Sexual dysfunction in patients with MDD treated with SSRIs - causes, measurement and prevention

Major Depressive Disorder(MDD) is serious psychiatric condition and they affect one in five people during their lifetime, the annual prevalence rates for the US population are 7.1% among adults, slightly more common among women (8.7%) than men (5.3%). Selective serotonin reuptake inhibitors are among the pharmacological agents most commonly used in the treatment of MDD. The mechanism of action of antidepressants is not yet fully understood. Currently, it is believed that the mechanism of the so-called down-regulation, i.e. reducing the density of receptors in the postsynaptic membrane, in this case mainly 5HT2 receptors. All of the antidepressants in use today have some common side effects. The side effect that will be discussed in the broadest possible way in this paper are sexual dysfunctions appearing during the therapy. Measuring the degree to which a given substance affects the sexual function of a patient diagnosed with MDD encounters many difficulties on its way. There are currently several questionnaires enabling such an assessment, the most common are CSFQ, ASEX and SexFX. Also the major problem is Post SSRI Sexual Disfunction. A number of animal studies have proven that prolonged exposure to SSRIs leave permanent changes in the CNS, but unfortunately, similar studies have not yet been conducted in humans. The aim of this study is to present the problem of sexual dysfunction as a side effect of SSRI therapy, to present the causes and to propose a strategy to combat SSRI-induced sexual dysfunctions.

Peripheral serotonin causes dengue virus–induced thrombocytopenia through 5HT2 receptors

Dengue virus (DENV) is the most prevalent vector-borne viral pathogen, infecting millions of patients annually. Thrombocytopenia, a reduction in circulating platelet counts, is the most consistent sign of DENV-induced disease, independent of disease severity. However, the mechanisms leading to DENV-induced thrombocytopenia are unknown. Here, we show that thrombocytopenia is caused by serotonin derived from mast cells (MCs), which are immune cells that are present in the perivascular space and are a major peripheral source of serotonin. We show that during DENV infection, MCs release serotonin, which prompts platelet activation, aggregation, and enhanced phagocytosis, dependent on 5HT2A receptors. MC deficiency in mice or pharmacologic inhibition of MCs reversed thrombocytopenia. Furthermore, reconstitution of MC-deficient mice with wild-type MCs, but not MCs lacking serotonin synthesis resulting from deficiency in the enzyme tryptophan hydroxylase-1, restored the thrombocytopenic phenotype. Exogenous serotonin was also sufficient to overcome the effects of drugs that inhibit platelet activation in vitro and to restore thrombocytopenia in DENV-infected MC-deficient mice. Therapeutic targeting of 5HT2A receptors during DENV infection effectively prevented thrombocytopenia in mice. Similarly, serotonin derived from DENV-activated human MCs led to increased human platelet activation. Thus, MC-derived serotonin is a previously unidentified mechanism of DENV-induced thrombocytopenia and a potential therapeutic target.

Vibrational Dynamics of 2-[3-(p-flourobenzoyl) Propyl]-1,2,3,4,6,7,12,12, a-octahydropyrazino[2′,1&prime:6,1] Pyrido [3,4-b] Indole [centbutindole]: A Potent Nuroleptic Drug

FITR spectra and normal mode analysis of compound 2-[3-(p-flourobenzoyl)propyl]-1,2,3,4,6,7,12,12, a-octahydropyrazino[2′,1′:6,1] pyrido [3,4-b] indole [centbutindole], which is a potent nuroleptic drug and belong to a series of 2-substituted pyrazino-pyrido indoles. It also blind with 5HT2 receptors. It has shown good antihypotensive activity. The well known Wilson’s G-F matrix method with Urey-Bradely force field has been used to evaluate the normal mode frequencies of vibration. Good agreement has been obtain between them and a set of 29 force field constants is established. The vibrational dynamics of the title compound is being reported using Urey Bradley force field. It has shown acute toxicity, gross behavior and central effects like anti convulsant activity, anti reserpine activity and stereo specificity of action. The conformation of the title compound was determined by X-ray diffraction. It is planned to determine the conformation in such cases by the application of Fourier Transform Infrared (FITR) spectroscopy and normal mode analysis. As a first step in this direction the FITR spectrum of the title compound has been recorded and its normal mode analysis is carried out. The assignments of the frequencies are based on the theoretically calculated frequencies have also been given their best assignment.

The Molecular Mechanisms of Serotonin in the Regulation of Megakaryocytopoiesis and TPO Production

Abstract 3347 We have reported that serotonin (5-HT) show a promoting effect on cord blood CD34+ stem/progenitor cells (Yang et al, Stem Cells 2007). We also demonstrated that serotonin enhances murine megakaryopoiesis via 5-HT2 receptors (Yang et al. Blood Coagul Fibrinol 1996). In this present study, we explored how serotonin regulated human megakaryocytopoiesis, proplatelet formation, and thrombopoietin (TPO) production. Our results indicated that serotonin significantly promoted human CFU-MK formation and reduced apoptosis in megakaryocytes through phosphorylation of Akt. These effects were attenuated by addition of ketanserin, a 5-HT2 receptor inhibitor. In addition, serotonin was able to stimulate the F-actin reorganization in megakaryocytes through activating the p-Erk1/2 expression. Bone marrow mesenchymal stromal cells (MSCs) are important in regulating megakaryocytopoiesis through stimulating release of thrombopoietic growth factor, such as TPO. Our studies suggested that when activated by serotonin, bone marrow MSCs were induced to release significant amount of TPO by q-PCR, ELISA and cytokine-array assays. Our findings demonstrated an important role of serotonin played on megakaryocytopoiesis. This effect was likely mediated via 5HT2 receptors with subsequent activation of Akt and Erk 1/2 phosphorylation, which led to survival of megakaryocytes and proplatelet formation. Serotonin also stimulated TPO released from MSCs, which indirectly promoted megakaryopoiesis. In present studies, we have demonstrated a positive “feed-back” control loop between MK-derived granule- serotonin and megakaryocytopoiesis. These findings improved our knowledge on megakaryocytopoiesis regulation and provided new clues on identifying novel thrombopoietic agents. It also deepened our understandings on how TPO production is regulated. Disclosures: No relevant conflicts of interest to declare.

Dynamics of platelet mobilisation into lungs in response to 5-hydroxytryptamine (serotonin) in mice

SummaryIn experimental animals, the lung rapidly removes intravenously injected 5-hydroxytryptamine (5HT), but the mechanism underlying this pulmonary 5HT removal (P-5HT-R) and the responsible cells remains unclear. 5HT reportedly induces rapid pulmonary platelet accumulation (P-PLT-A). Here, we examined the relationship between P-5HT-R and P-PLT-A in mice by comparing the platelet count in the blood with the endogenous 5HT in the tissues (a marker for platelets because the 5HT is largely contained within platelets). 5HT levels in murine blood and tissues were also examined after intravenous injection of 5HT. The data revealed that: (i) 5HT injection (at ≥ 0.04 μmol/kg) induced a transient P-PLT-A (occurring within 6 seconds), (ii) platelets rapidly took up injected 5HT, (iii) the P-5HT-R was saturated following injection of 5HT at 1 μmol/kg, (iv) ketanserin (5HT2-receptor antagonist) strongly inhibited P-PLT-A, (v) under fluoxetine (5HT-uptake inhibitor), 5HT levels at 6 seconds after 5HT injection were markedly higher in blood, but significantly lower in lung (versus fluoxetine-untreated mice), (vi) P-5HT-R was barely detectable in mutant mice with platelets lacking dense bodies, and was much reduced in platelet-depleted mice, (vii) 5HT injected intravenously at 10 μmol/kg had a half-life in the lung of < 20 seconds, and (viii) unlike 5HT, injected histamine was largely excreted by the kidney. These results demonstrate that platelets rapidly translocate into the lung upon stimulation of 5HT2 receptors, take up 5HT (and possibly swiftly metabolise it), and then return to the circulation. Hence, pulmonary platelet accumulation plays an important role in pulmonary 5HT removal in mice.