5-HTT genotype effect on prefrontal–amygdala coupling differs between major depression and controls
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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.
Keywords5-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.
- 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
- 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
- Lang PJ, Bradley MM, Cuthbert BN (1999) International Affective Picture System (IAPS) Instruction Manual and Affective Ratings. Gainesville, University of FloridaGoogle Scholar
- 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
- 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
- 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
- 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
- Wittchen HU, Zaudig M, Fydrich T (1997) SKID. Strukturiertes klinisches Interview für DSM-IV. Achse I und II. User manual. Göttingen: HogrefeGoogle Scholar
- 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