, Volume 205, Issue 2, pp 261–271 | Cite as

5-HTT genotype effect on prefrontal–amygdala coupling differs between major depression and controls

  • Eva FriedelEmail author
  • Florian Schlagenhauf
  • Philipp Sterzer
  • Soyoung Q. Park
  • Felix Bermpohl
  • Andreas Ströhle
  • Meline Stoy
  • Imke Puls
  • Claudia Hägele
  • Jana Wrase
  • Christian Büchel
  • Andreas Heinz
Original Investigation



In major depression, prefrontal regulation of limbic brain areas may be a key mechanism that is impaired during the processing of affective information. This prefrontal–limbic interaction has been shown to be modulated by serotonin (5-HTT) genotype, indicating a higher risk for major depressive disorder (MDD) with increasing number of 5-HTT low-expression alleles.


Functional magnetic resonance imaging was used to assess neural response to uncued unpleasant affective pictures in 21 unmedicated patients with MDD compared to 21 matched healthy controls, taking into account genetic influences of the 5-HTT (SCL6A4) high- and low-expression genotype.


Healthy controls displayed greater prefrontal activation (BA10) to uncued negative pictures compared to patients with MDD. While in healthy controls prefrontal (BA10) activation and BA10–amygdala coupling increased with the number of 5-HTT low-expression risk alleles, this effect was abolished, and even reversed, in patients with MDD. In MDD, connectivity decreased with severity of depressive symptoms (HAMD total score).


These findings suggest that increased medial prefrontal (BA10) activation and BA10–amygdala connectivity may counteract the risk for MDD in healthy carriers of 5-HTT low-expression alleles, while this protective factor might be lost in patients who actually suffer from MDD. Prefrontal–limbic regulation in risk populations could be a target of early interventions and should be the focus of further research.


5-HTT genotype Functional MRI Major depressive disorder Connectivity Emotion Regulation 



This study was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) DFG He 2597/4-3 and 7-3 and STE 1430/2-1.

Competing interest statement

The authors declare that they have no competing financial interests.

Supplementary material

213_2009_1536_MOESM1_ESM.doc (122 kb)
ESM 1 (DOC 121 kb)


  1. Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kalnin A, Lowe MJ (2005a) Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biol Psychiatry 57:1079–1088PubMedCrossRefGoogle Scholar
  2. Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kalnin A, Lowe MJ (2005b) Antidepressant effect on connectivity of the mood-regulating circuit: an FMRI study. Neuropsychopharmacology 30:1334–1344PubMedGoogle Scholar
  3. Anand A, Li Y, Wang Y, Gardner K, Lowe MJ (2007) Reciprocal effects of antidepressant treatment on activity and connectivity of the mood regulating circuit: an FMRI study. J Neuropsychiatry Clin Neurosci 19:274–282PubMedGoogle Scholar
  4. Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE, Champoux M, Suomi SJ, Linnoila MV, Higley JD (2002) Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 7:118–122PubMedCrossRefGoogle Scholar
  5. Bermpohl F, Pascual-Leone A, Amedi A, Merabet LB, Fregni F, Gaab N, Alsop D, Schlaug G, Northoff G (2006) Attentional modulation of emotional stimulus processing: an fMRI study using emotional expectancy. Hum Brain Mapp 27:662–77PubMedCrossRefGoogle Scholar
  6. Bishop S, Duncan J, Brett M, Lawrence AD (2004) Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat Neurosci 7:184–188PubMedCrossRefGoogle Scholar
  7. Brassen S, Kalisch R, Weber-Fahr W, Braus DF, Buchel C (2008) Ventromedial prefrontal cortex processing during emotional evaluation in late-life depression: a longitudinal functional magnetic resonance imaging study. Biol Psychiatry 64:349–355PubMedCrossRefGoogle Scholar
  8. Brown GW, Harris TO (2008) Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene–environment interaction. J Affect Disord 111:1–12PubMedCrossRefGoogle Scholar
  9. Canli T, Omura K, Haas BW, Fallgatter A, Constable RT, Lesch KP (2005) Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task. Proc Natl Acad Sci U S A 102:12224–12229PubMedCrossRefGoogle Scholar
  10. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389PubMedCrossRefGoogle Scholar
  11. Chen CH, Suckling J, Ooi C, Fu CH, Williams SC, Walsh ND, Mitterschiffthaler MT, Pich EM, Bullmore E (2008) Functional coupling of the amygdala in depressed patients treated with antidepressant medication. Neuropsychopharmacology 33:1909–1918PubMedCrossRefGoogle Scholar
  12. Dannlowski U, Ohrmann P, Bauer J, Kugel H, Baune BT, Hohoff C, Kersting A, Arolt V, Heindel W, Deckert J, Suslow T (2007) Serotonergic genes modulate amygdala activity in major depression. Genes Brain Behav 6:672–676PubMedCrossRefGoogle Scholar
  13. Dannlowski U, Ohrmann P, Bauer J, Deckert J, Hohoff C, Kugel H, Arolt V, Heindel W, Kersting A, Baune BT, Suslow T (2008) 5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression. Neuropsychopharmacology 33:418–424PubMedCrossRefGoogle Scholar
  14. Domschke K, Braun M, Ohrmann P, Suslow T, Kugel H, Bauer J, Hohoff C, Kersting A, Engelien A, Arolt V, Heindel W, Deckert J (2006) Association of the functional −1019C/G 5-HT1A polymorphism with prefrontal cortex and amygdala activation measured with 3 T fMRI in panic disorder. Int J Neuropsychopharmacol 9:349–355PubMedCrossRefGoogle Scholar
  15. Drevets WC (2007) Orbitofrontal cortex function and structure in depression. Ann N Y Acad Sci 1121:499–527PubMedCrossRefGoogle Scholar
  16. Gillespie NA, Whitfield JB, Williams B, Heath AC, Martin NG (2005) The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychol Med 35:101–111PubMedCrossRefGoogle Scholar
  17. Gitelman DR, Penny WD, Ashburner J, Friston KJ (2003) Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution. NeuroImage 19:200–207PubMedGoogle Scholar
  18. Gonda X, Fountoulakis KN, Juhasz G, Rihmer Z, Lazary J, Laszik A, Akiskal HS, Bagdy G (2008) Association of the s allele of the 5-HTTLPR with neuroticism-related traits and temperaments in a psychiatrically healthy population. Eur Arch Psychiatry Clin Neurosci 259:106–113PubMedCrossRefGoogle Scholar
  19. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62PubMedCrossRefGoogle Scholar
  20. Hariri AR, Tessitore A, Mattay VS, Fera F, Weinberger DR (2002) The amygdala response to emotional stimuli: a comparison of faces and scenes. NeuroImage 17:317–323PubMedCrossRefGoogle Scholar
  21. Hariri AR, Drabant EM, Munoz KE, Kolachana BS, Mattay VS, Egan MF, Weinberger DR (2005) A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry 62:146–152PubMedCrossRefGoogle Scholar
  22. Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grusser SM, Flor H, Schumann G, Mann K, Buchel C (2005) Amygdala–prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 8:20–21PubMedCrossRefGoogle Scholar
  23. Heinz A, Smolka MN, Braus DF, Wrase J, Beck A, Flor H, Mann K, Schumann G, Büchel C, Hariri AR, Weinberger DR (2007) Serotonin transporter genotype (5- HTTLPR): effects of neutral and undefined conditions on amygdala activation. Biol Psychiatry 61:1011–1014PubMedCrossRefGoogle Scholar
  24. Herwig U, Baumgartner T, Kaffenberger T, Brühl A, Kottlow M, Schreiter- Gasser U, Abler B, Jäncke L, Rufer M (2007) Modulation of anticipatory emotion and perception processing by cognitive control. Neuroimage 37:652–662PubMedCrossRefGoogle Scholar
  25. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive–compulsive disorder. Am J Hum Genet 78:815–826PubMedCrossRefGoogle Scholar
  26. Irwin W, Anderle MJ, Abercrombie HC, Schaefer SM, Kalin NH, Davidson RJ (2004) Amygdalar interhemispheric functional connectivity differs between the non-depressed and depressed human brain. NeuroImage 21:674–686PubMedCrossRefGoogle Scholar
  27. Johnstone T, van Reekum CM, Urry HL, Kalin NH, Davidson RJ (2007) Failure to regulate: counterproductive recruitment of top-down prefrontal–subcortical circuitry in major depression. J Neurosci 27:8877–8884PubMedCrossRefGoogle Scholar
  28. Juckel G, Hegerl U, Molnar M, Csepe V, Karmos G (1999) Auditory evoked potentials reflect serotonergic neuronal activity—a study in behaving cats administered drugs acting on 5-HT1A autoreceptors in the dorsal raphe nucleus. Neuropsychopharmacology 21:710–716PubMedCrossRefGoogle Scholar
  29. Kalisch R, Wiech K, Critchley HD, Dolan RJ (2006) Levels of appraisal: a medial prefrontal role in high-level appraisal of emotional material. NeuroImage 30:1458–1466PubMedCrossRefGoogle Scholar
  30. Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML (2005) A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals. Biol Psychiatry 58:495–503PubMedCrossRefGoogle Scholar
  31. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B (2005) The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 62:529–535PubMedCrossRefGoogle Scholar
  32. Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT (2000) Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 10:120–131PubMedCrossRefGoogle Scholar
  33. Lang PJ, Bradley MM, Cuthbert BN (1999) International Affective Picture System (IAPS) Instruction Manual and Affective Ratings. Gainesville, University of FloridaGoogle Scholar
  34. Lau JY, Goldman D, Buzas B, Fromm SJ, Guyer AE, Hodgkinson C, Monk CS, Nelson EE, Shen PH, Pine DS, Ernst M (2008) Amygdala function and 5-HTT gene variants in adolescent anxiety and major depressive disorder. Biol Psychiatry 65:349–355PubMedCrossRefGoogle Scholar
  35. Lee BT, Seok JH, Lee BC, Cho SW, Yoon BJ, Lee KU, Chae JH, Choi IG, Ham BJ (2008) Neural correlates of affective processing in response to sad and angry facial stimuli in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 32:778–785PubMedCrossRefGoogle Scholar
  36. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedCrossRefGoogle Scholar
  37. Lesch KP, Meyer J, Glatz K, Flugge G, Hinney A, Hebebrand J, Klauck SM, Poustka A, Poustka F, Bengel D, Mossner R, Riederer P, Heils A (1997) The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication. J Neural Transm 104:1259–1266PubMedCrossRefGoogle Scholar
  38. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19:1233–1239PubMedCrossRefGoogle Scholar
  39. Matthews SC, Strigo IA, Simmons AN, Yang TT, Paulus MP (2008) Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder. J Affect Disord 111:13–20PubMedCrossRefGoogle Scholar
  40. Mayberg HS (2002) Modulating limbic–cortical circuits in depression: targets of antidepressant treatments. Semin Clin Neuropsychiatry 7:255–268PubMedCrossRefGoogle Scholar
  41. Mayberg HS (2003) Modulating dysfunctional limbic–cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull 65:193–207PubMedCrossRefGoogle Scholar
  42. Mitterschiffthaler MT, Ettinger U, Mehta MA, Mataix-Cols D, Williams SC (2006) Applications of functional magnetic resonance imaging in psychiatry. J Magn Reson Imaging 23:851–861PubMedCrossRefGoogle Scholar
  43. Munafo MR, Brown SM, Hariri AR (2008) Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 63:852–857PubMedCrossRefGoogle Scholar
  44. Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5:32–38PubMedCrossRefGoogle Scholar
  45. Ochsner KN, Gross JJ (2005) The cognitive control of emotion. Trends Cogn Sci 9:242–249PubMedCrossRefGoogle Scholar
  46. Onoda K, Okamoto Y, Toki S, Ueda K, Shishida K, Kinoshita A, Yoshimura S, Yamashita H, Yamawaki S (2008) Anterior cingulate cortex modulates preparatory activation during certain anticipation of negative picture. Neuropsychologia 46:102–110PubMedCrossRefGoogle Scholar
  47. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR (2005) 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 8:828–834PubMedCrossRefGoogle Scholar
  48. Phan KL, Wager T, Taylor SF, Liberzon I (2002) Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. NeuroImage 16:331–348PubMedCrossRefGoogle Scholar
  49. Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S, Masellis M, Houle S, Meyer JH (2007) Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11) C] DASB positron emission tomography study. Biol Psychiatry 62:327–331PubMedCrossRefGoogle Scholar
  50. Ressler KJ, Mayberg HS (2007) Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci 10:1116–1124PubMedCrossRefGoogle Scholar
  51. Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S (2004) Limbic–frontal circuitry in major depression: a path modeling metanalysis. NeuroImage 22:409–418PubMedCrossRefGoogle Scholar
  52. 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 50:651–658PubMedCrossRefGoogle Scholar
  53. Siegle GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS (2002) Can’t shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals. Biol Psychiatry 51:693–707PubMedCrossRefGoogle Scholar
  54. Simpson JR Jr, Drevets WC, Snyder AZ, Gusnard DA, Raichle ME (2001) Emotion-induced changes in human medial prefrontal cortex: II during the anticipatory anxiety. Proc Natl Acad Sci U S A 98:688–693PubMedCrossRefGoogle Scholar
  55. Smolka MN, Buhler M, Schumann G, Klein S, Hu XZ, Moayer M, Zimmer A, Wrase J, Flor H, Mann K, Braus DF, Goldman D, Heinz A (2007) Gene–gene effects on central processing of aversive stimuli. Mol Psychiatry 12:307–317PubMedGoogle Scholar
  56. Spinelli S, Schwandt ML, Lindell SG, Newman TK, Heilig M, Suomi SJ, Higley JD, Goldman D, Barr CS (2007) Association between the recombinant human serotonin transporter linked promoter region polymorphism and behavior in rhesus macaques during a separation paradigm. Dev Psychopathol 19:977–987PubMedCrossRefGoogle Scholar
  57. Taylor SF, Phan KL, Decker LR, Liberzon I (2003) Subjective rating of emotionally salient stimuli modulates neural activity. NeuroImage 18:650–659PubMedCrossRefGoogle Scholar
  58. Ueda K, Okamoto Y, Okada G, Yamashita H, Hori T, Yamawaki S (2003) Brain activity during expectancy of emotional stimuli: an fMRI study. NeuroReport 14:51–55PubMedCrossRefGoogle Scholar
  59. Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, Lesch KP, Murphy DL, Holmes A (2007) Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci 27:684–691PubMedCrossRefGoogle Scholar
  60. Wittchen HU, Zaudig M, Fydrich T (1997) SKID. Strukturiertes klinisches Interview für DSM-IV. Achse I und II. User manual. Göttingen: HogrefeGoogle Scholar
  61. Zalsman G, Huang YY, Oquendo MA, Burke AK, Hu XZ, Brent DA, Ellis SP, Goldman D, Mann JJ (2006) Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. Am J Psychiatry 163:1588–1593PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Eva Friedel
    • 1
    Email author
  • Florian Schlagenhauf
    • 1
  • Philipp Sterzer
    • 1
  • Soyoung Q. Park
    • 1
  • Felix Bermpohl
    • 1
  • Andreas Ströhle
    • 1
  • Meline Stoy
    • 1
  • Imke Puls
    • 1
  • Claudia Hägele
    • 1
  • Jana Wrase
    • 1
  • Christian Büchel
    • 2
  • Andreas Heinz
    • 1
  1. 1.Department of PsychiatryCharité University Medicine Berlin, Campus Charité MitteBerlinGermany
  2. 2.NeuroImage Nord, Department of NeurologyUniversity Clinic Hamburg-EppendorfHamburgGermany

Personalised recommendations