Blood Serotonin Levels Research Articles

Platelet Serotonin Content and Transpulmonary Platelet Serotonin Gradient in Patients with Pulmonary Hypertension

Background: The serotonin system has repeatedly been associated with the pathogenesis of pulmonary hypertension (PH). Objective: To comparatively analyze plasmatic and intrathrombocytic serotonin levels in arterial and mixed venous blood of patients with PH and unaffected controls to elucidate pulmonary serotonin metabolisms. Patients and Methods: Catheters were placed in the radial and pulmonary artery in patients with PH (n = 13) for diagnosis and in age-matched controls (n = 6) undergoing percutaneous closure of the patent foramen ovale. Arterial and mixed venous blood samples were immediately centrifuged to obtain plasma and platelets and thereafter frozen at –20°C. After careful thawing, plasmatic and platelet serotonin levels were determined by ELISA. Results: PH was classified as arterial in 4 and chronic thromboembolic in 9 patients with a mean pulmonary artery pressure of 37 (interquartile range: 32–43) mm Hg. Platelet serotonin content was significantly lower in the PH patients than in the controls. The mean transpulmonary gradient (arterial-mixed venous) was negative in the PH group and positive in the controls. An inverse correlation was found between the arterial blood platelet serotonin content and pulmonary hemodynamics. Plasmatic serotonin levels did not differ between the PH and control groups. Conclusion: The lower platelet serotonin concentration in PH patients compared with unaffected controls is an unprecedented finding. The negative transpulmonary platelet serotonin gradient and the strong negative correlation of arterial blood platelet serotonin with pulmonary hemodynamics might indicate increased serotonin uptake in the lungs of PH patients.

Meta-analysis of whole blood serotonin levels at resting state in healthy subjects

Meta-analysis of whole blood serotonin levels at resting state in healthy subjects

Relationship between whole blood serotonin and repetitive behaviors in autism

This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated.

Impact of Therapeutics On Fatigue in Chronic Immune Thrombocytopenia (ITP).

Abstract 4455Complaints of tiredness, lethargy or lack of energy are common in patients with chronic Immune ThrombocytoPenia (ITP), however they are not well understood. This study assessed whether different clinical and laboratory aspects are related to fatigue and how different therapeutic modalities might impact these symptoms. MethodsPatients with chronic ITP older than 15 years old were enrolled from 2007-2008 at the Platelet Disorders Center at the Weill-Cornell Medical Center, NY. They completed the Short-Form 36 questionnaire (SF-36) and Fatigue severity scale (FSS) (2 standardized Health-related quality of life [HRQoL] questionnaires) and the Beck Depression Inventory (BDI). Laboratory testing included CBC, TSH, ferritin, iron + TIBC, and blood serotonin levels. Results83 patients with a mean age of 40.2 years (67.5% women) were enrolled. The mean platelet counts were 109,000/ul (range of 12,000-500,000/ul). Forty-one % of patients had duration of ITP of 10 years or more and 25% had had previous splenectomy. Sixty-one% were on treatment: 11% steroids, 23% Tpo-R agents and 28% “Other” (7.2 % Rigel, 13.3 % IVIG, 3.6 % anti-D, 2.4 % rituximab and 1.2% Danazol/Azathioprine). Surprisingly, analysis of the SF36 showed that the study (ITP) population is similar to the general US population and that they do not report increased fatigue or depression. These results contrast with a previous report by McMillan, AJH, 2007 (fig 1). However when the current patients were divided according to age, abnormal low scores on SF36 were observed on vitality domain (mean 50) for the age group of 45-55 years and on role physical domain (mean 48) for the age group of 55-65 years. Furthermore, differences were observed in patients stratified according to treatment (figure 2) where the mean scores for patients on the steroid group on the respective domains were lower: vitality 49 and role physical 42. The Tpo-R agonists group had better results in all SF36 domains; similar findings were seen with the FSS and BDI. The only laboratory finding is that patients with low ferritin levels had worse results on FSS. ConclusionAlthough fatigue and related symptoms have been previously reported by others including an improvement with successful treatment eg in studies of the TPO-R agonists, to our surprise we did not find the same results. Whether this study population is intrinsically different or receiving different treatments, eg avoidance of steroids, might impact these results here are 2 possible hypotheses. Use of different fatigue assessments as ITP-PAQ or CDC symptom inventory and further studies addressing the role of the pro-inflammatory cytokines in these patients would be useful. Disclosures:No relevant conflicts of interest to declare.

Serotonin Effects on Sleep and Emotional Disorders in Adolescent Migraine

To determine frequency of emotional disorders and sleep disturbances in adolescent migraineurs with episodic and chronic headaches. To determine the relationship of whole blood serotonin, caffeine consumption, and frequency of sleep and mood disorders. The neurotransmitter serotonin has been implicated to play a role in the initiation and maintenance of sleep and in modulating mood. A putative role in migraine pathophysiology is also known. Adolescents from 13 to 17 years of age were identified from our headache clinic with episodic or chronic migraine (according to International Classification of Headache Disorders-Second Edition criteria) and healthy controls enrolled. Psychological rating scales were completed, including Adolescent Symptom Inventory (4th Edition) and Child Depression Inventory. Sleep questionnaires (Pediatric Sleep Questionnaire and Child Sleep Habit Questionnaire) were completed by the teenager's parents/guardian. Whole blood serotonin levels were drawn and analyzed and caffeine consumption obtained by history. A total of 18 controls (8 girls) and 15 patients each with episodic migraines (9 girls) and chronic migraine (10 girls) were studied. Patients with headache had significantly more sleep problems than controls. Patients with chronic migraines had increased daytime sleepiness and dysthymia compared with teenagers with episodic migraines. Serotonin levels were not significantly different, and no association was noted between serotonin levels and sleep abnormalities or emotional rating scales. Increased caffeine intake was related to sleep and depressive complaints. Sleep and emotional disorders were common in adolescents with migraine. Sleep disorders and dysthymia were more prevalent with increased headache frequency. No correlation was noted with whole blood serotonin levels.

Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves

Heart valve disease and pulmonary hypertension, in patients with carcinoid tumors and people who used the fenfluramine-phentermine combination for weight control, have been associated with high levels of serotonin in blood. The mechanism by which serotonin induces valvular changes is not well understood. We recently reported that increased oxidative stress is associated with valvular changes in aortic valve stenosis in humans and mice. In this study, we tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species. Superoxide (O2*.-) was measured in heart valves from explanted human hearts that were not used for transplantation. (O2*.-) levels (lucigenin-enhanced chemoluminescence) were increased in homogenates of cardiac valves and blood vessels after incubation with serotonin. A nonspecific inhibitor of flavin-oxidases (diphenyliodonium), or inhibitors of monoamine oxidase [MAO (tranylcypromine and clorgyline)], prevented the serotonin-induced increase in (O2*.-). Dopamine, another MAO substrate that is increased in patients with carcinoid syndrome, also increased (O2*.-) levels in heart valves, and this effect was attenuated by clorgyline. Apocynin [an inhibitor of NAD(P)H oxidase] did not prevent increases in (O2*.-) during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated (O2*.-), and this effect was prevented by an MAO inhibitor. In conclusion, we have identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.

Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q

Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P <or= 1.3 x 10(-7)) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P = 7.3 x 10(-12) and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.

Hyperprolactinaemia and hyperserotoninaemia: their relationship to seminal quality.

Seminal quality and levels of blood serotonin (5-HT) and serum prolactin (PRL) were determined in 60 men attending an infertility service. Subjects were grouped according to normal or abnormal accessory sex gland function. Subjects with normal accessory sex gland function were further subdivided into groups with asthenozoospermia, polyzoospermia, normozoospermia, oligozoospermia, or azoospermia. Blood 5-HT levels were significantly higher in oligozoospermics (115.9 +/- 23.7 ng ml-1, P less than 0.05), and asthenozoospermics (90.0 +/- 8.2 ng ml-1, P less than 0.05), than in normals (68.5 +/- 5.3 ng ml-1), whereas serum PRL levels were higher in azoospermics (44.2 +/- 4.7 ng ml-1) than in normozoospermics (15.9 +/- 1.6 ng ml-1, P less than 0.01). Subjects with abnormal accessory sex gland function were also subdivided according sperm count and sperm motility categories. None of these subgroups showed differences in serum PRL levels or blood 5-HT levels. Men with hyperserotoninaemia had higher serum PRL levels, low sperm count, and low motile sperm concentration. Moreover, higher 5-HT levels may be observed in men with normal PRL levels and also associated with normal PRL levels and with hyperprolactinaemia, and hyperprolactinaemia may be observed also associated with normal serotonin levels. Hyperserotoninaemia was related to both diminished sperm count and sperm motility, whereas hyperprolactinaemia was related to low sperm count. When hyperprolactinaemia and hyperserotoninaemia were both present, additive effects were observed.

Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration

The serotonin transporter is implicated in the uptake of the vasoconstrictor serotonin from the circulation into the platelets, where 95% of all blood serotonin is stored and released in response to vascular injury. In vivo studies indicated that platelet-derived serotonin mediates liver regeneration after partial hepatectomy. We have recently generated serotonin transporter knockout rats and demonstrated that their platelets were almost completely depleted of serotonin. Here we show that these rats exhibit impaired hemostasis and contain about 1-6% of wild-type serotonin levels in the blood. Despite the marked reduction of serotonin levels in blood and platelets, efficient liver regeneration and collagen-induced platelet aggregation occur in rats lacking the serotonin transporter. These results provide evidence that liver regeneration is not dependent on the release of serotonin from platelets. Our findings indicate that very low levels of serotonin in blood are sufficient for liver regeneration.

Development of central and peripheral serotonin-producing systems in rats in ontogenesis

The work deals with study of development of central and peripheral serotonin-producing systems in rat ontogenesis before and after formation of the blood-brain barrier. By the method of highly efficient liquid chromatography it has been shown that the serotonin level in peripheral blood before formation of the blood-brain barrier (in fetuses and neonatal rats) is sufficiently high for realization of physiological effect on target cells and organs. At the period of formation of the blood-brain barrier the serotonin level in brain sharply rises, whereas the serotonin concentration and amount in plasma and duodenum increase insignificantly. Completion of formation of the blood-brain barrier is accompanied by a significant increase of the serotonin content in duodenum, probably for maintenance of the high serotonin level in blood. To evaluate secretory activity, the mean rate of daily increment of the serotonin in the studied tissues was calculated. In brain, this parameter was maximal at the period of formation of the blood-brain barrier and then sharply fell, whereas in duodenum it rose markedly after completion of the barrier formation. In plasma this parameter decreased statistically significantly at the period of formation of the blood-brain barrier - from the 4th to the 16th postnatal days. This allows thinking that brain before formation of the blood-brain barrier is a most important source of serotonin in peripheral blood.

Pathogenical meaning of serotoninergic mechanisms in the development of idiopatic generalised forms of epilepsy

Neurotransmitters disturbances with the certain role of serotoninergic system are in the basis of pathogenesis of epilepsy. 46 patients (29 females, 17-males) with idiopatic generalized epilepsy (mean age 21,8 ± 1,82) were investigated. In 30,4% of patients depressive disorders were revealed. Significant decreasing of blood serotonin level in patients with during the interictal period which decreased more after the generalised convulsive and myoclonic seasures was found by the immune assay method.

Clinical correlates of blood serotonin levels in patients with mastocytosis

Mastocytosis is a clonal disorder associated with an increased mast cell burden. We have recently demonstrated the ability of human mast cells to express and be activated through multiple serotonin receptors; to synthesize and release serotonin; and that mastocytosis patients may have abnormal serotonin levels. As serotonin has been implicated in the genesis of clinical symptoms found in association with some chronic diseases, we have now determined the whole blood serotonin levels in 29 patients diagnosed with mastocytosis, and correlated these levels with multiple clinical and laboratory parameters. Patients with mastocytosis were categorized according to disease variant. Blood serotonin values were determined and correlated with values reported for normal subjects; and clinical and laboratory features of the disease. Total blood serotonin levels followed a bimodal distribution in line with our earlier report, unlike the normal distribution reported for normal individuals. Serotonin levels did not correlate with platelet numbers, liver function tests or serum tryptase levels. Patients with lower serotonin values had greater rates of fatigue (P = 0.0001), migraine headaches (P = 0.0028), psychiatric symptoms (P = 0.0001), diarrhoea (P = 0.0407), flushing (0.0085), and abdominal and bone pain (P = 0.0001). Our study suggests that low blood serotonin levels help define a sub-group of patients with mastocytosis that are more likely to present with neurological and gastrointestinal complaints, and suggests that the use of pharmacologic agents that alter blood serotonin levels could be explored in selected patients.

Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum

Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.

Changes in Mood States and Biomarkers During Peginterferon and Ribavirin Treatment of Chronic Hepatitis C

Depression is a frequent side effect of interferon therapy in patients with chronic hepatitis C (CHC). The aim of this study was to identify baseline and on-treatment predictors of depression in CHC patients receiving peginterferon and ribavirin. In total, 201 prior nonresponders with advanced fibrosis were treated with peginterferon alfa-2a and ribavirin for 24 wk in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial. Of these, 74 continued on antiviral therapy through week 48. Mood states were assessed with the Beck Depression Inventory II and the Composite International Diagnostic Interview. Plasma cortisol and whole blood serotonin levels were measured in 101 subjects at weeks 0, 4, 24, 48, and 72. The incidence of interferon-induced depression was 23% and 42% at weeks 24 and 48, respectively. Although 22% of patients had baseline depression, the absence of a week 20 virological response was the only independent predictor of interferon-induced depression at week 24 (P = 0.0009). Plasma cortisol levels did not change during treatment nor correlate with depression. In contrast, whole blood serotonin/platelet levels significantly decreased during treatment, but did not correlate with interferon-induced depression through week 24 (P = 0.35), nor through week 48 (P = 0.51). Depression during peginterferon and ribavirin therapy was associated with a lower antiviral response. The significant reduction in whole blood serotonin levels over time suggest that further studies of the serotonergic pathway are warranted to identify the mediators of interferon-induced depression.

Comparison of whole blood serotonin (5-HT) level between pre- and post-menstrual phases in human.

Comparison of whole blood serotonin (5-HT) level between pre- and post-menstrual phases in human.

Lower levels of whole blood serotonin in obsessive-compulsive disorder and in schizophrenia with obsessive-compulsive symptoms

It has been reported that some schizophrenic patients suffer from obsessive-compulsive symptoms (OCS), and clozapine treatment is quite often associated with an occurrence/increase of OCS in schizophrenic patients. The aim of the study was to explore whether differences would exist in the clinical symptomatology and the whole blood serotonin (5-HT) concentrations in patients with obsessive-compulsive disorder (OCD), schizophrenic patients with and without OCS (S + OCS, S − OCS), and clozapine-treated schizophrenic patients with and without clozapine-induced OCS (CLZ + OCS, CLZ − OCS). We found that S + OCS patients ( n = 15) showed significantly lower scores on the Hamilton Anxiety Scale (HAMA), but similar levels of compulsions and obsessions using Yale-Brown Obsessive-Compulsive Scale (YBOCS) as compared to the patients ( n = 35) with OCD. S + OCS patients scored significantly lower on the Positive and Negative Syndrome Scale (PANSS) but higher on the Hamilton Depression Scale (HAMD) compared with S − OCS patients ( n = 19). However, CLZ + OCS patients ( n = 15) suffered from dominant compulsions but fewer obsessions compared with the OCD and S + OCS patients. OCD, S + OCS and CLZ + OCS groups had significantly lower levels of whole blood 5-HT than did the healthy volunteers ( n = 15), S − OCS and CLZ − OCS groups. It suggests that alterations in serotonin metabolism may be a common biological characteristic of OCS in OCD as well as in schizophrenia.

Ontogeny of brain and blood serotonin levels in 5‐HT1A receptor knockout mice: potential relevance to the neurobiology of autism

The most consistent neurochemical finding in autism has been elevated group mean levels of blood platelet 5-hydroxytryptamine (5-HT, serotonin). The origin and significance of this platelet hyperserotonemia remain poorly understood. The 5-HT(1A) receptor plays important roles in the developing brain and is also expressed in the gut, the main source of platelet 5-HT. Post-natal tissue levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan were examined in the brain, duodenum and blood of 5-HT(1A) receptor-knockout and wild-type mice. At 3 days after birth, the knockout mice had lower mean brain 5-HT levels and normal mean platelet 5-HT levels. Also, at 3 days after birth, the mean tryptophan levels in the brain, duodenum and blood of the knockout mice were around 30% lower than those of the wild-type mice. By 2 weeks after birth, the mean brain 5-HT levels of the knockout mice normalized, but their mean platelet 5-HT levels became 24% higher than normal. The possible causes of these dynamic shifts were explored by examining correlations between central and peripheral levels of 5-HT, 5-HIAA and tryptophan. The results are discussed in relation to the possible role of 5-HT in the ontogeny of autism.

Hyperserotoninemia and Altered Immunity in Autism

One of the most consistent biological findings in autism is elevated whole blood serotonin (5-HT) levels found in about 1/3 of cases. Immune abnormalities are also commonly observed in this disorder. Given 5-HT's role as an immunomodulator, possible connections between 5-HT and immune abnormalities in autism are explored in this review. Areas of focus include hyperserotoninemia and cellular immune function, autoantibodies to 5-HT receptors, and 5-HT's role in autoimmunity. Further research is needed to determine the interactions between neuropsychiatric and immune dysfunction in autism and related disorders.

Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample

A recent genome-scan identified the Leu33Pro polymorphism in the beta3 integrin (ITGB3) gene as a quantitative trait locus for whole blood serotonin level in a large Hutterite pedigree. Because both the Leu33Pro polymorphism and the serotonin system have been implicated in cardiovascular disease (CVD) risk and treatment response, we studied additional variation in ITGB3 and its relationship to intermediate phenotypes associated with CVD in the same population. We examined associations between 15 single nucleotide polymorphisms (SNPs) across ITGB3 and five CVD-related traits in the Hutterites: plasma levels of high density lipoprotein-cholesterol (HDL-c), triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), and lipoprotein(a) [Lp(a)] and blood pressure or hypertension. Seven of these SNPs in ITGB3 were associated with whole blood serotonin. Among the intermediate CVD-related phenotypes, only Lp(a) was associated with multiple ITGB3 SNPs, five of which were also associated with serotonin. A sex-stratified analysis revealed that the association between ITGB3 and Lp(a) is present only in females, whereas the association between ITGB3 and serotonin is concentrated in males. Our results suggest that variation in ITGB3 in addition to Leu33Pro could contribute to susceptibility to CVD and serotonin in a sex-specific manner.

Sex-Specific Genetic Architecture of Whole Blood Serotonin Levels

Recently, a quantitative-trait locus (QTL) for whole blood serotonin level was identified in a genomewide linkage and association study in a founder population. Because serotonin level is a sexually dimorphic trait, in the present study, we evaluated the sex-specific genetic architecture of whole blood serotonin level in the same population. Here, we use an extended homozygosity-by-descent linkage method that is suitable for large complex pedigrees. Although both males and females have high broad heritability (H2=0.99), females have a higher additive component (h2=0.63 in females; h2=0.27 in males). Furthermore, the serotonin QTL on 17q that was identified previously in this population, integrin beta 3 (ITGB3), and a novel locus on 2q influence serotonin levels only in males, whereas linkage to a region on chromosome 6q is specific to females. Both sexes contribute to linkage signals on 12q and 16p. There were, overall, more associations meeting criteria for suggestive significance in males than in females, including those of ITGB3 and the serotonin transporter gene (5HTT). This analysis is consistent with heritable sexual dimorphism in whole blood serotonin levels resulting from the effects of a combination of sex-specific and sex-independent loci.