All Title Author
Keywords Abstract

PLOS ONE  2013 

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

DOI: 10.1371/journal.pone.0068283

Full-Text   Cite this paper   Add to My Lib


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, χ2(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.


[1]  Di Mascio M, Di Giovanni G, Di Matteo V, Prisco S, Esposito E (1998) Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area. Brain Res Bull 46(6): 547–554.
[2]  Alvarez JC, Gluck N, Fallet A, Grégoire A, Chevalier JF, et al. (1999) Plasma serotonin level after 1 day of fluoxetine treatment: a biological predictor for antidepressant response? Psychopharmacology (Berl) 143(1): 97–101.
[3]  Dremencov E, El Mansari M, Blier P (2009) Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci 34(3): 223–229.
[4]  Thomas DN, Nutt DJ, Holman RB (1998) Sertraline, a selective serotonin reuptake inhibitor modulates extracellular noradrenaline in the rat frontal cortex. J Psychopharmacol 12(4): 366–370.
[5]  Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, et al. (2002) Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology (Berl) 160(4): 353–361.
[6]  Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, et al. (2010) Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. Eur J Pharmacol 647(1–3): 90–96.
[7]  Golembiowska K, Dziubina A (2000) Effect of acute and chronic administration of citalopram on glutamate and aspartate release in the rat prefrontal cortex. Pol J Pharmacol 52(6): 441–448.
[8]  Wang SJ, Su CF, Kuo YH (2003) Fluoxetine depresses glutamate exocytosis in the rat cerebrocortical nerve terminals (synaptosomes) via inhibition of P/Q-type Ca2+ channels. Synapse 48(4): 170–177.
[9]  Schipke CG, Heuser I, Peters O (2011) Antidepressants act on glial cells: SSRIs and serotonin elicit astrocyte calcium signaling in the mouse prefrontal cortex. J Psychiatr Res 45(2): 242–248.
[10]  Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159(4): 663–665.
[11]  Bhagwagar Z, Wylezinska M, Taylor M, Jezzard P, Matthews PM, et al. (2004) Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry 161(2): 368–370.
[12]  Marsteller DA, Barbarich-Marsteller NC, Patel VD, Dewey SL (2007) Brain metabolic changes following 4-week citalopram infusion: increased 18FDG uptake and gamma-amino butyric acid levels. Synapse 61(11): 877–881.
[13]  Sullivan GM, Oquendo MA, Simpson N, Van Heertum RL, Mann JJ, et al. (2005) Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety. Biol Psychiatry 58(12): 947–954.
[14]  Trivedi MH (2006) Major depressive disorder: remission of associated symptoms. J Clin Psychiatry 67 Suppl 627–32.
[15]  Charney DS (1998) Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 59 Suppl 1411–14.
[16]  Ressler KJ, Nemeroff CB (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12 Suppl 12–19.
[17]  Malhi GS, Parker GB, Greenwood J (2005) Structural and functional models of depression: from sub-types to substrates. Acta Psychiatr Scand 111(2): 94–105.
[18]  Nutt DJ (2006) The role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry 67 Suppl 63–8.
[19]  Leonard BE (2007) Psychopathology of depression. Drugs Today (Barc) 43(10): 705–716.
[20]  Nutt DJ (2008) Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 69 Suppl E14–7.
[21]  Insel TR, Wang PS (2009) The STAR*D trial: revealing the need for better treatments. Psychiatr Serv 60(11): 1466–1467.
[22]  Katz MM, Bowden CL, Frazer A (2010) Rethinking depression and the actions of antidepressants: uncovering the links between the neural and behavioral elements. J Affect Disord 120(1–3): 16–23.
[23]  Walsh BT, Seidman SN, Sysko R, Gould M (2002) Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287(14): 1840–1847.
[24]  Kirsch I (2008) Challenging received wisdom: antidepressants and the placebo effect. Mcgill J Med 11(2): 219–222.
[25]  Brunoni AR, Fraguas R, Fregni F (2009) Pharmacological and combined interventions for the acute depressive episode: focus on efficacy and tolerability. Ther Clin Risk Manag 5: 897–910.
[26]  Kaddurah-Daouk R, Krishnan KR (2009) Metabolomics: a global biochemical approach to the study of central nervous system diseases. Neuropsychopharmacology 34(1): 173–186.
[27]  Paige LA, Mitchell MW, Krishnan KR, Kaddurah-Daouk R, Steffens DC (2007) A preliminary metabolomic analysis of older adults with and without depression. Int J Geriatr Psychiatry 22(5): 418–423.
[28]  Steffens DC, Wei J, Krishnan KR, Karoly ED, Mitchell MW, et al. (2010) Metabolomic differences in heart failure patients with and without major depression. J Geriatr Psychiatry Neurol 23(2): 138–146.
[29]  Ji Y, Hebbring S, Zhu H, Jenkins GD, Biernacka J, et al. (2011) Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther 89(1): 97–104.
[30]  Kaddurah-Daouk R, Boyle S, Matson W, Sharma S, Matson S, et al.. (2011) Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept. Transl Psychiatry 1(7): pii: e26.
[31]  Rozen S, Cudkowicz ME, Bogdanov M, Matson WR, Kristal BS, et al. (2005) Metabolomic analysis and signatures in motor neuron disease. Metabolomics 1(2): 101–108.
[32]  Kristal BS, Shurubor YI, Kaddurah-Daouk R, Matson WR (2007) High-performance liquid chromatography separations coupled with coulometric electrode array detectors: a unique approach to metabolomics. Methods Mol Biol 358: 159–174.
[33]  Bogdanov M, Matson WR, Wang L, Matson T, Saunders-Pullman R, et al. (2008) Metabolomic profiling to develop blood biomarkers for Parkinson's disease. Brain 131(Pt 2): 389–396.
[34]  Johansen KK, Wang L, Aasly JO, White LR, Matson WR, et al. (2009) Metabolomic profiling in LRRK2-related Parkinson's disease. PLoS One 4(10): e7551.
[35]  Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100(16): 9440–9445.
[36]  Bismuth-Evenzal Y, Gonopolsky Y, Gurwitz D, Iancu I, Weizman A, et al. (2012) Decreased serotonin content and reduced agonist-induced aggregation in platelets of patients chronically medicated with SSRI drugs. J Affect Disord 136(1-2): 99–103.
[37]  Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, et al.. (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 15(4): 393–403. Epub 2009 Nov 17.
[38]  Mackay GM, Forrest CM, Christofides J, Bridel MA, Mitchell S, et al. (2009) Kynurenine metabolites and inflammation markers in depressed patients treated with fluoxetine or counselling. Clin Exp Pharmacol Physiol 36(4): 425–435.
[39]  Zhang F, Jia Z, Gao P, Kong H, Li X, et al. (2010) Metabonomics study of urine and plasma in depression and excess fatigue rats by ultra fast liquid chromatography coupled with ion trap-time of flight mass spectrometry. Mol Biosyst 6(5): 852–861.
[40]  Catena-Dell'Osso M, Bellantuono C, Consoli G, Baroni S, Rotella F, et al. (2011) Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development? Curr Med Chem 18(2): 245–255.
[41]  Beck-Friis J, Kjellman BF, Aperia B, Undén F, von Rosen D, et al. (1985) Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome. Acta Psychiatr Scand 71(4): 319–330.
[42]  Frazer A, Brown R, Kocsis J, Caroff S, Amsterdam J, et al.. (1986) Patterns of melatonin rhythms in depression. J Neural Transm Suppl 21: 269–290.
[43]  van Bemmel AL (1997) The link between sleep and depression: the effects of antidepressants on EEG sleep. J Psychosom Res 42(6): 555–564.
[44]  Hale A, Corral RM, Mencacci C, Ruiz JS, Severo CA, et al. (2010) Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study. Int Clin Psychopharmacol 25(6): 305–314.
[45]  Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, et al. (2010) Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry 71(2): 109–120.
[46]  Di Giannantonio M, Di Iorio G, Guglielmo R, De Berardis D, Conti CM, et al. (2011) Major depressive disorder, anhedonia and agomelatine: an open-label study. J Biol Regul Homeost Agents 25(1): 109–114.
[47]  Uz T, Manev H (1999) Chronic fluoxetine administration increases the serotonin N-acetyltransferase messenger RNA content in rat hippocampus. Biol Psychiatry 45(2): 175–179.
[48]  Jang SW, Liu X, Pradoldej S, Tosini G, Chang Q, et al. (2010) N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc Natl Acad Sci U S A 107(8): 3876–81.
[49]  Pevet P, Balemans MG, Legerstee WC, Vivien-Roels B (1980) Circadian rhythmicity of the activity of hydroxyindole-O-methyl transferase (HIOMT) in the formation of melatonin and 5-methoxytryptophol in the pineal, retina, and harderian gland of the golden hamster. J Neural Transm 49(4): 229–245.
[50]  Hofman MA, Skene DJ, Swaab DF (1995) Effect of photoperiod on the diurnal melatonin and 5-methoxytryptophol rhythms in the human pineal gland. Brain Res 671(2): 254–260.
[51]  Kostoglou-Athanassiou I, Forsling ML (1998) Effect of 5-hydroxytryptamine and pineal metabolites on the secretion of neurohypophysial hormones. Brain Res Bull 46(5): 417–422.
[52]  Rom-Bugoslavskaia ES, Shcherbakova VS (1985) [Comparative experimental study of the effect of melatonin and 5-methoxytryptamine on the thyroid gland of rats]. Farmakol Toksikol 48(5): 84–89.
[53]  Galzin AM, Eon MT, Esnaud H, Lee CR, Pévet P, et al. (1988) Day-night rhythm of 5-methoxytryptamine biosynthesis in the pineal gland of the golden hamster (Mesocricetus auratus). J Endocrinol 118(3): 389–397.
[54]  Healy D, Waterhouse JM (1995) The circadian system and the therapeutics of the affective disorders. Pharmacol Ther 65(2): 241–263.
[55]  Duncan WC Jr (1996) Circadian rhythms and the pharmacology of affective illness. Pharmacol Ther 71(3): 253–312.
[56]  Gorka Z, Moryl E, Papp M (1996) Effect of chronic mild stress on circadian rhythms in the locomotor activity in rats. Pharmacol Biochem Behav 54(1): 229–234.
[57]  Millan MJ (2006) Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 110(2): 135–370.
[58]  Gannon RL, Millan MJ (2007) Evaluation of serotonin, noradrenaline and dopamine reuptake inhibitors on light-induced phase advances in hamster circadian activity rhythms. Psychopharmacology (Berl) 195(3): 325–332.


comments powered by Disqus