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Differential modulation of emotion processing brain regions by noradrenergic and serotonergic antidepressants

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Abstract

Rationale

Most widely used antidepressant drugs affect the serotonergic and noradrenergic pathways. However, there are currently no neurobiological criteria for selecting between these targets and predicting the treatment response in individual depressed patients.

Objectives

The current study is aimed at differentiating brain regions known to be pathophysiologically and functionally involved in depression-related emotion processing with respect to their susceptibility to serotonergic and noradrenergic modulation.

Methods

In a single-blind pseudo-randomized crossover study, 16 healthy subjects (out of 21 enrolled) were included in analysis after ingesting a single dose of citalopram (a selective serotonin-reuptake inhibitor, 40 mg), reboxetine (a selective noradrenaline-reuptake inhibitor, 8 mg), or placebo at three time points prior to functional magnetic resonance imaging (fMRI). During fMRI, subjects anticipated and subsequently viewed emotional pictures. Effects of serotonergic and noradrenergic modulation versus placebo on brain activity during the perception of negative pictures were analyzed with a repeated measures ANOVA in the whole brain and in specific regions of interest relevant to depression.

Results

Noradrenergic modulation by reboxetine increased brain activity in the thalamus, right dorsolateral prefrontal cortex and occipital regions during the perception of negative emotional stimuli. Citalopram primarily affected the ventrolateral prefrontal cortical regions.

Conclusion

The brain regions involved in the processing of negative emotional stimuli were differentially modulated by selective noradrenergic and serotonergic drugs: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. Thus, dysfunction in these regions, which could be identified in depressed patients, may predict treatment responses to either noradrenergic or serotonergic antidepressants.

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References

  • Anderson IM, Del-Ben CM, McKie S, Richardson P, Williams SR, Elliott R, Deakin JF (2007) Citalopram modulation of neuronal responses to aversive face emotions: a functional MRI study. NeuroReport 18:1351–1355

    Article  PubMed  CAS  Google Scholar 

  • Arce E, Simmons AN, Lovero KL, Stein MB, Paulus MP (2008) Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacol Berl 196:661–672

    Article  CAS  Google Scholar 

  • Bigos KL, Pollock BG, Aizenstein HJ, Fisher PM, Bies RR, Hariri AR (2008) Acute 5-HT reuptake blockade potentiates human amygdala reactivity. Neuropsychopharmacology 33:3221–3225

    Article  PubMed  CAS  Google Scholar 

  • Bruder GE, Sedoruk JP, Stewart JW, McGrath PJ, Quitkin FM, Tenke CE (2008) Electroencephalographic alpha measures predict therapeutic response to a selective serotonin reuptake inhibitor antidepressant: pre- and post-treatment findings. Biol Psychiatry 63:1171–1177

    Article  PubMed  CAS  Google Scholar 

  • Brühl AB, Kaffenberger T, Herwig U (2010) Serotonergic and noradrenergic modulation of emotion processing by single dose antidepressants. Neuropsychopharmacology 35:521–533

    Article  PubMed  Google Scholar 

  • Bschor T (2010) Therapy-resistant depression. Expert Rev Neurother 10:77–86

    Article  PubMed  Google Scholar 

  • Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 373:746–758

    Article  PubMed  CAS  Google Scholar 

  • Cools R, Roberts AC, Robbins TW (2008) Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci 12:31–40

    Article  PubMed  Google Scholar 

  • Daly E, Deeley Q, Hallahan B, Craig M, Brammer M, Lamar M, Cleare A, Giampietro V, Ecker C, Page L, Toal F, Phillips ML, Surguladze S, Murphy DG (2010) Effects of acute tryptophan depletion on neural processing of facial expressions of emotion in humans. Psychopharmacol Berl 210:499–510

    Article  CAS  Google Scholar 

  • Davidson RJ, Irwin W, Anderle MJ, Kalin NH (2003) The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 160:64–75

    Article  PubMed  Google Scholar 

  • Donnici L, Tiraboschi E, Tardito D, Musazzi L, Racagni G, Popoli M (2008) Time-dependent biphasic modulation of human BDNF by antidepressants in neuroblastoma cells. BMC Neurosci 9:61

    Article  PubMed  Google Scholar 

  • Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ (2002) The neural basis of mood-congruent processing biases in depression. Arch Gen Psychiatry 59:597–604

    Article  PubMed  Google Scholar 

  • Evers EA, Van der Veen FM, Van Deursen JA, Schmitt JA, Deutz NE, Jolles J (2006) The effect of acute tryptophan depletion on the BOLD response during performance monitoring and response inhibition in healthy male volunteers. Psychopharmacol Berl 187:200–208

    Article  CAS  Google Scholar 

  • Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ (2008) A meta-analytic study of changes in brain activation in depression. Hum Brain Mapp 29:683–695

    Article  PubMed  Google Scholar 

  • Fleishaker JC (2000) Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. Clin Pharmacokinet 39:413–427

    Article  PubMed  CAS  Google Scholar 

  • Frodl T, Scheuerecker J, Schoepf V, Linn J, Koutsouleris N, Bokde AL, Hampel H, Moller HJ, Bruckmann H, Wiesmann M, Meisenzahl E (2011) Different effects of mirtazapine and venlafaxine on brain activation: an open randomized controlled fMRI study. J Clin Psychiatry (in press)

  • Fu CHY, Williams SCR, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET (2004) Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatry 61:877–889

    Article  PubMed  Google Scholar 

  • Fusar-Poli P, Allen P, Lee F, Surguladze S, Tunstall N, Fu CH, Brammer MJ, Cleare AJ, McGuire PK (2007) Modulation of neural response to happy and sad faces by acute tryptophan depletion. Psychopharmacol Berl 193:31–44

    Article  CAS  Google Scholar 

  • Grefkes C, Wang LE, Eickhoff SB, Fink GR (2010) Noradrenergic modulation of cortical networks engaged in visuomotor processing. Cereb Cortex 20:783–797

    Article  PubMed  Google Scholar 

  • Harmer CJ, Bhagwagar Z, Perrett DI, Vollm BA, Cowen PJ, Goodwin GM (2003) Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 28:148–152

    Article  PubMed  CAS  Google Scholar 

  • Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM (2004) Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry 161:1256–1263

    Article  PubMed  Google Scholar 

  • Herwig U, Kaffenberger T, Baumgartner T, Jancke L (2007) Neural correlates of a ‘pessimistic’ attitude when anticipating events of unknown emotional valence. Neuroimage 34:848–858

    Article  PubMed  Google Scholar 

  • Herwig U, Brühl AB, Kaffenberger T, Baumgartner T, Boeker H, Jäncke L (2010) Neural correlates of ‘pessimistic’ attitude in depression. Psychol Med 40:789–800

    Article  PubMed  CAS  Google Scholar 

  • Horacek J, Zavesicka L, Tintera J, Dockery C, Platilova V, Kopecek M, Spaniel F, Bubenikova V, Hoschl C (2005) The effect of tryptophan depletion on brain activation measured by functional magnetic resonance imaging during the Stroop test in healthy subjects. Physiol Res 54:235–244

    PubMed  CAS  Google Scholar 

  • Hyttel J (1982) Citalopram—pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol Biol Psychiatry 6:277–295

    Article  PubMed  CAS  Google Scholar 

  • Joubert AF, Sanchez C, Larsen F (2000) Citalopram. Hum Psychopharmacol 15:439–451

    Article  PubMed  CAS  Google Scholar 

  • Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP, Berman N, Frazer A (2004) Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 29:566–579

    Article  PubMed  CAS  Google Scholar 

  • Keedwell P, Drapier D, Surguladze S, Giampietro V, Brammer M, Phillips M (2009) Neural markers of symptomatic improvement during antidepressant therapy in severe depression: subgenual cingulate and visual cortical responses to sad, but not happy, facial stimuli are correlated with changes in symptom score. J Psychopharmacol 23:775–788

    Article  PubMed  CAS  Google Scholar 

  • Kerestes R, Labuschagne I, Croft RJ, O’Neill BV, Bhagwagar Z, Phan KL, Nathan PJ (2009) Evidence for modulation of facial emotional processing bias during emotional expression decoding by serotonergic and noradrenergic antidepressants: an event-related potential (ERP) study. Psychopharmacol Berl 202:621–634

    Article  CAS  Google Scholar 

  • Kukolja J, Schlapfer TE, Keysers C, Klingmuller D, Maier W, Fink GR, Hurlemann R (2008) Modeling a negative response bias in the human amygdala by noradrenergic–glucocorticoid interactions. J Neurosci 28:12868–12876

    Article  PubMed  CAS  Google Scholar 

  • Kumari V, Mitterschiffthaler MT, Teasdale JD, Malhi GS, Brown RG, Giampietro V, Brammer M, Poon L, Simmons A, Williams SCR, Checkley S, Sharma T (2003) Neural abnormalities during cognitive affect in treatment-resistant depression. Biol Psychiatry 54:777–791

    Article  PubMed  Google Scholar 

  • Laruelle M, Vanisberg MA, Maloteaux JM (1988) Regional and subcellular localization in human brain of [3H]paroxetine binding, a marker of serotonin uptake sites. Biol Psychiatry 24:299–309

    Article  PubMed  CAS  Google Scholar 

  • Little JT, Ketter TA, Kimbrell TA, Dunn RT, Benson BE, Willis MW, Luckenbaugh DA, Post RM (2005) Bupropion and venlafaxine responders differ in pretreatment regional cerebral metabolism in unipolar depression. Biol Psychiatry 57:220–228

    Article  PubMed  CAS  Google Scholar 

  • Martin-Soelch C (2010) Neurobiological and neuropsychological perspectives on substance dependence. Z Neuropsychol 21:153–166

    Article  Google Scholar 

  • Mayberg HS (2003) Modulating dysfunctional limbic–cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull 65:193–207

    Article  PubMed  Google Scholar 

  • McKie S, Del-Ben C, Elliott R, Williams S, Del Vai N, Anderson I, Deakin JF (2005) Neuronal effects of acute citalopram detected by pharmacoMRI. Psychopharmacol Berl 180:680–686

    Article  CAS  Google Scholar 

  • Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161:826–835

    Article  PubMed  Google Scholar 

  • Miskowiak K, Papadatou-Pastou M, Cowen PJ, Goodwin GM, Norbury R, Harmer CJ (2007) Single dose antidepressant administration modulates the neural processing of self-referent personality trait words. Neuroimage 37:904–911

    Article  PubMed  Google Scholar 

  • Murphy SE, Norbury R, O’Sullivan U, Cowen PJ, Harmer CJ (2009) Effect of a single dose of citalopram on amygdala response to emotional faces. Br J Psychiatry 194:535–540

    Article  PubMed  Google Scholar 

  • Norbury R, Mackay CE, Cowen PJ, Goodwin GM, Harmer CJ (2008) The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study. Mol Psychiatry 13:1011–1020

    Article  PubMed  CAS  Google Scholar 

  • Onur OA, Walter H, Schlaepfer TE, Rehme AK, Schmidt C, Keysers C, Maier W, Hurlemann R (2009) Noradrenergic enhancement of amygdala responses to fear. Soc Cogn Affect Neurosci 4:119–126

    Article  PubMed  Google Scholar 

  • Phillips ML, Drevets WC, Rauch SL, Lane R (2003) Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 54:515–528

    Article  PubMed  Google Scholar 

  • Rubia K, Lee F, Cleare AJ, Tunstall N, Fu CH, Brammer M, McGuire P (2005) Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI. Psychopharmacol Berl 179:791–803

    Article  CAS  Google Scholar 

  • Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10:211–223

    Article  PubMed  CAS  Google Scholar 

  • Schloss P, Henn FA (2004) New insights into the mechanisms of antidepressant therapy. Pharmacol Ther 102:47–60

    Article  PubMed  CAS  Google Scholar 

  • Schou M, Halldin C, Pike VW, Mozley PD, Dobson D, Innis RB, Farde L, Hall H (2005) Post-mortem human brain autoradiography of the norepinephrine transporter using (S, S)-[18F]FMeNER-D2. Eur Neuropsychopharmacol 15:517–520

    Article  PubMed  CAS  Google Scholar 

  • Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA (2001) Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry 50:651–658

    Article  PubMed  CAS  Google Scholar 

  • Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249–258

    Article  PubMed  CAS  Google Scholar 

  • Varnas K, Halldin C, Hall H (2004) Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 22:246–260

    Article  PubMed  Google Scholar 

  • Wagner G, Koch K, Schachtzabel C, Sobanski T, Reichenbach JR, Sauer H, Schlosser RG (2010) Differential effects of serotonergic and noradrenergic antidepressants on brain activity during a cognitive control task and neurofunctional prediction of treatment outcome in patients with depression. J Psychiatry Neurosci 35:247–257

    Article  PubMed  Google Scholar 

  • Wingen M, Kuypers KP, Van de Ven V, Formisano E, Ramaekers JG (2008) Sustained attention and serotonin: a pharmaco-fMRI study. Hum Psychopharmacol 23:221–230

    Article  PubMed  Google Scholar 

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Competing interests

All authors report no competing interests.

Financial support

Supported by Swiss National Funds grant 112 631 to Prof. Dr. U. Herwig. The authors thank Dr. Caitriona Obermann for critical comments on the manuscript.

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Correspondence to Annette Beatrix Brühl.

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Brühl, A.B., Jäncke, L. & Herwig, U. Differential modulation of emotion processing brain regions by noradrenergic and serotonergic antidepressants. Psychopharmacology 216, 389–399 (2011). https://doi.org/10.1007/s00213-011-2227-2

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  • DOI: https://doi.org/10.1007/s00213-011-2227-2

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