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Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder

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Abstract

Background

Serotonergic antidepressants [selective serotonin reuptake inhibitor (SSRI)] are first-line treatments for generalised anxiety disorder (GAD); however, it is not known if synaptic serotonin (5-HT) availability is important for SSRI efficacy. The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion (ATD), would reverse the therapeutic effect of the SSRIs in GAD patients.

Methods

Twelve patients (six males) with GAD, who showed sustained clinical improvement with SSRI treatment, underwent ATD in a double-blind, placebo-controlled, within-subjects design over 2 days, 1 week apart. At the peak time of depletion, the participants inhaled 7.5% CO2 and air in random order for at least 12 min each. Psychological responses were measured using the Spielberger State Anxiety Inventory (STAI-S) and GAD-symptom visual analogue scales (VASs; e.g., worry and tense) and Profile of Mood States.

Results

Free plasma tryptophan to large neutral amino acid (LNAA) ratio decreased by 92% on the depletion day and decreased by 2% on the control day. Irrespective of depletion condition, 7.5% CO2 inhalation significantly increased STAI-S and GAD-related VAS scores (all p < 0.05) compared with air inhalation. ATD had no effect on any of these measures despite the substantial reduction in free tryptophan/LNAA ratio.

Conclusions

Although SSRIs treat GAD effectively, the present results suggest that the mechanism of action is different to that seen in panic, social anxiety, and post-traumatic stress disorders. Successful SSRI treatment of GAD may involve long-term receptor changes or alterations in other neurotransmitter systems downstream of serotonin.

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References

  • American Psychiatric Association (1980) Diagnostic and statistical manual of mental disorders. APA, Washington

    Google Scholar 

  • American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders. APA, Washington

    Google Scholar 

  • Ardis T, Cahir M, Elliott J, Bell R, Reynolds G, Cooper S (2009) Effect of acute tryptophan depletion on noradrenaline and dopamine in the rat brain. J Psychopharmacol 23:51–55

    Article  CAS  PubMed  Google Scholar 

  • Argyropoulos SV, Bailey JE, Hood SD, Kendrick AH, Rich AS, Laszlo G, Nash JR, Lightman SL, Nutt DJ (2002) Inhalation of 35% CO(2) results in activation of the HPA axis in healthy volunteers. Psychoneuroendocrinology 27:715–729

    Article  CAS  PubMed  Google Scholar 

  • Argyropoulos SV, Hood SD, Adrover M, Bell CJ, Rich AS, Nash JR, Rich NC, Witchel HJ, Nutt DJ (2004) Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder. Biol Psychiatry 56:503–509

    Article  CAS  PubMed  Google Scholar 

  • Bailey JE, Argyropoulos SV, Kendrick AH, Nutt DJ (2005) Behavioral and cardiovascular effects of 7.5% CO2 in human volunteers. Depress Anxiety 21:18–25

    Article  PubMed  Google Scholar 

  • Bailey JE, Kendrick A, Diaper A, Potokar JP, Nutt DJ (2007) A validation of the 7.5% CO2 model of GAD using paroxetine and lorazepam in healthy volunteers. J Psychopharmacol 21:42–49

    Article  CAS  PubMed  Google Scholar 

  • Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, Den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU (2005) Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 19:567–596

    Article  CAS  PubMed  Google Scholar 

  • Barr LC, Goodman WK, McDougle CJ, Delgado PL, Heninger GR, Charney DS, Price LH (1994) Tryptophan depletion in patients with obsessive–compulsive disorder who respond to serotonin reuptake inhibitors. Arch Gen Psychiatry 51:309–317

    CAS  PubMed  Google Scholar 

  • Bell C, Abrams J, Nutt D (2001) Tryptophan depletion and its implications for psychiatry. Br J Psychiatry 178:399–405

    Article  CAS  PubMed  Google Scholar 

  • Bell C, Forshall S, Adrover M, Nash J, Hood S, Argyropoulos S, Rich A, Nutt DJ (2002) Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine. J Psychopharmacol 16:5–14

    Article  CAS  PubMed  Google Scholar 

  • Bell CJ, Hood SD, Nutt DJ (2005) Acute tryptophan depletion. Part II: clinical effects and implications. Aust N Z J Psychiatry 39:565–574

    PubMed  Google Scholar 

  • Berney A, Sookman D, Leyton M, Young SN, Benkelfat C (2006) Lack of effects on core obsessive–compulsive symptoms of tryptophan depletion during symptom provocation in remitted obsessive–compulsive disorder patients. Biol Psychiatry 59:853–857

    Article  CAS  PubMed  Google Scholar 

  • Bond AJ, Lader MH (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychology 47:211–218

    Google Scholar 

  • Cahir M, Ardis TC, Elliott JJ, Kelly CB, Reynolds GP, Cooper SJ (2008) Acute tryptophan depletion does not alter central or plasma brain-derived neurotrophic factor in the rat. Eur Neuropsychopharmacol 18:317–322

    Article  CAS  PubMed  Google Scholar 

  • Carpenter LL, Anderson GM, Pelton GH, Gudin JA, Kirwin PD, Price LH, Heninger GR, McDougle CJ (1998) Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 19:26–35

    Article  CAS  PubMed  Google Scholar 

  • Corchs F, Nutt DJ, Hood S, Bernik M (2009) Serotonin and sensitivity to trauma-related exposure in selective serotonin reuptake inhibitors-recovered posttraumatic stress disorder. Biol Psychiatry 66:17–24

    Google Scholar 

  • Czermak C, Hauger R, Drevets WC, Luckenbaugh DA, Geraci M, Charney DS, Neumeister A (2008) Plasma NPY concentrations during tryptophan and sham depletion in medication-free patients with remitted depression. J Affect Disord 110:277–281

    Article  CAS  PubMed  Google Scholar 

  • Davies SJ, Hood SD, Argyropoulos SV, Morris K, Bell C, Witchel HJ, Jackson PR, Nutt DJ, Potokar JP (2006) Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders. J Clin Psychopharmacol 26:414–418

    Article  CAS  PubMed  Google Scholar 

  • Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, Moreno FA, Heninger GR, Charney DS (1999) Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry 46:212–220

    Article  CAS  PubMed  Google Scholar 

  • Fernstrom JD (1979) Diet-induced changes in plasma amino acid pattern: effects on the brain uptake of large neutral amino acids, and on brain serotonin synthesis. J Neural Transm Suppl (15):55–67

  • Harmer CJ (2008) Serotonin and emotional processing: Does it help explain antidepressant drug action? Neuropharmacology 55:1023–1028

    Article  CAS  PubMed  Google Scholar 

  • Hettema JM (2008) The nosologic relationship between generalized anxiety disorder and major depression. Depress Anxiety 25:300–316

    Article  PubMed  Google Scholar 

  • Hood SD, Argyropoulos SV, Potokar J, Bell C, Shufflebotham J, Rich AS, Nutt DJ (2004) A meta-analysis of acute tryptophan depletion studies in anxiety disorders using individual patients’ data. J Psychopharmacol 18:22

    Google Scholar 

  • Hood SD, Bell CJ, Nutt DJ (2005) Acute tryptophan depletion. Part I: rationale and methodology. Aust N Z J Psychiatry 39:558–564

    PubMed  Google Scholar 

  • Hood SD, Hince DA, Robinson H, Cirillo M, Christmas D, Kaye JM (2006) Serotonin regulation of the human stress response. Psychoneuroendocrinology 31:1087–1097

    Article  CAS  PubMed  Google Scholar 

  • Kulz AK, Meinzer S, Kopasz M, Voderholzer U (2007) Effects of tryptophan depletion on cognitive functioning, obsessive-compulsive symptoms and mood in obsessive–compulsive disorder: preliminary results. Neuropsychobiology 56:127–131

    Article  PubMed  Google Scholar 

  • McNair DM, Lorr M, Droppleman LF (1988) Manual for the profile of mood states. Educational and Industrial Testing Service, San Diego

  • Melichar JK, Haida A, Rhodes C, Reynolds AH, Nutt DJ, Malizia AL (2001) Venlafaxine occupation at the noradrenaline reuptake site: in-vivo determination in healthy volunteers. J Psychopharmacol 15:9–12

    Article  CAS  PubMed  Google Scholar 

  • Mennin DS, Heimberg RG, Fresco DM, Ritter MR (2008) Is generalized anxiety disorder an anxiety or mood disorder? Considering multiple factors as we ponder the fate of GAD. Depress Anxiety 25:289–299

    Article  PubMed  Google Scholar 

  • Praschak-Rieder N, Wilson AA, Hussey D, Carella A, Wei C, Ginovart N, Schwarz MJ, Zach J, Houle S, Meyer JH (2005) Effects of tryptophan depletion on the serotonin transporter in healthy humans. Biol Psychiatry 58:825–830

    Article  CAS  PubMed  Google Scholar 

  • Redrobe JP, Bourin M, Colombel MC, Baker GB (1998) Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity. Psychopharmacology (Berl) 138:1–8

    Article  CAS  Google Scholar 

  • Ruhe HG, Mason NS, Schene AH (2007) Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry 12:331–359

    Article  CAS  PubMed  Google Scholar 

  • Schaechter JD, Wurtman RJ (1990) Serotonin release varies with brain tryptophan levels. Brain Res 532:203–210

    Article  CAS  PubMed  Google Scholar 

  • Schruers K, Klaassen T, Pols H, Overbeek T, Deutz NE, Griez E (2000) Effects of tryptophan depletion on carbon dioxide provoked panic in panic disorder patients. Psychiatry Res 93:179–187

    Article  CAS  PubMed  Google Scholar 

  • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33

    PubMed  Google Scholar 

  • Shlik J, Aluoja A, Vasar V, Vasar E, Podar T, Bradwejn J (1997) Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine response to cholecystokinin tetrapeptide challenge in patients with panic disorder. J Psychiatry Neurosci 22:332–340

    CAS  PubMed  Google Scholar 

  • Smith KA, Fairburn CG, Cowen PJ (1997) Relapse of depression after rapid depletion of tryptophan. Lancet 349:915–919

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Toru I, Shlik J, Maron E, Vasar V, Nutt DJ (2006) Tryptophan depletion does not modify response to CCK-4 challenge in patients with panic disorder after treatment with citalopram. Psychopharmacology (Berl) 186:107–112

    Article  CAS  Google Scholar 

  • van Megen HJ, Westenberg HG, Den Boer JA, Slaap B, Scheepmakers A (1997) Effect of the selective serotonin reuptake inhibitor fluvoxamine on CCK-4 induced panic attacks. Psychopharmacology (Berl) 129:357–364

    Article  Google Scholar 

  • Williams WA, Shoaf SE, Hommer D, Rawlings R, Linnoila M (1999) Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J Neurochem 72:1641–1647

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (2004) International statistical classification of diseases and related health problems: tenth revision. World Health Organization, Geneva

    Google Scholar 

  • Wurtman RJ, Wurtman JJ, Regan MM, McDermott JM, Tsay RH, Breu JJ (2003) Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios. Am J Clin Nutr 77:128–132

    CAS  PubMed  Google Scholar 

  • Young SN, Smith SE, Pihl RO, Ervin FR (1985) Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology (Berl) 87:173–177

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Data from a preliminary analysis of this dataset were presented in poster form at the British Association of Psychopharmacology Summer Meeting, Harrogate UK, July 2008. We would like to acknowledge the substantial help of Ann Rich, Jon Nash, and Kelly Morris at the Bristol, UK site. Dr. Mike Franklin at Oxford, UK performed the amino acid assays. Dr. Caroline Bell played a pivotal role in securing funding for this project. Dr. Jenny Palmer, Dr. Simone Forward, and Dr. Lucinda Morris contributed significantly to the conduct of the study at the Perth, Australia site.

Financial disclosures

This study was funded by Raine Medical Research Foundation Priming Grant, Perth, Australia and Wellcome Trust Project Grant, Bristol, UK. Dr Dana Hince, Dr John Potokar and Dr Hayley Robinson have no conflicts of interest to declare. Professor David Nutt states that, over the past 20 years, he and his research group have received funds (research grants, speaker’s fees, or consultancy payments) from every major pharmaceutical company with an interest in the psychiatric field. He has undertaken Consultancies/advisory board work for Pfizer, GSK, Novartis, Organon, Cypress, Lilly, Janssen, Lundbeck, BMS, Astra Zeneca, Sanofi, Servier, Hythiam, and Sepracor and received speaking honoraria from these companies as well as Wyeth, Reckitt-Benkiser, and Cephalon. He has received grants or clinical trial payments from MSD, GSK, Novartis, Servier, Janssen, Lundbeck, Pfizer, Wyeth, and Organon. He has also received legal fees from companies, medical defense organizations, and the British Legal Aid board in relation to court cases regarding the effects of psychotropic drugs. Associate Professor Hood has undertaken advisory board work for Eli Lilly/Boehringer-Ingelheim and GlaxoSmithKline and received travel sponsorship/speakers fees from Eli Lilly, GlaxoSmithKline, Pfizer, Organon, Janssen, Lundbeck, Bristol-Myers-Squibb, Astra Zeneca, Servier, Sanofi-Aventis, Wyeth, and Cephalon. He has received clinical trials payments from Servier & Sanofi-Aventis. Dr. Simon Davies has no direct conflict of interest in relation to this manuscript. However, he has performed consultancy for Roche on one occasion and has undertaken speaking engagements for Pfizer and Lilly, with fees in all cases being paid to the University of Bristol. He was previously funded to produce educational materials for the Lundbeck Institute.

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Authors and Affiliations

  1. School of Psychiatry and Clinical Neurosciences (M521), University of Western Australia, Perth, Australia

    Sean D. Hood, Dana A. Hince & Hayley Robinson

  2. Psychopharmacology Unit, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK

    Sean D. Hood, Dana A. Hince, Simon J. C. Davies, Spilios Argyropoulos, John Potokar & David J. Nutt

  3. Section of Neurobiology of Psychosis, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK

    Spilios Argyropoulos

  4. Department of Neuropsychopharmacology and Molecular Imaging, Division of Neuroscience & Mental Health, Imperial College London, Burlington Danes Building, Hammersmith Campus, 160 Du Cane Road, London, W12 ONN, UK

    David J. Nutt

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  1. Sean D. Hood
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Correspondence to Sean D. Hood.

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Clinical Trial Registration Information

Public title: The effect of acute tryptophan depletion vs. sham depletion on disorder specific symptoms in people with selective serotonin reuptake inhibitor-remitted generalised anxiety disorder and obsessive compulsive disorder

Number: ACTRN12609000170224

http://www.ANZCTR.org.au/ACTRN12609000170224.aspx

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Hood, S.D., Hince, D.A., Davies, S.J.C. et al. Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder. Psychopharmacology 208, 223–232 (2010). https://doi.org/10.1007/s00213-009-1722-1

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