Venlafaxine and &lt;em&gt;O&lt;em&gt;-Desmethylvenlafaxine Concentrations in Plasma and Cerebrospinal Fluid

Paulzen, Michael; Groppe, Sarah E.; Tauber, Simone C.; Veselinović, Tanja; Hiemke, Christoph; Gründer, Gerhard

doi:10.4088/jcp.13m08921

Cited by 18 publications

(7 citation statements)

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“…The concentration of antidepressants used in these studies are within a similar range as the concentrations observed in the brain after a treatment dose in humans (Nikisch et al, 2004(Nikisch et al, , 2005Paulzen et al, 2015); therefore, our results support microglial activation as one key pharmacological mechanism behind antidepressant action. Moreover, while this review has limitations including differences in the concentrations of antidepressants, LPS and cytokines used, in the cellular models employed, as well as in the heterogeneity of the method used to quantify cytokines production (e.g.…”

Section: Discussionsupporting

confidence: 78%

Modulation of microglial activation by antidepressants

2022

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Background: Recent studies have suggested that microglial activation plays a key role in the pathogenesis of depression. In fact, neuroinflammation is associated with a phenotypic change of microglia, consisting of morphological differences, increased release of cytokines and oxidative stress products, which may contribute to the development and maintenance of depression. Antidepressants, including selective serotonin re-uptake inhibitors and serotonin–norepinephrine reuptake inhibitors, have been shown to act on the immune and oxidative stress mechanisms commonly found to be disrupted in depression. Thus, the inhibition of microglial activation may be one of the mechanisms through which they exert an antidepressant action. Aim: This is the first review summarising in vitro and ex vivo studies investigating the effects of different classes of antidepressants on microglia activation, by examining cellular changes and/or via measuring the production of immune and/or oxidative stress signalling molecules, in microglia models of neuroinflammation with either lipopolysaccharide (LPS) or cytokines. A total of 23 studies were identified, 18 using LPS stimulation and 5 using cytokines stimulation. Results: Overall, the studies show that antidepressants, such as selective serotonin re-uptake inhibitors, serotonin–norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants prevented microglial activation, including reduced microglial reactivity and decreased immune and oxidative stress products, in both models. However, specific antidepressants, such as bupropion and agomelatine did not prevent interferon-gamma (IFN-γ)-induced microglial activation; and for other antidepressants, including phenelzine, venlafaxine and sertraline, the results of different studies were inconsistent. Conclusions: Overall, results summarised in this review support the hypothesis that the action of at least certain classes of antidepressants may involve regulation of microglial activation, especially when in presence of increased levels of inflammation.

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Section: Discussionsupporting

confidence: 78%

Modulation of microglial activation by antidepressants

2022

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“…As ROC analysis revealed that only patients with a minimally active moiety serum concentration of 393.0 ng/mL in week 4 reached remission, we suggest that 400 ng/mL as the upper limit of the therapeutic reference possibly is too low for adequate drug therapy with venlafaxine. Since in everyday clinical settings active moiety concentrations above the therapeutic reference range were often reported (Hansen et al, 2017;Paulzen et al, 2015;Unterecker et al, 2012Unterecker et al, , 2015, it can be assumed that clinicians deliberately go beyond the therapeutic reference range in order to achieve a better drug effect. Even if previously no difference in frequencies of adverse drug reactions related to venlafaxine in patients with active moiety concentrations higher and lower than the alert level (800 ng/mL; Hiemke et al, 2018) was shown, there were reports of QTc prolongation during venlafaxine therapy (Bavle, 2015;Hefner et al, 2019;Jasiak and Bostwick, 2014;Schoretsanitis et al, 2019b;Wenzel-Seifert et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…However, one study reported an association between response and ODV serum concentrations (Stamm et al, 2014). Nevertheless, in retrospective clinical studies of TDM in many cases active moiety concentrations above the therapeutic reference range were reported, but without considering clinical parameters (Hansen et al, 2017; Paulzen et al, 2015; Unterecker et al, 2012, 2015). Accordingly, a prior study (Schoretsanitis et al, 2019b) did not show different frequencies of adverse drug reactions related to venlafaxine in patients with active moiety concentrations higher and lower than the laboratory alert level (800 ng/mL).…”

Section: Introductionmentioning

confidence: 99%

Higher venlafaxine serum concentrations necessary for clinical improvement? Time to re-evaluate the therapeutic reference range of venlafaxine

et al. 2020

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Background: The therapeutic reference range for venlafaxine in antidepressant treatment has been defined as 100 to 400 ng/mL. However, in an everyday setting active moiety concentrations above the therapeutic reference range were often reported. Aim: The aim of this study was to re-evaluate the therapeutic reference range of venlafaxine. Methods: In-patients (⩽60 years) with major depressive episodes receiving antidepressant monotherapy with venlafaxine during routine clinical treatment were included in this observational study. Depressive symptom severity was evaluated on a weekly basis using the Hamilton Depression Rating Scale (HAMD-21), and therapeutic drug monitoring analyses were performed. Resting electrocardiograms were analyzed in week 3, week 5 and week 7 of study participation. Results: Clinical improvement from baseline to week 4 was significantly associated with increasing serum concentrations of the active moiety of venlafaxine ( N = 23, Pearson correlation, p = 0.009), but not with the dose of venlafaxine. Patients achieving remission showed significantly higher serum concentrations than patients achieving response/non-response (Kruskal–Wallis test, p = 0.019). Moreover, in patients with serum concentrations above 400 ng/mL time to remission and time to response was significantly shorter than in patients with concentrations below 400 ng/mL (Mantel–COX test, p = 0.001; p = 0.010). QTc time was below the upper limit of a normal QTc time (450 ms) for all patients. Conclusion: The serum concentration of the active moiety and not the dose determined the effect of venlafaxine. Shorter remission times without ECG alterations in patients with serum concentrations above the therapeutic reference range suggest a re-evaluation of the therapeutic reference range for venlafaxine in larger studies.

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“…For example, imipramine in CSF is approximately 10% of blood plasma levels in humans with major depressive disorder [33]. The calculated CSF-to-blood plasma ratio for venlafaxine is 0.74 [34], and the ratio for mirtazapine (bound and unbound faction) varies from 0.08 to 0.48 with a mean ± SD of 0.16 ± 0.11 [35]. For nortriptyline, the ratio is 0.091 ± 0.025 [36].…”

Section: Discussionmentioning

confidence: 99%

Neural cell adhesion molecule peptide mimetics modulate emotionality: pharmacokinetic and behavioral studies in rats and non-human primates

Turner

Lyons

Buckmaster

et al. 2018

Neuropsychopharmacol

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Recent evidence highlights the fibroblast growth factor (FGF) family in emotion modulation. Although ligands that activate FGF receptors have antidepressant and anxiolytic effects in animal models, FGF ligands have a broad range of actions both in the brain and the periphery. Therefore, identifying molecular partners that may function as allosteric modulators could offer new avenues for drug development. Since neural cell adhesion molecule (NCAM) activates FGF receptors, we asked whether peripherally administered NCAM peptide mimetics penetrate the brain and alter the behavior of standardized tests that have predictive validity for drug treatments of anxiety or depression. The NCAM peptide mimetic, plannexin, acutely increased and chronically decreased anxiety, but did not have antidepressant effects in rats. Another NCAM peptide mimetic, FGL, had acute anxiogenic effects and chronic antidepressant effects in rats. A related NCAM peptide mimetic, FGL, had antidepressant effects without modulating anxiety-like behavior, and these antidepressant effects were blocked by an AMPA receptor antagonist. Cisternal cerebrospinal fluid (CSF) levels of FGLs correlated with blood plasma levels in rats and non-human primates, and CSF-to-blood ratios of FGL were comparable in both species. Results indicate that NCAM peptide mimetics penetrate the brain and support the suggestion that FGL may be a candidate for further development as a novel treatment for major depressive disorder in humans.

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Venlafaxine and <em>O<em>-Desmethylvenlafaxine Concentrations in Plasma and Cerebrospinal Fluid

Cited by 18 publications

References 0 publications

Modulation of microglial activation by antidepressants

Modulation of microglial activation by antidepressants

Higher venlafaxine serum concentrations necessary for clinical improvement? Time to re-evaluate the therapeutic reference range of venlafaxine

Neural cell adhesion molecule peptide mimetics modulate emotionality: pharmacokinetic and behavioral studies in rats and non-human primates

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