Skip to main content
Log in

Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature

  • Review
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

There is a growing psychopharmacological literature on the use of Acute Tryptophan Depletion (ATD) for experimental modulation of the serotonergic system. To date, no systematic review has been undertaken assessing the neurophysiological effects following this acute central 5-HT manipulation.

Materials and methods

A comprehensive MEDLINE, EMBASE, PsycINFO search was performed for reports on neural substrates of Acute Tryptophan Depletion in healthy individuals and in clinical population.

Results

Twenty-eight placebo-controlled studies were included in the review. Although tryptophan depletion reduced plasma serotonin levels in all studies, significant effects on mood were only observed in studies with recovered depressed patients. In functional neuroimaging studies ATD was consistently found to modulate cortical activity in prefrontal areas implicated in mnemonic and executive functions and in orbitofrontal, cingulate, and subcortical regions associated with emotional processing. Electrophysiological studies indicated that ATD has a significant effect on both “selective” and “involuntary” attention.

Conclusions

The combination of ATD with modern brain imaging techniques allows the investigation of the neurophysiological effects of reduced 5-HT synthesis on global brain activity, executive functions, memory, attention, and affect.

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

Similar content being viewed by others

Abbreviations

ATD:

Acute tryptophan depletion

5-HT:

5-hydroxyitryptamine

References

  • Ahveninen J, Kahkonen S, Pennanen S, Liesivuori J, Ilmoniemi RJ, Jaaskelainen IP (2002) Tryptophan depletion effects on EEG and MEG responses suggest serotonergic modulation of auditory involuntary attention in humans. NeuroImage 16:1052–1061

    Article  PubMed  Google Scholar 

  • Ahveninen J, Jaaskelainen IP, Pennanen S, Liesivuori J, Ilmoniemi RJ, Kahkonen S (2003) Auditory selective attention modulated by tryptophan depletion in humans. Neurosci Lett 340:181–184

    Article  PubMed  CAS  Google Scholar 

  • Allen P, Cleare AJ, Lee F, Fusar-Poli P, Tunstall N, Fu CH, Brammer M, McGuire P (2006) The effects of acute tryptophan depletion on prefrontal engagement. Psychopharmacology: submitted

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

    Article  PubMed  Google Scholar 

  • Biggio G, Fadda F, Fanni P (1974) Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindolacetice acid by a tryptophan free diet. Life Sci 14:1321–1329

    Article  PubMed  CAS  Google Scholar 

  • Booij L, Van der Does A, Benkelfat C (2003) Monoamine depletion in psychiatry and healthy populations. Mol Psychiatry 8:951–973

    Article  PubMed  CAS  Google Scholar 

  • Booij L, Van der Does AJ, Haffmans PM, Riedel WJ, Fekkes D, Blom MJ (2005) The effects of high-dose and low-dose trytophan depletion on mood and cognitive functions of remitted depressed patients. J Psychopharmacol 19(3):267–275

    Article  PubMed  CAS  Google Scholar 

  • Bremmer J, Innis R, Salomon R (1997) Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. Arch Gen Psychiatry 54:364–374

    Google Scholar 

  • Carpenter L, Anderson G, Pelton G, Gudin J (1999) Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 19:26–35

    Article  Google Scholar 

  • Clark L, Cools R, Robbins TW (2004) The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning. Brain Cogn 55:41–53

    Article  PubMed  CAS  Google Scholar 

  • Cools R, Clark L, Owen AM, Robbins TW (2002) Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. J Neurosci 22:4563–4567

    PubMed  CAS  Google Scholar 

  • Cools R, Calder AJ, Lawrence AD, Clark L, Bullmore E, Robbins TW (2005) Individual differences in threat sensitivity predict serotonergic modulation of amygdala response to fearful faces. Psychopharmacology (Berl) 180:670–679

    Article  CAS  Google Scholar 

  • Davidson R, Pizzagalli S, Nitschke J (2002) Depression: perspective from affective neuroscience. Am J Psychiatry 160:64–75

    Article  Google Scholar 

  • Davidson R, Irwin W, Anderle M (2003) The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 160:64–75

    Article  PubMed  Google Scholar 

  • Debener S, Strobel A, Kurschner K, Kranczioch C, Hebenstreit J, Maercker A, Beauducel A, Brocke B (2002) Is auditory evoked potential augmenting/reducing affected by acute tryptophan depletion? Biol Psychol 59:121–133

    Article  PubMed  Google Scholar 

  • Dierks T, Barta S, Demisch L, Schmeck K, Englert E, Kewitz A, Maurer K, Poustka F (1999) Intensity dependence of auditory evoked potentials (AEPs) as biological marker for cerebral serotonin levels: effects of tryptophan depletion in healthy subjects. Psychopharmacology (Berl) 146:101–107

    Article  CAS  Google Scholar 

  • Drevets W (2001) Neuroimaging and neuropathological studies of depression: implication for the cognitive emotional features of mood disorders. Curr Opin Neurobiol 11:240–249

    Article  PubMed  CAS  Google Scholar 

  • Ekman P (1982) Emotion in the human face. Cambridge University Press, Cambridge University

  • Evers EA, Cools R, Clark L, van der Veen FM, Jolles J, Sahakian BJ, Robbins TW (2005) Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning. Neuropsychopharmacology 30:1138–1147

    Article  PubMed  CAS  Google Scholar 

  • Evers EA, van der Veen FM, Jolles J, Deutz NE, Schmitt JA (2006a) Acute tryptophan depletion improves performance and modulates the BOLD response during a Stroop task in healthy females. Neuroimage 32(1):248–255

    Article  CAS  Google Scholar 

  • Evers EA, van der Veen FM, van Deursen JA, Schmitt JA, Deutz NE, Jolles J (2006b) The effect of acute tryptophan depletion on the BOLD response during performance monitoring and response inhibition in healthy male volunteers. Psychopharmacology (Berl) 187(2):200–208

    Article  CAS  Google Scholar 

  • Femstrom J, Faller D (1978) Neutral amino acids in the brain: changes in response to food ingestion. J Neurochem 30:1531–1538

    Article  Google Scholar 

  • Fu C, Williams S, Cleare A (2004) Attenuation of neural response to sad faces in major depression by antidepressant treatment. Arch Gen Psychiatr 61:877–889

    Article  PubMed  Google Scholar 

  • Gallinat J, Heinz A (2006) Combination of multimodal imaging and molecular genetic information to investigate complex psychiatric disorders. Pharmacopsychiatry 39 (Suppl 1):76–79

    Article  Google Scholar 

  • Goldberg E, Bougakov D (2005) Neuropsychologic assessment of frontal lobe dysfunction. Psychiatr Clin North Am 28:567–580, 578–579

    Article  PubMed  Google Scholar 

  • Hackley SA, Woldorff M, Hillyard SA (1990) Cross-modal selective attention effects on retinal, myogenic, brainstem, and cerebral evoked potentials. Psychophysiology 27:195–208

    Article  PubMed  CAS  Google Scholar 

  • Honey GD, Fletcher PC, Bullmore ET (2002) Functional brain mapping of psychopathology. J Neurol Neurosurg Psychiatry 72:432–439

    PubMed  CAS  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

    Article  PubMed  Google Scholar 

  • Horacek J, Zavesicka L, Tintera J (2005) The effect of tryptophan depletion on brain activation measured by functional magnetic resonance imaging during the Stroop test in healthy subjects. Physiol Res 54:235–244

    PubMed  CAS  Google Scholar 

  • Hughes JR, John ER (1999) Conventional and quantitative electroencephalography in psychiatry. J Neuropsychiatry Clin Neurosci 11:190–208

    PubMed  CAS  Google Scholar 

  • Hughes JH, Ashton CH, Matthews D, Young AH (2000) Acute depletion of plasma tryptophan does not alter electrophysiological variables in healthy males. Psychopharmacology (Berl) 152:119–121

    Article  CAS  Google Scholar 

  • Hughes JH, Gallagher P, Young AH (2002) Effects of acute tryptophan depletion on cognitive function in euthymic bipolar patients. Eur Neuropsychopharmacol 12:123–128

    Article  PubMed  CAS  Google Scholar 

  • Hughes JH, Gallagher P, Stewart ME, Matthews D, Kelly TP, Young AH (2003) The effects of acute tryptophan depletion on neuropsychological function. J Psychopharmacol 17:300–309

    Article  PubMed  CAS  Google Scholar 

  • Kahkonen S, Ahveninen J (2002) Combination of magneto- and electroencephalography in studies of monoamine modulation on attention. Methods Find Exp Clin Pharmacol 24(Suppl C):27–34

    PubMed  CAS  Google Scholar 

  • Kahkonen S, Jaaskelainen IP, Pennanen S, Liesivuori J, Ahveninen J (2002a) Acute tryptophan depletion decreases intensity dependence of auditory evoked magnetic N1/P2 dipole source activity. Psychopharmacology (Berl) 164:221–227

    Article  CAS  Google Scholar 

  • Kahkonen S, Ahveninen J, Pennanen S, Liesivuori J, Ilmoniemi RJ, Jaaskelainen IP (2002b) Serotonin modulates early cortical auditory processing in healthy subjects: evidence from MEG with acute tryptophan depletion. Neuropsychopharmacology 27:862–868

    Article  PubMed  CAS  Google Scholar 

  • Kahkonen S, Ahveninen J, Jaaskelainen IP, Pennanen S, Liesivuori J, Nikulin VV (2003) Acute tryptophan depletion does not change somatosensory evoked magnetic fields. Psychopharmacology (Berl) 170:332–333

    Article  CAS  Google Scholar 

  • Knott VJ, Howson AL, Perugini M, Ravindran AV, Young SN (1999) The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects. Biol Psychiatry 46:229–238

    Article  PubMed  CAS  Google Scholar 

  • Koed K, Linnet K (2000) Opposing changes in serotonin and norepinephrine transporter mRNA levels after serotonin depletion. Eur Neuropsychopharmacol 10:501–509

    Article  PubMed  CAS  Google Scholar 

  • Lennox B, Jacob R, Calder A (2004) Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania. Psychological Medicine 34:795–802

    Article  PubMed  CAS  Google Scholar 

  • McAllister-Williams RH, Massey AE, Rugg MD (2002) Effects of tryptophan depletion on brain potential correlates of episodic memory retrieval. Psychopharmacology (Berl) 160:434–442

    Article  CAS  Google Scholar 

  • McGuire P, Matsumoto K (2004) Functional neuroimaging in mental disorders. World Psychol 3:6–11

    Google Scholar 

  • McGuire PK, Silbersweig DA, Murray RM, David AS, Frackowiak RS, Frith CD (1996) Functional anatomy of inner speech and auditory verbal imagery. Psychol Med 26:29–38

    Article  PubMed  CAS  Google Scholar 

  • Moja E, Cipollo P, Castoldi D, Tofanetti O (1989) Dose-response decrease in plasma tryptophan and brain tryptophan and serotonin after tryptophan-free amino acids mixtures in rats. Life Sci 44:971–976

    Article  PubMed  CAS  Google Scholar 

  • Moresco R, Messa C, Lucignani G, Rizzo GG, Todde S, Carla Gilardi M, Grimaldi A, Fazio F (2001) PET in psychopharmacology. Pharmacol Res 44:151–159

    Article  CAS  Google Scholar 

  • Morris JS, Smith KA, Cowen PJ, Friston KJ, Dolan RJ (1999) Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. NeuroImage 10:163–172

    Article  PubMed  CAS  Google Scholar 

  • Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002) The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacology (Berl) 163:42–53

    Article  CAS  Google Scholar 

  • Naatanen R (2003) Mismatch negativity: clinical research and possible applications. Int J Psychophysiol 48:179–188

    Article  PubMed  Google Scholar 

  • Neumeister A, Nugent A, Waldeck T (2004) Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted MDD and controls. Arch Gen Psychiatry 61:765–773

    Article  PubMed  CAS  Google Scholar 

  • Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, Blier P, Diksic M (1997) Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci U S A 94:5308–5313

    Article  PubMed  CAS  Google Scholar 

  • Olendorf W, Szabo J (1976) Amino acid assignment to one of three blood–brain barrier amino acid carriers. Am J Physiol 230:94–98

    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  PubMed  CAS  Google Scholar 

  • Preece MA, Dalley JW, Theobald DE, Robbins TW, Reynolds GP (2004) Region specific changes in forebrain 5-hydroxytryptamine1A and 5-hydroxytryptamine2A receptors in isolation-reared rats: an in vitro autoradiography study. Neuroscience 123:725–732

    Article  PubMed  CAS  Google Scholar 

  • Reilly J, McTavish S, Young A (1997) Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. J Psychopharmacol 11:381–392

    Article  PubMed  CAS  Google Scholar 

  • Reite M, Teale P, Rojas DC (1999) Magnetoencephalography: applications in psychiatry. Biol Psychiatry 45:1553–1563

    Article  PubMed  CAS  Google Scholar 

  • Riedel WJ (2004) Cognitive changes after acute tryptophan depletion: what can they tell us? Psychol Med 34:3–8

    Article  PubMed  Google Scholar 

  • Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM (1999) Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl) 141:362–369

    Article  CAS  Google Scholar 

  • Riedel WJ, Klaassen T, Schmitt JA (2002) Tryptophan, mood, and cognitive function. Brain Behav Immun 16:581–589

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW (2000) Chemical neuromodulation of frontal-executive functions in humans and other animals. Exp Brain Res 133:130–138

    Article  PubMed  CAS  Google Scholar 

  • Rogers RD, Blackshaw AJ, Middleton HC, Matthews K, Hawtin K, Crowley C, Hopwood A, Wallace C, Deakin JF, Sahakian BJ, Robbins TW (1999) Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behavior. Psychopharmacology (Berl) 146:482–491

    Article  CAS  Google Scholar 

  • Roiser JP, Blackwell AD, Cools R, Clark L, Rubinsztein DC, Robbins TW, Sahakian BJ (2006) Serotonin transporter polymorphism mediates vulnerability to loss of incentive motivation following acute tryptophan depletion. Neuropsychopharmacology. DOI 10.1038/sj.npp1301055

  • Rubia K, Lee F, Cleare AJ, Tunstall N, Fu CH, Brammer M, McGuire P (2005) Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI. Psychopharmacology (Berl) 179:791–803

    Article  CAS  Google Scholar 

  • Schlosser R, Hutchinson M, Joseffer S, Rusinek H, Saarimaki A, Stevenson J, Dewey SL, Brodie JD (1998) Functional magnetic resonance imaging of human brain activity in a verbal fluency task. J Neurol Neurosurg Psychiatry 64:492–498

    PubMed  CAS  Google Scholar 

  • Schmitt JA, Jorissen BL, Sobczak S, van Boxtel MP, Hogervorst E, Deutz NE, Riedel WJ (2000) Tryptophan depletion impairs memory consolidation but improves focussed attention in healthy young volunteers. J Psychopharmacol 14:21–29

    Article  PubMed  CAS  Google Scholar 

  • Sheline Y, Barch D, Donnelly J (2001) Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: a fMRI study. Psychiatry Res 83:127–138

    Google Scholar 

  • Smith GS, Koppel J, Goldberg S (2003) Applications of neuroreceptor imaging to psychiatry research. Psychopharmacol Bull 37:26–65

    PubMed  Google Scholar 

  • Smith KA, Morris JS, Friston KJ, Cowen PJ, Dolan RJ (1999) Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion. Br J Psychiatry 174:525–529

    Article  PubMed  CAS  Google Scholar 

  • Stroop J (1935) Studies of interference in serial verbal reaction. J Exp Psychol 1:643–662

    Article  Google Scholar 

  • Talbot PS, Cooper SJ (2006) Anterior cingulate and subgenual prefrontal blood flow changes following tryptophan depletion in healthy males. Neuropsychopharmacology 31(8):1757–1767

    Article  PubMed  CAS  Google Scholar 

  • Van der Does A (2001) The effects of tryptophan depletion on mood and psychiatric symptoms. J Affect Disord 64:107–119

    Article  PubMed  Google Scholar 

  • van der Veen FM, Evers EA, van Deursen JA, Deutz NE, Backes WH, Schmitt JA (2006) Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task. Neuroimage 31(3):1188–1196

    Article  PubMed  Google Scholar 

  • Voderholzer U, Hornyak M, Thiel B, Huwig-Poppe C, Kiemen A, Konig A, Backhaus J, Riemann D, Berger M, Hohagen F (1998) Impact of experimentally induced serotonin deficiency by tryptophan depletion on sleep EEG in healthy subjects. Neuropsychopharmacology 18:112–124

    Article  PubMed  CAS  Google Scholar 

  • Warwick JM (2004) Imaging of brain function using SPECT. Metab Brain Dis 19:113–123

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Yatham LN, Liddle PF, Shiah IS, Lam RW, Adam MJ, Zis AP, Ruth TJ (2001) Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study. Br J Psychiatry 178:448–453

    Article  PubMed  CAS  Google Scholar 

  • Young AH, Hughes JH, Marsh VR, Ashton CH (2002) Acute tryptophan depletion attenuates auditory event related potentials in bipolar disorder: a preliminary study. J Affect Disord 69:83–92

    Article  PubMed  CAS  Google Scholar 

  • Young SN, Leyton M (2002) The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav 71:857–865

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant of the Italian Ministry of Health to Biological Psychiatric Unit, the IRCCS-FBF, Italy, and by the European Union (six framework Program) grant for project GENDEP (contract LSHB-CT2003-503428) to J. P. and A. P.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paolo Fusar-Poli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fusar-Poli, P., Allen, P., McGuire, P. et al. Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature. Psychopharmacology 188, 131–143 (2006). https://doi.org/10.1007/s00213-006-0493-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-006-0493-1

Keywords

Navigation