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Randomized Controlled Trial
. 2016 May;22(5):404-12.
doi: 10.1111/cns.12513. Epub 2016 Feb 5.

Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects

John J Sramek  1 , Larry W Hardy  2 , Peter Bieck  1 , Cynthia Zamora  3 , Mark Versavel  2 , Jahnavi Kharidia  2 , Todd Grinnell  2 , Yu-Luan Chen  2 , Michael Sullivan  3 , Hong Ding  1 , Neal R Cutler  1
Affiliations
Randomized Controlled Trial

Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects

John J Sramek et al. CNS Neurosci Ther. 2016 May.

Abstract

Introduction: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT.

Methods: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry.

Results: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings.

Conclusion: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.

Keywords: Biomarkers; Cerebrospinal fluid; Duloxetine; Monoamine reuptake inhibitor; SEP-432.

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Conflict of interest statement

This study was sponsored by Sunovion Pharmaceuticals Inc.

Drs. Hardy, Versavel, Kharidia, Grinnell, and Chen are (or were at the time the studies described were conducted) employees of Sunovion Pharmaceuticals Inc. Drs. Sramek, Bieck, Zamora, Cutler, and Mr. Sullivan and Mr. Ding are employees of Worldwide Clinical Trials, Inc.

Drs. Sramek, Bieck, Zamora, Cutler, and Mr. Sullivan and Mr. Ding, in the past 2 years, have not received any direct research support and/or consulting fees.

Figures

Figure 1
Figure 1
Average Values of Hourly DHPG Concentration in CSF, Comparing Day 1 (Predose Baseline) to Day 14 (the 0–24 Hour Time Points) after Treatment with Placebo, Duloxetine (60 mg), or SEP‐432 (300 mg).
Figure 2
Figure 2
Average Values of Hourly 5‐HT Concentrations in CSF, Comparing Day 1 (Predose Baseline) to Day 14 (the 0–24 Hour Time Points) after Treatment with Duloxetine (60 mg), SEP 432 (300 mg), and Placebo (n.s., nonsignificant).
Figure 3
Figure 3
Mean Values for SEP‐432 Plasma and CSF Concentrations over 24 h (Day 14) after 300 mg Dosing to Steady State (note that the SEP‐432 concentrations are displayed on a log10 scale; error bars indicate SEM).
See this image and copyright information in PMC

References

    1. Praag HM. The Harold E. Himwich Memorial Lecture. Significance of biochemical parameters in the diagnosis, treatment, and prevention of depressive disorders. Biol Psychiatry 1977;12:101–131. - PubMed
    1. Aberg‐Wistedt A, Jostell KG, Ross SB, Westerlund D. Effects of zimelidine and desipramine on serotonin and noradrenaline uptake mechanisms in relation to plasma concentrations and to therapeutic effects during treatment of depression. Psychopharmacology 1981;74:297–305. - PubMed
    1. Little JT, Ketter TA, Mathe AA, Frye MA, Luckenbaugh D, Post RM. Venlafaxine but not bupropion decreases cerebrospinal fluid 5‐hydroxyindoleacetic acid in unipolar depression. Biol Psychiatry 1999;45:285–289. - PubMed
    1. Sheline Y, Bardgett ME, Csernansky JG. Correlated reductions in cerebrospinal fluid 5‐HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1997;17:11–14. - PubMed
    1. Golden RN, Rudorfer MV, Sherer MA, Linnoila M, Potter WZ. Bupropion in depression. I. Biochemical effects and clinical response. Arch Gen Psychiatry 1988;45:139–143. - PubMed

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