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)

Monoamine oxidase(MAO) inhibitors had been used in the treatment of depression since 1950s, but there is no MAO inhibitor available clinically in Japan. Liver dysfunction and tyramine's effect are main problems with MAO inhibitors. Reversible inhibitors of MAO-A(RIMA), new and improved MAO inhibitors, were developed and are widely used in Europe. RIMA causes less tyramine's effect and less liver dysfunction than classical MAO inhibitors do. Moclobemide, a RIMA, is under development in Japan(Phase II). An introduction of RIMA in Japan will be useful for the treatment of refractory depression and other anxiety disorders. We discussed pharmacological properties, clinical efficacy and safety of RIMA.
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PMID:[Reversible inhibitor of MAO-A(RIMA)]. 1151 53

Disturbances of the serotonergic pathway have been implicated in many psychiatric disorders, including alcoholism, aggression, schizophrenia and depression. The personality dimension of harm avoidance is correlated positively with the activity of mesolimbic serotonergic neurons. The goal of this study was to determine the role of the genes in this pathway in the development of type II alcoholism. A sample of alcoholics and normal controls were screened with the variations in tryptophan hydroxylase (TPH), serotonin receptors (5-HT2A and 5-HT2C), serotonin transporter (5-HTT), and monoamine oxidase A (MAO-A) genes. The results of association studies for type II alcoholics were the most significant with 5-HTT (P = 0.011) and MAO-A (P = 0.029) genes. However, after correction for multiple comparisons, none of the results reached the significance level. These data indicate that the genes in the serotonergic pathway may be involved in the development of type II alcoholism but the gene effects are very small.
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PMID:Serotonergic pathway genes and subtypes of alcoholism: association studies. 1152 23

The disruptive effect of excessive serotonin (5-HT) levels on the development of cortical sensory maps is mediated by 5-HT1B receptors, as shown in barrelless monoamine oxidase A knock-out mice, in which the additional inactivation of 5-HT1B receptors restores the barrels. However, it is unclear whether 5-HT1B receptors mediate their effect on barrel formation by a trophic action or an activity-dependent effect. To test for a possible effect of 5-HT1B receptors on activity, we studied the influence of 5-HT on the thalamocortical (TC) synaptic transmission in layer IV cortical neurons. In TC slices of postnatal day 5 (P5)-P9 neonate mice, we show that 5-HT reduces monosynaptic TC EPSCs evoked by low-frequency internal capsule stimulation and relieves the short-term depression of the EPSC evoked by high-frequency stimulation. We provide evidence that 5-HT decreases the presynaptic release of glutamate: 5-HT reduces similarly the AMPA-kainate and NMDA components and the paired pulse depression of TC EPSCs. We show also that 5-HT1B receptors mediate exclusively the effect of 5-HT: first, the effect of 5-HT on the TC EPSC is correlated with the transient expression of 5-HT1B receptor mRNAs in the ventrobasal thalamic nucleus during postnatal development; second, it is mimicked by a 5-HT1B agonist; third, 5-HT has no effect in 5-HT1B receptor knock-out mice. Our results show that in the developing barrel field of the neonatal mice, 5-HT1B receptors mediate an activity-dependent regulation of the TC EPSC that could favor the propagation of high-frequency TC activity.
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PMID:Activity-dependent presynaptic effect of serotonin 1B receptors on the somatosensory thalamocortical transmission in neonatal mice. 1182 18

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.
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PMID:Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study. 1200 77

The aim of the present study was to test a possible effect of the monoamine oxidase A (MAOA) and serotonin receptor 2A (5-HT-2A) gene variants on the antidepressant activity of fluvoxamine and paroxetine in a sample of major (n = 248) and bipolar (n = 195) depressives, with or without psychotic features. A total of 443 in-patients were treated with 300 mg fluvoxamine (n = 307) or 20-40 mg paroxetine (n = 136) for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). Allele variants were determined in each subject using a PCR-based technique. We observed a marginal association between 5-HT-2A variants and antidepressant response while MAOA genotypes were not associated. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, HAMD scores at baseline, pindolol augmentation and SSRIs plasma levels did not significantly influence the observed results. The investigated MAOA and 5-HT-2A gene variants, therefore, do not seem to play a major role in SSRI antidepressant activity.
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PMID:Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. 1205 29

Abnormalities in brain monoamine oxidase A activity have been implicated in the pathogenesis of depressive illness and suicidal behavior. The present investigation was to determine whether there is an association between MAO-A gene polymorphism and depressed suicide. The EcoRV polymorphism in MAO-A gene with alleles associated with enzyme activity was studied in postmortem brain samples from 44 depressed suicide victims and 92 control subjects of the same ethnic background. We have found significant differences in genotype/allele distribution between depressed suicide victims and controls in males (p = 0.012) but not in females or the total sample. The odds ratio (OR) for the high activity-related allele of the MAO-A gene associated with depressed suicide in males was 3.1. Our finding suggests that MAO-A may be a susceptibility gene in depressed male suicide victims. The results thus provide further evidence that genetic factors can modulate risk for depression, suicide or both by influencing monoaminergic activity in sexually dimorphic manner.
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PMID:High activity-related allele of MAO-A gene associated with depressed suicide in males. 1215 68

There is some evidence that major depression is accompanied by activation of the inflammatory-response system (IRS). It has been hypothesized that increased production of proinflammatory cytokines may play a role in the etiology of major depression. If increased production of proinflammatory cytokines is at all involved in the etiology of depression, one would expect antidepressive treatments to have negative immunoregulatory effects. This paper reviews the effects of antidepressants, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), heterocyclic antidepressants (HCAs), serotonin-noradrenaline reuptake inhibitors (SNRIs), lithium, l-5-hydroxytroptophan (L-5-HTP), reversible inhibitors of MAO-A (RIMA) on the production of proinflammatory cytokines, e.g. interferon-gamma (IFNgamma), and negative immunoregulatory cytokines and agents, e.g. interleukin-10 (IL-10). In depressed patients, prolonged treatment with antidepressants and mood stabilizers normalizes signs of activation of the IRS, such as increased serum IL-6 and acute phase protein concentrations. In vitro, it has been shown that various types of antidepressive drugs, including TCAs (imipramine; clomipramine); SSRIs (citalopram, fluoxetine, sertraline); lithium; SNRIs (venlafaxine); HCAs (trazodone); RIMAs (moclobemide) and L-5-HTP significantly suppress the ratio of IFNgamma/IL-10 production by peripheral blood immunocytes. These antidepressant drugs appear to have a common effect on the IRS, i.e. in vitro they increase the production of IL-10 by peripheral blood leukocytes. Thus, the results suggest that antidepressants have negative immunoregulatory effects. It may be speculated that antidepressants exert some of their antidepressant effects through their negative immunoregulatory capacities. Copyright 2001 John Wiley & Sons, Ltd.
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PMID:The immunoregulatory effects of antidepressants. 1240 4

TV-3326 is a novel cholinesterase inhibitor that produces irreversible brain-selective inhibition of monoamine oxidase (MAO)-A and B and has antidepressant-like activity in rats after chronic oral administration. This study determined whether TV-3326 would cause less potentiation than other irreversible MAO-inhibitors of the blood pressure (BP) response to oral tyramine in conscious rabbits. Dose-response curves were established for the increase in BP induced by tyramine (5-200 mg/kg) administered orally via a naso-pharyngeal tube. From these, the dose that increased BP by 30 mmHg (ED(30)) was computed for each rabbit before and after oral administration of clorgyline, 1 mg/kg for one week, tranylcypromine 10 mg/kg, once, moclobemide, 20 mg/kg 3 times and TV-3326, 26 mg/kg for 2 weeks. Clorgyline, tranylcypromine and TV-3326 inhibited brain MAO-A by 90%; the former two inhibited intestinal MAO-A by 85-97% but TV-3326 had no effect. Tranylcypromine and clorgyline produced 6 and 20-fold increases in the pressor response to tyramine while TV-3326, like moclobemide, only potentiated it 2-fold. If TV-3326 is found to produce as little potentiation of the tyramine response in human subjects, it may be a potentially useful therapeutic agent for the treatment of Alzheimer's disease with depression.
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PMID:Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor, TV-3326 in conscious rabbits. 1242 69

Monoamine oxidase inhibitors (MAOIs), which ushered in the modern era of psychopharmacology in the 1950s, have remained useful in the treatment of depression despite important safety concerns, such as acute hypertensive episodes brought on by ingestion of foods with high-tyramine content. Experience has shown that MAOIs are broadly effective in the treatment of depressive disorders, including atypical, chronic, and double depressions. Newer selective and reversible inhibitors of the two forms of mitochondrial monoamine oxidase (MAO) enzymes, MAO-A and MAO-B, have been developed in an effort to improve the safety and tolerability of MAOIs. Selegiline, a selective inhibitor of MAO-B has been shown to be effective in the treatment of depression at higher oral doses where selectivity for MAO-B is lost. Transdermal delivery of selegiline bypasses first-pass metabolism and avoids impairment of the gastrointestinal barrier provided by MAO-A of the gastrointestinal mucosa. Studies have shown that the selegiline transdermal system (STS) does not significantly affect sensitivity to ingested tyramine, unlike tranylcypromine, which markedly increases sensitivity. STS has been found to be efficacious in the treatment of patients with major depression in placebo-controlled trials, without the need for dietary precautions. The favorable safety profile of STS should allow this MAOI to be a broadly used antidepressant drug.
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PMID:Monoamine oxidase inhibitors: a new generation. 1247 70

Serotonin modulates numerous processes in the central nervous system related to anxiety and fear, mood, aggression, sleep, ingestive behaviors, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several neuropsychiatric conditions but efforts to develop more specific pharmacological agents have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of serotonin as well as several enzymes that control its synthesis and metabolism but very few pharmacological agents are able to selectively target a single receptor. Several groups including ours have used a genetic strategy to ablate specific serotonin receptors in an effort to dissect out their functions in the central nervous system. The strength of this approach is the high degree of specificity that can be achieved in the knockout (gene inactivation) approach since a single receptor gene can be selectively targeted. To date several inactivation mutations of specific serotonin receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases knockout mice have been able to confirm what has already been suspected based on pharmacological studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior. In this review, the current literature regarding phenotypic changes in mice bearing inactivation mutations of serotonin receptors, the serotonin transporter, and the monoamine oxidase A will be discussed and major findings emphasized.
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PMID:Mutational analysis of the serotonergic system: recent findings using knockout mice. 1276 5


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