Research Report| Volume 65, ISSUE 4, P349-355, February 15, 2009

Download started.


Amygdala Function and 5-HTT Gene Variants in Adolescent Anxiety and Major Depressive Disorder


      Associations between a functional polymorphism in the serotonin transporter gene and amygdala activation have been found in healthy, depressed, and anxious adults. This study explored these gene–brain associations in adolescents by examining predictive effects of serotonin transporter gene variants (S and LG allele carriers vs. LA allele homozygotes) and their interaction with diagnosis (healthy vs. patients) on amygdala responses to emotional faces.


      Functional magnetic resonance data were collected from 33 healthy adolescents (mean age: 13.71, 55% female) and 31 medication-free adolescents with current anxiety or depressive disorders (or both; mean age: 13.58, 56% female) while viewing fearful, angry, happy, and neutral facial expressions under varying attention states.


      A significant three-way genotype-by-diagnosis-by-face-emotion interaction characterized right amygdala activity while subjects monitored internal fear levels. This interaction was decomposed to map differential gene–brain associations in healthy and affected adolescents. First, consistent with healthy adult data, healthy adolescents with at least one copy of the S or LG allele showed stronger amygdala responses to fearful faces than healthy adolescents without these alleles. Second, patients with two copies of the LA allele exhibited greater amygdala responses to fearful faces relative to patients with S or LG alleles. Third, although weaker, genotype differences on amygdala responses in patients extended to happy faces. All effects were restricted to the fear-monitoring attention state.


      S/LG alleles in healthy adolescents, as in healthy adults, predict enhanced amygdala activation to fearful faces. Contrary findings of increased activation in patients with LALA relative to the S or LG alleles require further exploration.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Beesdo K.
        • Bittner A.
        • Pine D.S.
        • Stein M.B.
        • Hofler M.
        • Lieb R.H.
        • et al.
        Incidence of social anxiety disorder and the consistent risk for secondary depression in the first three decades of life.
        Arch Gen Psychiatry. 2007; 64: 903-912
        • Pine D.S.
        • Cohen P.
        • Gurley D.
        • Brook J.
        • Ma Y.
        The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders.
        Arch Gen Psychiatry. 1998; 55: 56-64
        • Gross C.
        • Hen R.
        The developmental origins of anxiety.
        Nat Rev Neuroscience. 2004; 5: 545-552
        • Munafo M.R.
        • Brown S.M.
        • Hariri A.R.
        Serotonin transporter (5-HTTLPR) genotype and amygdala activation: A meta-analysis.
        Biol Psychiatry. 2008; 63: 852-857
        • Thomas K.M.
        • Drevets W.C.
        • Dahl R.E.
        • Ryan N.D.
        • Birmaher B.
        • Eccard C.H.
        • et al.
        Amygdala response to fearful faces in anxious and depressed children.
        Arch Gen Psychiatry. 2001; 58: 1057-1063
        • Killgore W.D.
        • Yurgelun-Todd D.A.
        Social anxiety predicts amygdala activation in adolescents viewing fearful faces.
        Neuroreport. 2005; 16: 1671-1675
        • McClure E.B.
        • Monk C.S.
        • Nelson E.E.
        • Parrish J.M.
        • Adler A.
        • Blair R.J.R.
        • et al.
        Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder.
        Arch Gen Psychiatry. 2007; 64: 97-106
        • Roberson-Nay R.
        • McClure E.B.
        • Monk C.S.
        • Nelson E.E.
        • Guyer A.E.
        • Fromm S.J.
        • et al.
        Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An FMRI study.
        Biol Psychiatry. 2006; 60: 966-973
        • Perez-Edgar K.
        • Roberson-Nay R.
        • Hardin M.G.
        • Poeth K.
        • Guyer A.E.
        • Nelson E.E.
        • et al.
        Attention alters neural responses to evocative faces in behaviorally inhibited adolescents.
        NeuroImage. 2007; 35: 1538-1546
        • Monk C.S.
        • Telzer E.H.
        • Mogg K.
        • Bradley B.P.
        • Mai X.
        • Louro H.M.
        • et al.
        Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder.
        Arch Gen Psychiatry. 2008; 65: 568-576
        • Lesch K.P.
        • Bengel D.
        • Heils A.
        • Sabol S.Z.
        • Greenberg B.D.
        • Petri S.
        • et al.
        Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.
        Science. 1996; 274: 1527-1531
        • Hu X.Z.
        • Lipsky R.H.
        • Zhu G.
        • Akhtar L.A.
        • Taubman J.
        • Greenberg B.D.
        • et al.
        Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder.
        American J Hum Genet. 2006; 78: 815-826
        • Hariri A.R.
        • Holmes A.
        Genetics of emotional regulation: The role of the serotonin transporter in neural function.
        Trends Cogn Sci. 2006; 10: 182-191
      1. Munafo MR, Clark TG, Moore LR, Payne E, Walton R, Flint J. Genetic polymorphisms and personality in healthy adults: A systematic review and meta-analysis. Mol Psychiatry 8:471–484.

        • Sen S.
        • Burmeister M.
        • Ghosh D.
        Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits.
        Am J Med Genet B Neuropsychiatr Genet. 2004; 127B: 85-99
        • Ebstein R.P.
        • Levine J.
        • Geller V.
        • Auerbach J.
        • Gritsenko I.
        • Belmaker R.H.
        Dopamine D4 receptor and serotonin transporter promoter in the determination of neonatal temperament.
        Mol Psychiatry. 1998; 3: 238-246
        • Battaglia M.
        • Ogliari A.
        • Zanoni A.
        • Citterio A.
        • Pozzoli U.
        • Giorda R.
        • et al.
        Influence of the serotonin transporter promoter gene and shyness on children's cerebral responses to facial expressions.
        Arch Gen Psychiatry. 2005; 62: 85-94
        • Arbelle S.
        • Benjamin J.
        • Golin M.
        • Kremer I.
        • Belmaker R.H.
        • Ebstein R.P.
        Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism.
        Am J Psychiatry. 2003; 160: 671-676
        • Jorm A.F.
        • Prior M.
        • Sanson A.
        • Smart D.
        • Zhang Y.
        • Easteal S.
        Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: A longitudinal study from infancy to the mid-teens.
        Mol Psychiatry. 2000; 5: 542-547
        • Cicchetti D.
        • Rogosch F.A.
        • Sturge-Apple M.L.
        Gene–environment interaction.
        Dev Psychopathol. 2007; 19: 957-959
        • Eley T.C.
        • Sugden K.
        • Corsico A.
        • Gregory A.M.
        • Sham P.
        • McGuffin P.
        • et al.
        Gene–environment interaction analysis of serotonin system markers with adolescent depression.
        Mol Psychiatry. 2004; 9: 908-915
        • Fox N.A.
        • Nichols K.E.
        • Henderson H.A.
        • Rubin K.
        • Schmidt L.
        • Hamer D.
        • et al.
        Evidence for a gene–environment interaction in predicting behavioral inhibition in middle childhood.
        Psychol Sci. 2005; 16: 921-926
        • Kaufman J.
        • Yang B.Z.
        • Douglas-Palumberi H.
        • Houshyar S.
        • Lipschitz D.
        • Krystal J.H.
        • et al.
        Social supports and serotonin transporter gene moderate depression in maltreated children.
        Proc Natl Acad Sci U S A. 2004; 101: 17316-17321
        • Smolka M.N.
        • Buhler M.
        • Schumann G.
        • Klein S.
        • Hu X.Z.
        • Moayer M.
        • et al.
        Gene–gene effects on central processing of aversive stimuli.
        Mol Psychiatry. 2007; 12: 307-317
        • Dannlowski U.
        • Ohrmann P.
        • Bauer J.
        • Kugel H.
        • Baune B.T.
        • Hohoff C.
        • et al.
        Serotonergic genes modulate amygdala activity in major depression.
        Genes Brain Behav. 2007; 6: 672-676
        • Dannlowski U.
        • Ohrmann P.
        • Bauer J.
        • Deckert J.
        • Hohoff C.
        • Kugel H.
        • et al.
        5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression.
        Neuropsychopharmacology. 2008; 33: 418-424
        • Furmark T.
        • Tillfors M.
        • Garpenstrand H.
        • Marteinsdottir I.
        • Langstrom B.
        • Oreland L.
        • et al.
        Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia.
        Neurosci Lett. 2004; 362: 189-192
        • Domschke K.
        • Braun M.
        • Ohrmann P.
        • Suslow T.
        • Kugel H.
        • Bauer J.
        • et al.
        Association of the functional -1019C/G 5-HT1A polymorphism with prefrontal cortex and amygdala activation measured with 3T fMRI in panic disorder.
        Int J Neuropsychopharmacol. 2006; 9: 349-355
        • Guyer A.E.
        • Monk C.S.
        • McClure-Tone E.B.
        • Nelson E.E.
        • Roberson-Nay R.
        • Adler A.D.
        • et al.
        A developmental examination of amygdala response to facial expressions.
        J Cogn Neurosci. 2008; 20: 1565-1582
      2. Hodgkinson C, Xu K, Qiaoping Y, Pei-Hong S, Heinz E, Lobos EA, et al. Addictions biology: Haplotype based analysis for 130 candidate genes on a single array. Alcohol Alcohol 43:505–515.

        • Kaufman J.
        • Birmaher B.
        • Brent D.
        • Rao U.
        • Flynn C.
        • Moreci P.
        • et al.
        Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 980-988
        • Monk C.S.
        • McClure E.B.
        • Nelson E.E.
        • Zarahn E.
        • Bilder R.M.
        • Leibenluft E.
        • et al.
        Adolescent immaturity in attention-related brain engagement to emotional facial expressions.
        NeuroImage. 2003; 20: 420-428
        • Pine D.S.
        • Klein R.G.
        • Mannuzza S.
        • Moulton 3rd, J.L.
        • Lissek S.
        • Guardino M.
        • et al.
        Face-emotion processing in offspring at risk for panic disorder.
        J Am Acad Child Adolesc Psychiatry. 2005; 44: 664-672
        • Rich B.A.
        • Vinton D.T.
        • Roberson-Nay R.
        • Hommer R.E.
        • Berghorst L.H.
        • McClure E.B.
        • et al.
        Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder.
        Proc Natl Acad Sci U S A. 2006; 103: 8900-8905
        • Ekman P.
        • Friesen W.V.
        Pictures of Facial Affect.
        Consulting Psychology Press, Palo Alto, CA1976
        • Gur R.C.
        • Ragland J.D.
        • Moberg P.J.
        • Turner T.H.
        • Bilker W.B.
        • Kohler C.
        • et al.
        Computerized neurocognitive scanning, I: methodology and validation in healthy people.
        Neuropsychopharmacology. 2001; 25: 766-776
      3. Tottenham N, Tanaka J, Leon AC, McCarry T, Nurse M, Hare TA, et al.(in press): The NimStim set of facial expressions: judgements from untrained research participants. Psychiatry Res.

        • Zarahn E.
        • Aguirre G.
        • D'Esposito M.
        A trial-based experimental design for fMRI.
        Neuroimage. 1997; 6: 122-138
        • Holmes A.P.
        • Friston K.J.
        Generalisability, random effects and population inference.
        Neuroimage. 1998; 7: S754
        • Hariri A.R.
        • Mattay V.S.
        • Tessitore A.
        • Kolachana B.
        • Fera F.
        • Goldman D.
        • et al.
        Serotonin transporter genetic variation and the response of the human amygdala.
        Science. 2002; 297: 400-403
        • Szeszko P.R.
        • Robinson D.
        • Alvir J.M.
        • Bilder R.M.
        • Lencz T.
        • Ashtari M.
        • et al.
        Orbital frontal and amygdala volume reductions in obsessive compulsive disorder.
        Arch Gen Psychiatry. 1999; 56: 913-919
        • Birmaher B.
        • Khetarpal S.
        • Brent D.
        • Cully M.
        • Balach L.
        • Kaufman J.
        • Neer S.M.
        The Screen for Child Anxiety Related Emotional Disorders (SCARED): Scale construction and psychometric characteristics.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 545-553
        • Kovacs M.
        The Children's Depression Inventory (CDI).
        Psychopharmacol Bull. 1985; 21: 995-998
        • Barr C.S.
        • Newman T.K.
        • Shannon C.
        • Parker C.
        • Dvoskin R.L.
        • Becker M.L.
        • et al.
        Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques.
        Biol Psychiatry. 2004; 55: 733-738
        • Caspi A.
        • Sugden K.
        • Moffitt T.E.
        • Taylor A.
        • Craig I.W.
        • Harrington H.
        • et al.
        Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.
        Science. 2003; 301: 386-389
        • Monk C.S.
        • Klein R.G.
        • Telzer E.H.
        • Schroth E.A.
        • Mannuzza S.
        • Moulton 3rd, J.L.
        • et al.
        Amygdala and nucleus accumbens activation to emotional facial expressions in children and adolescents at risk for major depression.
        Am J Psychiatry. 2008; 165: 90-98
      4. Guyer AE, Lau JYF, McClure EB, Parrish J, Shiffrin ND, Blair RJR, et al. (in press): Amygdala and Ventrolateral Prefrontal Cortex Function during Anticipated Peer Evaluation in Pediatric Social Anxiety. Arch Gen Psychiatry.

        • Dugas M.J.
        • Buhr K.
        • Ladouceur R.
        The role of intolerance of uncertainty in etiology and maintenance.
        in: Heimberg R.G. Turk C.L. Mennin D.S. Generalized Anxiety Disorder: Advances in Research and Practice. Guilford Press, New York2004: 143-163
        • Bradley B.P.
        • Mogg K.
        • White J.
        • Groom C.
        • de Bono J.
        Attentional bias for emotional faces in generalized anxiety disorder.
        Br J Clin Psychol. 1999; 38: 267-278
        • Monk C.S.
        • Nelson E.E.
        • McClure E.B.
        • Mogg K.
        • Bradley B.P.
        • Leibenluft E.
        • et al.
        Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder.
        Am J Psychiatry. 2006; 163: 1091-1097