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Acute fluoxetine modulates emotional processing in young adult volunteers

  • L. P. Capitão (a1), S. E. Murphy (a1), M. Browning (a1), P. J. Cowen (a1) and C. J. Harmer (a1)...



Fluoxetine is generally regarded as the first-line pharmacological treatment for young people, as it is believed to show a more favourable benefit:risk ratio than other antidepressants. However, the mechanisms through which fluoxetine influences symptoms in youth have been little investigated. This study examined whether acute administration of fluoxetine in a sample of young healthy adults altered the processing of affective information, including positive, sad and anger cues.


A total of 35 male and female volunteers aged between 18 and 21 years old were randomized to receive a single 20 mg dose of fluoxetine or placebo. At 6 h after administration, participants completed a facial expression recognition task, an emotion-potentiated startle task, an attentional dot-probe task and the Rapid Serial Visual Presentation. Subjective ratings of mood, anxiety and side effects were also taken pre- and post-fluoxetine/placebo administration.


Relative to placebo-treated participants, participants receiving fluoxetine were less accurate at identifying anger and sadness and did not show the emotion-potentiated startle effect. There were no overall significant effects of fluoxetine on subjective ratings of mood.


Fluoxetine can modulate emotional processing after a single dose in young adults. This pattern of effects suggests a potential cognitive mechanism for the greater benefit:risk ratio of fluoxetine in adolescent patients.


Corresponding author

* Address for correspondence: L. P. Capitão, Oxford University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. (Email:


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American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th edn: DSM-5. American Psychiatric Association: Arlington, VA.
Anderson, AK, Phelps, EA (2001). Lesions of the human amygdala impair enhanced perception of emotionally salient events. Nature 411, 305309.
Arnone, D, Horder, J, Cowen, PJ, Harmer, CJ (2009). Early effects of mirtazapine on emotional processing. Psychopharmacology 203, 685691.
Beck, AT (1976). Cognitive Therapy and the Emotional Disorders. International Universities Press: New York.
Beck, AT, Ward, CH, Mendelson, M, Mock, J, Erbaugh, J (1961). An inventory for measuring depression. Archives of General Psychiatry 4, 561.
Birmaher, B, Ryan, ND, Williamson, DE, Brent, DA, Kaufman, J, Dahl, RE, Perel, J, Nelson, B (1996). Childhood and adolescent depression: a review of the past 10 years. Part I. Journal of the American Academy of Child and Adolescent Psychiatry 35, 14271439.
Bishop, SJ, Dalgleish, T, Yule, W (2004). Memory for emotional stories in high and low depressed children. Memory (Hove, England) 12, 214230.
Bjork, JM, Dougherty, DM, Moeller, FG, Swann, AC (2000). Differential behavioral effects of plasma tryptophan depletion and loading in aggressive and nonaggressive men. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 22, 357369.
Bond, A, Lader, M (1974). The use of analogue scales in rating subjective feelings. British Journal of Medical Psychology 47, 211218.
Bond, AJ, Wingrove, J, Critchlow, DG (2001). Tryptophan depletion increases aggression in women during the premenstrual phase. Psychopharmacology 156, 477480.
Bradley, MM, Lang, PJ (1999). Affective Norms for English Words (ANEW): Instruction Manual and Affective Ratings. Center for Research in Psychophysiology, University of Florida: Gainesville, FL.
Brøsen, K (2004). Some aspects of genetic polymorphism in the biotransformation of antidepressants. Thérapie 59, 512.
Browning, M, Holmes, EA, Charles, M, Cowen, PJ, Harmer, CJ (2012). Using attentional bias modification as a cognitive vaccine against depression. Biological Psychiatry 72, 572579.
Browning, M, Reid, C, Cowen, PJ, Goodwin, GM, Harmer, CJ (2007). A single dose of citalopram increases fear recognition in healthy subjects. Journal of Psychopharmacology (Oxford, England) 21, 684690.
Burghardt, NS, Sullivan, GM, McEwen, BS, Gorman, JM, LeDoux, JE (2004). The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine. Biological Psychiatry 55, 11711178.
Cleare, AJ, Bond, AJ (1995). The effect of tryptophan depletion and enhancement on subjective behavioral aggression in normal male subjects. Psychopharmacology 118, 7281.
Coccaro, EF, Kavoussi, RJ (1997). Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Archives of General Psychiatry 54, 10811088.
Coltheart, M (1981). The MRC psycholinguistic database. Quarterly Journal of Experimental Psychology Section A 33, 497505.
Crawford, JR, Henry, JD (2004). The Positive and Negative Affect Schedule (PANAS): construct validity, measurement properties and normative data in a large non-clinical sample. British Journal of Clinical Psychology 43, 245265.
Dalili, MN, Penton-Voak, IS, Harmer, CJ, Munafò, MR (2014). Meta-analysis of emotion recognition deficits in major depressive disorder. Psychological Medicine. Published online 14 November 2014. doi:10.1017/S0033291714002591.
Davis, M, Falls, WA, Campeau, S, Kim, M (1993). Fear-potentiated startle: a neural and pharmacological analysis. Behavioural Brain Research 58, 175198.
De Martino, B, Strange, BA, Dolan, RJ (2008). Noradrenergic neuromodulation of human attention for emotional and neutral stimuli. Psychopharmacology 197, 127136.
Dougherty, LR, Smith, VC, Bufferd, SJ, Stringaris, A, Leibenluft, E, Carlson, GA, Klein, DN (2013). Preschool irritability: longitudinal associations with psychiatric disorders at age 6 and parental psychopathology. Journal of the American Academy of Child and Adolescent Psychiatry 52, 13041313.
Ekman, P, Friesen, WV (1976). Pictures of Facial Affect. Consulting Psychologists Press: Palo Alto, CA.
Eysenck, HJ, Eysenck, BJ (1975). Eysenck Personality Inventory. Hodder and Stoughton: London.
Fava, M, Hwang, I, Rush, AJ, Sampson, N, Walters, EE, Kessler, RC (2010). The importance of irritability as a symptom of major depressive disorder: results from the National Comorbidity Survey Replication. Molecular Psychiatry 15, 856867.
First, MB, Spitzer, RL, Gibbon, M, Williams, JBW (1997). Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). American Psychiatric Press: Washington, DC.
Gibbons, RD, Brown, CH, Hur, K, Marcus, SM, Bhaumik, DK, Erkens, JA, Herings, RMC, Mann, JJ (2007). Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. American Journal of Psychiatry 164, 13561363.
Grillon, C, Levenson, J, Pine, DS (2007). A single dose of the selective serotonin reuptake inhibitor citalopram exacerbates anxiety in humans: a fear-potentiated startle study. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 32, 225231.
Gur, RC, Erwin, RJ, Gur, RE, Zwil, AS, Heimberg, C, Kraemer, HC (1992). Facial emotion discrimination: II. Behavioral findings in depression. Psychiatry Research 42, 241251.
Hammad, TA, Laughren, T, Racoosin, J (2006). Suicidality in pediatric patients treated with antidepressant drugs. Archives of General Psychiatry 63, 332339.
Harmer, CJ, Bhagwagar, Z, Perrett, DI, Völlm, BA, Cowen, PJ, Goodwin, GM (2003 a). Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 28, 148152.
Harmer, CJ, Cowen, PJ, Goodwin, GM (2011). Efficacy markers in depression. Journal of Psychopharmacology (Oxford, England) 25, 11481158.
Harmer, CJ, Heinzen, J, O'Sullivan, U, Ayres, RA, Cowen, PJ (2008). Dissociable effects of acute antidepressant drug administration on subjective and emotional processing measures in healthy volunteers. Psychopharmacology 199, 495502.
Harmer, CJ, Hill, SA, Taylor, MJ, Cowen, PJ, Goodwin, GM (2003 b). Toward a neuropsychological theory of antidepressant drug action: increase in positive emotional bias after potentiation of norepinephrine activity. American Journal of Psychiatry 160, 990992.
Hoffman, BJ, Mezey, E, Brownstein, MJ (1991). Cloning of a serotonin transporter affected by antidepressants. Science 254, 579580.
Jick, H, Kaye, JA, Jick, SS (2004). Antidepressants and the risk of suicidal behaviours. JAMA 292, 338343.
Joormann, J, Talbot, L, Gotlib, IH (2007). Biased processing of emotional information in girls at risk for depression. Journal of Abnormal Psychology 116, 135143.
Judd, LL, Schettler, PJ, Coryell, W, Akiskal, HS, Fiedorowicz, JG (2013). Overt irritability/anger in unipolar major depressive episodes: past and current characteristics and implications for long-term course. JAMA Psychiatry 70, 11711180.
Jureidini, JN, Doecke, CJ, Mansfield, PR, Haby, MM, Menkes, DB, Tonkin, AL (2004). Efficacy and safety of antidepressants for children and adolescents. BMJ (Clinical Research Edition) 328, 879883.
Kennett, GA, Wood, MD, Bright, F, Trail, B, Riley, G, Holland, V, Avenell, KY, Stean, T, Upton, N, Bromidge, S, Forbes, IT, Brown, AM, Middlemiss, DN, Blackburn, TP (1997). SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36, 609620.
Kent, JM, Coplan, JD, Gorman, JM (1998). Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety. Biological Psychiatry 44, 812824.
Kovacs, M, Goldston, D, Gatsonis, C (1993). Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation. Journal of the American Academy of Child and Adolescent Psychiatry 32, 820.
Kronenberg, S, Apter, A, Brent, D, Schirman, S, Melhem, N, Pick, N, Gothelf, D, Carmel, M, Frisch, A, Weizman, A (2007). Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders. Journal of Child and Adolescent Psychopharmacology 17, 741750.
Kučera, H, Francis, WN (1967). Computational Analysis of Present-Day American English. Brown University Press: Providence, RI.
Kurt, M, Arik, AC, Celik, S (2000). The effects of sertraline and fluoxetine on anxiety in the elevated plus-maze test in mice. Journal of Basic and Clinical Physiology and Pharmacology 11, 173180.
Lang, PJ, Bradley, MM, Cuthbert, BN (1990). Emotion, attention, and the startle reflex. Psychological Review 97, 377395.
Lang, PJ, Bradley, MM, Cuthbert, BN (2005). International Affective Picture System (IAPS): Affective Ratings of Pictures and Instruction Manual. NIMH Center for the Study of Emotion and Attention: Gainesville, FL.
Leibenluft, E, Cohen, P, Gorrindo, T, Brook, JS, Pine, DS (2006). Chronic versus episodic irritability in youth: a community-based, longitudinal study of clinical and diagnostic associations. Journal of Child and Adolescent Psychopharmacology 16, 456466.
Lu, CY, Zhang, F, Lakoma, MD, Madden, JM, Rusinak, D, Penfold, RB, Simon, G, Ahmedani, BK, Clarke, G, Hunkeler, EM, Waitzfelder, B, Owen-Smith, A, Raebel, MA, Rossom, R, Coleman, KJ, Copeland, LA, Soumerai, SB (2014). Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study. BMJ 348, g3596g3596.
Martin, JR, Ballard, TM, Higgins, GA (2002). Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety. Pharmacology, Biochemistry, and Behavior 71, 615625.
Martinez, C, Rietbrock, S, Wise, L, Ashby, D, Chick, J, Moseley, J, Evans, S, Gunnell, D (2005). Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case–control study. BMJ (Clinical Research Edition) 330, 389.
Matsumoto, D, Ekman, P (1988). Japanese and Caucasian Facial Expressions of Emotion (JACFEE) [Slides]. Intercultural and Emotion Research Laboratory, Department of Psychology, San Francisco State University: San Francisco, CA.
Murphy, SE, Downham, C, Cowen, PJ, Harmer, CJ (2008). Direct effects of diazepam on emotional processing in healthy volunteers. Psychopharmacology 199, 503513.
Nakamura, K, Kurasawa, M (2001). Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism. European Journal of Pharmacology 420, 3343.
National Institute for Health and Clinical Excellence (2005). CG28 Depression in Children and Young People: NICE Guideline. National Institute for Health and Clinical Excellence: London.
Nelson, HE, Wilson, J (1991). The Revised National Adult Reading Test – Test Manual. NFER-Nelson: Windsor, UK.
Ni, YG, Miledi, R (1997). Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac). Proceedings of the National Academy of Sciences of the United States of America 94, 20362040.
Pälvimäki, E-P, Kuoppamäki, M, Syvälahti, E, Hietala, J (1999). Differential effects of fluoxetine and citalopram treatments on serotonin 5-HT2C receptor occupancy in rat brain. International Journal of Neuropsychopharmacology/Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 2, 9599.
Patrick, CJ, Berthot, BD, Moore, JD (1996). Diazepam blocks fear-potentiated startle in humans. Journal of Abnormal Psychology 105, 8996.
Perlis, RH, Fava, M, Trivedi, MH, Alpert, J, Luther, JF, Wisniewski, SR, Rush, AJ (2009). Irritability is associated with anxiety and greater severity, but not bipolar spectrum features, in major depressive disorder. Acta Psychiatrica Scandinavica 119, 282289.
Perlis, RH, Mischoulon, D, Smoller, JW, Wan, Y-JY, Lamon-Fava, S, Lin, K-M, Rosenbaum, JF, Fava, M (2003). Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biological Psychiatry 54, 879883.
Pringle, A, Browning, M, Cowen, PJ, Harmer, CJ (2011). A cognitive neuropsychological model of antidepressant drug action. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 15861592.
Raymond, JE, Shapiro, KL, Arnell, KM (1992). Temporary suppression of visual processing in an RSVP task: an attentional blink? Journal of Experimental Psychology. Human Perception and Performance 18, 849860.
Reinecke, A, Waldenmaier, L, Cooper, MJ, Harmer, CJ (2013). Changes in automatic threat processing precede and predict clinical changes with exposure-based cognitive–behavior therapy for panic disorder. Biological Psychiatry 73, 10641070.
Rossi, A, Barraco, A, Donda, P (2004). Fluoxetine: a review on evidence based medicine. Annals of General Hospital Psychiatry 3, 2.
Ryan, ND, Puig-Antich, J, Ambrosini, P, Rabinovich, H, Robinson, D, Nelson, B, Iyengar, S, Twomey, J (1987). The clinical picture of major depression in children and adolescents. Archives of General Psychiatry 44, 854861.
Safer, DJ (2009). Irritable mood and the Diagnostic and Statistical Manual of Mental Disorders. Child and Adolescent Psychiatry and Mental Health 3, 35.
Schepman, K, Taylor, E, Collishaw, S, Fombonne, E (2012). Face emotion processing in depressed children and adolescents with and without comorbid conduct disorder. Journal of Abnormal Child Psychology 40, 583593.
Schreiber, R, Melon, C, De Vry, J (1998). The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test. Psychopharmacology 135, 383391.
Sinclair, LI, Christmas, DM, Hood, SD, Potokar, JP, Robertson, A, Isaac, A, Srivastava, S, Nutt, DJ, Davies, SJC (2009). Antidepressant-induced jitteriness/anxiety syndrome: systematic review. British Journal of Psychiatry: The Journal of Mental Science 194, 483490.
Smith, EG (2009). Association between antidepressant half-life and the risk of suicidal ideation or behavior among children and adolescents: confirmatory analysis and research implications. Journal of Affective Disorders 114, 143148.
Spielberger, CD, Gorsuch, RL, Edward, LR (1970). STAI Manual for the State-Trait Anxiety Inventory (‘Self-Evaluation Questionnaire’). Consulting Psychologists Press: Palo Alto, CA.
Steinberg, EM, Cardoso, GMP, Martinez, PE, Rubinow, DR, Schmidt, PJ (2012). Rapid response to fluoxetine in women with premenstrual dysphoric disorder. Depression and Anxiety 29, 531540.
Stringaris, A, Cohen, P, Pine, DS, Leibenluft, E (2009). Adult outcomes of youth irritability: a 20-year prospective community-based study. American Journal of Psychiatry 166, 10481054.
Stringaris, A, Goodman, R (2009). Three dimensions of oppositionality in youth. Journal of Child Psychology and Psychiatry, and Allied Disciplines 50, 216223.
Stringaris, A, Maughan, B, Copeland, WS, Costello, EJ, Angold, A (2013). Irritable mood as a symptom of depression in youth: prevalence, developmental, and clinical correlates in the Great Smoky Mountains Study. Journal of the American Academy of Child and Adolescent Psychiatry 52, 831840.
Stringaris, A, Zavos, H, Leibenluft, E, Maughan, B, Eley, T (2012). Adolescent irritability: phenotypic associations and genetic links with depressed mood. American Journal of Psychiatry 169, 4754.
Strober, M, Green, J, Carlson, G (1981). Phenomenology and subtypes of major depressive disorder in adolescence. Journal of Affective Disorders 3, 281290.
Uher, R, Farmer, A, Henigsberg, N, Rietschel, M, Mors, O, Maier, W, Kozel, D, Hauser, J, Souery, D, Placentino, A, Strohmaier, J, Perroud, N, Zobel, A, Rajewska-Rager, A, Dernovsek, MZ, Larsen, ER, Kalember, P, Giovannini, C, Barreto, M, McGuffin, P, Aitchison, KJ (2009). Adverse reactions to antidepressants. British Journal of Psychiatry 195, 202210.
van Beek, Y, Dubas, JS (2008). Decoding basic and non-basic facial expressions and depressive symptoms in late childhood and adolescence. Journal of Nonverbal Behavior 32, 5364.
van Beek, Y, van Dolderen, MSM, Demon Dubas, JJS (2006). Gender-specific development of nonverbal behaviours and mild depression in adolescence. Journal of Child Psychology and Psychiatry, and Allied Disciplines 47, 12721283.
Verhoeven, FEA, Booij, L, Van der Wee, NJA, Penninx, BWHJ, Van der Does, AJW (2011). Clinical and physiological correlates of irritability in depression: results from the Netherlands Study of Depression and Anxiety. Depression Research and Treatment 2011, 126895.
Weissman, MM, Wolk, S, Goldstein, RB, Moreau, D, Adams, P, Greenwald, S, Klier, CM, Ryan, ND, Dahl, RE, Wickramaratne, P (1999). Depressed adolescents grown up. JAMA 281, 17071713.
Whittington, CJ, Kendall, T, Fonagy, P, Cottrell, D, Cotgrove, A, Boddington, E (2004). Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 363, 13411345.
Young, AW, Rowland, D, Calder, AJ, Etcoff, NL, Seth, A, Perrett, DI (1997). Facial expression megamix: tests of dimensional and category accounts of emotion recognition. Cognition 63, 271313.
Young, SN (2013). The effect of raising and lowering tryptophan levels on human mood and social behaviour. Philosophical Transactions of the Royal Society. Series B, Biological Sciences 368, 20110375.



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