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)

We have examined the effects of two monoamine oxidase (MAO) inhibitors with different mechanisms of action--phenelzine and brofaromine--on peripheral serotonergic (5-hydroxytryptamine [5-HT]) measures, sensitive to the inhibition of MAO-A (intra- and extracellular 5-HT and related metabolites in blood). Both drugs increased the concentration of 5-HT in platelet-free plasma (254%, p less than 0.001) in patients with depressive illness (DSM-III-R) after 6 weeks of daily treatment. Platelet 5-HT was also increased significantly in both drug treatment groups but more marked in the patient group treated with phenelzine. The acid/amine ratio at 6 weeks was 30% of pretreatment values (p less than 0.000) and individual variability correlated significantly with the Hamilton Rating Scale for Depression. Plasma 5-HT increased more markedly in responders than in nonresponders and a significant inverse relationship surfaced between plasma 5-HT and the Hamilton Rating Scale for Depression. The results support other reports of comparable antidepressant efficacy for brofaromine and phenelzine, both inhibitors of MAO-A in humans. The consistent relationship we found between the biochemical and clinical changes again suggests and supports a key role of 5-HT in the antidepressant effect of these MAO inhibitors.
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PMID:Monoamine oxidase inhibitors phenelzine and brofaromine increase plasma serotonin and decrease 5-hydroxyindoleacetic acid in patients with major depression: relationship to clinical improvement. 128 22

Whilst tricyclic antidepressants are efficacious in all depressive syndromes, classical MAO-inhibitors differ substantially from them in their action. They are considered less effective in general and not very effective in endogenous depression, but recommended for the treatment of 'atypical' depression. A new class of RIMA (Reversible Inhibitors of MAO-A) represented by moclobemide requires a change in clinical thinking on antidepressants. Moclobemide shows the same efficacy in depression as tricyclics: its effects are similar in unipolar and bipolar affective disorders, and in patients with major depressive episode superimposed on dysthymia (double depression). As with classical antidepressants, the response rate tends to be lower, but is still present in psychotic depression. Agitated depressives do not respond less well than non-agitated patients to moclobemide. Patients meeting DSM-III-R criteria for major depression with melancholia tend to respond better than non-melancholics, but this may be associated with the significantly higher baseline severity observed in melancholics. A slightly higher response rate in patients without concomitant benzodiazepine treatment, compared to those with benzodiazepine comedication, may also be related to baseline differences in the severity of depression. Elderly depressives respond less well than younger patients to classical antidepressants, but with moclobemide, elderly patients do as well as younger ones.
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PMID:Efficacy of moclobemide in different patient groups: a meta-analysis of studies. 134 58

Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression--characterized by pathological hyperarousal and atypical depression--associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after prolonged administration. In situ hybridization histochemistry was used to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of 3 different classes of activating antidepressant drugs which tend to be preferentially effective in treating atypical depressions, on the expression of central nervous system genes thought to be dysregulated in major depression. Daily administration (5 mg/kg, i.p.) of the selective 5-hydroxytryptophan (5-HT) reuptake inhibitor fluoxetine, the selective alpha 2-adrenergic receptor antagonist idazoxan, and the nonspecific monoamine oxidase A and B inhibitor phenelzine increased tyrosine hydroxylase mRNA levels by 70-150% in the locus coeruleus after 2 weeks of drug and by 71-115% after 8 weeks. The 3 drugs decreased corticotropin-releasing hormone mRNA levels by 30-48% in the paraventricular nucleus of the hypothalamus. The decreases occurred at 8 weeks but not at 2 weeks. No consistent change in steroid hormone receptor mRNA levels was seen in the hippocampus with the 3 drugs, but fluoxetine and idazoxan increased the level of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA, respectively, after 8 weeks of drug administration. Proopiomelanocortin (POMC) mRNA levels in the anterior pituitary and plasma adrenocorticotropic-hormone (ACTH) levels were not altered after 2 or 8 weeks of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. 135 83

Depression is common in patients with senile dementia of the Alzheimer type (SDAT) and may precede the onset of the dementia; the underlying biological and neurotransmitter mechanisms may be common to both diseases, so far as norepinephrine lesions are concerned. The major routes of metabolism of amines in the brain utilize the monoamine oxidase (MAO) enzymes. Due to the consistent severity of norepinephrine lesions in the locus coeruleus of patients with pre-senile dementia or SDAT and the fact that MAO-A enzyme is the major metabolizing enzyme present in the locus coeruleus in man, the new specific, reversible MAO-A inhibitors may have a place in the treatment of depression associated with SDAT.
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PMID:Depression and senile dementia of the Alzheimer type: a role for moclobemide. 154 30

A review of the clinical efficacy of four structurally distinct antidepressant drugs is presented. Their antidepressant activity can be rationalised within current pharmacological hypotheses of drug action, despite markedly different effects on "in vitro" testing. Fluoxetine, a specific serotonin re-uptake inhibitor, has proven safe, effective treatment for depressive illness and may have a role to play in the treatment of obsessive-compulsive disorder and panic attacks. While it has few of the anticholinergic side effects of the tricyclic antidepressants, nausea, tremor, headache, weight loss, nervousness and sweating are side effects most frequently reported. Minaprine, a compound with weak MAO inhibiting properties and effects on serotonergic receptors, has clinical efficacy in the treatment of depression based on several comparative studies. It is claimed that minaprine lacks anticholinergic and sedative properties. Moclobemide, a specific, reversible inhibitor of MAO-A, has been extensively evaluated in depressive illness. The major advantage of this agent over other irreversible, non-specific MAO inhibitors, is the significant attenuation of the so-called "cheese effect" with doses of tyramine likely to be encountered in foodstuffs. Rolipram, a phosphodiesterase inhibitor, represents a new approach to antidepressant treatment. Limited clinical data suggest that the drug may be an effective antidepressant with few side effects. The place of these agents in therapy is yet to be established.
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PMID:New pharmacological approaches to the management of depression: from theory to clinical practice. 158 Aug 88

Irreversible and unspecific inhibitors of MAO were the first modern antidepressants, but after an initial success they fell into discredit due to adverse side effects. In the past two decades interest in MAO inhibitors has been renewed because of progress in basic research, a milestone being the finding that there are two subtypes of MAO, MAO-A and MAO-B. These are distinct proteins with high amino acid homology, coded by separate genes both located on the short arm of the human chromosome X. The enzyme subforms show different substrate specificities in vitro and different distributions within the central nervous system and in peripheral organs. In the central nervous system of man MAO-A seems to be mainly involved in the metabolism of 5 HT and noradrenaline, whereas 2-phenylethylamine and probably dopamine are predominantly deaminated by MAO-B. In the intestinal tract tyramine is mainly metabolized by MAO-A. These characteristics indicate distinct physiological functions of the two MAO-subforms. Several irreversible and reversible non-hydrazine inhibitors with relative selectivities for one of the MAO-subforms have been developed. They belong to various chemical classes with different modes of enzyme inhibition. These range from covalent mechanism based interaction (e.g. by propargyl- and allylamine derivatives) to pseudosubstrate inhibition (e.g. by 2-aminoethyl-carboxamides) and non-covalent interaction (e.g. by brofaromine, toloxatone and possibly moclobemide). The most important pharmacological effects of the new types of MAO inhibitors are those observed in neuropsychiatric disorders. The inhibitors of MAO-A show a favorable action in various forms of mental depression. The drugs seem to have about the same activity as other types of antidepressants, including tricyclic and related compounds as well as classical MAO inhibitors. The onset of action of the MAO-A inhibitors is claimed to be relatively fast. Other possible indications of these drugs include disorders with cognitive impairment, e.g. dementia of the Alzheimer type. In subjects with Parkinson's disease the MAO-B inhibitor L-deprenyl exerts a L-dopa-sparing effect, prolongs L-dopa action and seems to have a favorable influence regarding on-off disabilities. The action is in general transitory (months to several years). In addition L-deprenyl has been shown to delay the necessity for L-dopa treatment in patients with early parkinsonism. Whether the drug influence the progression of the disease is still a matter of debate. L-deprenyl also appears to have some antidepressant effect (especially in higher doses) and to exert a beneficial influence in other disorders, e.g. dementia of the Alzheimer type.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The new generation of monoamine oxidase inhibitors. 160 14

The centrally active cholinesterase inhibitor physostigmine induces a behavioral syndrome which is thought to represent a model of spontaneous depression. In the present acute trial in 6 healthy volunteers, this model depression was accompanied by clearcut cardiovascular, metabolic and neuroendocrine phenomena of stress. The extent of the changes from baseline, however, scarcely correlated between the behavioral and physiologic phenomena. The behavioral and physiological phenomena could not be antagonized by brofaromine, a putative antidepressant reversibly and selectively inhibiting monoamine oxidase A (MAO-A), contrasting to the complete inhibition by the central cholinolytic scopolamine. This is further evidence that antidepressant efficacy depends on long-term adaptive changes secondary to the enhancement of aminergic neurotransmission rather than this enhancement itself.
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PMID:Adrenergic-cholinergic imbalances: the physostigmine-syndrome is not antagonized by the MAO-A inhibitor brofaromine. 196 18

N = 53 inpatients with major depressive disorder have been treated with the reversible, selective MAO-A-inhibitors moclobemide (double-blind versus maprotiline) and brofaromine (open study), respectively. Clinically, significant improvement of depression and an activating profile of action could be observed, typical side effects were sleep disturbances, agitation and weight loss. The neurobiochemical data showed an increase of noradrenaline plasma concentrations under treatment with moclobemide. Visual reaction times improved with antidepressant treatment. MAO-A inhibitors proved to be effective antidepressants in the treatment of hospitalized patients with predominantly endogenous depressions.
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PMID:Clinical, biochemical and psychometric findings with the new MAO-A-inhibitors moclobemide and brofaromine in patients with major depressive disorder. 208 89

2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol, hydrochloride (JO 1017) is a novel antidepressant drug. Its biochemical and pharmacological properties were investigated in mice, rats, dogs, rabbits and guinea pigs. In vitro, it selectively inhibited serotonin uptake and had a high affinity for the 3H-paroxetine and 3H-imipramine binding sites. Biochemical studies demonstrated the lack of MAO-A and MAO-B inhibition and the absence of marked affinity for muscarinic, histaminic or other conventional brain receptors. Chronic treatment with JO 1017 induced a decrease in the Bmax values for imipramine sites but did not modify the Bmax for beta-adrenergic and 5-HT2 receptors. The neuropsychopharmacological profile of JO 1017 is characterized by a decrease of the immobility times in behavioural despair tests with mice, a decrease of the escape failures in the rat learned helplessness test, a strong potentiation of L-5-HT P-induced head-twitches in mice and an antagonism of reserpine-induced ptosis in rabbits. It weakly antagonized oxotremorine-induced hypothermia and did not influence the hypothermia induced by apomorphine. In contrast to most other antidepressants, a high dose of JO 1017 induced hypermotility in mice placed in an activity meter without producing stereotyped behaviour and group toxicity. Unlike tricyclic antidepressants, JO 1017 was devoid of severe cardiotoxicity in guinea pigs and had no central anticholinergic nor antihistaminic properties. These results suggest that JO 1017 is a selective serotonin uptake inhibitor with a high safety margin. JO 1017 may have a potential clinical utility both in the treatment of depression and for indications where serotonin transmission is involved, e.g., anxiety, panic attack, obsessive compulsive disorder, obesity and alcohol consumption.
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PMID:Biochemical and pharmacological evaluation of the novel antidepressant and serotonin uptake inhibitor 2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol hydrochloride. 216 3

The design and the main therapeutic results of 3 controlled double-blind studies comparing moclobemide with tricyclics and/or placebo in depressed patients are presented. Moclobemide, a reversible inhibitor of monoamine oxidase (RIMA), preferentially inhibits MAO-A. It showed good efficacy in major depression (DSM-III), both endogenous and non-endogenous. The 3 studies included a total of 763 patients. The therapeutic results are similar to those observed with tricyclics (2/3 good responders). Tolerability was significantly better. The onset of action was evaluated in 2 studies and was faster in the patients treated with moclobemide. The fact that reversible inhibitors of MAO-A demonstrate good efficacy independently of the diagnostic category of depression is an important new finding.
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PMID:Efficacy of reversible inhibitors of monoamine oxidase-A in various forms of depression. 224 63


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