Effect and mechanism of serotonin-selective reuptake inhibitor on bone metabolism / 中国药房

Serotonin-selective reuptake inhibitor （SSRI） is the first-line drug for treating depression. SSRI mainly include fluoxetine， paroxetine， sertraline， fluvoxamine， citalopram and escitalopram， etc. SSRI has dual impact on bone metabolism. Short- term use of SSRI may have a positive impact on bone， but long-term use may lead to bone problems. This article summarizes the effects and mechanisms of SSRI on bone metabolism， indicating that SSRI can affect bone formation， bone resorption， mesenchymal stem cell differentiation， and regulate the expression of inflammatory cytokines. The impact of SSRI on bone metabolism can be achieved by affecting classical signaling pathways such as cAMP/PKA/CREB， Wnt/β-catenin， BMP/Smad， OPG/RANKL/RANK， and through centrally mediated effects.

Fluoxetine-induced urinary retention in a cat.

Case summary: A 2-year-old neutered male domestic shorthair cat presented for a history of several weeks of infrequent urination and hyporexia progressing to anorexia. The cat had been normal prior to being placed on fluoxetine to treat inter-cat aggression, after which it began to display weight loss, hyporexia and abnormal urination habits. The cat had been seen by various veterinary hospitals previously and treated for suspected feline lower urinary tract disease. When the patient still had urinary retention despite perineal urethrostomy surgery, it was presented for ongoing care. Contrast urethrogram showed a mild questionable proximal ureteral narrowing, but other diagnostics were unremarkable. The patient was trialed on various medications, including alpha-antagonists, cholinergics, non-steroidal anti-inflammatory drugs and different analgesics with no improvement, but would reproducibly urinate only following administration of midazolam intravenously. Ultimately, the cat began urinating normally following the discontinuation of fluoxetine. The cat was urinating normally upon discharge, and when it presented for another complaint several months later, its weight, appetite and urination habits were normal. Relevance and novel information: Fluoxetine is a commonly utilized medication in behavioral medicine. Despite its common use and reports of urinary retention secondary to this medication in humans, this potential side effect is not reported in various veterinary pharmacologic textbooks or the veterinary literature. To our knowledge, this is the first report in veterinary medicine to describe urinary retention suspected to be secondary to prolonged administration of fluoxetine at an excessive dose.

Fluoxetine attenuates apoptosis in early brain injury after subarachnoid hemorrhage through Notch1/ASK1/p38 MAPK signaling pathway.

Subarachnoid hemorrhage (SAH) is a severe brain condition associated with a significantly high incidence and mortality. As a consequence of SAH, early brain injury (EBI) may contribute to poor SAH patient outcomes. Apoptosis is a signaling pathway contributing to post-SAH early brain injury and the diagnosis of the disease. Fluoxetine is a well-studied serotonin selective reuptake inhibitor (SSRI). However, its role in apoptosis has not been clearly understood. The present investigation assessed the effects of Fluoxetine in apoptosis and the potential Notch1/ASK1/p38 MAPK signaling pathway in EBI after SAH. Adult C57BL/6 J mice were subjected to SAH. Study mice (56) were randomly divided into 4 groups: the surgery without SAH (sham (n = 8), SAH+ vehicle; (SAH+V) (n = 16), surgery+ Fluoxetine (Fluox), (n = 16) and SAH+ Fluoxetine (n = 16). Various parameters were investigated 12, 24, 48, and 72 h after induction of SAH. Western blot analysis, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, Immunohistochemistry (IHC), and flow cytometry were carried out in every experimental group. According to the findings, the SAH downregulated NOTCH1 signaling pathway, Jlk6 inhibited Notch1, Notch1 inactivation increased apoptotic protein expression and suppressed Bax, and cytochrome C. Fluoxetine reversed the effects of notch1 inhibition in SAH. The Neuroprotective Fluoxetine effects involved suppression of apoptosis post-SAH. In summary, early Fluoxetine treatment significantly attenuates apoptosis and the expression of apoptosis-related proteins after 72 h post-SAH. Fluoxetine may ameliorate early brain injury after subarachnoid hemorrhage through anti-apoptotic effects and Notch1/ASK1/p38 MAPK signaling pathway.

In Utero Exposure to Citalopram Mitigates Maternal Stress Effects on Fetal Brain Development.

Human epidemiological and animal-model studies suggest that separate exposure to stress or serotonin-selective reuptake inhibitor (SSRI) antidepressants during pregnancy increases risks for neurodevelopmental disorders in offspring. Yet, little is known about the combined effects of maternal stress and SSRIs with regard to brain development in utero. We found that the placenta is highly permeable to the commonly prescribed SSRI (±)-citalopram (CIT) in humans and mice, allowing rapid exposure of the fetal brain to this drug. We investigated the effects of maternal chronic unpredictable stress in mice with or without maternal oral administration of CIT from embryonic day (E)8 to E17. We assessed fetal brain development using magnetic resonance imaging and quantified changes in serotonergic, thalamocortical, and cortical development. In utero exposure to maternal stress did not affect overall fetal brain growth. However, serotonin tissue content in the fetal forebrain was increased in association with maternal stress; this increase was reversed by maternal CIT. In utero exposure to stress increased the numbers of deep-layer neurons in specific cortical regions, whereas CIT increased overall cell numbers without changing the proportions of layer-specific neurons to offset the effects of stress on deep-layer cortical development. These findings suggest that stress and SSRI exposure in utero differentially impact serotonin-dependent fetal neurodevelopment such that CIT reverses key effects of maternal gestational stress on offspring brain development.

Quantitative prediction of fetal plasma concentration of fluvoxamine during dosage-tapering to the mother.

INTRODUCTION: Although selective serotonin reuptake inhibitors have been used during pregnancy for the treatment of depression and anxiety disorders, the fetal plasma concentration profiles of them remained unclear. Therefore, the aim of this study was to develop a pharmacokinetic model to estimate fetal plasma concentration profiles of fluvoxamine, and to clarify the differences with those of paroxetine. METHODS: Perfusion studies using human placentae obtained from full-term pregnant women were conducted to estimate transplacental pharmacokinetic parameters for fluvoxamine. The characteristics of placental permeability were compared with those of paroxetine in our previous report. Using a developed model and these parameters, fetal plasma concentration profiles of fluvoxamine administered to mothers were simulated. RESULTS: The results of perfusion studies and transplacental transfer kinetic parameters indicated that fluvoxamine is less efficiently distributed to placental tissue than paroxetine. The model predicted a maternal-fetal plasma concentration ratio of 0.376 after repeated maternal administration of fluvoxamine, similar to the ratio for paroxetine. However, if the mother ceased taking drug, the model predicted a half-life of fluvoxamine in fetal plasma of 35 h, which is longer than that of paroxetine (10 h). We used the model to evaluate a proposed taper regimen for full-term pregnant women taking fluvoxamine that would minimize the risk of neonatal withdrawal syndrome. DISCUSSION: The obtained parameters and developed model enabled us to predict the fetal plasma concentration profiles of fluvoxamine. The risk of neonatal withdrawal syndrome due to abrupt discontinuation may be less with fluvoxamine than with paroxetine.

Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening.

Rational design of lead compounds targeting monoamine transporters (MATs) is critical to developing novel therapeutics to treat psychiatric disorders including depression and substance abuse. A 3-D dopamine transporter (DAT) computer model was used to virtually screen a commercially available small molecule library for high DAT affinity drug-like compounds. One hit, coded "MI-4", inhibited human dopamine, norepinephrine, and serotonin transporters in vitro. In vivo administration in mice induced robust, dose-dependent antidepressant-like behaviors in learned helplessness models (tail suspension and forced swim tests). Moreover, chronic administration (21day, 10mg/kg, bid) reduced drinking latencies comparable to fluoxetine (10mg/kg, bid) in the novelty-induced hypophagia test, which requires chronic treatment to produce antidepressant-like effects. MI-4 (10mg/kg, bid) produced rapid (three-day) antidepressant-like effects in the social avoidance test following 10days of social defeat stress. Unlike ketamine, chronic administration of MI-4 increased social interaction scores while improving resiliency to the mood-altering effects of stress to over 70%. Importantly, MI-4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and dopamine in vivo microdialysis). MI-4 was found to be Ro-25-6981, an ifenprodil analog and reputed NMDA antagonist. The data suggest that Ro-25-6981, previously known for rapid-acting glutamatergic antidepressant actions, may also functionally inhibit monoamine reuptake and produces sustained antidepressant effects in vivo. This demonstrates, as proof of principle, the viability of combining these mechanisms to produce rapid and sustained antidepressant-like effects. Overall, these findings suggest MAT computational model-based virtual screening is a viable method for identifying antidepressant lead compounds of unique scaffold.

Protein-drug interactome analysis of SSRI-mediated neurorecovery following stroke.

Serotonin selective reuptake inhibitors (SSRIs) have been widely used as first-line drugs in the treatment of a range of depressive and anxiety disorders. Recently, clinical studies found that this class of agents also shows significant efficacy in promoting neurogenesis, neuroplasticity and neurorecovery following stroke. Here, we attempt to elucidate molecular mechanism and biological implication underlying the SSRI-mediated neurorecovery. In the procedure, a comprehensive protein-drug interactome (PDI) was constructed for various SSRIs and their major metabolites as well as a group of control drugs across a large panel of human neuroproteins via a high-throughput molecular docking approach. The obtained PDI was then analyzed at systematic level to extract unexpected targets for SSRIs/metabolites. Biological network analysis and gene ontology (GO) enrichment solidified that the inferred targets have high potential to be directly or indirectly involved in diverse neural events, and further molecular dynamics (MD) simulation and post molecular mechanics-Poisson Boltzmann/surface area (MM-PB/SA) characterization revealed a stable complex architecture and high-affinity interaction between the targets and SSRIs/metabolites. Specifically, two human proteins, i.e. neurogenic locus notch homolog protein 1 (NOTCH 1) and Rho-associated protein kinase 1 (ROCK 1), were suggested as promising regulators in the SSRI-mediated neurorecovery, which can be targeted efficiently by fluoxetine and paroxetine, respectively, as well as other SSRIs and metabolites.