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

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Zhu H, Bogdanov MB, Boyle SH, Matson W, Sharma S, Matson S, Churchill E, Fiehn O, Rush JA, Krishnan RR, Pickering E, Delnomdedieu M, Kaddurah-Daouk R

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

PLoS One. 2013 Jul 17;8(7):e68283. doi: 10.1371/journal.pone.0068283. Print 2013.

PubMed ID

23874572 [ View in PubMed

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Abstract

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, chi(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.

DrugBank Data that Cites this Article

Pharmaco-metabolomics

Drug	Drug Groups	Metabolite	Change	Description
Sertraline	Approved	5-hydroxyindoleacetic acid	decreased	Sertraline decreases the level of 5-hydroxyindoleacetic acid in the blood
Sertraline	Approved	Melatonin	increased	Sertraline increases the level of Melatonin in the blood
Sertraline	Approved	4-Hydroxyphenylacetic Acid	increased	Sertraline increases the level of 4-Hydroxyphenylacetic Acid in the blood
Sertraline	Approved	3,4-Dihydroxymandelic Acid	increased	Sertraline increases the level of 3,4-Dihydroxymandelic Acid in the blood
Sertraline	Approved	Homogentistic Acid	increased	Sertraline increases the level of Homogentistic Acid in the blood
Sertraline	Approved	4-Hydroxyphenyllactic Acid	increased	Sertraline increases the level of 4-Hydroxyphenyllactic Acid in the blood
Sertraline	Approved	Alpha-tocopherol	increased	Sertraline increases the level of Alpha-tocopherol in the blood
Sertraline	Approved	Delta-Tocopherol	increased	Sertraline increases the level of Delta-Tocopherol in the blood
Sertraline	Approved	Methionine	increased	Sertraline increases the level of Methionine in the blood
Sertraline	Approved	Serotonin	decreased	Sertraline decreases the level of Serotonin in the blood
Sertraline	Approved	5-methoxytryptamine	decreased	Sertraline decreases the level of 5-methoxytryptamine in the blood
Sertraline	Approved	Uric acid	decreased	Sertraline decreases the level of Uric acid in the blood
Sertraline	Approved	Tyrosine	increased	Sertraline increases the level of Tyrosine in the blood
Sertraline	Approved	Tryptophan	increased	Sertraline increases the level of Tryptophan in the blood