Antidepressants reduce whole-body norepinephrine turnover while enhancing 6-hydroxymelatonin output

The effects of antidepressant treatment on noradrenergic function were studied in 27 patients with a major affective disorder. Twenty-four-hour urinary excretion of 6-hydroxymelatonin and "whole-body norepinephrine (NE) turnover," ie, 24-hour urinary output of NE and its major metabolites 3-methoxy-4-hydroxyphenylglycol, vanillylmandelic acid, and normetanephrine, were measured before and after treatment with the tricyclic desipramine hydrochloride, the aminoketone bupropion hydrochloride, the nonselective monoamine oxidase (MAO) inhibitor tranylcypromine sulfate, and the specific MAO type A inhibitor clorgiline. 6-Hydroxymelatonin excretion increased following antidepressant treatment, while at the same time whole-body NE turnover was reduced. These findings support the hypothesis that antidepressant therapy increases noradrenergic "efficiency," in that functional output, as measured by 6-hydroxymelatonin, is maintained while total NE production is decreased.     

Clinical studies on norepinephrine metabolism: how to interpret the numbers

Metabolism, synthesis rates, and pharmacokinetics of major metabolites of endogenous norepinephrine were investigated in 38 drug-free depressed patients receiving a low monoamine diet on a closed ward. In a group of 21 patients, plasma and cerebrospinal fluid (CSF) concentrations of 3-methoxy-4-hydroxyphenyl-glycol (MHPG) correlated positively, but not significantly. In two groups of eight patients each, effects of desipramine and zimelidine on the central production rate of MHPG were examined using CSF and urine data. Both desipramine and zimelidine significantly reduced the central production rate of MHPG.     

Enhanced norepinephrine output during long-term desipramine treatment: a possible role for the extraneuronal monoamine transporter (SLC22A3)

To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m. plasma samples were measured at baseline and after 1, 4, and 6 weeks of desipramine treatment. Desipramine treatment produced significant increases in urinary norepinephrine (NE) and normetanephrine (NMN) and plasma NE at Weeks 4 and 6, but not at Week 1. The ratio of urinary NE/NMN was increased at Weeks 4 and 6, suggesting a reduction in the metabolism of NE to NMN at extraneuronal sites by Weeks 4 and 6. The increases in urinary NE and NMN and plasma NE at Weeks 4 and 6 of desipramine treatment were associated with a reduction in the conversion of NE to NMN. This would be compatible with a blockade of the extraneuronal monoamine transporter (organic cation transporter 3; SLC22A3) by NMN. Inhibition of the extraneuronal monoamine transporter may be an important component in the clinical pharmacology of the norepinephrine reuptake inhibitor antidepressant drugs, such as desipramine.     

Selective antidepressants and cerebrospinal fluid. Lack of specificity on norepinephrine and serotonin metabolites

Cerebrospinal fluid concentrations of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid, were measured in depressed patients before and after treatment with three putatively specific antidepressants. The expected specificity of action on these three neurotransmitter metabolites was not observed. Desipramine hydrochloride, a norepinephrine uptake inhibitor, reduced 5-HIAA as well as MHPG concentrations; zimeldine hydrochloride, a serotonin uptake inhibitor, reduced MHPG as well as 5-HIAA concentrations; and clorgyline, a selective monoamine oxidase type A inhibitor, which might be predicted to most affect 5-HIAA, dramatically reduced MHPG, moderately reduced homovanillic acid, and only modestly reduced 5-HIAA concentrations.     

Reduction of norepinephrine turnover by serotonergic drug in man

Zimelidine (ZIM), a relatively specific serotonin reuptake inhibitor, was administered to 12 hospitalized healthy young male volunteers. Chronic but not acute ZIM caused a modest (23%) but significant elevation of plasma norepinephrine (NE) measured in the standing but not in the supine position. The 24-hr urinary excretion of NE itself was unchanged on chronic drug, whereas "whole-body" NE turnover was reduced by 1 week of ZIM, as evidenced by lowered excretion rates (both individually and summed with NE) of the metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NM), and vanillylmandelic acid. Lack of effect of ZIM on the NM/MHPG excretion ratio (which is increased by desipramine) indicated that ZIM and its major metabolite, horzimelidine (NZIM) are not acting by NE reuptake blockade. These data are consistent with modulating serotonergic influence on the noradrenergic system. Reduction of NE turnover and increasing the efficiency of the NE neurotransmission may be a common pathway of all clinically effective antidepressant treatments.     

Plasma levels of tumor necrosis factor-alpha in patients with panic disorder: effect of alprazolam therapy

Studies comparing urinary norepinephrine (NE) and its metabolites in unipolar or bipolar depressed patients and healthy volunteers have not yielded consistent findings. However, in unipolar depressed patients, most studies in non-elderly populations consistently report elevated concentrations of plasma NE, at least following an orthostatic challenge. Expanding upon previous studies which showed elevated plasma NE in depression, we compared the urinary excretion of NE, normetanephrine (NMN), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA) in age- and sex-matched unipolar and bipolar depressed patients versus healthy volunteers hospitalized at an inpatient unit at the National Institute of Mental Health. Only depressed subjects with a minimum 4-week drug-free period were included. Total turnover (NE + NMN + MHPG + VMA) was reduced in this sample of unipolar and bipolar depressed patients. MHPG concentration did not distinguish unipolar from bipolar depressed patients and was not significantly different from that in healthy volunteers. A construct of the average fractional extraneuronal concentration of NE (NE + NMN/NE + NMN + MHPG + VMA) was significantly higher in unipolar and bipolar depressed patients than in healthy volunteers. This finding extends data suggesting that unmedicated unipolar and bipolar depressed patients have a 'hyperresponsive' noradrenergic system and provides a framework which ties together plasma and urinary findings.     

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.     

Presynaptic adrenergic receptor sensitivity in depression. The effect of long-term desipramine treatment

Stimulation of presynaptic alpha 2-adrenergic receptors located on norepinephrine (NE)-containing cells in the brain decreases the firing rate and turnover of NE in these neurons. To assess whether abnormalities in the regulation of the NE system during desipramine hydrochloride treatment may be present in depressed patients, the effects of an alpha 2-agonist, clonidine hydrochloride, on plasma levels of the NE metabolite 3-methoxy-4-hydroxy/phenethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in ten depressed patients before and during long-term desipramine treatment. Long-term desipramine treatment significantly attenuated the effects of clonidine on plasma MHPG level and BP, indicating that during desipramine treatment alpha 2-adrenergic receptors had become subsensitive. In addition, plasma MHPG levels were significantly reduced during long-term desipramine treatment. These findings are discussed in relation to the hypothesized therapeutic mechanism of action of desipramine and the hypotheses relating noradrenergic function and depression.     

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.     

A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous depression. II. Biochemical findings

In a comparative evaluation of zimelidine, a potent serotonin (5-HT) uptake inhibitor, and desipramine, a potent noradrenaline (NA) uptake inhibitor, 65 hospitalized patients with endogenous depression were evaluated for the following biochemical variables: 5-HT uptake in platelets, 5-HT concentration in whole blood, inhibition of the 5-HT and NA accumulation in rat hypothalamic synaptosomes incubated in the patients' plasma, the excretion of 4-hydroxy-3-methoxyphenyl glycol (HMPG) in urine and the pretreatment levels of the amine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and HMPG in cerebrospinal fluid (CSF). results of the biochemical studies confirmed that zimelidine and desipramine have different profiles with respect to monoamine uptake. Thus zimelidine caused more marked inhibition of 5-HT uptake than desipramine, especially in rat brain synaptosomes incubated in the patient's plasma. Desipramine plasma was much more effective than zimelidine plasma in inhibiting NA uptake in the same preparation. The urinary excretion of HMPG decreased significantly during desipramine treatment but remained unchanged during zimelidine treatment. The combined clinical and biochemical results indicated that patients with low pretreatment levels of 5-HIAA and HVA in CSF responded significantly better to zimelidine than patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of HMPG in CSF tended to respond better to desipramine than those with low levels of this NA metabolite.     

Platelet MAO inhibition, urinary MHPG, and leukocyte beta-adrenergic receptors in depressed patients treated with phenelzine

The authors investigated three biochemical indices of peripheral catecholamine activity in 36 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Platelet MAO activity, urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), and leukocyte beta-adrenergic receptor functions were measured before and during the 4th week of phenelzine treatment. There were significant reductions in platelet MAO activity, urinary MHPG excretion, and depressive symptoms in all of the patients. Responders had the same decrease in MHPG as nonresponders. There were no changes in leukocyte beta-receptor function in a small subgroup of the patients.     

CSF and urinary biogenic amines and metabolites in depression and mania. A controlled, univariate analysis

Levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF, and norepinephrine (NE), epinephrine (E), vanillylmandelic acid, normetanephrine, metanephrine, and MHPG in the urine, were measured in 151 hospitalized patients with affective disorders and in 80 healthy controls following a two-week drug-free period. Unipolar and bipolar depressed subjects differed only in NE and E levels. Compared with controls, depressed subjects had higher CSF MHPG levels, women had higher 5-HIAA levels, and men had lower HVA levels. All urinary metabolites were elevated in depression and mania, with the exception of MHPG. The patterns of NE-E differences discriminated among the forms of affective disorders. These data suggest an imbalance of monoamine transmission in depression, characterized by the hyperactive sympathetic nervous system and adrenal medulla. However, MHPG may not be the measure of choice to reflect this imbalance, necessitating measurement of total body monoamine output.     

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.     

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.     

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.     

Metabolism of (-) deprenyl to amphetamine and methamphetamine may be responsible for deprenyl's therapeutic benefit: a biochemical assessment

The urinary excretion of some important phenylethylamines, catecholamines, their metabolites, amphetamine, and methamphetamine were measured in parkinsonian patients on Sinemet (L-dopa plus carbidopa, a peripheral dopadecarboxylase inhibitor) and depressed patients after chronic (-) deprenyl treatment. Deprenyl was efficiently metabolized to amphetamine and methamphetamine. It increased the excretion of phenylethylamine and of m- and p-tyramine, and reduced the output of norepinephrine metabolites, but failed to alter the excretion of dopamine-deaminated metabolites. These changes were attributed more to amphetamine and methamphetamine than to inhibition of monoamine oxidase type B. Sinemet treatment alone increased the excretion of dopamine, 3-methoxytyramine, and their respective deaminated metabolites, 3, 4-dihydroxyphenylacetic acid and homovanillic acid. It is concluded that conversion of deprenyl to amphetamine and methamphetamine may contribute to some of the therapeutic benefits of deprenyl.     

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.

Common mechanism of action of biochemically "specific" antidepressants

NE turnover in depressed patients treated with three drugs which have specifically different primary biochemical effects is compared before and after treatment. Turnover is quantitated as the sum of NE and its major metabolites excreted in the urine using a new mass spectrometric assay. Clorgyline , a MAOI specific for Type A; desipramine, a selective NE uptake inhibitor; and zimelidine, a selective 5HT uptake inhibitor, were used. All three antidepressants, including zimelidine, reduced NE turnover although producing very different effects on the metabolic profile of NE. It remains likely that effects on NE are related to therapeutic effect.     

Relative activity of metabolic pathways for norepinephrine in endogenous depression

Thirteen patients with endogenous depression, compared to 25 normal controls, had a significantly greater ratio of the urinary excretion of norepinephrine plus its metabolite normetanephrine to either the sum of the two urinary norepinephrine metabolites 3-methoxy-4-hydroxyphenylglycol plus vanillylmandelic acid or to the sum of urinary norepinephrine and all of its metabolites. As urinary levels of norepinephrine and normetanephrine are derived from an extraneuronal metabolic pathway, while levels of 3-methoxy-4-hydroxyphenylglycol and vanillylmandelic acid are more representative of total norepinephrine metabolism, these results suggest that there is a shift in endogenous depression to extraneuronal metabolic pathways for norepinephrine and its metabolites.     

Urinary excretion of metabolites of norepinephrine in Tourette’s syndrome

Urinary excretion of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NME) was measured in Tourette’s Syndrome (TS) patients and in control subjects matched for age and education. The 24-h excretion (expressed per gram of creatinine) of total MHPG and of free and total (free + conjugated) NME was significantly lower in TS patients than in the normal subjects.