{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T04:19:28Z","timestamp":1793161168287,"version":"4.5.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vulnerability markers for onset of anxiety disorders are scarce. In depression, patients at risk tend to respond with a negative mood to \u2018acute tryptophan depletion\u2019 (ATD), while healthy volunteers and current patients do not. The serotonergic system thus provides indications for vulnerability for depression. It is unknown whether ATD reveals vulnerability in anxiety too. This study systematically reviews the effects of ATD on anxiety and assesses whether challenging anxiety modifies the response. PubMed, Embase and PsychInfo were systematically searched up to April 2019 for studies in which (1) healthy volunteers or patients with a (remitted) anxiety disorder underwent ATD and (2) levels of anxiety were reported. In total, 21 studies were included. Studies conducted in healthy volunteers (<jats:italic>n<\/jats:italic>\u2009=\u200913), and patients with a remitted (<jats:italic>n<\/jats:italic>\u2009=\u20096) or current (panic, social or generalised) anxiety disorder (<jats:italic>n<\/jats:italic>\u2009=\u20094). Studies were mostly of poor quality and heterogeneous regarding population, challenge test used and outcome measures. ATD did not consistently affect anxiety in any of the groups. Moreover, a challenge test after ATD (<jats:italic>n<\/jats:italic>\u2009=\u200917 studies) did not consistently provoke anxiety in healthy volunteers or remitted patients. A 35% CO<jats:sub>2<\/jats:sub> challenge did consistently increase anxiety in patients with a current panic disorder (PD). To conclude, this systematic review found no clear indications that ATD provokes anxiety in those at risk for anxiety disorders. Hence, unlike in depression, ATD does not indicate vulnerability to develop an anxiety disorder. Because included studies were heterogeneous and mostly of poor quality, there is an urgent need for high quality research in homogeneous samples.<\/jats:p>","DOI":"10.1038\/s41398-021-01219-8","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T17:08:34Z","timestamp":1613063314000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Effects of tryptophan depletion on anxiety, a systematic review"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1492-6950","authenticated-orcid":false,"given":"Simone M. E.","family":"Schopman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3143-9345","authenticated-orcid":false,"given":"Renske C.","family":"Bosman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna D. T.","family":"Muntingh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton J. L. M.","family":"van Balkom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeltje M.","family":"Batelaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"1219_CR1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.jad.2016.02.025","volume":"195","author":"WD Scholten","year":"2016","unstructured":"Scholten, W. D. et al. Diagnostic instability of recurrence and the impact on recurrence rates in depressive and anxiety disorders. J. Affect Disord. 195, 185\u2013190 (2016).","journal-title":"J. Affect Disord."},{"key":"1219_CR2","doi-asserted-by":"crossref","unstructured":"Batelaan N. M., Rhebergen D., Spinhoven P., van Balkom AJLM, Penninx BWJH. Two-year course trajectories of anxiety disorders: do DSM classifications matter? J. Clin. Psychiatry. 75, 985\u2013993 (2014)","DOI":"10.4088\/JCP.13m08837"},{"key":"1219_CR3","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.janxdis.2016.10.011","volume":"44","author":"P Spinhoven","year":"2016","unstructured":"Spinhoven, P. et al. Prediction of 6-yr symptom course trajectories of anxiety disorders by diagnostic, clinical and psychological variables. J. Anxiety Disord. 44, 92\u2013101 (2016).","journal-title":"J. Anxiety Disord."},{"key":"1219_CR4","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.jad.2011.03.027","volume":"133","author":"BWJH Penninx","year":"2011","unstructured":"Penninx, B. W. J. H. et al. Two-year course of depressive and anxiety disorders: results from the Netherlands Study of Depression and Anxiety (NESDA). J. Affect Disord. 133, 76\u201385 (2011).","journal-title":"J. Affect Disord."},{"key":"1219_CR5","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.jad.2013.01.009","volume":"149","author":"R De Graaf","year":"2013","unstructured":"De Graaf, R., Ten Have, M., Tuithof, M. & Van Dorsselaer, S. First-incidence of DSM-IV mood, anxiety and substance use disorders and its determinants: results from the Netherlands Mental Health Survey and Incidence Study-2. J. Affect Disord. 149, 100\u2013107 (2013).","journal-title":"J. Affect Disord."},{"key":"1219_CR6","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.jad.2012.10.031","volume":"147","author":"WD Scholten","year":"2013","unstructured":"Scholten, W. D. et al. Recurrence of anxiety disorders and its predictors. J. Affect Disord. 147, 180\u2013185 (2013).","journal-title":"J. Affect Disord."},{"key":"1219_CR7","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.psyneuen.2012.06.006","volume":"38","author":"K Hek","year":"2013","unstructured":"Hek, K. et al. Anxiety disorders and salivary cortisol levels in older adults: a population-based study. Psychoneuroendocrinology 38, 300\u2013305 (2013).","journal-title":"Psychoneuroendocrinology"},{"key":"1219_CR8","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1097\/PSY.0b013e3181d2f0c8","volume":"72","author":"SA Vreeburg","year":"2010","unstructured":"Vreeburg, S. A. et al. Salivary cortisol levels in persons with and without different anxiety disorders. Psychosom. Med. 72, 340\u2013347 (2010).","journal-title":"Psychosom. Med."},{"key":"1219_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2013.27","volume":"3","author":"N Vogelzangs","year":"2013","unstructured":"Vogelzangs, N., Beekman, A. T. F., de Jonge, P. & Penninx, B. W. J. H. Anxiety disorders and inflammation in a large adult cohort. Transl. Psychiatry 3, e249 (2013).","journal-title":"Transl. Psychiatry"},{"key":"1219_CR10","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1016\/j.bbi.2010.03.003","volume":"24","author":"A O\u2019Donovan","year":"2010","unstructured":"O\u2019Donovan, A. et al. Clinical anxiety, cortisol and interleukin-6: evidence for specificity in emotion-biology relationships. Brain Behav. Immun. 24, 1074\u20131077 (2010).","journal-title":"Brain Behav. Immun."},{"key":"1219_CR11","doi-asserted-by":"crossref","unstructured":"Ressler K. J., Nemeroff C. B. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12, 2\u201319 (2000).","DOI":"10.1002\/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4"},{"key":"1219_CR12","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/mp.2011.9","volume":"16","author":"EL van Donkelaar","year":"2011","unstructured":"van Donkelaar, E. L. et al. Mechanism of acute tryptophan depletion: is it only serotonin? Mol. Psychiatry 16, 695\u2013713 (2011).","journal-title":"Mol. Psychiatry"},{"key":"1219_CR13","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1080\/j.1440-1614.2005.01627.x","volume":"39","author":"SD Hood","year":"2005","unstructured":"Hood, S. D., Bell, C. J. & Nutt, D. J. Acute tryptophan depletion. Part I: rationale and methodology. Aust. N. Z. J. Psychiatry 39, 558\u2013564 (2005).","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"1219_CR14","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/sj.mp.4001949","volume":"12","author":"HG Ruh\u00e9","year":"2007","unstructured":"Ruh\u00e9, H. G., Mason, N. S. & Schene, A. H. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol. Psychiatry 12, 331\u2013359 (2007).","journal-title":"Mol. Psychiatry"},{"key":"1219_CR15","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/sj.mp.4001423","volume":"8","author":"L Booij","year":"2003","unstructured":"Booij, L. Van der Does A. J. W., & Riedel, W. J. Monoamine depletion in psychiatric and healthy populations: review. Mol. Psychiatry 8, 951\u2013973 (2003).","journal-title":"Mol. Psychiatry"},{"key":"1219_CR16","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1080\/j.1440-1614.2005.01628.x","volume":"39","author":"CJ Bell","year":"2005","unstructured":"Bell, C. J., Hood, S. D. & Nutt, D. J. Acute tryptophan depletion. Part II: clinical effects and implications. Aust. N. Z. J. Psychiatry 39, 565\u2013574 (2005).","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"1219_CR17","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1385\/NMM:5:1:027","volume":"5","author":"JA Gordon","year":"2004","unstructured":"Gordon, J. A. & Hen, R. The serotonergic system and anxiety. NeuroMolecular Med. 5, 27\u201340 (2004).","journal-title":"NeuroMolecular Med."},{"key":"1219_CR18","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1001\/jamapsychiatry.2015.0125","volume":"72","author":"A Frick","year":"2015","unstructured":"Frick, A. et al. Serotonin synthesis and reuptake in social anxiety disorder. JAMA Psychiatry 72, E1\u2013E9 (2015).","journal-title":"JAMA Psychiatry"},{"key":"1219_CR19","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1177\/0269881114525674","volume":"28","author":"DS Baldwin","year":"2014","unstructured":"Baldwin, D. S. et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J. Psychopharmacol. 28, 403\u2013439 (2014).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR20","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3109\/13651501.2012.667114","volume":"16","author":"B Bandelow","year":"2012","unstructured":"Bandelow, B. et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive\u2013compulsive disorder and posttraumatic stress disorder in primary care. Int J. Psychiatry Clin. Pract. 16, 77\u201384 (2012).","journal-title":"Int J. Psychiatry Clin. Pract."},{"key":"1219_CR21","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.jclinepi.2009.06.006","volume":"62","author":"A Liberati","year":"2009","unstructured":"Liberati, A. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J. Clin. Epidemiol. 62, e1\u2013e34 (2009).","journal-title":"J. Clin. Epidemiol."},{"key":"1219_CR22","doi-asserted-by":"publisher","DOI":"10.1186\/2046-4053-4-1","volume":"4","author":"D Moher","year":"2015","unstructured":"Moher, D. et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 4, 1 (2015).","journal-title":"Syst. Rev."},{"key":"1219_CR23","doi-asserted-by":"publisher","first-page":"d5928","DOI":"10.1136\/bmj.d5928","volume":"343","author":"JPT Higgins","year":"2011","unstructured":"Higgins, J. P. T. et al. The Cochrane Collaboration\u2019s tool for assessing risk of bias in randomised trials. BMJ 343, d5928\u2013d5928 (2011).","journal-title":"BMJ"},{"key":"1219_CR24","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1177\/026988119701100416","volume":"11","author":"JG Reilly","year":"1997","unstructured":"Reilly, J. G., Mctavish, S. F. B. & Young, A. H. Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. J. Psychopharmacol. 11, 381\u2013392 (1997).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR25","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/S0893-133X(97)00198-X","volume":"19","author":"LL Carpenter","year":"1998","unstructured":"Carpenter, L. L. et al. Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 19, 26\u201335 (1998).","journal-title":"Neuropsychopharmacology"},{"key":"1219_CR26","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1046\/j.1471-4159.1999.721641.x","volume":"72","author":"WA Williams","year":"1999","unstructured":"Williams, W. A., Shoaf, S. E., Hommer, D., Rawlings, R. & Linnoila, M. Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J. Neurochem. 72, 1641\u20131647 (1999).","journal-title":"J. Neurochem."},{"key":"1219_CR27","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1001\/archpsyc.1990.01810170011002","volume":"47","author":"PL Delgado","year":"1990","unstructured":"Delgado, P. L. Serotonin function and the mechanism of antidepressant action. Arch. Gen. Psychiatry 47, 411 (1990).","journal-title":"Arch. Gen. Psychiatry"},{"key":"1219_CR28","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1503\/jpn.120209","volume":"38","author":"SN Young","year":"2013","unstructured":"Young, S. N. Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects. J. Psychiatry Neurosci. 38, 294\u2013305 (2013).","journal-title":"J. Psychiatry Neurosci."},{"key":"1219_CR29","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s00213-006-0351-1","volume":"186","author":"I T\u00f5ru","year":"2006","unstructured":"T\u00f5ru, I., Shlik, J., Maron, E., Vasar, V. & Nutt, D. J. Tryptophan depletion does not modify response to CCK-4 challenge in patients with panic disorder after treatment with citalopram. Psychopharmacol. 186, 107\u2013112 (2006).","journal-title":"Psychopharmacol."},{"key":"1219_CR30","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1038\/npp.2012.43","volume":"37","author":"OJ Robinson","year":"2012","unstructured":"Robinson, O. J., Overstreet, C., Allen, P. S., Pine, D. S. & Grillon, C. Acute tryptophan depletion increases translational indices of anxiety but not fear: serotonergic modulation of the bed nucleus of the stria terminalis? Neuropsychopharmacology 37, 1963\u20131971 (2012).","journal-title":"Neuropsychopharmacology"},{"key":"1219_CR31","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s00213-009-1722-1","volume":"208","author":"SD Hood","year":"2010","unstructured":"Hood, S. D. et al. Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder. Psychopharmacol. 208, 223\u2013232 (2010).","journal-title":"Psychopharmacol."},{"key":"1219_CR32","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1177\/026988110201600116","volume":"16","author":"C Bell","year":"2002","unstructured":"Bell, C. et al. Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine. J. Psychopharmacol. 16, 5\u201314 (2002).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR33","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.biopsych.2004.07.006","volume":"56","author":"SV Argyropoulos","year":"2004","unstructured":"Argyropoulos, S. V. et al. Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder. Biol. Psychiatry 56, 503\u2013509 (2004).","journal-title":"Biol. Psychiatry"},{"key":"1219_CR34","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/0006-3223(94)90091-4","volume":"36","author":"AW Goddard","year":"1994","unstructured":"Goddard, A. W. et al. Effects of tryptophan depletion in panic disorder. Biol. Psychiatry 36, 775\u2013777 (1994).","journal-title":"Biol. Psychiatry"},{"key":"1219_CR35","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/0006-3223(94)00223-P","volume":"38","author":"AW Goddard","year":"1995","unstructured":"Goddard, A. W. et al. Effects of tryptophan depletion on responses to yohimbine in healthy human subjects. Biol. Psychiatry 38, 74\u201385 (1995).","journal-title":"Biol. Psychiatry"},{"key":"1219_CR36","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1177\/026988110001400205","volume":"14","author":"FM Shansis","year":"2000","unstructured":"Shansis, F. M. et al. Behavioural effects of acute tryptophan depletion in healthy male volunteers. J. Psychopharmacol. 14, 157\u2013163 (2000).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR37","first-page":"182188","volume":"176","author":"HEJ Miller","year":"2000","unstructured":"Miller, H. E. J., Deakin, J. F. W. & Anderson, I. M. Effect of acute tryptophan depletion on CO2-induced anxiety in patients with panic disorder and normal volunteers. Br. J. Psychiatry 176, 182188 (2000).","journal-title":"Br. J. Psychiatry"},{"key":"1219_CR38","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1007\/s00213-009-1696-z","volume":"213","author":"C Bell","year":"2011","unstructured":"Bell, C. et al. Rapid tryptophan depletion following cognitive behavioural therapy for panic disorder. Psychopharmacol. 213, 593\u2013602 (2011).","journal-title":"Psychopharmacol."},{"key":"1219_CR39","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/0165-1781(96)02840-5","volume":"64","author":"JM Kent","year":"1996","unstructured":"Kent, J. M. et al. Ventilatory effects of tryptophan depletion in panic disorder: a preliminary report. Psychiatry Res. 64, 83\u201390 (1996).","journal-title":"Psychiatry Res."},{"key":"1219_CR40","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1016\/0006-3223(95)00479-3","volume":"40","author":"D Koszycki","year":"1996","unstructured":"Koszycki, D., Zabarcko, R. M., Le Melledo, J.-M., Young, S. & Bradwejn, J. Effect of acute tryptophan depletion on behavioral, cardiovascular, and hormonal sensitivity to cholecystokinin tetrapeptide challenge in healthy volunteers. Biol. Psychiatry 40, 648\u2013655 (1996).","journal-title":"Biol. Psychiatry"},{"key":"1219_CR41","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S0165-1781(98)00004-3","volume":"77","author":"T Klaassen","year":"1998","unstructured":"Klaassen, T., Klumperbeek, J., Deutz, N. E. P., van Praag, H. M. & Griez, E. Effects of tryptophan depletion on carbon dioxide provoked panic in panic disorder patients. Psychiatry Res. 77, 167\u2013174 (1998).","journal-title":"Psychiatry Res."},{"key":"1219_CR42","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1590\/S0100-879X2000000500013","volume":"33","author":"PC Monteiro-Dos-Santos","year":"2000","unstructured":"Monteiro-Dos-Santos, P. C. et al. Effects of tryptophan depletion on anxiety induced by simulated public speaking. Braz. J. Med. Biol. Res. 33, 581\u2013587 (2000).","journal-title":"Braz. J. Med. Biol. Res."},{"key":"1219_CR43","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/S0165-1781(00)00117-7","volume":"93","author":"K Schruers","year":"2000","unstructured":"Schruers, K. et al. Effects of tryptophan depletion on carbon dioxide provoked panic in panic disorder patients. Psychiatry Res. 93, 179\u2013187 (2000).","journal-title":"Psychiatry Res."},{"key":"1219_CR44","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1007\/s00213-011-2177-8","volume":"215","author":"A Colasanti","year":"2011","unstructured":"Colasanti, A. et al. Effects of tryptophan depletion and tryptophan loading on the affective response to high-dose CO 2 challenge in healthy volunteers. Psychopharmacol. 215, 739\u2013748 (2011).","journal-title":"Psychopharmacol."},{"key":"1219_CR45","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1097\/01.jcp.0000227704.79740.c0","volume":"26","author":"SJC Davies","year":"2006","unstructured":"Davies, S. J. C. et al. Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders. J. Clin. Psychopharmacol. 26, 414\u2013418 (2006).","journal-title":"J. Clin. Psychopharmacol."},{"key":"1219_CR46","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1001\/archpsyc.1994.03950090019003","volume":"51","author":"C Benkelfat","year":"1994","unstructured":"Benkelfat, C., Ellenbogen, M. A., Dean, P., Palmour, R. M. & Young, S. N. Mood-lowering effect of tryptophan depletion. Arch. Gen. Psychiatry 51, 687\u2013697 (1994).","journal-title":"Arch. Gen. Psychiatry"},{"key":"1219_CR47","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1007\/BF02245252","volume":"118","author":"AJ Cleare","year":"1995","unstructured":"Cleare, A. J. & Bond, A. J. The effect of tryptophan depletion and enhancement on subjective and behavioural aggression in normal male subjects. Psychopharmacol. 118, 72\u201381 (1995).","journal-title":"Psychopharmacol."},{"key":"1219_CR48","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1007\/BF00216010","volume":"91","author":"SE Smith","year":"1987","unstructured":"Smith, S. E., Pihl, R. O., Young, S. N. & Ervin, F. R. A test of possible cognitive and environmental influences on the mood lowering effect of tryptophan depletion in normal males. Psychopharmacol. 91, 451\u2013457 (1987).","journal-title":"Psychopharmacol."},{"key":"1219_CR49","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/0028-3908(94)90089-2","volume":"33","author":"SB Park","year":"1994","unstructured":"Park, S. B. et al. Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology 33, 575\u2013588 (1994).","journal-title":"Neuropharmacology"},{"key":"1219_CR50","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1177\/0269881114527363","volume":"28","author":"L Goossens","year":"2014","unstructured":"Goossens, L. et al. Brainstem response to hypercapnia: a symptom provocation study into the pathophysiology of panic disorder. J. Psychopharmacol. 28, 449\u2013456 (2014).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR51","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nn.3323","volume":"16","author":"JS Feinstein","year":"2013","unstructured":"Feinstein, J. S. et al. Fear and panic in humans with bilateral amygdala damage. Nat. Neurosci. 16, 270\u2013272 (2013).","journal-title":"Nat. Neurosci."},{"key":"1219_CR52","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1038\/mp.2015.197","volume":"21","author":"T Otowa","year":"2016","unstructured":"Otowa, T. et al. Meta-analysis of genome-wide association studies of anxiety disorders. Mol. Psychiatry 21, 1391\u20131399 (2016).","journal-title":"Mol. Psychiatry"},{"key":"1219_CR53","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1111\/pcn.12291","volume":"69","author":"M Shimada-Sugimoto","year":"2015","unstructured":"Shimada-Sugimoto, M., Otowa, T. & Hettema, J. M. Genetics of anxiety disorders: genetic epidemiological and molecular studies in humans. Psychiatry Clin. Neurosci. 69, 388\u2013401 (2015).","journal-title":"Psychiatry Clin. Neurosci."},{"key":"1219_CR54","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.jpsychires.2006.07.009","volume":"40","author":"NB Schmidt","year":"2006","unstructured":"Schmidt, N. B., Zvolensky, M. J. & Maner, J. K. Anxiety sensitivity: prospective prediction of panic attacks and {Axis} {I} pathology. J. Psychiatr. Res. 40, 691\u2013699 (2006).","journal-title":"J. Psychiatr. Res."},{"key":"1219_CR55","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.brat.2010.02.006","volume":"48","author":"M Burstein","year":"2010","unstructured":"Burstein, M. & Ginsburg, G. S. The effect of parental modeling of anxious behaviors and cognitions in school-aged children: an experimental pilot study. Behav. Res. Ther. 48, 506\u2013515 (2010).","journal-title":"Behav. Res. Ther."},{"key":"1219_CR56","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/0005-7967(95)00067-4","volume":"34","author":"P Muris","year":"1996","unstructured":"Muris, P., Steerneman, P., Merckelbach, H. & Meesters, C. The role of parental fearfulness and modeling in children\u2019s fear. Behav. Res. Ther. 34, 265\u2013268 (1996).","journal-title":"Behav. Res. Ther."},{"key":"1219_CR57","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1159\/000439114","volume":"1","author":"FA Moreno","year":"2015","unstructured":"Moreno, F. A. et al. Association study of genotype by depressive response during acute tryptophan depletion in subjects recovered from major depression. Mol. Neuropsychiatry 1, 165\u2013174 (2015).","journal-title":"Mol. Neuropsychiatry"},{"key":"1219_CR58","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/sj.mp.4000962","volume":"7","author":"FA Moreno","year":"2002","unstructured":"Moreno, F. A. et al. Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion. Mol. Psychiatry 7, 213\u2013216 (2002).","journal-title":"Mol. Psychiatry"},{"key":"1219_CR59","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1001\/archpsyc.63.9.978","volume":"63","author":"A Neumeister","year":"2006","unstructured":"Neumeister, A. et al. Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls. Arch. Gen. Psychiatry 63, 978 (2006).","journal-title":"Arch. Gen. Psychiatry"},{"key":"1219_CR60","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1177\/0269881113503508","volume":"27","author":"JFW Deakin","year":"2013","unstructured":"Deakin, J. F. W. The origins of \u20185-HT and mechanisms of defence\u2019 by Deakin and Graeff: a personal perspective. J. Psychopharmacol. 27, 1084\u20131089 (2013).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR61","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1177\/0269881115590603","volume":"29","author":"F Corchs","year":"2015","unstructured":"Corchs, F. et al. Evidence for serotonin function as a neurochemical difference between fear and anxiety disorders in humans? J. Psychopharmacol. 29, 1061\u20131069 (2015).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR62","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1001\/archpsyc.56.10.921","volume":"56","author":"RF Krueger","year":"1999","unstructured":"Krueger, R. F. The structure of common mental disorders. Arch. Gen. Psychiatry 56, 921 (1999).","journal-title":"Arch. Gen. Psychiatry"},{"key":"1219_CR63","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1016\/S0893-133X(02)00361-5","volume":"27","author":"L Booij","year":"2002","unstructured":"Booij, L. et al. Predictors of mood response to acute tryptophan depletion: a reanalysis. Neuropsychopharmacology 27, 884\u2013885 (2002).","journal-title":"Neuropsychopharmacology"},{"key":"1219_CR64","doi-asserted-by":"publisher","first-page":"334","DOI":"10.3109\/15622975.2013.804195","volume":"14","author":"M Bauer","year":"2013","unstructured":"Bauer, M. et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J. Biol. Psychiatry 14, 334\u2013385 (2013).","journal-title":"World J. Biol. Psychiatry"},{"key":"1219_CR65","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1177\/0269881115581093","volume":"29","author":"AJ Cleare","year":"2015","unstructured":"Cleare, A. J. et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J. Psychopharmacol. 29, 459\u2013525 (2015).","journal-title":"J. Psychopharmacol."},{"key":"1219_CR66","unstructured":"National Institute for Health and Clinical Excellence. Generalised Anxiety Disorder and Panic Disorder (with or without agoraphobia) in Adults. Management in Primary, Secondary and Community Care (National Institute for Health and Care Excellence, 2011)."},{"key":"1219_CR67","unstructured":"National Institute for Health and Clinical Excellence. Depression in Adults: Recognition and Management (National Institute for Health and Care Excellence, 2009)."},{"key":"1219_CR68","unstructured":"National Institute for Health and Clinical Excellence. Social Anxiety Disorder: Recognition, Assessment and Treatment (National Institute for Health and Care Excellence, 2013)."}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01219-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01219-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01219-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T15:25:57Z","timestamp":1669821957000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01219-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,11]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["1219"],"URL":"https:\/\/doi.org\/10.1038\/s41398-021-01219-8","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,11]]},"assertion":[{"value":"14 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 October 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 November 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"118"}}