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)

Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness and suicidal behavior. Studies have shown that the number of brain and platelet serotonin transporter binding sites are reduced in patients with depression and in suicide victims, and that the density of 5-HT2A receptors is increased in brain regions of depressed in suicide victims and in platelets of depressed suicidal patients. Genes that code for proteins, such as tryptophan hydroxylase, 5-HT transporter, and 5-HT2A receptor, involved in regulating serotonergic neurotransmission, have thus been major candidate genes for association studies of suicide and suicidal behavior. Recent studies by our group and by others have shown that genetic variations in the serotonin-system-related genes might be associated with suicidal ideation and completed suicide. We have shown that the 102 C allele in 5-HT2A receptor gene was significantly associated with suicidal ideation (chi2 = 8.5. p < .005) in depressed patients. Patients with a 102 C/C genotype had a significantly higher mean HAMD item #3 score (indication of suicidal ideation) than T/C or T/7 genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression and not with depression itself. We also found that the 5-HT transporter gene S/L polymorphism was significantly associated with completed suicide. The frequency of the L/L genotype in depressed suicide victims was almost double of that found in control group (48.6% vs. 26.2%). The odds ratio for the L allele was 2.1 (95% CI 1.2-3.7). The association between polymorphism in serotonergic genes and suicidality supports the hypothesis that genetic factors can modulate suicide risk by influencing serotonergic activity.
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PMID:Serotonergic genes and suicidality. 1172 94

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for the in vivo visualisation and measurement of, e.g. the serotonergic system in the brain of depressed patients. Currently, the available ligands permit the investigation of 5-HT2A and 5-HT1A receptors, the serotonin transporter and serotonin synthesis. 5-HT2A receptors have most extensively been investigated and increases, decreases or no differences in ligand binding have been found. Previous treatment and suicidality could be major confounding variables. Tricyclics seem to decrease ligand binding, while SSRIs in most studies increase ligand binding. A few studies have looked at the 5-HT1A receptor and demonstrated decreases in binding. The one study which looked at the effect of an SSRI treatment did not find any effect. The serotonin transporter availability seems to be reduced in depression. Tryptophane depletion studies have demonstrated effects on brain metabolism in serotonin related regions and on 5-HT2A receptors. Finally, serotonin synthesis studies have shown interesting differences between males and females.
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PMID:Imaging the serotonergic system in depression. 1182 43

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

Dysthymic disorder, described by the Diagnostic and Statistical Manual of Mental Disorders--4th edition (DSM-IV) criteria as a chronically depressed mood that occurs most of the day more days than not for at least 2 years and has a lifetime prevalence rate of approximately 3.3% [Gwirtsman, 1994. Psychopharmacol. Bull. 30 (1994) 45.]. This disorder, which is disabling, often goes unrecognized and its sufferers are often undertreated, but recent evidence has suggested that people with dysthymia may respond to antidepressant treatment. Based on effective outcomes in previous studies using fluoxetine (a 5-HT reuptake inhibitor) and ritanserin (a 5-HT2A antagonist), it was hypothesized that nefazodone, which is both a serotonin (5-HT) reuptake inhibitor (rather weak) and a 5-HT2A receptor antagonist, may provide an effective treatment for patients with dysthymic disorder. Six participants completed this 24-week pilot trial. A decrease in the Hamilton Rating Scale for Depression (HAM-D) scores was observed from baseline to Week 24, although most changes occurred in the first 4 weeks of participation. There was an improvement in anxiety symptomatology, both physiological and psychological. General functioning did not improve as observed by Global Assessment of Functioning Scale (GAF) scores. There may be some benefit to nefazodone for treatment of dysthymia, as indicated by positive results on HAM-D, Hamilton Anxiety Scale (HAM-AD), and Hopkins Symptom Checklist (HCL) scores within the first 4 weeks; however, it is possible that such dramatic results may be due to entry into the study alone, and not to medication.
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PMID:Nefazodone treatment of dysthymic disorder an open, long-term, prospective pilot study. 1218 98

SSRI-induced sexual dysfunction affects 30% to 50% or more of individuals who take these drugs for depression. Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5HT2 and 5HT3 receptors; decreased dopamine; blockade of cholinergic and alpha-1 adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Five approaches to treatment include conservative approaches such as wait and see, decrease dosage, and drug holidays. More aggressive strategy for treating SSRI-induced sexual dysfunction are changing antidepressants and augmentation.
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PMID:Mechanisms and treatments of SSRI-induced sexual dysfunction. 1238 82

There is extensive evidence to implicate dysregulation of noradrenergic, serotonergic, and dopaminergic neurotransmission in the pathophysiology of mood disorders. The receptor profile for risperidone, an atypical antipsychotic with demonstrated efficacy in schizophrenia, is consistent with possible antidepressant activity. Specifically, risperidone is a potent antagonist of central 5-HT2A receptors, addressing symptoms such as insomnia, agitation, and weight loss and may indirectly enhance 5-HT1A-mediated neurotransmission. A search of the worldwide medical literature published through December 2000 revealed 24 publications pertinent to the clinical use of risperidone in the treatment of patients with depressive symptomatology. In schizophrenia, in which depression is a common comorbid condition, the results of eight randomized, blinded, and controlled trials consistently demonstrated that treatment with risperidone significantly reduced scores on various measures of depressive symptoms. Moreover, these effects were distinct from improvements in negative and positive symptoms. Antidepressant effects also were observed in two large meta-analyses of trials in patients with schizophrenia or schizoaffective disorder. Observations from uncontrolled studies and case reports of risperidone therapy of other psychiatric disorders were similarly suggestive of antidepressant activity. Collectively, the evidence we present in this review indicates that risperidone's therapeutic benefits in psychiatric medicine extend beyond potent and effective antipsychotic activity and may include effectiveness in treating depression and related affective disorders. Systematic studies are now needed to evaluate the utility of concomitant therapy with an atypical antipsychotic in psychotic, bipolar, and treatment-resistant depressive syndromes.
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PMID:Risperidone: review of its therapeutic utility in depression. 1239 61

Nefazodone has been widely used as an antidepressant, but it has not been tested for depression with anger attacks. In an open study, we administered nefazodone (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with anger attacks. Assessment instruments comprised the Structured Clinical Interview for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated. Three subjects underwent positron emission tomography (PET) with [18F]-setoperone for 5-HT2 binding potential (BP) and [11C]-SCH-23,390 for D1 BP, both at baseline and after 6 weeks of treatment. Eight subjects underwent PET with [18F]-setoperone and with [11C]-SCH-23,390 at baseline only. In an examination of whether D1 and 5HT2 (data available in six subjects) receptor BP predicted treatment response, we found significant decreases in the HAM-D-17, CGI-S, weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as >or=50% decrease in HAM-D-17 score), and 44% reported disappearance of anger attacks. A statistically significant percentage decrease in 5HT2 BP was observed for the right mesial frontal and left parietal regions after 6 weeks of treatment. No significant change was observed in D1 BP in any region. Although CGI-I scores correlated significantly with D1 BP in the left thalamic region, the correlation was not significant after Bonferroni correction. The effectiveness of nefazodone for depression with anger attacks may be related to widespread changes in 5HT2 receptor BP.
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PMID:An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding. 1247 99

The nonselective serotonin (5-HT)-2A antagonists ritanserin, mianserin, and cyproheptadine were found efficacious in neuroleptic-induced akathisia (NIA). Mirtazapine is structurally and pharmacologically similar to mianserin, and the authors sought to determine its anti-NIA activity. Twenty-six neuroleptic-treated schizophrenic patients with DSM-IV diagnosis of NIA received add-on mirtazapine (15 mg/day) or placebo for 5 days in a double-blind design. Patients were assessed at baseline and days 3 and 5 with the Barnes Akathisia Scale (BAS), Positive and Negative Symptom Scale, Hamilton Rating Scale for Depression, and Simpson-Angus Scale for parkinsonism. Analysis of covariance with repeated measurements revealed significant group x time effects in favor of the mirtazapine group in both completers (n = 10 in each group) and intent-to-treat analysis (n = 13 in each group) for the BAS global subscale (F [1, 17] = 14.87, p = 0.001, and F [1, 23] = 13.24, p = 0.01, respectively) and objective subscale (F [1, 17] = 8.25, p = 0.011, and F [1, 23] = 7.35, p = 0.012, respectively) and borderline significant superiority for the BAS subjective subscale (F [1, 17] = 4.39, p = 0.051, and F [1, 23] = 4.12, p = 0.054, respectively) and distress subscale (F [1, 17] = 4.21, p = 0.056, and F [1, 23] = 3.80, p = 0.064, respectively). Significantly more mirtazapine-than placebo-treated patients (53.8% [7/13] vs. 7.7% [1/13], respectively; chi2 = 8.3, p = 0.004) met operational response criterion, a reduction of at least two points on the BAS global subscale. Mirtazapine treatment was associated with modest improvement of psychotic and parkinsonian symptoms. Mild sedation was the only side effect. Our study demonstrated that mirtazapine (15 mg/day) is an efficacious and well-tolerated therapeutic option in NIA. Marked 5HT2A/2C antagonistic activity of mirtazapine apparently accounts for its anti-NIA activity. The role of mirtazapine in the treatment of akathisia induced by atypical antipsychotic agents merits further investigation.
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PMID:Efficacy of low-dose mirtazapine in neuroleptic-induced akathisia: a double-blind randomized placebo-controlled pilot study. 1282 92

Serotonin (5-hydroxytryptamine, 5-HT)-containing neurons in the midbrain directly innervate corticotropin-releasing hormone (CRH)-containing cells located in paraventricular nucleus of the hypothalamus. Serotonergic inputs into the paraventricular nucleus mediate the release of CRH, leading to the release of adrenocorticotropin, which triggers glucocorticoid secretion from the adrenal cortex. 5-HT1A and 5-HT2A receptors are the main receptors mediating the serotonergic stimulation of the hypothalamic-pituitary-adrenal axis. In turn, both CRH and glucocorticoids have multiple and complex effects on the serotonergic neurons. Therefore, these two systems are interwoven and communicate closely. The intimate relationship between serotonin and the hypothalamic-pituitary-adrenal axis is of great importance in normal physiology such as circadian rhythm and stress, as well as pathophysiological disorders such as depression, anxiety, eating disorders, and chronic fatigue.
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PMID:Serotonin and the neuroendocrine regulation of the hypothalamic--pituitary-adrenal axis in health and disease. 1285 56

The serotonergic system plays a key role in regulating basic behaviors. Deficits in serotonergic neurotransmission have been implicated in psychiatric disorders, such as schizophrenia and depression. Here we have optimized a behavioral screen and performed a small scale genetic screen to identify genes involved in serotonin responsiveness in the mouse. Treatment of mice with serotonin, serotonin precursors, or serotonin agonists results in a quantifiable head twitch response (HTR), which is drug dosage-dependent and dependent on the 5-HT2A receptor system. This assay can uncover variation in serotonin responsiveness as shown by our identification of inbred strains with high, medium, and low head twitch responses to administration of the serotonin agonist DOI (+-1-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). We chose C57Bl/6J mice for our mutagenesis screen, because of their robust HTR and because of the availability of their complete genomic sequence. We optimized this assay by examining dose and age dependence of DOI-induced HTR in 6-week and 3-month-old C57BL/6J mice. HTR decreases only slightly in 3-month-old mice, and a substantial but submaximal HTR is induced by 0.75-1 mg/kg of DOI. We assayed HTR in response to DOI of 247 G1 C57BL/6J progeny from C57BL/6J males, which had been mutagenized with ethylnitrososurea (ENU), and recovered one provisionally heritable hyper-responsive mutation. This and future mutations recovered via this protocol may provide ideal subjects for the study of human psychiatric disorders, such as depression and schizophrenia, and thereby aid in the development of better therapeutic strategies for these disorders. Thus, it is well worth expanding on this genetic screen in its current form and by addition of further pharmacologic assays in the future.
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PMID:A genetic screen for mouse mutations with defects in serotonin responsiveness. 1287 87


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