Human brain fluoxetine concentrations

Karson, Craig N.; Newton, Joseph E. O.; Livingston, R. H.; Jolly, Jim; Cooper, Thomas R.; Sprigg, Jay; Komoroski, Richard A.

doi:10.1176/jnp.5.3.322

Cited by 183 publications

(29 citation statements)

References 13 publications

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“…Therapeutic doses of fluoxetine for depression patients are in the range of 20-60 mg/day and brain concentration of fluoxetine can reach up to about 30 μM [19-22]. Thus, we first investigated the effects of 0-30 μM fluoxetine application on the viability of glioma cells.…”

Section: Resultsmentioning

confidence: 99%

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

et al. 2014

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The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients' quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca2+ influx. The rise in the intracellular calcium concentration ([Ca2+]i) causes mitochondrial Ca2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease.

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Section: Resultsmentioning

confidence: 99%

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

et al. 2014

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“…We found significant drug effects at < 1 mM for lithium and < 3 µM for FLUO (Supplemental Figure S5). Both concentrations are therapeutically relevant: lithium blood levels are 0.4–1.0 mEq/l and human brain levels of FLUO reach 10–15 µM during treatment for depression 60 . Note that FLUO is known to accumulate inside cells 61 , and we assume that the effects on inositol and PIns are due to intracellular FLUO (as are the effects of lithium intracellular).…”

Section: Discussionmentioning

confidence: 99%

Lithium and fluoxetine regulate the rate of phosphoinositide synthesis in neurons: a new view of their mechanisms of action in bipolar disorder

Saiardi

Mudge

2018

Transl Psychiatry

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Lithium is widely used to treat bipolar disorder, but its primary mechanism of action is uncertain. One proposal has been that lithium’s ability to inhibit the enzyme inositol monophosphatase (IMPase) reduces the supply of recycled inositol used for membrane phosphoinositide (PIns) synthesis. This 28-year-old hypothesis is still widely debated, however, largely because total levels of PIns in brain or in cultured neurons do not decrease after lithium treatment. Here we use mature cultured cortical neurons to show that, although lithium has little effect on steady-state levels of either inositol or PIns, it markedly inhibits the rate of PIns synthesis. Moreover, we show that rapid synthesis of membrane PIns preferentially uses inositol newly imported from the extracellular space. Unexpectedly, we also find that the antidepressant drug fluoxetine (FLUO: Prozac) stimulates the rate of PIns synthesis. The convergence of both lithium and FLUO in regulating the rate of synthesis of PIns in opposite ways highlights PIns turnover in neurons as a potential new drug target, as well as for understanding mood control in BD. Our results also indicate new avenues for investigation of how neurons regulate their supply of inositol.

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“…However, fluoxetine and norfluoxetine concentrations in the central nervous system are up to 20-fold higher than those in serum. 9 A study using fluorine-19 magnetic resonance spectroscopy in 22 adult psychiatric patients receiving fluoxetine, 20 to 40 mg/d, found mean (SD) brain concentrations of fluoxetine and norfluoxetine of 4.24 (2.83) μg/mL (approximately 14 μM), although the exact concentration was dependent on both the dose and duration of therapy. 9 Actual brain concentrations may really be higher than those estimated by fluorine-19 magnetic resonance spectroscopy.…”

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confidence: 99%

Rationale for the Evaluation of Fluoxetine in the Treatment of Enterovirus D68-Associated Acute Flaccid Myelitis

Tyler

2015

JAMA Neurol

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Human brain fluoxetine concentrations

Cited by 183 publications

References 13 publications

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

Lithium and fluoxetine regulate the rate of phosphoinositide synthesis in neurons: a new view of their mechanisms of action in bipolar disorder

Rationale for the Evaluation of Fluoxetine in the Treatment of Enterovirus D68-Associated Acute Flaccid Myelitis

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