Article

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

University of Strasbourg, Strasburg, Alsace, France
Neuropsychopharmacology (Impact Factor: 7.83). 09/2003; 28(9):1685-93. DOI: 10.1038/sj.npp.1300209
Source: PubMed

ABSTRACT 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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    • "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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    • "Duloxetine HCl (DUL) – (3S)-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan- 1-amine hydrochloride [1] – has an empirical formula of C 18 H 19 NOS⋅HCl and a molecular weight of 333.38 g/moL (Figure 1). It is a potent inhibitor of serotonin and norepinephrine reuptake and thus it is used for major depressive disorders [2] [3] [4]. Furthermore, it provides evidence of an effect on pain in the case of urinary incontinence [5] [6] independent of its effect on depression. "
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    • "Duloxetine , at the recommended maximum dose of 60 mg daily, attenuates TYR30 slightly (Turcotte et al., 2001), in a dose-related manner which does not plateau, even at 240 mg day À1 (Vincent et al., 2004). Chalon et al. (2003) found no effect of duloxetine at a dose of 80 mg. Since the most parsimonious assumption is that a large effect on the TYR30 is required, rather than a barely detectable one, it is curious that these authors concluded, '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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