetic acid than patients who never attempted suicide or control subjects. These data suggest that urinary outputs of homovanillic acid may be peripheral correlates of suicidality in depression. These data add to data on the low levels of homovanillic acid in cerebrospinal fluid in suggesting that diminished dopaminergic neurotransmission may play a part in suicidal behavior in depression.

Effect of low-dose clorgyline on 24-hour urinary monoamine excretion in patients with rapidly cycling bipolar affective disorder.

Effects of clorgyline on urinary excretion of norepinephrine, dopamine, tyramine, and their major metabolites, 5-hydroxyindoleacetic acid and phenylethylamine, were studied in four women who suffered from primary, bipolar affective disorder. All patients had rapid mood cycles and were nonresponsive to lithium carbonate. During placebo administration, a strong correlation was found between the excretion rates of norepinephrine and dopamine and their respective metabolites. Clorgyline, 5 to 10 mg every or every other day, reduced overall-body norepinephrine turnover by 55% and increased tyramine but did not alter 5-hydroxyindoleacetic acid, phenylethylamine, or p-hydroxyphenylacetic acid excretion. These findings demonstrate the clinical actions of low-dose clorgyline and clorgyline's specificity as a monoamine oxidase A (MAO-A) inhibitor in vivo in humans, as well as the effects of specific MAO-A inhibition on monoamine metabolism.

High correlation of norepinephrine and its major metabolite excretion rates.

Twenty-four-hour urinary excretion rates of norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, and (vanillylmandelic) acid were repeatedly measured in 12 depressed patients. High (greater than. 83) positive correlations were found between the excretion rates of these four substances. Based on these findings, the conclusion was reached that in depressed patients the 24-hour urinary excretion rates of norepinephrine and any of its three major metabolites reflect total norepinephrine production in the body.

Effects of antidepressant treatments on dopamine turnover in depressed patients.

Effects of five antidepressant treatments--clorgyline, desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients, reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive treatment and zimelidine were without major effects, whereas desipramine had variable effects on these indexes of dopamine metabolism. Three patients, two receiving desipramine and one receiving clorgyline, who had increased HVA output during the drug treatments, became severely agitated and delusional.

Electroconvulsive treatment and lithium carbonate. Their effects on norepinephrine metabolism in patients with primary, major depressions.

Effects of electroconvulsive treatment (ECT) and lithium carbonate on norepinephrine metabolism were investigated in eight patients with primary, major depressions. A series of 12 ECTs reduced urinary norepinephrine and normetanephrine output significantly, and showed a tendency to reduce urinary vanillylmandelic acid output as well as whole-body norepinephrine turnover. Treatment with lithium carbonate significantly reduced urinary norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid output as well as whole-body norepinephrine turnover. These findings point to a common effect of antidepressant treatments since they are similar to results produced by administration of three other types of antidepressant drugs: clorgiline, a specific monoamine oxidase A inhibitor; desipramine, a relatively specific norepinephrine reuptake Inhibitor; and zimelidine, a relatively specific serotonin reuptake Inhibitor. These drugs reduce total production of norepinephrine and/or its major metabolites in depressed patients. Thus, five antidepressant treatments with different mechanisms of action have a common overall effect on the system.

Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression.

Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients.

High intercorrelations among urinary outputs of norepinephrine and its major metabolites. A replication in depressed patients and controls.

We examined the intercorrelations among urinary outputs of norepinephrine (NE) and its three major metabolites in unipolar depressed patients (n = 28) and normal controls (n = 24). Among the depressed patients, levels of NE correlated with normetanephrine (NM), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA), and VMA correlated with NM and MHPG. In the total group of depressed and control subjects (n = 52), the sum of NE and its major metabolites correlated with urinary outputs of NE, NM, MHPG, and VMA. These highly significant correlations among urinary outputs of NE and its major metabolites replicate a previous report of strong correlations among these same four urinary substances in a smaller group of depressed patients.

Alteration of norepinephrine metabolism with desipramine and zimelidine in depressed patients.

Twelve patients with a major affective disorder were treated during the depressed phase of their illness with desipramine hydrochloride and/or zimelidine hydrochloride, and urinary excretion rates of norepinephrine and its major metabolites were examined. During treatment with desipramine, daily urinary excretion of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid was reduced, but urinary normetanephrine excretion was not significantly changed. In all patients, the proportion of urinary norepinephrine metabolites represented by normetanephrine was increased during desipramine treatment. Independent of treatment outcome, desipramine seemed to decrease total formation and metabolism of norepinephrine, which was reflected in decreases in the excretion rate of the catecholamine and its metabolites. These results are consistent with known actions of desipramine on the disposition of norepinephrine and represent alterations in the rate of norepinephrine formation and metabolism, resulting from inhibition of norepinephrine reuptake. Zimelidine, a new antidepressant, which is a relatively specific serotonin-uptake inhibitor, significantly reduced only urinary MHPG excretion without appearing to alter "whole-body" norepinephrine turnover. This effect of zimelidine on norepinephrine metabolism was unexpected. Current and previous findings concerning clorgyline, a relatively specific monoamine oxidase A inhibitor, suggest that three pharmacologically distinct classes of antidepressants, norepinephrine and serotonin-reuptake and monoamine oxidase type A inhibitors, all reduce central norepinephrine turnover in depressed patients.

Preliminary evidence of reduced combined output of dopamine and its metabolites in chronic schizophrenia.

The mean combined total body excretion of dopamine (DA) and its metabolites, measured by summing the molar excretion of DA and its metabolites in 24-hour urine samples (Sum DA), was reduced in 20 patients with schizophrenia who had not been receiving medication for at least two weeks. These patients were relatively resistant to treatment, as they were unable to live independently outside institutional settings despite conventional neuroleptic therapy. In contrast, sum norepinephrine (Sum NE), measured by summing the molar excretion of NE and its metabolites, was not reduced. These results are highlighted by expressing the data in terms of the ratio of Sum DA/Sum NE. Patients with schizophrenia had a significantly lower ratio. Treatment with haloperidol normalized the low ratio. Urinary excretion of 5-hydroxyindoleacetic acid was normal in the schizophrenic patients. These results suggest that chronic schizophrenia is more likely to be associated with a low rather than a high state of DA activity.

Treatment of hyperactive children with monoamine oxidase inhibitors. II. Plasma and urinary monoamine findings after treatment.

Urinary monoamines and metabolites as well as plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol were measured in 14 boys (mean age, 9.2 years) with Attention Deficit Disorder With Hyperactivity during an initial placebo period, after four weeks of treatment with either dextroamphetamine sulfate (N=5) or a monoamine oxidase inhibitor (N=9) and at the end of a subsequent two-week placebo "washout" period. Both dextroamphetamine and monoamine oxidase inhibitors produced persistent changes in monoamines and metabolites, which were most marked and consistent for NE and its metabolite 3-methoxy-4-hydroxyphenylglycol. These changes did not correlate in a consistent fashion with clinical response during drug treatment. Moreover, there was rapid clinical relapse following cessation of either treatment while the alterations in NE metabolism remained during the two weeks following drug, further demonstrating the independence of these changes from clinical state. Future studies with dextroamphetamine need drug-free periods that are greater than 14 days to obtain true "baseline" conditions.

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.

Decreased DOPAC in the anterior cingulate cortex of individuals with schizophrenia.

The dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was found to be decreased in the anterior cingulate cortex of individuals with schizophrenia compared with normal controls. The finding does not appear to be solely related to the presence of antipsychotic medications, age, postmortem interval, or freezer time. No changes in norepinephrine and its metabolites were found.

Plasma phenylethylamine and phenylalanine in chronic schizophrenic patients.

The hypothesis that phenylethylamine (PEA) is an endogenous psychotogen in schizophrenics, particularly those with the paranoid subtype, has been previously studied by measuring PEA levels in urine and cerebrospinal fluid (CSF) of schizophrenic patients. However, plasma PEA may more accurately reflect simultaneous alterations of PEA in many organ systems, as might occur in a genetic disorder of PEA metabolism. No study to date has examined phenylalanine (Phe), which is thought to be a precursor of PEA, in the same patients who had PEA measured. In this study, we measure both plasma PEA and Phe in 17 drug-free schizophrenic patients and 17 matched controls. Plasma PEA in normal controls was found to be lower by three orders of magnitude compared to normal controls from previous studies--a finding that has not previously been reported. PEA was significantly lower in those schizophrenic patients who had a Research Diagnostic Criteria diagnosis of paranoid schizophrenia. PEA did not differ between patients and controls, and the correlation between plasma Phe and PEA was not significant.

Central catecholamines, cognitive impairment, and affective state in elderly schizophrenics and controls.

Central catecholamine concentrations were determined in autopsy samples from older schizophrenic and control subjects for both the hypothalamus and the nucleus accumbens. The results of these analyses and demographic variables were regressed on antemortem measures of cognitive function and mood state. In the hypothalamus, there are significant direct relationships of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) with depressed mood, as measured by an adaptation of the Hamilton Rating Scale for depression. In the nucleus accumbens, dopamine (DA) and MHPG had significant inverse relationships with antemortem cognitive function, as measured by an adaptation of the Mini Mental State Exam. Results in this sample indicate that after controlling for age, the catecholamine concentrations accounted for approximately 50% of the variance in the antemortem measures of mood or cognition, depending on the loci measured.

Suicidal behavior in depression: relationship to noradrenergic function.

We examined for relationships between suicidal behavior and noradrenergic function in depression. We compared depressed patients who had or had never attempted suicide and controls on cerebrospinal fluid, plasma, and urinary indices of noradrenergic function. There was no consistent pattern of significant findings in relationship to depressed patients who had attempted suicide. Thus, these essentially negative results suggest that the noradrenergic system is probably not a major determinant of suicidal behavior in depressed patients.

Phenylacetic acid excretion in schizophrenia and depression: the origins of PAA in man.

Urinary phenylacetic acid (PAA) excretion was found to be decreased in a group of chronic schizophrenic patients, particularly in a nonparanoid subtype. No significant change in PAA excretion was observed in a group of 21 unipolar depressed patients. Urinary PAA was studied following the administration of phenylethylamine, monoamine oxidase inhibitors, a dopa decarboxylase inhibitor, a low phenylalanine diet, and phenylalanine loads in several groups of psychiatric patients and normal volunteers. While Phenylethylamine ingestion increased urine PAA, inhibition of both phenylethylamine metabolism and synthesis failed to alter urine PAA. These studies suggest that urine PAA is primarily derived from phenylalanine transamination or pathways not involving monoamine oxidase or both. The observed decrease in PAA excretion in some schizophrenic patients may reflect an alteration in this pathway. The high phenylethylamine excretion previously reported in some chronic schizophrenic patients is not directly related to the observed low PAA excretion. Therefore measurement of urine PAA is not expected to be useful in assessing any phenylethylamine abnormalities in psychiatric disorders. The possible contribution of reduced phenylalanine transamination and its subsequent increased availability for the possible synthesis of phenylethylamine in schizophrenia is discussed.