10.1371/journal.pone.0068283PLoS ONE87-POLN

A Hale

AL van Bemmel

AM Galzin

AR Brunoni

BE Leonard

BS Kristal

BT Walsh

CG Schipke

D Healy

DA Marsteller

DC Steffens

DJ Nutt

DN Thomas

DS Charney

E Dremencov

Erik Churchill

ES Rom-Bugoslavskaia

Eve Pickering

F Zhang

FP Bymaster

G Sanacora

GM Mackay

GM Sullivan

GS Malhi

Hongjie Zhu

I Kirsch

I Kostoglou-Athanassiou

J Beck-Friis

Jacob Guy Bundy

JC Alvarez

JD Storey

John A. Rush

K Golembiowska

KJ Ressler

KK Johansen

LA Paige

M Bogdanov

M Catena-Dell'Osso

M Di Giannantonio

M Di Mascio

MA Hofman

Marielle Delnomdedieu

MH Trivedi

Mikhail B. Bogdanov

MJ Millan

MM Katz

Oliver Fiehn

P Pevet

Pharmacometabolomics Research Network

R Kaddurah-Daouk

Ranga R. Krishnan

Rima Kaddurah-Daouk

RL Gannon

S Kasper

S Rozen

Samantha Matson

SJ Wang

Stephen H. Boyle

SW Jang

Swati Sharma

T Uz

TR Insel

Wayne Matson

WC Duncan Jr

Y Bismuth-Evenzal

Y Ji

Y Kitaichi

Z Bhagwagar

Z Gorka

PLoS ONE

PubMed

Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ(2)(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL

Mikhail B Bogdanov

Stephen H Boyle

John A Rush

Ranga R Krishnan

Directory of Open Access Journals

Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder - possible role for methoxyindole pathway.

Crossref

Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder – Possible Role for Methoxyindole Pathway

<div><p>Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD<sub>17</sub>). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ<sup>2</sup>(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.</p></div

Hongjie Zhu (152174)

Mikhail B. Bogdanov (434286)

Stephen H. Boyle (348270)

Wayne Matson (434287)

Swati Sharma (5655640)

Samantha Matson (434288)

Erik Churchill (387886)

Oliver Fiehn (17098)

John A. Rush (434289)

Ranga R. Krishnan (434290)

Eve Pickering (229526)

Marielle Delnomdedieu (434291)

Rima Kaddurah-Daouk (152187)

Pharmacometabolomics Research Network (434292)

The Francis Crick Institute

Zhu Hongjie

Bogdanov Mikhail B.

Boyle Stephen H.

Matson Wayne

Sharma Swati

Matson Samantha

Churchill Erik

Fiehn Oliver

Rush John A.

Krishnan Ranga R.

Pickering Eve

Delnomdedieu Marielle

Kaddurah-Daouk Rima

Network Pharmacometabolomics Research

Public Library of Science (PLOS)

Zhu, Hongjie

Bogdanov, Mikhail B

Boyle, Stephen H

Matson, Wayne

Sharma, Swati

Matson, Samantha

Churchill, Erik

Fiehn, Oliver

Rush, John A

Krishnan, Ranga R

Pickering, Eve

Delnomdedieu, Marielle

Kaddurah-Daouk, Rima

Network, Pharmacometabolomics Research

eScholarship - University of California

English

http://scholarbank.nus.edu.sg/bitstream/10635/110608/1/2013-pharmacometabolomics_response_sertraline_placebo_major-published.pdf

Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder - Possible Role for Methoxyindole Pathway

Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder - Possible Role for Methoxyindole Pathway

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Directory of Open Access Journals

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The Francis Crick Institute

Public Library of Science (PLOS)

eScholarship - University of California