Platelet activation and secretion in patients with major depression,thoracic aortic atherosclerosis,or renal dialysis treatment

Relatively little is known concerning the magnitude of alterations of platelet activation and secretion markers of patients with major depression when compared to patients at increased risk for, or with current, clinically significant atherosclerosis. Markers of in vivo platelet stimulation and secretion were measured under basal conditions in normal comparison subjects (n = 12) and three patient groups: patients diagnosed with DSM-IV major depression (n = 15), dialysis-dependent patients (n = 12), and patients with severe thoracic aortic atherosclerosis (n = 10). In comparison to normal comparison subjects, depressed patients and patients with thoracic aortic atherosclerosis exhibited the greatest platelet stimulation as detected by increased anti-LIBS platelet binding. Dialysis-dependent patients exhibited the highest plasma concentrations of the renally-excreted platelet-specific secretion protein, beta-thromboglobulin. This study extends previous observations of increased platelet activation in patients with major depression and documents similar alterations in patients with transesophageal echocardiography (TEE)-documented thoracic aortic atherosclerosis. Future studies will determine whether the magnitude of platelet stimulation and secretion in patients with comorbid depression and atherosclerotic aortic disease is greater than that observed in nondepressed patients with atherosclerotic aortic disease or major depression alone. These findings provide further evidence for either increased platelet activation and/or intrinsic heightened platelet reactivity as one of the biological substrates underlying the increased risk of depressed patients for cardiovascular disease.     

A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder

Serotonergic mechanisms are thought to play an important role in the pathogenesis of seasonal affective disorder (SAD). The expression of the serotonin transporter (5-HTT) is regulated in part by an insertion/deletion polymorphism in the serotonin transporter gene promoter region (5-HTTLPR). The 5-HTTLPR short allele (s) has been associated with anxiety-related personality traits and depression, and one study observed an association between the 5-HTTLPR s-allele and SAD and the trait of seasonality. We genotyped 138 SAD patients and 146 healthy volunteers with low seasonality for 5-HTTLPR. No difference between patients and controls was found for genotype distribution and s-allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depression subtypes. Melancholic depression was associated with the 5-HTTLPR long (l) allele and atypical depression with the 5-HTTLPR s-allele (two-sided Fisher's exact test: genotype distribution: P=0.0038; allele frequencies: P=0.007). Our data are compatible with the hypothesis of a disease process that is not causally related to 5-HTTLPR, but involves 5-HT neurotransmission and 5-HTTLPR somewhere on its way to phenotypic disease expression.     

Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients

OBJECTIVE: To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration. METHODS: Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used. RESULTS: There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. CONCLUSION: The results demonstrate a concentration-response relation for paroxetine in late-life depression and support the hypothesis for both a direct main effect and a moderating influence of 5-HTTLPR alleles on this concentration-response relation.     

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism.

BACKGROUND: A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS: SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS: Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS: Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.     

Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders

OBJECTIVE: The aim of this study was to examine the association between polymorphism in the serotonin transporter gene and citalopram effectiveness and side effects in children and adolescents with major depressive disorder (MDD) and/or anxiety disorders. METHODS: Outpatients, aged 7- 18 years with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) MDD and/or anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. Subjects were genotyped with respect to short (s) versus long (l) forms of the 5-HTTLPR polymorphism of the serotonin transporter, and the relationship between genotype and outcome and side effects was assessed. RESULTS: Subjects with 5-HTTLPR ss genotype showed a less vigorous response with regard to depressive symptoms measured by the Children's Depression Rating Scale-Revised (CDRS-R) scores over time compared to subjects with sl/ll genotypes (beta = 0.67, z = 2.02, p = 0.04). In addition, the 5-HTTLPR ss group exhibited lower rates of agitation compared to those with sl/ll genotype (6.3% vs. 32.8%, p = 0.05). Also, subjects with 5-HTTLPR ss genotype had consistently higher scores of suicidality at each week compared to the sl/ll group (beta = 0.76, z = 2.04, p = 0.04) as measured by item number 13 of the CDRS-R. CONCLUSIONS: The 5-HTTLPR ss genotype was associated with a poorer clinical response with regard to depressive symptoms as well with fewer reports of agitation. The 5-HTTLPR polymorphism may be a genetic marker of response to citalopram in children and adolescents with depression and/or anxiety.     

Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression

OBJECTIVE: The lower expressing allele of the serotonin transporter gene 5' promoter region (5-HTTLPR) polymorphism is reported to be associated with susceptibility to depression and suicidality in response to stressful life events. The authors examined the relationship of a triallelic 5-HTTLPR polymorphism to stressful life events, severity of major depression, and suicidality. METHOD: Mood disorder subjects (N=191) and healthy volunteers (N=125), all Caucasian subjects of European origin, were genotyped for the triallelic 5-HTTLPR polymorphism (higher expressing allele: L(A); lower expressing alleles: L(G), S). All subjects underwent structured clinical interviews to determine DSM-IV diagnoses, ratings of psychopathology, stressful life events, developmental history, and suicidal behavior. CSF 5-HIAA was assayed in a subgroup of subjects. RESULTS: Lower expressing alleles independently predicted greater depression severity and predicted greater severity of major depression with moderate to severe life events compared with the higher expressing L(A) allele. No associations with suicidal behavior and CSF 5-HIAA were found. CONCLUSIONS: Lower expressing transporter alleles, directly and by increasing the impact of stressful life events on severity, explain 31% of the variance in major depression severity. The biological phenotype responsible for these effects remains to be elucidated.     

Serotonin transporter polymorphisms and persistent, pervasive childhood aggression

OBJECTIVE: The purpose of this study was to examine the potential association of the serotonin transporter (5-HTT) gene and childhood aggression by testing the 5-HTT variable-number-tandem-repeat and serotonin transporter promoter polymorphism (5-HTTLPR), including the recently discovered Lg allelic variant of 5-HTTLPR. METHOD: Clinically referred children displaying extreme aggression, with a minimum 2-year history, were genotyped for 5-HTTLPR (N=77) and 5-HTT variable-number-tandem-repeat (N=78). Analyses compared genotype frequencies of the aggressive children with healthy comparison subjects. RESULTS: The "low expressing" genotypic variants of the 5-HTTLPR polymorphism (S/S, Lg/S, Lg/Lg) were significantly associated with childhood aggression. CONCLUSIONS: This is the first study to report a significant association between the 5-HTTLPR gene and childhood aggression.     

Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents

OBJECTIVE: To investigate possible associations between serotonin transporter (5-HTT) promoter genotypic variants (l/l, l/s, and s/s) and differential regulation of platelet 5-HTT functionality parameters in a group of drug-naive depressed children and adolescents and healthy controls. METHOD: Children and adolescents with major depression (n = 18) defined by DSM-III-R criteria and normal controls (n = 21) were assessed both for platelet serotonin functionality and for genotypic variants on 5-HTT promoter region. Four parameters were considered: (1) serotonin uptake rate (Vmax); (2) serotonin dissociation constant (K(m)); (3) paroxetine binding and density of site (Bmax); and (4) paroxetine dissociation constant (Kd). RESULTS: Depressed children had lower Vmax and K(m). Control subjects with l/l genotype had significantly higher Vmax than control subjects with l/s and s/s genotype. Control subjects with l/l genotype also had significantly higher Vmax than their depressed homologs. In contrast, Vmax was not significantly different between depressed and nondepressed subjects who carried the other 2 genotypes. The 5-HTT promoter genotype, diagnoses, or their interaction had no effect on the other serotonin parameters. CONCLUSIONS: While showing a significant decrease of Vmax and K(m) in a group of drug-naive depressed children and adolescents, these data suggest that l/l genotype has a substantial effect on the decrease of Vmax during a depressive episode.     

5-羟色胺基因多态性与抑郁症的相关性研究

目的：探讨5-羟色胺转运体(5-HTT)基因启动子区多态性(5-HTTLPR)与抑郁症的相关性及其对抗抑郁药疗效的影响。方法：运用聚合酶链反应技术(PCR)检测51例抑郁症患者(患者组)和60名健康对照者(对照组)5-HTTLPR的分布频率；并予文拉法辛治疗，用汉密尔顿抑郁量表(HAMD)观察疗效。结果：患者组5-HTTLPR的短重复序列／短重复序列(short／short，S／S)基因型和短重复序列(short，S)等位基因频率分别为71％和81％，对照组为45％和69％差异显著。治疗4周后，长重复序列／长重复序列(long／long，L／L)基因型患者的减分率显著高于其他两型。结论：5-HTTLPR的S／S基因型可能是抑郁症的易感基因之一，L／L基因型可能和更好的选择性5-羟色胺受体阻滞剂类(SSRIs)疗效有关。     

The influence of selective serotonin reuptake inhibitors on human platelet serotonin

Clinical depression has been proposed to be an independent risk factor for cardiovascular disease. While it is suggested that selective serotonin reuptake inhibitors (SSRIs) reduce the risk of acute cardiovascular problems of depressed patients, the effect of SSRIs on platelets, the only blood cells committed to serotonin (5-HT) transport, remains largely unknown.The goal of this pilot study was to measure the 5-HT levels in platelets of untreated and SSRI-treated depressed patients and normal subjects and to determine whether the interaction of SSRIs with platelets can explain their possible cardiovascular benefit in patients with depression. Platelet 5-HT was determined by an immunocytochemical assay and high-pressure liquid chromatography with electrochemical detection (HPLC-ECD). In normal control subjects without cardiovascular disease, 78 +/- 8% of platelets were 5-HT-positive (n = 14). Depression caused a significant reduction in platelet 5-HT to 46 +/- 21% in untreated patients (n = 13) and 22 +/- 13% in SSRI-treated patients (n = 14). As a class, all selective serotonin reuptake inhibitors significantly reduced the 5-HT concentration in patient platelets. An inverse relationship of 5-HT level and dose of medication might be suggested.These results correlated well with 5-HT data from HPLC (r = 0.8509, p < 0.001). SSRIs did not affect platelet aggregation and dense granule release in response to thrombin, but significantly reduced ADP-induced platelet aggregation and dense granule release in both patient and normal control samples. The active inhibition of platelet aggregation by SSRIs might explain their cardiovascular benefit.     

Depressed patients have higher body temperature: 5-HT transporter long promoter region effects

BACKGROUND: Depression has been associated with a decrease in intracellular serotonin (5-HT) reuptake through its transporter, SERT. The 5-HT transporter long promoter region (5-HTTLPR) deletion in the SERT gene has also been associated with a decrease in 5-HT reuptake. Conversely, increases in extracellular 5-HT have been associated with increased temperature. It has not been established, however, whether body temperature in depressed patients is different from controls. Here, we hypothesized that temperature would be increased in depressed patients as well as in those with the 5-HTTLPR deletion. METHODS: A strict oral temperature protocol employed single, cross-sectional, naturalistic time-of-day temperature measures in 125 subjects (46 normal controls, 79 outpatients with major depression). Controls and depressed patients were free of psychotropic medication and classified by the Structured Clinical Interview for Psychiatric Diagnoses. Eighty-one of the subjects (68 depressed, 13 normal) were additionally genotyped for 5-HTTLPR polymorphisms. RESULTS: Depressed patients had a significantly higher uncorrected body temperature (mean +/- SD 98.38 +/- 0.61 degrees F) than controls (mean +/- SD 98.13 +/- 0.59 degrees F; F = 4.8, p = 0.03). An age (F = 14.09, p < 0.001) and time-of-day (11.4, p = 0.001) correction revealed a more robust (F = 14.02, p < 0.001) difference between depressed patients (mean +/- SD 98.44 +/- 0.55 degrees F) and controls (mean +/- SD 98.02 +/- 0.56 degrees F). When normalized for age and circadian differences between subjects, random, outpatient oral temperatures had a sensitivity of 63% and a specificity of 76% in identifying the depressed subjects from the controls. Independent of depression, subjects with the 5-HTTLPR deletion (short SERT allele) were warmer (mean +/- SD 98.33 +/- 0.65 degrees F) than those lacking the short allele on either chromosome (mean +/- SD 97.91 +/- 0.69 degrees F; F = 7.0, p = 0.01). However, the genotype did not explain the temperature differences between controls and depressed patients. CONCLUSION: This is the first demonstration of an increased daytime body temperature in cases with major depression. Subjects with a corrected temperature above 98.3 degrees F were 2.6-fold more likely to be depressed. The results may strengthen the hypothesis of an inflammatory component of depression. In addition, the findings suggest a potential link between genetic differences in 5-HT transport and body temperature.     

A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide

BACKGROUND: Major depression and suicide are associated with fewer serotonin transporter (5-HTT) sites. The 5'-flanking promoter region of the 5-HTT gene has a biallelic insertion/deletion (5-HTTLPR). We assayed prefrontal cortical (PFC) 5-HTT binding in major depression and suicide and examine the relationship to the 5-HTTLPR allele. METHODS: Postmortem brain samples from 220 individuals were genotyped for the 5-HTTLPR polymorphism. Binding of 5-HTT was assayed by quantitative autoradiography in the PFC of a subset of subjects (n = 159). Clinical information, including DSM-III-R Axis I diagnoses, was obtained by psychological autopsy and medical chart review. RESULTS: Binding to 5-HTT was lower in the ventral PFC of suicides compared with nonsuicides and was lower throughout the PFC of subjects with a history of major depression. The 5-HTTLPR genotype was associated with major depression but not with suicide or 5-HTT binding. CONCLUSIONS: A diffuse reduction of 5-HTT binding in the PFC of individuals with major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathologic features in major depression. The localized reduction in 5-HTT binding in the ventral PFC of suicides may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. The 5-HTTLPR genotype was not related to the level of 5-HTT binding and does not explain why 5-HTT binding is lower in major depression or suicide. Arch Gen Psychiatry. 2000;57:729-738     

Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia

The well-replicated platelet hyperserotonemia of autism has stimulated interest in serotonin (5-HT) in autism. We have examined the effects of the serotonin transporter gene (5-HTT, locus SLC6A4) promoter polymorphism (5-HTTLPR) on platelet 5-HT physiology in autism. Platelet 5-HT uptake rates and affinities (V(max) and K(m)), uptake site densities (B(max)) and 5-HT levels were examined in 31 French individuals with autism genotyped with respect to the 5-HTTLPR. Platelet 5-HT uptake and 5-HT levels were measured using HPLC; uptake sites were determined by radioligand binding. A 1.5-fold increased rate (V(max)) of platelet 5-HT uptake was observed in ll genotype individuals compared to those with ls and ss genotypes (Mann- Whitney U-test, P = 0.022). However, no significant relationship was observed between genotype and uptake site density (U-test, P = 0.51). Although median levels of platelet 5-HT in platelet-rich plasma were higher in the ll group, only trend level significance was observed (U-test, P= 0.069); platelet 5-HT content measured in whole blood was similar across genotypes. Uptake rates were well correlated with B(max) values (r = 0.66, P = 0.002); correlations between uptake and platelet 5-HT levels and between B(max) values and 5-HT levels were somewhat lower. While 5-HTTLPR alleles had an appreciable effect on platelet 5-HT uptake rates, effects on 5-HT levels and uptake site density were smaller or absent. Based on these preliminary data and prior studies of allele frequencies, we conclude that the 5-HTTLPR is not a major determinant of the group mean platelet serotonin elevation seen in autism. However, a role for increased uptake in the hyperserotonemia of autism can not be ruled out. In addition, it appears that studies of platelet 5-HT measures in autism and other disorders should take account of the effects of 5-HTTLPR genotype on 5-HT uptake     

Fluoxetine-induced alterations in human platelet serotonin transporter expression: serotonin transporter polymorphism effects

OBJECTIVE: Long-term antidepressant drug exposure may regulate its target molecule - the serotonin transporter (SERT). This effect could be related to an individual's genotype for an SERT promoter polymorphism (human serotonin transporter coding [5-HTTLPR]). We aimed to determine the effects of fluoxetine exposure on human platelet SERT levels. METHOD: We harvested platelet samples from 21 healthy control subjects. The platelets were maintained alive ex vivo for 24 hours while being treated with 0.1 muM fluoxetine or vehicle. The effects on SERT immunoreactivity (IR) were then compared. Each individual's SERT promoter genotype was also determined to evaluate whether fluoxetine effects on SERT were related to genotype. RESULTS: Fluoxetine exposure replicably altered SERT IR within individuals. Both the magnitude and the direction of effect were related to a person's SERT genotype. People who were homozygous for the short gene (SS) displayed decreased SERT IR, whereas those who were homozygous for the long gene (LL) demonstrated increased SERT IR. A mechanistic experiment suggested that some individuals with the LL genotype might experience increased conversion of complexed SERT to primary SERT during treatment. CONCLUSIONS: These preliminary results suggest that antidepressant effects after longer-term use may include changes in SERT expression levels and that the type and degree of effect may be related to the 5-HTTLPR polymorphism.     

Possible association between serotonin transporter promoter region polymorphism and impulsivity in Koreans

Serotonin has become the major focus of biological studies of suicidal behavior and impulsive-aggressive behavior in humans. The serotonin transporter (5-HTT) gene is one of the important genes involved in the regulation of serotonin transmission. We examined the association of impulsivity in Korean populations with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). We recruited 186 adolescent prisoners and 64 medical students. Impulsivity was measured using the Barratt Impulsiveness Scale and we divided all subjects into three groups: impulsive subjects (IS, N=121), non-impulsive subjects (NIS, N=115) and an intermediate group (excluded, N=14). The 5-HTTLPR genotype was determined by polymerase chain reaction. All subjects were Korean men unrelated to each other. There were no significant differences in the genotype frequency of 5-HTTLPR-S/S, S/L and -L/L between the two groups in the Korean population (IS vs. NIS: 47.9 vs. 61.7%; 43.0 vs. 32.2%; and 9.1 vs. 6.1%, respectively). However, there was a statistically significant difference in allelic frequency of 5-HTTLPR-S and 5-HTTLPR-L between the two groups in the Korean population (IS vs. NIS: 69.4 vs. 77.8%; and 30.6 vs. 22.2%, respectively. From our results, this 5-HTTLPR polymorphism appears to be a possible candidate gene for impulsivity in the Korean population.