Skip to main content
Log in

Escitalopram effects on insula and amygdala BOLD activation during emotional processing

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The amygdala and insular cortex are integral to the processing of emotionally salient stimuli. We have shown in healthy volunteers that an anxiolytic agent, lorazepam, dose-dependently attenuates activation of limbic structures.

Objective

The current study investigated whether administration of a selective serotonin reuptake inhibitor (SSRI), escitalopram, alters the activation of limbic structures. We hypothesized that subchronic (21 days) SSRI treatment attenuates the activation of the amygdala and insula during processing of emotional faces.

Materials and methods

Thirteen healthy volunteers participated in a double-blind, placebo-controlled, crossover, randomized study. After 21 days of treatment with either escitalopram or placebo, participants underwent functional magnetic resonance imaging (fMRI) during which all subjects completed an emotion face assessment task, which has been shown to elicit amygdala and insula activation.

Results

Subjects activated the bilateral insula and amygdala after treatment with both escitalopram and placebo. In subjects who were adherent to the protocol (as evidenced by sufficiently high urine concentrations of escitalopram), a reduction in amygdala activation was seen in the escitalopram condition compared to placebo.

Conclusion

The current investigation provides further evidence for the mechanism of action of SSRIs through the attenuation of activation in brain regions responsible for emotion processing and provides support for the use of blood oxygenation level-dependent fMRI with pharmacological probes to help identify the specific therapeutic effect of these agents in patients with anxiety and mood disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Arce E, Miller DA, Feinstein JS, Stein MB, Paulus MP (2006) Lorazepam dose-dependently decreases risk-taking related activation in limbic areas. Psychopharmacology (Berl) 189:105–116

    Article  CAS  Google Scholar 

  • Beck AT, Ward CH, Medelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571

    PubMed  CAS  Google Scholar 

  • Breiter HC, Rosen BR (1999) Functional magnetic resonance imaging of brain reward circuitry in the human. Ann NY Acad Sci 877:523–547

    Article  PubMed  CAS  Google Scholar 

  • Browning M, Reid C, Cowen PJ, Goodwin GM, Harmer CJ (2007) A single dose of citalopram increases fear recognition in healthy subjects. J Psychopharmacol 21:684–690

    Article  PubMed  CAS  Google Scholar 

  • Buchel C, Morris J, Dolan RJ, Friston KJ (1998) Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 20:947–957

    Article  PubMed  CAS  Google Scholar 

  • Canli T, Zhao Z, Brewer J, Gabrieli JD, Cahill L (2000) Event-related activation in the human amygdala associates with later memory for individual emotional experience. J Neurosci 20:RC99

    PubMed  CAS  Google Scholar 

  • Carrasco JL, Sandner C (2005) Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview. Int J Clin Pract 59:1428–1434

    Article  PubMed  CAS  Google Scholar 

  • Charney DS (2003) Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand Suppl 147:38–50

    Article  Google Scholar 

  • Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E, Bullmore E (2007) Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment. Biol Psychiatry 62:407–414

    Article  PubMed  CAS  Google Scholar 

  • Craig AD (2002) How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 3:655–666

    PubMed  CAS  Google Scholar 

  • Critchley HD, Wiens S, Rotshtein P, Ohman A, Dolan RJ (2004) Neural systems supporting interoceptive awareness. Nat Neurosci 7:189–195

    Article  PubMed  CAS  Google Scholar 

  • Del-Ben CM, Deakin JF, Mckie S, Delvai NA, Williams SR, Elliott R, Dolan M, Anderson IM (2005) The effect of citalopram pretreatment on neuronal responses to neuropsychological tasks in normal volunteers: an FMRI study. Neuropsychopharmacology 30:1724–1734

    Article  PubMed  CAS  Google Scholar 

  • Derogatis LR, Melisaratos N (1983) The brief symptom inventory: an introductory report. Psychol Med 13(3):595–605

    Article  PubMed  CAS  Google Scholar 

  • Ernst M, Bolla K, Mouratidis M, Contoreggi C, Matochik JA, Kurian V, Cadet JL, Kimes AS, London ED (2002) Decision-making in a risk-taking task. A PET Study. Neuropsychopharmacology 26:682–691

    Article  Google Scholar 

  • Fu CH, Williams SC, Brammer MJ, Suckling J, Kim J, Cleare AJ, Walsh ND, Mitterschiffthaler MT, Andrew CM, Pich EM, Bullmore ET (2007) Neural responses to happy facial expressions in major depression following antidepressant treatment. Am J Psychiatry 164:599–607

    Article  PubMed  Google Scholar 

  • Fu CH, Williams SC, 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 

  • Garavan H, Pendergrass JC, Ross TJ, Stein EA, Risinger RC (2001) Amygdala response to both positively and negatively valenced stimuli. Neuroreport 12:2779–2783

    Article  PubMed  CAS  Google Scholar 

  • Gottfried JA, O'Doherty J, Dolan RJ (2002) Appetitive and aversive olfactory learning in humans studied using event-related functional magnetic resonance imaging. J Neurosci 22:10829–10837

    PubMed  CAS  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, Mackay CE, Reid CB, Cowen PJ, Goodwin GM (2006) Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry 59:816–820

    Article  PubMed  CAS  Google Scholar 

  • Harmer CJ, Rogers RD, Tunbridge E, Cowen PJ, Goodwin GM (2003) Tryptophan depletion decreases the recognition of fear in female volunteers. Psychopharmacology 167:411–417

    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 

  • Hoehn-Saric R, Schlund MW, Wong SH (2004) Effects of citalopram on worry and brain activation in patients with generalized anxiety disorder. Psychiatry Res 131:11–21

    Article  PubMed  CAS  Google Scholar 

  • Hogg S, Michan L, Jessa M (2006) Prediction of anti-panic properties of escitalopram in the dorsal periaqueductal grey model of panic anxiety. Neuropharmacology 51:141–145

    Article  PubMed  CAS  Google Scholar 

  • Kent JM, Coplan JD, Gorman JM (1998) Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety. Biological Psychiatry 44:812–824

    Article  PubMed  CAS  Google Scholar 

  • Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, et al (2000) Automated Talairach atlas labels for functional brain mapping. Hum Brain Map 10:120–131

    Article  CAS  Google Scholar 

  • Lorberbaum JP, Kose S, Johnson MR, Arana GW, Sullivan LK, Hamner MB, Ballenger JC, Lydiard RB, Brodrick PS, Bohning DE, George MS (2004) Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport 15:2701–2705

    PubMed  Google Scholar 

  • Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ (1998) Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 55:715–720

    Article  PubMed  CAS  Google Scholar 

  • Masand PS, Gupta S (1999) Selective serotonin-reuptake inhibitors: An update. Harv Rev Psychiatr 7:69–84

    Article  CAS  Google Scholar 

  • Mataix-Cols D, Rauch SL, Manzo PA, Jenike MA, Baer L (1999) Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive- compulsive disorder. Am J Psychiatry 156:1409–1416

    PubMed  CAS  Google Scholar 

  • Mattick RP, Clarke JC (1998) Development and validation of measures of social phobia scrutiny fear and social interaction anxiety. Behav Res Ther 36(4):455–470

    Article  PubMed  CAS  Google Scholar 

  • Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA (2000) Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–843

    Article  PubMed  CAS  Google Scholar 

  • Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT (1999) Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 156:675–682

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Mendlewicz J (1999) Predicting response: serotonin reuptake inhibition. Int Clin Psychopharmacol 14(Suppl 1):S17–S20

    Article  PubMed  Google Scholar 

  • Morris JS, Friston KJ, Buchel C, Frith CD, Young AW, Calder AJ, Dolan RJ (1998) A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 121:47–57

    Article  PubMed  Google Scholar 

  • Norusis MJ (1990) SPSS Base System User's Guide. SPSS Inc, Chicago

    Google Scholar 

  • Nutt DJ, Forshall S, Bell C, Rich A, Sandford J, Nash J, Argyropoulos S (1999) Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Eur Neuropsychopharmacology 9:S81–S86

    Article  CAS  Google Scholar 

  • Ongur D, Price JL (2000) The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 10:206–219

    Article  PubMed  CAS  Google Scholar 

  • Paulus MP, Rogalsky C, Simmons A, Feinstein JS, Stein MB (2003) Increased activation in the right insula during risk-taking decision making is related to harm avoidance and neuroticism. Neuroimage 19:1439–1448

    Article  PubMed  Google Scholar 

  • Paulus MP, Stein MB (2006) An insular view of anxiety. Biol Psychiatry 60:383–387

    Article  PubMed  Google Scholar 

  • Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB (2005) Dose-Dependent Decrease of Activation in Bilateral Amygdala and Insula by Lorazepam During Emotion Processing. Arch Gen Psychiatry 62:282–288

    Article  PubMed  CAS  Google Scholar 

  • Phillips ML, Drevets WC, Rauch SL, Lane R (2003) Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry 54:504–514

    Article  PubMed  Google Scholar 

  • Phillips ML, Young AW, Scott SK, Calder AJ, Andrew C, Giampietro V, Williams SC, Bullmore ET, Brammer M, Gray JA (1998) Neural responses to facial and vocal expressions of fear and disgust. Proc Biol Sci 265:1809–1817

    Article  PubMed  CAS  Google Scholar 

  • Rauch SL, Savage CR, Alpert NM, Fischman AJ, Jenike MA (1997) The functional neuroanatomy of anxiety: a study of three disorders using positron emission tomography and symptom provocation. Biol Psychiatry 42:446–452

    Article  PubMed  CAS  Google Scholar 

  • Rauch SL, Shin LM, Wright CI (2003) Neuroimaging studies of amygdala function in anxiety disorders. Ann NY Acad Sci 985:389–410

    Article  PubMed  Google Scholar 

  • Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, Orr SP, Pitman RK (2000) Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 47:769–776

    Article  PubMed  CAS  Google Scholar 

  • Reynolds SM, Zahm DS (2005) Specificity in the projections of prefrontal and insular cortex to ventral striatopallidum and the extended amygdala. J Neurosci 25:11757–11767

    Article  PubMed  CAS  Google Scholar 

  • Rogers RD, Tunbridge EM, Bhagwagar Z, Drevets WC, Sahakian BJ, Carter CS (2003) Tryptophan depletion alters the decision-making of healthy volunteers through altered processing of reward cues. Neuropsychopharmacology 28:153–162

    Article  PubMed  CAS  Google Scholar 

  • Rose EJ, Simonotto E, Spencer EP, Ebmeier KP (2006) The effects of escitalopram on working memory and brain activity in healthy adults during performance of the n-back task. Psychopharmacology (Berl) 185:339–347

    Article  CAS  Google Scholar 

  • Sanchez C, Bergqvist PB, Brennum LT, Gupta S, Hogg S, Larsen A, Wiborg O (2003) Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology (Berl) 167:353–362

    CAS  Google Scholar 

  • Sanchez C, Gruca P, Bien E, Papp M (2003) R-citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety. Pharmacol Biochem Behav 75:903–907

    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 

  • Simmons A, Matthews SC, Stein MB, Paulus MP (2004) Anticipation of emotionally aversive visual stimuli activates right insula. Neuroreport 15:2261–2265

    Article  PubMed  Google Scholar 

  • Simmons A, Strigo I, Matthews SC, Paulus MP, Stein MB (2006) Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects. Biol Psychiatry 60:402–409

    Article  PubMed  Google Scholar 

  • Sogaard B, Mengel H, Rao N, Larsen F (2005) The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects. J Clin Pharmacol 45:1400–1406

    Article  PubMed  CAS  Google Scholar 

  • Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA (1983) Manual for the State-Trait Anxiety Inventory Palo Alto, CA Consulting Psychologists

  • Stein MB, Goldin PR, Sareen J, Zorrilla LT, Brown GG (2002) Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry 59:1027–1034

    Article  PubMed  Google Scholar 

  • Stein MB, Simmons AN, Feinstein JS, Paulus MP (2007) Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry 164:318–327

    Article  PubMed  Google Scholar 

  • Stein MB, Simmons AN, Thorp SR, Paulus MP (2006) Insula response during anticipation of aversion in intimate partner violence-related PTSD. Biol Psychiatry 59:179S

    Google Scholar 

  • Stutzmann GE, Ledoux JE (1999) GABAergic antagonists block the inhibitory effects of serotonin in the lateral amygdala: a mechanism for modulation of sensory inputs related to fear conditioning. J Neurosci 19:RC8

    PubMed  CAS  Google Scholar 

  • Talairach J, Tournoux P (1998) Co-planar Stereotaxic Atlas of the Human Brain: 3-Dimensional Proportional System: An Approach to Cerebral Imaging. New York, NY, Thieme Medical Publishers, Inc

  • Vaswani M, Linda FK, Ramesh S (2003) Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 27:85–102

    Article  PubMed  CAS  Google Scholar 

  • Vollm B, Richardson P, Mckie S, Elliott R, Deakin JF, Anderson IM (2006) Serotonergic modulation of neuronal responses to behavioural inhibition and reinforcing stimuli: an fMRI study in healthy volunteers. Eur J Neurosci 23:552–560

    Article  PubMed  Google Scholar 

  • Waugh J, Goa KL (2003) Escitalopram: a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 17:343–362

    Article  PubMed  CAS  Google Scholar 

  • Whalen PJ, Bush G, McNally RJ, Wilhelm S, McInerney SC, Jenike MA, Rauch SL (1998) The emotional counting Stroop paradigm: A functional magnetic resonance imaging probe of the anterior cingulate affective division. Biol Psychiatry 44:1219–1228

    Article  PubMed  CAS  Google Scholar 

  • Wright CI, Martis B, McMullin K, Shin LM, Rauch SL (2003) Amygdala and insular responses to emotionally valenced human faces in small animal specific phobia. Biol Psychiatry 54:1067–1076

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the assistance of Ryan Pepin. This study was supported by grants from NIMH (MH65413 and MH075792). Dr. Stein is a consultant for Forest Laboratories, the makers of escitalopram. He is also a consultant to numerous other pharmaceutical companies that market antidepressants and other psychotropic medications.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Estibaliz Arce.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arce, E., Simmons, A.N., Lovero, K.L. et al. Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacology 196, 661–672 (2008). https://doi.org/10.1007/s00213-007-1004-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-1004-8

Keywords

Navigation