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)

There is evidence that disturbances in central serotonin (5-HT) function have a role in impulsive aggression, violence, and criminality. A deletion/insertion polymorphism within the 5-HT transporter (5-HTT) promoter gene (5-HTT gene-linked polymorphic region, 5-HTTLPR) is thought to be associated with several psychopathological phenotypes related to disturbed impulse control, anxiety and depression. This study examined the association of the 5-HTTLPR with violent behavior in a sample of 153 male Caucasians referred for a forensic psychiatric examination. We found a significant excess of the short (s) allele and the s/s genotype in patients characterized by recurrent and overt physical violent behavior. This genetic variance explained 5% of the variance of violent behavior. When controlled for the impact of several psychopathologies related to violent behavior, this association was observed in individuals with a history of childhood attention deficit/hyperactivity disorder (ADHD)-related symptoms, but not presenting with personality disorder or increased impulsiveness. In conclusion, the results (i). suggest an association between serotonergic dysfunction and violent behavior, (ii). provide evidence for an-at least partial-genetic regulation of violent behavior in a subgroup of male offenders, and (iii). suggest a significant role for 5-HT transporter functionality for violent behavior.
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PMID:Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology. 1521 60

A polymorphism in the human serotonin transporter gene promoter (5-HTTLPR) is associated with anxiety and increased risk for developing depression in the face of adversity. Here, we report that among infant rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) interacts with adversity in the form of peer rearing to influence adrenocorticotropic hormone (ACTH) response to stress and, further, that this interaction is sexually dichotomous. ACTH responses to separation are higher in l/s than in l/l males. In females, however, it is only among those with a history of adversity that the s allele is associated with increased ACTH responses to stress. Of interest, peer-reared animals, in particular females carrying the s allele, also exhibit lower cortisol responses to stress, a pattern that has been recognized in association with certain stress-related neuropsychiatric disorders. By extension, our findings suggest the intriguing possibility that human females carrying the 5-HTTLPR s allele could be more vulnerable to the effects of early adversity. This interactive effect may underlie the increased incidence of certain stress-related disorders in women.
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PMID:Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques. 1530 39

Polymorphisms in the promoter region (5-HTTLPR) of the serotonin transporter and a variable number of tandem repeats polymorphism in the second intron have been widely studied. However, the results of association studies examining unipolar depression (MDD) or bipolar disorder depression (BPD) have been mixed. To precisely ascertain small associations with both polymorphisms, a meta-analysis was performed involving several thousand subjects, using random-effects modeling. For MDD, the effect of the 5-HTTLPR genotype was significant (chi2=6.1, P<0.05), with 21% of MDD subjects and 17% of controls homozygous for the short (S) allele (odds ratio, 1.16). Similar findings were noted in BPD, with a higher frequency of S/S genotypes in affected patients, although the results did not reach statistical significance. Results of transmission disequilibrium tests trended in a similar direction but also did not reach statistical significance. No consistent effect of the variable number of tandem repeats polymorphism was revealed for either MDD or BPD. The results suggest that the S allele, or a neighboring allele in linkage disequilibrium, is recessive for MDD and possibly BPD. Notably, the association is very small. With these small associations, confounding issues such as population stratification require addressing. Significant heterogeneity between studies was also evident, possibly reflecting differences in diagnosis, different control populations, and different ethnic populations. These factors should Influence the interpretation of the association found in this analysis.
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PMID:Meta-analysis of serotonin transporter polymorphisms and affective disorders. 1531 24

Several studies have demonstrated the involvement of 5-HT1A receptors in the pathogenesis of depression and in the antidepressant response to SSRIs. A functional new variant in the promoter region of the 5-HT1A gene was recently reported (-1019 C>G). The aim of this study is to investigate a possible association between this 5-HT1A receptor variant and antidepressant response to fluvoxamine in a sample of 262 mood-disorder subjects (151 major depressed and 111 bipolars) treated with fluvoxamine for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). 5-HT1A variants did not influence antidepressant response in the whole sample and in unipolar subjects. In bipolars, 5-HT1A*C/C genotype carriers showed a better response to fluvoxamine (p=0.036), independently from clinical variables. The 5-HT1A polymorphism effect on antidepressant response was independent from the previously reported effect of the 5-HTTLPR polymorphism. In conclusion, 5-HT1A variants could influence the antidepressant efficacy in bipolar subjects, even if results must be verified on larger samples.
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PMID:The C(-1019)G polymorphism of the 5-HT1A gene promoter and antidepressant response in mood disorders: preliminary findings. 1568 51

Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI. In both models, 5-HTT inhibition had significant detrimental effects on bone mineral accrual. 5-HTT null mutant mice had a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties, whereas bone mineral accrual was impaired in growing mice treated with a SSRI. These phenotypes resulted from a reduction in bone formation without an increase in bone resorption and were not influenced by effects on skeletal mechanosensitivity or serum biochemistries. These findings indicate a role for the 5-HTT in the regulation of bone accrual in the growing skeleton and point to a need for further research into the prescription of SSRIs to children and adolescents.
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PMID:Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. 1553 50

In this study, measures of the quality and availability of social supports were found to moderate risk for depression associated with a history of maltreatment and the presence of the short (s) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR). The present investigation (i) replicates research in adults showing that 5-HTTLPR variation moderates the development of depression after stress, (ii) extends the finding to children, and (iii) demonstrates the ability of social supports to further moderate risk for depression. Maltreated children with the s/s genotype and no positive supports had the highest depression ratings, scores that were twice as high as the non-maltreated comparison children with the same genotype. However, the presence of positive supports reduced risk associated with maltreatment and the s/s genotype, such that maltreated children with this profile had only minimal increases in their depression scores. These findings are consistent with emerging preclinical and clinical data suggesting that the negative sequelae associated with early stress are not inevitable. Risk for negative outcomes may be modified by both genetic and environmental factors, with the quality and availability of social supports among the most important environmental factors in promoting resiliency in maltreated children, even in the presence of a genotype expected to confer vulnerability for psychiatric disorder.
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PMID:Social supports and serotonin transporter gene moderate depression in maltreated children. 1558 23

Increasing focus is being given to identify possible combinations of genes related to specific clinical phenotypes. In our sample of 814 patients comprising 114 with schizophrenia, 416 with bipolar affective disorder and 284 with unipolar affective disorder, we studied interactions between the tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR), and the dopamine receptor (DRD4) genes in relation to five major psychiatric symptomatology scores. There was significant interaction between the TPH and the 5-HTTLPR genes. With an increasing number of short (s) alleles of 5-HTTLPR, the scores for delusions, disorganization and negative symptoms were significantly decreasing among subjects having the TPH genotype AA but increasing among subjects having the TPH genotype AC, yielding the highest scores for the combinations AA x ll and AC x ss. Since high scores on just delusions, disorganization and negative symptoms but low scores on excitement and depression were found among subjects with schizophrenia, we conducted comparisons among the three diagnostic categories and controls as regards the combined TPH x 5-HTTLPR genotype distribution. Schizophrenia subjects had a significantly different distribution of the genotype combination for TPH x 5-HTTLPR as compared to 241 controls or to unipolar or bipolar subjects, and had significantly higher frequencies of AA x ll and of AC x ss. Thus, an interaction between TPH and 5-HTTLPR genes constitutes susceptibility to schizophrenia, thereby yielding apparent relationships between the major psychiatric symptomatology scores and genotype combinations in samples that are obtained by pooling schizophrenia with other diagnostic categories.
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PMID:Interaction between the tryptophan hydroxylase gene and the serotonin transporter gene in schizophrenia but not in bipolar or unipolar affective disorders. 1562 7

The present study aimed to compare the effects of two currently used selective serotonin reuptake inhibitors (SSRIs) in Japan taking the individual background in 5-HTT gene-linked polymorphic region (5HTTLPR) genotype into account. Clinical responses to paroxetine and fluvoxamine were evaluated by total and cluster depressive symptoms for 81 Japanese patients who were diagnosed with major depression. Patients with the l allele had a greater percentage reduction on the total score (P=0.059) and somatic anxiety items (P=0.026) of the 21-item Hamilton Depression Rating Scale (HAM-D) score compared to s/s genotype carriers. Paroxetine was significantly more effective than fluvoxamine in the s/s carriers, as evaluated on the percentage reduction in total score (P=0.012) and core (P=0.049) HAM-D after 4 weeks of medication, but not in the l/s carriers. These findings suggest that the genetic test may be useful in investigating the efficacy of the two SSRIs, and that normalization by the 5HTTLPR genotypes may lead to improvement of the precision of comparative analysis.
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PMID:Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism. 1581 65

Allelic variants in the promoter region of the serotonin transporter (5-HTT) gene have been implicated in several psychiatric disorders and personality traits. In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele. The aim of this study was to compare the basal cerebral metabolic activity of non-psychiatric subjects in fronto-limbic structures to determine whether differences exist in basal metabolic activity within this functional polymorphism. PET scans with fluorine-18 fluorodeoxyglucose as radiotracer were performed in 71 non-psychiatric subjects previously screened for psychopathology and subsequently genotyped for SLC6A4; PET images were compared with SPM2 according to s/s (n = 27), s/l (n = 25), and l/l (n = 19) groups considering a significance threshold in a priori selected areas of P < 0.001 and an extent threshold > or =5 voxels. The analysis showed an effect of interest among the three genotype groups in right anterior cingulate gyrus (ACC), left middle frontal gyrus, and left posterior cingulate gyrus (PCC). Comparison between l/l vs. s/s showed increased metabolism for l/l in left middle frontal gyrus and an increase for s/s in right ACC and left PCC. Comparison between s/s vs. s/l showed an increase for s/s in left PCC and right ACC. Increased basal metabolism in fronto-limbic structures for the s/s group may be conceived as an "overactive metabolic state" of these structures, possibly related to an increased susceptibility for developing an anxiety-depression spectrum disorder.
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PMID:Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. 1585 Jul 37

Depressive disorders are among the most common psychiatric diseases, with prevalence estimates ranging from 5% to a maximum of 20%. Despite their high prevalence and socioeconomic impact, little is known about their etiology. Heritability estimates demonstrate up to a 50% genetic component based on family aggregation and contrasting monozygotic and dizygotic twin studies. The low relative risk to siblings ( lambda sib <1.5) makes the search for their genetic determinants very tedious. Gene-environment interaction has been recognized for a long time in the pathophysiology of depression, and its best biological substratum at present is represented by the serotonin transporter (5-HTT) gene, where several copies of its short allele culminate in depression and suicide in response to lifelong stress events. Many total genome scans have been performed with variable results, the most authoritative being the one of Utah pedigrees with a strong family history of major depression. It identified a locus on chromosome 12 encompassing a gene cluster and sex-specific predisposition. Nevertheless, recent genome scan meta-analysis yielded somewhat disappointing conclusions with a relatively low significance for quantitative trait loci on chromosomes 9, 10, 14, and 18. Studies on animal models have contributed to the chromosomal mapping of many behavioral traits, including anxiety, the stress response, and depression. Although F2 crosses constitute a classical approach, novel models of recombinant inbred strain and recombinant congenic strain animals allow for a rapid initial localization of any traits. This type of analysis has led us to uncover significant loci for the stress response and anxiety in rats and mice.
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PMID:Genetics and genomics of depression. 1587 6


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