Possible reasons for why a new study could not replicate our

Possible reasons for why a new study could not replicate our finding that the serotonin reuptake inhibitor citalopram decreased amyloid concentrations in the cerebrospinal fluid of healthy volunteers. of escitalopram, the active in their Letter) will clarify the discrepancies in the results. These methodological differences relate with drug timing and dose of CSF sampling. Escitalopram includes a half-life around 28 hours (3). As a result, considering that Emilsson offered the first dosage Riociguat of escitalopram 27 hours before CSF sampling, the medication concentration was decreased by 50% by enough time of CSF sampling. Further, predicated on kinetic research, it requires 6 hours after Mouse monoclonal to SORL1 amyloid precursor proteins (APP) can be cleaved for adjustments in A to become recognized in the CSF (4, 5). Consequently, sampling CSF at 4 hours following the second medication dosage implies that the effect of that dosage would not however be there in the CSF. We believe the analysis of Emilsson Notice (1). We’ve conducted parallel research in mouse types of Advertisement also. To date, we’ve examined five SSRIs (6) for his or her influence on A concentrations in the mind ISF of APP transgenic and wild-type mice. In all full cases, the SSRIs decreased ISF A by 15 to 30%. We now have also examined the A-lowering aftereffect of escitalopram Riociguat utilizing a solitary dosage of escitalopram in youthful APP/PS1+/? mice. We discovered that, like the additional SSRIs, there is a 16% decrease in ISF A by a day after dosing (= 0.03, = 6) in comparison to automobile (= 6) (Fig. 1). In earlier function Riociguat (6), citalopram given at 10 mg/kg also decreased ISF A concentrations in mice by 26% (= 0.001, = 4) (Fig. 1). Escitalopram and Citalopram had been given at similar active-form dosages towards the APPswe/PS1dE9 hemizygous mice, and there is no factor between both of these medicines (= 0.302) regarding their results on ISF A. Having said that, the result of escitalopram on ISF A had not been as powerful as the result of citalopram, recommending that half of a dosage of escitalopram is probably not quite as effectual as citalopram in decreasing A. Importantly, immediate infusion of serotonin in to the mouse mind also mimicked the consequences from the SSRIs (6). These data support our interpretation that increased serotonin signaling suppresses brain A production, as opposed to an off-target effect of citalopram or one of the drugs metabolites. We hope that future studies will define the signaling pathways that link serotonin receptors to A metabolism, providing more confidence in the mechanism underlying this phenomenon. Fig. 1 Effect of SSRIs on ISF A concentrations in APP/PS1 transgenic mice In summary, although Emilsson and colleagues present interesting findings in their Letter, differences in sampling times and drug dosing between their study and ours make it difficult to compare the two sets of results. Additional studies of the effects of SSRIs on A in humans are needed, and especially studies that use higher doses of escitalopram and better CSF sampling methods, which would enable assaying of the maximal CSF concentrations of the drug. REFERENCES AND NOTES 1. Emilsson JF, Andreasson U, Blennow K, Eriksson E, Zetterberg H. Comment on An anti-depressant decreases CSF A production in healthy individuals and in transgenic AD mice Sci Transl Med. 2014;6:268le5. [PubMed] 2. Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher JR, Ficker WD, Yan P, Xiong C, Frederiksen C, Grzelak MV, Chott R, Bateman RJ, Morris JC, Mintun MA, Lee JM, Cirrito JR. An antidepressant decreases CSF A production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014;6:236re4. [PMC free article] [PubMed] 3. Prescribing informationForest Laboratories. www.frx.com/pi/lexapro_pi.pdf. 4. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris J, Yarasheski K, Bateman R. Decreased Riociguat clearance of CNS -amyloid in Alzheimers disease. Science. 2010;330:1774. [PMC Riociguat free article] [PubMed] 5. Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju Y, Kasten T, Morris J, Mintun M, Duntley S, Bateman R. Effects of age group and amyloid deposition on the dynamics in the human being central nervous program. Arch Neurol. 2012;69:51C58. [PMC free of charge content] [PubMed].