UMLS:C0011570 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vivo evaluation of MAO-A would be of great value for the diagnosis and follow-up of therapy of depression. In order to perform this exploration by SPECT, we developed an iodinated derivative of the reversible MAO-A inhibitor, moclobemide. Ro 11-9900 was synthesized and analysed by IR, NMR and HPLC. Radioiodination was carried out by nucleophilic exchange of [125I] on the brominated precursor, and yielded [125I]-Ro 11-9900 with high specific activity. In vitro experiments on rat brain homogenates showed that Ro 11-9900 had poor inhibitory activity on MAO-A, as already described for moclobemide. By contrast, in vivo biodistribution in the rat brain showed that [125I]-Ro 11-990 accumulated in a region corresponding to the localization of locus coeruleus known for its high density of MAO-A. Moreover, preinjection of the irreversible MAO-A inhibitor clorgyline (10 mg.kg-1) prevented accumulation of radioactivity by 40 to 60% and we found that the radioactivity in the brain corresponded exclusively to [125I]-Ro 11-9900 and not to a metabolite. [125I]-Ro 11-9900 was highly accumulated in the pineal gland, both on MAO-A and on MAO-B sites. We concluded that the unmetabolized iodinated derivative of moclobemide, Ro 11-9900, preferentially labeled MAO-A in vivo in the rat brain. This compound would therefore be a potential tracer for evaluation of MAO-A by SPECT.
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PMID:An iodinated derivative of moclobemide as potential radioligand for brain MAO-A exploration. 861 67

After initial enthusiasm, the use of monoamine oxidase inhibitors (MAOIs) has been limited by the wide range of MAOI-drug and MAOI-food interactions that are possible, particularly with sympathomimetic medications or tyramine-containing foods, resulting in hypertensive reactions. Despite their clinical benefits, this has led to a reduction in use of such medications. Discovery of the 2 main subgroups of monoamine oxidase, types A and B, led to the synthesis of MAOIs selective for one or other of these isoenzymes. Consequently, selegiline (deprenyl), a selective MAO-B inhibitor, was developed for the treatment of idiopathic Parkinson's disease. This drug is useful in the treatment of the early stages of the disease and later on as an adjunct to other drug therapies. Although the selective MAO-A inhibitor, clorgiline (clorgyline), was found to be effective in the treatment of depression, it still retained the potential to cause hypertensive reactions. Recently, agents that are not only selective, but reversible in their inhibition of MAO-A (RIMAs) have been synthesised (e.g. moclobemide and toloxatone), and have proven antidepressant efficacy. Whilst they are less likely to induce hypertensive reactions with the concomitant administration of sympathomimetic drugs or with tyramine-rich foodstuffs, it still seems wise to advocate care in co-prescribing potentially interacting medications and to advise a degree of caution with regard to the dietary intake of foodstuffs likely to contain a high tyramine content. Although these newer drugs represent an advance in safety, their use has, as yet, only been established in the treatment of depression. RIMAs also retain a potential for adverse interaction with other drugs. Concomitant prescription of serotonin-enhancing drugs should only be undertaken with caution for patients on moclobemide, toloxatone or selegiline. Coprescription of sympathomimetic drugs should also be avoided with these newer MAOIs and patients should be advised against purchasing over-the-counter preparations that may contain sympathomimetic drugs.
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PMID:Monoamine oxidase inhibitors. An update on drug interactions. 871 90

The literature on alpha 2-adrenoceptors in depression is replete with seemingly contradictory findings, including reports of both hypersensitive and hyposensitive alterations. Now, with the discovery of nonadrenergic imidazoline receptors (I receptors) and an endogenous I receptor ligand (agmatine), new light is being shed on this controversy. Specifically, those studies that had utilized allegedly "alpha 2-selective" imidazoline radioligands, i.e., 3H-clonidine, could be reinterpreted in terms of increased I receptors in depression. Although the molecular identity of the I1 binding site remains unknown, an I2 receptive site has been reported to be encoded by monoamine oxidase genes (both MAO-A and MAO-B), suggesting a novel explanation for the antidepressant efficacy of idazoxan, a prototypic I2 ligand. Platelet I1 binding sites are also reported to be elevated in patients with unipolar depression and are lowered by antidepressant treatments. Furthermore, clonidine challenge and animal studies of the behavioral effects of imidazolines may be reinterpreted to support a role for I1 sites in the central control of behavior. A hypothesis for depletion of brain clonidine-displacing substance (CDS) in depression is presented. Lowered concentrations of CDS could account for an elevation of I receptors, via compensatory upregulation. Our model offers an explanation for a number of previously discrepant observations as well as testable hypotheses for the study of imidazoline receptors in depression.
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PMID:Psychopharmacology of imidazoline and alpha 2-adrenergic receptors: implications for depression. 882 3

Unlike older monoamine oxidase inhibitors, which irreversibly and nonselectively bind monoamine oxidase (MAO), moclobemide is a reversible and selective inhibitor of the MAO-A isozyme. Moclobemide only weakly potentiates the pressor response induced by tyramine or other indirectly acting sympathomimetics; therefore, there is no need to avoid dietary tyramine or over-the-counter decongestants with moclobemide as there is with older MAO inhibitors. Recent clinical trials and meta-analyses have confirmed the efficacy of moclobemide in the treatment of depressive disorders. Moclobemide has been shown to have similar efficacy to tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and nonselective, irreversible MAO inhibitors. Long term follow-up studies of 6 to 12 months' duration have demonstrated that the antidepressant efficacy of moclobemide is maintained. Moclobemide, given alone or in combination with another antidepressant, has shown some efficacy in patients with refractory depression; however, comparative trials are required to confirm these findings. Data are also available to show clinical efficacy of moclobemide in the management of social phobia. Comparative studies have established that moclobemide is better tolerated at therapeutic dosages and has less toxicity in overdose than TCAs and nonselective, irreversible MAO inhibitors. Moclobemide lacks the anticholinergic, sedative and cardiovascular effects associated with many of the older antidepressants. Compared with SSRIs, moclobemide has a similar overall tolerability, although it tends to cause fewer gastrointestinal effects than the SSRIs and has not been reported to interfere with sexual function. In summary, recent data which confirm and extend its comparative therapeutic efficacy and low potential for adverse effects have established moclobemide as an effective treatment in depressive disorders. The drug is also effective in patients with a primary diagnosis of social phobia. Its lack of adverse anticholinergic, cardiovascular, cognitive and psychomotor effects makes moclobemide a particularly useful option in the elderly or patients with cardiac disease.
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PMID:Moclobemide. An update of its pharmacological properties and therapeutic use. 887 33

Social phobia is a common disorder which is associated with considerable suffering and impairment. Effective treatments have now been developed and they represent an important advance in the management of the disorder. Moclobemide is a reversible inhibitor of monoamine oxidase A (RIMA) which has an established place in the treatment of depression. The efficacy of moclobemide in social phobia has been demonstrated in short-term treatment for up to 12 weeks in three placebo-controlled studies. It has also proved to be effective in long-term treatment in a placebo-controlled study and in open treatment studies. This paper reviews the efficacy of moclobemide in social phobia.
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PMID:Moclobemide in the treatment of social phobia. 892 14

It is generally accepted that the clinical efficacy of monoamine oxidase inhibitors (MAOI) is related to inhibition of this enzyme. In order to evaluate the predictive ability of monoamine oxidase-A inhibition for therapeutic efficacy, the start of treatment effects of moclobemide, a selective, reversible monoamine oxidase-A inhibitor, on plasma concentrations of monoamines and monoamine metabolites were determined. The plasma levels of 3,4-dihydroxyphenylglycol (DHPG, deaminated metabolite of noradrenaline), 5-hydroxyindoleacetic acid (5-HIAA, deaminated metabolite of serotonin), 3,4-dihydroxyphenylacetic acid and homovanillic acid (DOPAC and HVA, deaminated metabolites of dopamine), L-dihydroxyphenylalanine (L-dopa) and noradrenaline were investigated and related to treatment outcome. This was a randomized double blind parallel group study in 47 patients with criteria of major depression according to DSM III R. Moclobemide 300 mg/day, 450 mg/day or 600 mg/day was administered continuously for 6 weeks. Plasma concentrations of monoamine metabolites and monoamines were determined just before treatment by moclobemide, 4 h after the first dose, 24 h after the first dose, before the first dose on day 7, and 4 h after the first dose, on day 7. Each moclobemide dose improved depression as measured by MADRS (Montgomery-Asberg Depression Rating scale) but there was no difference between the three doses. Moclobemide dose-dependently reduced plasma concentration of DHPG, L-dopa and HVA. No dose-dependent treatment effect was observed for plasma 5-HIAA, noradrenaline and DOPAC. The clinical outcome as defined by the final MADRS score was not related to any start of treatment changes in plasma monoamine metabolites reflecting inhibition of MAO-A. It is concluded that monoamine oxidase-A inhibition at the beginning of the treatment does not predict clinical outcome.
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PMID:Initial monoamine oxidase-A inhibition by moclobemide does not predict the therapeutic response in patients with major depression. A double blind, randomized study. 892 74

The efficacy and safety of pirlindole (300 mg/day), a new reversible inhibitor of monoamine oxidase A, have been evaluated in a multicentre placebo-controlled double-blind randomized trial in 103 in-patients suffering from unipolar major depression (DSM-III-R 296.2, 296.3) over a 42-day period after a run-in placebo period of 6 days. Pirlindole produced a significantly greater decrease than placebo in the Hamilton depression score (from day 28), the Hamilton anxiety score (from day 28) and the Montgomery-Asberg depression score (on day 42). On day 42, the Hamilton depression score was < or = 7, > or = 8 and < or = 15, or > or = 16 in 21%, 45% and 34%, respectively, in the placebo group compared to 72%, 24% and 3.4%, respectively, in the pirlindole group (P < 0.001). The differences between the two groups in terms of tolerance and safety were not statistically significant.
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PMID:A double-blind randomized placebo-controlled study of the efficacy and safety of pirlindole, a reversible monoamine oxidase A inhibitor, in the treatment of depression. 902 Sep 90

The efficacy and tolerability of the selective reversible monoamine oxidase A inhibitor, moclobemide (300 mg/day) and the selective serotonin uptake inhibitor, fluoxetine (200 mg/day), were compared in a six-week single-centre double-blind fixed-dose study in patients (n = 42) with double depression (DSM-III-R: dysthymia with superimposed major depressive episode) using weekly assessment on the Hamilton depression rating scale (HDRS-17 items) and clinical global impression (CGI) scale. The primary efficacy outcome measure was a decrease > or = 50% in end of treatment HDRS score, secondary measures were the mean total endpoint HDRS scores and percentages of CGI very good and good responses. Tolerability was measured by the frequency and severity of volunteered adverse events. There were no significant differences in secondary efficacy outcome measures, but more patients achieved a > or = 50% decrease in HDRS score on moclobemide (71% vs 38%, p < 0.05). The only adverse event was mild transient anxiety (n = 1) with moclobemide. The results suggest that moclobemide and fluoxetine are equally well tolerated and at least similar in efficacy in double depression. Evidence that moclobemide may be more effective requires confirmation in a larger comparative study incorporating a placebo control group.
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PMID:Moclobemide versus fluoxetine for double depression: a randomized double-blind study. 902 88

Monoamine oxidases are key enzymes in the metabolism of amine neurotransmitters and neuromodulators and are targets for drug therapy in depression, Parkinson's and Alzheimer's diseases. Knowledge of their distribution in the brain is essential to understand their physiological role. To study the regional distribution and abundance of monoamine oxidases A and B in human brain, pituitary and superior cervical ganglion, we used quantitative enzyme radioautography with radioligands [3H]Ro41-1049 and [3H]lazabemide, respectively. Furthermore, 35S-labelled oligonucleotides complementary to isoenzyme messengerRNAs were used to map the cellular location of the respective transcripts in adjacent sections by in situ hybridization histochemistry. A markedly different pattern of distribution of the isoenzymes was observed. Highest levels of monoamine oxidase A were measured in the superior cervical ganglion, locus coeruleus, interpeduncular nucleus and ventromedial hypothalamic nucleus. The corresponding messengerRNA was detected only in the noradrenergic neurons of the superior cervical ganglion and locus coeruleus. In contrast to rat brain, monoamine oxidase B was much more abundant in most human brain regions investigated. Highest levels were measured in the ependyma of ventricles, stria terminalis and in individual hypothalamic neurons. Monoamine oxidase B transcripts were detected in serotoninergic raphe neurons, histaminergic hypothalamic neurons and in dentate gyrus granule cells of the hippocampal formation. We conclude that [3H]Ro41-1049 and [3H]azabemide are extremely useful radioligands for high-resolution analyses of the abundance and distribution of catalytic sites of monoamine oxidases A and B, respectively, in human brain sections. From levels of messenger RNA detected, the cellular sites of synthesis of the isoenzymes are the noradrenergic neurons of the locus coeruleus (for monoamine oxidase A) and the serotoninergic and histaminergic neurons of the raphe and posterior hypothalamus, respectively (for monoamine oxidase B). The combination of quantitative enzyme radioautography with in situ hybridization histochemistry is a useful approach to study, with high resolution, both the physiology and pathophysiology of monoamine oxidases in human brain.
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PMID:Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry. 904 87

Altered biogenic amine metabolism and function are believed to underlie certain of the neuropsychiatric symptoms, e.g., depression, mania, and anxiety, encountered in clinical hepatic encephalopathy (HE). We therefore investigated the activity of the degradative enzyme monoamine oxidase (MAO) and its binding parameters using [3H]Ro 41-1049 (defining MAO-A) and [3H]Ro 19-6327 (Lazabemide; defining MAO-B) in autopsied brain tissue from male cirrhotic patients with HE. The MAO-B parameters in HE patient tissue were not significantly different from those determined for control tissue. In contrast, increases in MAO-A activities in HE patient frontocortical (by approximately 50%) and cerebellar (by approximately 145%) tissues were observed, confirming our previous findings using comparable tissues. Increases in the abundance of the active MAO-A protein were of the same order of magnitude, e.g., in frontal cortex by approximately 85% and in cerebellum by approximately 225%. Reverse transcriptase-polymerase chain reaction indicated an increase in the level of gene expression (by approximately 155%) and thus offers some of the first evidence of a transcriptional event potentially mediating MAO-A function in human brain tissue. The levels of biogenic amine acid metabolites were increased as expected. As HE patients are most often treated for their hepatic symptoms rather than their neuropsychiatric manifestations, they represent an important "untreated" psychiatric population. The present findings are therefore not only important for our understanding of the pathophysiology of HE but also extremely relevant to our understanding of the pharmacotherapy of other neuropsychiatric disorders in which biogenic amine and MAO-A dysfunction is indicated.
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PMID:Increased density of catalytic sites and expression of brain monoamine oxidase A in humans with hepatic encephalopathy. 904 67

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