Duloxetine Increases Serotonin and Norepinephrine Availability in Healthy Subjects: A Double-Blind, Controlled Study

University of Strasbourg, Strasburg, Alsace, France
Neuropsychopharmacology (Impact Factor: 7.05). 09/2003; 28(9):1685-93. DOI: 10.1038/sj.npp.1300209
Source: PubMed


Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, three-period crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p=0.07; 60 mg b.i.d.: p=0.02; combined regimens: p=0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (p<0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD30 increased significantly with desipramine dosing (p<0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.

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Available from: Peter Bieck, Mar 17, 2015
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    • "The fact that duloxetine does not directly inhibit DATs might be the reason for the lack of an observed increase in plasma HVA levels. By contrast, Chalon et al.8) reported that 5-6 days of duloxetine significantly decreased urinary MHPG levels in healthy volunteers. The discrepancy between the studies could be due to differences in sampling methods or study periods. "
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    ABSTRACT: Objective We investigated the effects of duloxetine on the plasma levels of catecholamine metabolites and serum brain-derived neurotrophic factor (BDNF) in 64 patients with major depressive disorder (MDD). Methods Major depressive episode was diagnosed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-fourth edition (DSM-IV) according to the DSM-IV text revision (DSM-IV-TR) criteria. The severity of depression was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17). Blood sampling and clinical evaluation were performed on days 0, 28, and 56. Results Duloxetine treatment for 8 weeks significantly increased the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels but not the homovanillic acid (HVA) levels in responders with MDD. Conclusion These results imply that noradrenaline plays an important role in alleviating depressive symptoms.
    Clinical Psychopharmacology and Neuroscience 04/2014; 12(1):37-40. DOI:10.9758/cpn.2014.12.1.37
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    • "Usually duloxetine is administered in the form of capsules dosage form containing 20, 30 or 60 mg of active constituent in enteric-coated pellets and the most common doses for the treatment of major depression are 40–60 mg daily. As per the literature, numerous analytical methods have been reported for the determination of duloxetine which include liquid chromatography–tandem mass spectrometric methods (LC–MS/MS) [7] [8] [9] [10] [11] [12], liquid chromatography with single-quadrupole mass spectrometric method (LC–MS) [13] [14], gas chromatographic mass spectrometric method [15], capillary electrophoresis method [16] and high performance liquid chromatographic (HPLC) methods [17] [18]. "
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    ABSTRACT: This paper describes a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry assay for the determination of cycloserine in human plasma using carbamazepine as internal standard (IS). Analyte and the IS were extracted from the 50μL of human plasma via protein precipitation using acetonitrile. The chromatographic separation was achieved on a C(18) column by using a mixture of acetonitrile-0.5% formic acid buffer (60:40, v/v) as the mobile phase at a flow rate of 0.8mL/min. The calibration curve obtained was linear (r(2)≥0.99) over the concentration range of 50-15,000ng/mL. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 2.5min for each sample made it possible to analyze more number of samples in short time, thus increasing the productivity. The proposed method was found to be applicable to pharmacokinetic studies.
    Journal of pharmaceutical and biomedical analysis 12/2012; 76C(1):21-27. DOI:10.1016/j.jpba.2012.11.036 · 2.98 Impact Factor
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    • "Venlafaxine, reboxetine, and duloxetine appear capable of stimulating cardiac sympathetic activity, which may manifest as a modest increase in heart rate and systemic blood pressure.44,45 For example, duloxetine increases peripheral norepinephrine concentrations and sympathetic tone, and reboxetine has been shown to increase sympathetic influence on heart rate variability.46,47 Excess sympathetic activity might predispose to an increased risk of more serious tachyarrhythmia, as identified in the context of cardiomyopathy.48 "
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    ABSTRACT: A number of different psychotropic agents have been associated with an increased risk of cardiovascular disease, and these relationships have been difficult to interpret due to the presence of confounding factors. Recently, there has been renewed interest in the potential for certain antidepressants to cause QT prolongation, which is a predisposing factor for arrhythmia. However, the optimum means of determining QT remains contentious due to discrepancies between methods that may be readily applied in a clinical setting versus more detailed techniques during regulatory assessment. A number of different pharmacological mechanisms might explain the occurrence of adverse cardiac effects, and these differ according to the type of antidepressant agent. Emerging data indicate that citalopram exhibits a dose-effect relationship for QT prolongation. Whereas cardiotoxicity is readily apparent in the context of intentional antidepressant overdose, the occurrence of cardiac effects as a result of therapeutic administration is less certain. Pre-existing cardiac disease and other factors that independently predispose to arrhythmia are important considerations. Therefore, clinical judgment is needed to evaluate the overall risk or benefit of a particular antidepressant in any patient. Close monitoring should be considered for those at greatest risk of QT prolongation and arrhythmia.
    Drug, Healthcare and Patient Safety 08/2012; 4(1):93-101. DOI:10.2147/DHPS.S28804
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