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)

The 5-hydroxytryptamine transporter (5-HTT) regulates 5-hydroxytryptamine (5-HT) neurotransmission by removing 5-HT from the synaptic cleft. Emerging evidence from clinical and genetic studies implicates the 5-HTT in various neuropsychiatric conditions, including anxiety and depression. Here we report that a 5-HTT null mutant mouse line was generated by gene trapping that disrupted the sequence encoding the C-terminus of 5-HTT. This mutation resulted in significant reduction of 5-HTT mRNA and loss of 5-HTT protein. Brain levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid, were markedly decreased in C-terminus 5-HTT -/- mice, while 5-HT uptake or 5-HT content in platelets was absent. Behavioral phenotyping showed that C-terminus 5-HTT -/- mice were normal on a screen for gross behavioral, neurological, and sensory functions. In the tail suspension test for depression-related behavior, C-terminus 5-HTT -/- mice showed increased immobility relative to their +/+ controls. By comparison, a previously generated line of 5-HTT -/- mice lacking exon 2, encoding the N-terminus of the 5-HTT, showed abnormally high immobility in response to repeated, but not acute, exposure to the tail suspension test. In a novel, brightly-lit open field, both C-terminus 5-HTT -/- mice and N-terminus 5-HTT -/- mice displayed decreased center time and reduced locomotor activity compared with their +/+ controls. Both mutant lines buried significantly fewer marbles than their +/+ controls in the marble burying test. These findings further demonstrate the neurobiological functions of the 5-HTT and add to a growing literature linking genetic variation in 5-HTT function with emotional abnormalities.
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PMID:Insertion mutation at the C-terminus of the serotonin transporter disrupts brain serotonin function and emotion-related behaviors in mice. 1654 82

Serotonin transporter gene is known to be implicated with various psychological and psychiatric phenotypes. The present study aimed at searching for relationship of the gene polymorphism 5-HTTLPR to personality traits and P300 wave in patients with schizophrenia (n = 71) and their non-psychotic relatives (n = 74). To reduce an influence of the P300 amplitude range, which may vary widely in population, subjects have been divided into 2 groups: with amplitude higher (group m+) and lower (group m-) than a mean sample value. Between-amplitude differences were highly significant (p < 0.0001) for all the leads. The groups were similar by age, sex ratio and emotional level measured with personality inventories. When compared by 5-HTTLPR genotype, mean P300 amplitude values were similar in the group m-. In the group m+, significant differences for this component were found between the II genotype and the ss genotype at frontal (p = 0.02) and central (p = 0.005) leads, with the ss genotype subjects having the lowest amplitude. Subjects with the ss genotype in this group as compared to those with the II genotype were also featured by higher anxiety- and depression-related personality traits in relatives and marked clinical symptoms related to anxiety and depression in patients. The fact that association between 5-HTTLPR polymorphism and with P300 amplitude as well as personality traits was found only in the group with higher amplitudes, but not in the group with lower amplitudes, may be partly explained by the assumption that these groups represent different phenotypes. Subjects with inherent lower amplitude are thought to have reduced ability of behavior self-regulation. In conclusion, 5-HTTLPR polymorphism seems to contribute to information processing related to P300 generation and to anxiety and depression traits in patients with schizophrenia and their relatives.
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PMID:[Acoustic evoked potentials, serotonin transporter gene polymorphism and some psychopathological and psychological features in patients with schizophrenia and their relatives]. 1654 74

Altered cytokine secretion as a mechanism in the etiology of depression is still obscure. The serotonin transporter (5-HTT) may play an important role in the termination of serotonergic neurotransmission by serotonin (5-HT) uptaking into presynaptic neurons and representing as an initial action site for selective 5-HTT reuptake inhibitors (SSRI). In our study, we evaluated whether cytokines and 5-HTT acted as biological markers for depression. Blood samples were collected from 42 participants. The differences in cytokine and 5-HTT mRNA expressions of leukocytes were assessed between the patients with major depression (n=20) and the healthy controls (n=22), along with the measurements prior and after treatment with a SSRI, fluoxetine, for 3 months in the follow-up patient group (n=8). The results revealed that the mRNA expressions of IL-1beta, IL-6, IFNgamma, TNFalpha, and 5-HTT were higher in the depressed patients than those of the healthy controls. The higher level of mRNA expressions of IFNgamma and 5-HTT diminished after fluoxetine treatment. Furthermore, we found a positive correlation between 5-HTT and cytokines mRNA expressions in total participants, which suggested that pro-inflammatory cytokines and 5-HTT might play critical roles in the pathogenesis of major depression and that their levels were affected by chronic treatment with 5-HTT inhibitors.
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PMID:Cytokines and serotonin transporter in patients with major depression. 1661 82

Gene targeting approaches greatly facilitate insight into the functioning of monoamine transporters, the targets of potent antidepressants. The serotonin transporter (5-HTT) is the molecular target of a large number of antidepressants. To assess the clearance of serotonin (5-HT) in the absence of the 5-HTT, we have generated double knockout mice lacking both the 5-HTT and the catabolizing enzyme monoamine oxidase A (MAOA). We found aberrant 5-HT accumulation in the striatum of these MAOA/5-HTT double knockout mice. By additional ablation of the dopamine transporter (DAT), this aberrant 5-HT accumulation was abolished in MAOA/5-HTT/DAT triple knockout mice. Thus, aberrant uptake of 5-HT occurs in dopaminergic terminals under conditions of elevated 5-HT levels, and this aberrant uptake is mediated by the DAT. These findings have important consequences for antidepressant therapy, since during treatment of depression with selective serotonin reuptake inhibitors, clearance of 5-HT by dopaminergic neurons may reduce the desired therapeutic elevation of extracellular 5-HT levels. This provides a molecular rationale for improving antidepressant efficacy by additional pharmacological inhibition of the DAT.
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PMID:Aberrant accumulation of serotonin in dopaminergic neurons. 1663 24

In serotonin transporter knock-out (5-HTT-/-) mice, extracellular serotonin (5-HT) levels are markedly elevated in the brain, and rapid eye movement sleep (REMS) is enhanced compared with wild-type mice. We hypothesized that such sleep impairment at adulthood results from excessive serotonergic tone during early life. Thus, we assessed whether neonatal treatment with drugs capable of limiting the impact of 5-HT on the brain could normalize sleep patterns in 5-HTT-/- mutants. We found that treatments initiated at postnatal day 5 and continued for 2 weeks with the 5-HT synthesis inhibitor para-chlorophenylalanine, or for 4 weeks with the 5-HT(1A) receptor (5-HT(1A)R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), induced total or partial recovery of REMS, respectively, in 5-HTT-/- mutants. Early life treatment with WAY 100635 also reversed the depression-like behavior otherwise observed in these mutants. Possible adaptive changes in 5-HT(1A)R after neonatal treatment with WAY 100635 were investigated by measuring 5-HT(1A) binding sites and 5-HT(1A) mRNA in various REMS- and/or depression-related brain areas, as well as 5-HT(1A)R-mediated hypothermia and inhibition of neuronal firing in the dorsal raphe nucleus. None of these characteristics were modified in parallel with REMS recovery, suggesting that 5-HT(1A)Rs involved in wild-type phenotype rescue in 5-HTT-/- mutants are located in other brain areas or in 5-HT(1A)R-unrelated circuits where they could be transiently expressed during development. The reversal of sleep alterations and depression-like behavior after early life blockade of 5-HT(1A)R in 5-HTT-/- mutants might open new perspectives regarding preventive care of sleep and mood disorders resulting from serotonin transporter impairments during development.
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PMID:Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter. 1670 6

Panic disorder may be associated with defective serotonin (5-HT) neurotransmission. This study was to investigate the association between the tryptophan hydroxylase (TPH) gene and a serotonin transporter gene promoter polymorphism (5-HTTLPR), with panic disorder in a Korean population. 244 Korean patients with panic disorder and the 227 controls were genotyped by a polymerase chain reaction-based method. The severity of panic disorders was assessed by number of panic attacks during the previous 1 month, as well as scores for anticipatory anxiety, panic distress, and agoraphobic distress, as determined by a visual analogue scale (VAS). All the subjects completed the assessment measures including Spielberger State-Trait Anxiety Inventory-State (STAI-S), Spielberger State-Trait Anxiety Inventory-Trait (STAI-T), Beck Depression Inventory (BDI), Symptom Checklist-90-Revised (SCL-90-R), Revised Anxiety Sensitivity Index (ASI-R), Clinical Global Impression Scale--Severity of Illness (CGI-S), Panic Disorder Severity Scale (PDSS), and the Hamilton Depression Rating Scale (HAMD). Responder analyses were conducted based on changes in CGI-I scores after 10 weeks of treatment. We found no significant differences in the genotype and allele frequencies in TPH A218C and 5-HTTLPR polymorphisms between the panic patients and the control group. Subgroup analyses in terms of comorbidities, response, and other primary clinical variables, indicated no differences in these polymorphisms. Our findings suggest that the TPH A218C polymorphism and 5-HTTLPR play no significant roles in the pathogenesis and clinical symptomatologies, at least in a Korean population.
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PMID:Tryptophan hydroxylase and serotonin transporter gene polymorphism does not affect the diagnosis, clinical features and treatment outcome of panic disorder in the Korean population. 1682 1

A functional insertion/deletion (*l/*s) repeat polymorphism within the promoter region of the serotonin transporter (5-HTTLPR) has been described. An association between *l variant and a better and faster response to serotonin selective reuptake inhibitors in depressed patients was reported in Caucasians. The value of the explained variance due to the 5-HTTLPR, however, was 7% only, and different *l and *s variants were reported according to the nucleotide sequence of repeats. In this study, we investigated the antidepressant response to fluvoxamine in individuals carrying different *l and *s variants according to the Nakamura findings. Two hundred and twenty-eight patients affected by bipolar disorder and major depression were administered a daily dose of fluvoxamine up to 300 mg and evaluated at baseline and weekly thereafter until week 7, using the 21-item Hamilton Rating Scale for Depression. We found a marginally significant difference in genotype and allele (P=0.04, data not shown) distribution (*l and *s traditional variants) according to diagnosis (bipolar disorder vs. major depression). We confirmed a better and faster response in our depressed patients bearing the *l variant, but we also found significant differences in response among *l carriers according to the type of *l allele. In fact, 16F *l carriers showed only a partial response, while 16D *l carriers showed a marginally significantly better response than 16A *l allele carriers. These results, although very preliminary, can represent a further step toward a better understanding of the molecular genetics of antidepressant response.
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PMID:Serotonin transporter gene-linked polymorphic region: possible pharmacogenetic implications of rare variants. 1682 82

Identification of gene-environment and gene-gene interactions has become increasingly important in understanding psychiatric disorders. Dysfunction of central serotonergic neurotransmission has been implicated in alcoholism, depression, and anxiety. We review the literature on nonhuman primates that assesses the interaction between the genetic constitution of the regulatory region ofthe serotonin transporter (5-HTT) and environmental factors. Prospective studies in nonhuman primates that underwent social stress found a reduction of theserotonin turnover rate among carriers of one or two short alleles in a functional polymorphism of the 5-HTT promoter. In these primates, brain imaging studies showed a relative increase in the availability of raphe serotonin transporters. A low serotonin turnover rate and a high availability of serotonin transporters were associated with reduced response to excessive alcohol intake, anxiety, and impulsive aggression. Animal experiments point to a relationship between serotonergic dysfunction, negative mood states, and excessive alcohol intake, which may in part be mediated by reduced alcohol-induced sedation.
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PMID:Serotonergic dysfunction: brain imaging and behavioral correlates. 1686 29

Polymorphism at the serotonin transporter linked polymorphic region (5-HTTLPR) has been associated with neuroticism, increased risk for affective disorders and greater vulnerability to mood change following serotonin (5-HT) depletion. The aim of the present study was to investigate whether the cognitive effects of 5-HT depletion were differentially affected by genotype at the 5-HTTLPR polymorphism, using neuropsychological measures of memory and attention. We utilized the acute tryptophan depletion (ATD) technique to temporarily reduce 5-HT synthesis in two groups of healthy volunteers pre-selected on the basis of 5-HTTLPR genotype, 15 of the ll genotype and 15 of the ss genotype, in a double-blind, placebo-controlled crossover design. As expected, ATD resulted in a robust reduction in plasma tryptophan concentration in both genotype groups. However, the genotype groups differed in terms of the effect of ATD on cognitive performance. The ss genotype group showed impaired verbal recall following depletion, while episodic memory was unimpaired by ATD in the ll genotype group. Averaging across depletion condition, the ss genotype group outperformed the ll genotype group on tests of episodic memory and attention. Neither group was significantly affected by ATD on measures of emotional state. These data confirm previous reports that ss individuals are particularly vulnerable to 5-HT depletion, but extend these findings to the cognitive domain. The unexpected finding that ss volunteers showed improved memory and attention relative to ll volunteers suggests a possible evolutionary advantage to possession of the s allele, which may offset the disadvantage of vulnerability to depression following stressful life events.
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PMID:The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention. 1689 93

Few studies of gene-environment interactions for the serotonin transporter promoter polymorphism (5-HTTLPR), life stressors and depression have considered women separately or examined specific types of stressful life events. None have looked at depression during pregnancy. In the Pregnancy Outcomes and Community Health (POUCH) Study, women were queried about history of stressful life events and depressive symptoms at the time of enrollment (15-27 weeks gestation). Stressful life events were grouped a priori into "subconstructs" (e.g. economic, legal, abuse, loss) and evaluated by subconstruct, total subconstruct score and total stressful life event score. The effect of genotype on the association between stressful life events and elevated depressive symptoms was assessed in 568 white non-Hispanic participants. The relationship between exposure to abuse and elevated depressive symptoms was more pronounced in the s/s group (OR = 24.5) than in the s/l group (OR = 3.0) and the l/l group (OR = 7.7), but this significant interaction was detected only after excluding 73 (13%) women with recent use of psychotropic medications. There was no evidence of gene-environment interaction in analytic models with other stressful life events subconstructs, total subconstruct score or total stressful life events score. These data offer modest support to other reports of gene-environment interaction and highlight the importance of considering specific stressful life events.
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PMID:Depressive symptoms in mid-pregnancy, lifetime stressors and the 5-HTTLPR genotype. 1696 82


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