Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5-hydroxytryptamine, 5-HT) partial agonist active at the 5-HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo-controlled, parallel group studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM-D] and Hamilton anxiety [HAM-A] scales greater than or equal to 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p less than 0.05) improvement in mean HAM-D, HAM-A, and Clinical Global Impression-Global Improvement scale ratings for buspirone-treated compared with placebo-treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms (judged by higher initial HAM-D or HAM-A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5-HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5-HT1A receptor function, have clinically important antidepressant properties.
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PMID:Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. 219 3

We report the findings of a randomized, double-blind, placebo-controlled, parallel, generalized anxiety disorder (GAD) outpatient study. The purpose of the study was to compare the efficacy, safety, and tolerability of ipsapirone, an azapirone and 5-HT1A agonist, given at a total daily dose of 10 mg to 30 mg, with a total daily dose of 2 mg to 6 mg of lorazepam or placebo in 90 outpatients with GAD of moderate or greater severity. At baseline, all patients had a Hamilton Anxiety Scale (HAM-A) score of > or = 18 and Covi anxiety score of > or = 8. After a 1-week single-blind washout, patients entered a 4-week double-blind period with an optional extension for another 4 weeks, followed by a 2-week single-blind placebo washout. Ipsapirone and lorazepam ratings on the HAM-A and Clinical Global Impressions (CGI) were significantly (p < .05) superior to placebo at the end of the acute and maintenance periods of the trial, with a 50 percent HAM-A reduction on active drugs vs. 20 percent on placebo. The anxiety of patients receiving lorazepam, but not ipsapirone, rebounded during the final placebo washout.
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PMID:The safety and efficacy of ipsapirone vs. lorazepam in outpatients with generalized anxiety disorder (GAD): single site findings from a multicenter trial. 790 61

Compounds active at the serotonin (5-HT)1A receptor (mostly azapirones) have shown some evidence of antidepressant effect. We report here the results of an antidepressant trial with zalospirone, a novel cyclic imide with 5-HT1A partial agonist activity. Two hundred eighty-seven outpatients (mean age 44 years, 55% men, 45% nonfertile women) who met criteria for unipolar major depression with a minimum 21-item Hamilton Rating Scale for Depression (HAM-D) score of 20 were randomly assigned to receive 6 weeks of double-blind treatment with either placebo or one of three fixed doses of zalospirone (6, 15, or 45 mg/day), administered three times daily. The high dose (45 mg) of zalospirone produced a significant antidepressant effect compared with placebo from week 2 on with mean improvement (change from baseline) in HAM-D total score of 12.8 versus 8.4 (p < 0.05) at week 6. Clinical improvement with the high dose of zalospirone was consistent across all outcome measures, however, only in the observed cases and not the last-observation-carried-forward analyses. Improvement with the 6-mg or 15-mg doses was greater than that with placebo, but not significantly so, suggesting a dose-response effect. Although the 45-mg dose of zalospirone seemed to have significant antidepressant efficacy, it was not well tolerated. Dizziness and nausea were noted in almost half of the patients, and by week six, 51% of patients in the high-dose group had dropped out. Whether or not tolerance to this high dose might be improved by gradual drug titration, only future research can answer.
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PMID:Zalospirone in major depression: a placebo-controlled multicenter study. 878 52

Alterations induced by social isolation (1 day to 18 weeks) in low- and high-active mice (LAM and HAM) were studied in respect to serotonin metabolism, [3H]-8-OH-DPAT binding of presynaptic (midbrain), postsynaptic (hippocampus) 5-HT1A receptors and [3H]-ketanserin binding of cortical 5-HT2A receptors. Individual housing of mice was associated with reduction of serotonin metabolism, depending on isolation time and brain structure. Whereas a transient decrease in the striatum and cortex was detected between 1 week and 6 weeks, reduction of cerebellar and hippocampal serotonin metabolism was found later (12-18 weeks). Serotonergic systems of HAM were found to be more reactive to environmental disturbances, and their serotonin metabolism was more affected by social isolation. Isolation-induced upregulation of cortical 5-HT2A receptors was measured only in HAM. Densities of postsynaptic 5-HT1A receptors in the hippocampus did differ either in grouped or isolated mice. However, there were significant differences in hippocampal 5-HT1A receptor affinity, especially between 1 day and 3 weeks. Transient downregulation of presynaptic 5-HT1A receptors in the midbrain was found in isolated mice between 3 and 6 weeks. These results are discussed in terms of interactions between serotonergic alterations and isolation-induced aggression.
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PMID:Dynamic alterations of serotonergic metabolism and receptors during social isolation of low- and high-active mice. 958 45

Ipsapirone, an azapirone with 5-hydroxytryptamine (5-HT1A) partial agonist activity, has been shown in preliminary studies to be effective in the treatment of major depressive disorder. This 8-week, randomized, double-blind study compared the efficacy, safety, and tolerability of three fixed doses of controlled-release ipsapirone (10-, 30-, and 50-mg dose once daily) with placebo in 410 patients with moderate to severe major depression (Hamilton Rating Scale for Depression [HAM-D] score > or = 20). The 10-mg ipsapirone treatment arm was discontinued early in the study. A total of 390 patients were eligible for evaluation in the intent-to-treat sample. The primary efficacy variable was the change in HAM-D total score from baseline to visit 8. There was no significant difference in efficacy in the two treatment groups versus the placebo group. The overall treatment response, defined as a 50% decrease in the HAM-D total score from baseline, was 43% with ipsapirone 50 mg given once daily, 34% with ipsapirone 30 mg given once daily, and 35% with placebo. In subanalyses, ipsapirone 50 mg given once daily was superior to placebo according to the HAM-D Core Depression (mood, guilt, interest, psychomotor activity) subtotal (p = 0.0453) and Melancholic item (p = 0.0225). Ipsapirone 30 mg given once daily was superior to placebo only in patients with moderate depression (baseline HAM-D total score < or = 25; p = 0.0100). The most common adverse effect in all groups was headache. The only dose-dependent adverse effects were dizziness and nausea.
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PMID:A Canadian multicenter study of three fixed doses of controlled-release ipsapirone in outpatients with moderate to severe major depression. 969 Jun 91

We investigated the effects of a 5-hydroxytryptamine (5-HT) 1A receptor gene polymorphism on the clinical response to fluvoxamine (FLV) in 65 depressed outpatients who gave written consent to participate in the study. Patients visited every 2 weeks after the first examination until the week 12 end point and were evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17) at each visit. FLV dose was changed in response to their clinical symptoms. The Gly272Asp polymorphism of the 5-HT1A receptor gene was identified by a PCR method. The subjects with the Asp allele had a significantly higher % reduction in the HAM-D-17 score than those with the Gly/Gly genotype at week 2 (P=0.009), week 6 (P=0.036), and week 12 (P=0.031). There was a significant difference in the genotype distribution between the responders and nonresponders. These results suggest that the Gly272Asp polymorphism of the 5-HT1A receptor gene may predict the response to FLV.
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PMID:The effects of a 5-hydroxytryptamine 1A receptor gene polymorphism on the clinical response to fluvoxamine in depressed patients. 1514 1

Pindolol, a 5-HT1A autoreceptor antagonist, given in combination with selective serotonin reuptake inhibitors (SSRIs), may enhance and/or accelerate the therapeutic efficacy of SSRIs. Fifty patients, meeting ICD-10 criteria for major depressive disorder or bipolar depression, were enrolled in our randomized, placebo-controlled, double-blind trial. One group received paroxetine plus pindolol (2.5 mg t.i.d.), and the other group received paroxetine plus placebo. The proportion of patients with sustained response (>or=50% reduction of baseline HAM-D 17 score maintained until the endpoint; p=0.252) and the proportion of patients with remission (HAM-D 17 <or=8 at last visit; p=0.769) did not differ significantly between the two treatment groups. However, a significantly greater proportion of patients who were not previously treated with antidepressants (n=15; p=0.041) and of patients with bipolar depression (n=11; p=0.015) had a sustained response in the paroxetine plus pindolol group compared to the paroxetine plus placebo group; furthermore there was a trend for first episode depressed patients to have a greater response in the paroxetine plus pindolol group (n=12; p=0.071). Summarizing, the entire study population showed no antidepressive benefit from pindolol augmentation. Nevertheless patients with bipolar depression irrespective of previous treatments and duration of illness, and unipolar patients not previously treated demonstrated a significant benefit from pindolol augmentation.
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PMID:Paroxetine with pindolol augmentation: a double-blind, randomized, placebo-controlled study in depressed in-patients. 1805 9

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5-HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of the HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P < 0.0001), rs6295G/G (P < 0.0001) and rs1364043T/T (P = 0.018) genotype carriers (minor allele homozygotes), independently from clinical variables. Furthermore minor allele homozygous carriers in all these three SNPs were associated with treatment response by various assessment such as HAM-D score change over time (P = 0.001), week 2 (P < 0.0001), 4 (P = 0.007), and 6 (P = 0.048) as well as response rate (P = 0.0005) and remission rate (P = 0.004). We also pointed out the genotyping mis-definition of rs6295C/G in the previous four articles. In conclusion, this is the first study that reports a significant association of antidepressant response with rs10042486C/T and rs1364043T/G variants of HTR1A and also with rs10042486-rs6295-rs1364043 combination. This finding adds an important information for the pathway of detecting the genetics of antidepressant response even if results must be verified on larger samples.
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PMID:Effect of 5-HT1A gene polymorphisms on antidepressant response in major depressive disorder. 1848 82

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5-HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P < 0.0001), rs6295G/G (P < 0.0001) and rs1364043T/T (P = 0.018) genotype carriers, independently from clinical variables. Furthermore minor allele homozygous carriers in all these 3 SNPs were associated with treatment response by various assessments such as HAM-D score change over time (P = 0.001), week 2 (P < 0.0001), 4 (P = 0.007), and 6 (P = 0.048) as well as response rate (P = 0.0005) and remission rate (P = 0.004). We also pointed out the genotyping mis-definition of rs6295C/G in the previous four papers.
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PMID:[5-HT1A gene polymorphisms contributed to antidepressant response in major depression]. 1932 13