Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635

Molecular Psychiatry volume 9, pages 386–392 (2004)Cite this article

Abstract

Positron emission tomography (PET) studies with the selective 5-HT1A receptor ligand, [11C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT1A receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [11C]WAY-100635 in conjunction with PET imaging to compare 5-HT1A BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT1A receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT1A BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT1A BP as measured by [11C]WAY-100635 in recovered depressed men. Lowered 5-HT1A receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Smith KA, Cowen PJ . Serotonin and depression. In: Honig A, van Praag HM (eds). Depression: Neurobiological, Psychopathological and Therapeutic Advances. John Wiley & Sons Ltd: Chichester, 1997 pp 129–146.

    Google Scholar 

  2. Shapira B, Cohen J, Newman ME, Lerer B . Prolactin response to fenfluramine and placebo challenge following maintenance pharmacotherapy withdrawal in remitted depressed patients. Biol Psychiatry 1993; 33: 531–535.

    Article  CAS  Google Scholar 

  3. Flory JD, Mann JJ, Manuck SB, Muldoon MF . Recovery from major depression is not associated with normalization of serotonergic function. Biol Psychiatry 1998; 43: 320–326.

    Article  CAS  Google Scholar 

  4. Bhagwagar Z, Whale R, Cowen PJ . State and trait abnormalities in serotonin function in major depression. Br J Psychiatry 2002; 180: 24–28.

    Article  Google Scholar 

  5. Golden RN, Heine AD, Ekstrom D, Bebchuk JM, Leatherman ME, Garbutt JC . A longitudinal study of serotonergic function in depression. Neuropsychopharmacology 2002; 26: 653–659.

    Article  CAS  Google Scholar 

  6. Booij L, Van der Does W, Benkelfat C, Bremner JD, Cowen PJ, Fava M et al. Predictors of mood response to acute tryptophan depletion: a reanalysis. Neuropsychopharmacology 2002; 27: 852–861.

    Article  CAS  Google Scholar 

  7. Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J et al. Brain serotonin1A receptor binding measured by positron emission tomography with [11C] WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000; 57: 174–180.

    Article  CAS  Google Scholar 

  8. Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW et al. Conceptionisation and rationale for consensus definition of terms in major depressive disorder: remission, recovery, relapse and recurrence. Arch Gen Psychiatry 1991; 48: 851–855.

    Article  CAS  Google Scholar 

  9. First MB, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I disorders — Clinician Version (SCID-CV). American Psychiatric Press: Washington, DC, 1997.

    Google Scholar 

  10. Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence AD et al. A database of [11C]WAY-100635 binding to 5-HT1A receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables. NeuroImage 2002; 15: 620–632.

    Article  Google Scholar 

  11. Spinks TJ, Jones T, Bailey DL, Townsend DW, Grootoonk S, Bloomfield PM et al. Physical performance of a positron tomograph for brain imaging with retractable septa. Phys Med Biol 1992; 37: 1637–1655.

    Article  CAS  Google Scholar 

  12. Grootoonk S, Spinks TJ, Sashin D, Spyrou NM, Jones T . Correction for scatter in 3D brain PET using a dual energy window method. Phys Med Biol 1996; 41: 2757–2774.

    Article  CAS  Google Scholar 

  13. McCarron J, Turton D, Pike V, Poole K . Remotely controlled production of the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635, via 11C-carboxylation of an immobilized Gringard reagent. J Label Comp Radiopharm 1996; 38: 941–953.

    Article  CAS  Google Scholar 

  14. Lammertsma AA, Hume SP . Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4: 153–158.

    Article  CAS  Google Scholar 

  15. Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW et al. Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET. Neuroimage 1998; 8: 426–440.

    Article  CAS  Google Scholar 

  16. Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA et al. Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635. Brain Res 1997; 745: 96–108.

    Article  CAS  Google Scholar 

  17. Meyer JH, Gunn RN, Myers R, Grasby PM . Assessment of spatial normalization of PET ligand images using ligand-specific templates. Neuroimage 1999; 9: 545–553.

    Article  CAS  Google Scholar 

  18. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ et al. PET imaging of serotonin1A receptor binding in depression. Biol Psychiatry 1999; 46: 1375–1387.

    Article  CAS  Google Scholar 

  19. Mann JJ, Oquendo M, Simpson N, Huang Y, Van Heertum R, Arango V et al. Altered 5HT-1A binding in major depression: an [11C]WAY100635 PET study. NeuroImage 2002; 16: S105.

    Google Scholar 

  20. Tauscher J, Verhoeff NP, Christensen BK, Hussey D, Meyer JH, Kecojevic A et al. Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET. Neuropsychopharmacology 2001; 24: 522–530.

    Article  CAS  Google Scholar 

  21. Cidis Meltzer C, Drevets WC, Price JC et al. Gender-specific aging effects on the serotonin 1A receptor. Brain Res 2001; 895: 9–17.

    Article  CAS  Google Scholar 

  22. Farde L, Ito H, Swahn CG, Pike VW, Halldin C . Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. J Nucl Med 1998; 39: 1965–1971.

    CAS  PubMed  Google Scholar 

  23. Parsey RV, Slifstein M, Hwang DR et al. Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions. J Cereb Blood Flow Metab 2000; 20: 1111–1133.

    Article  CAS  Google Scholar 

  24. Gunn RN, Lammertsma AA, Grasby PM . Quantitative analysis of [carbonyl-(11)C]WAY-100635 PET studies. Nucl Med Biol 2000; 27: 477–482.

    Article  CAS  Google Scholar 

  25. Slifstein M, Parsey RV, Laruelle M . Derivation of [11C]WAY-100635 binding parameters with reference tissue models: effect of violations of model assumptions. Nucl Med Biol 2000; 27: 487–492.

    Article  CAS  Google Scholar 

  26. Ito H, Halldin C, Farde L . Localization of 5-HT1A receptors in the living human brain using [carbonyl-11C]WAY-100635: PET with anatomic standardization technique. J Nucl Med 1999; 40: 102–109.

    CAS  PubMed  Google Scholar 

  27. Martinez D, Hwang D, Mawlawi O et al. Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology 2001; 24: 209–229.

    Article  CAS  Google Scholar 

  28. Rabiner EA, Gunn RN, Castro ME et al. β-Blocker binding to human 5-HT1A receptors in vivo and in vitro: implications for antidepressant therapy. Neuropsychopharmacology 2000; 23: 285–293.

    Article  CAS  Google Scholar 

  29. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS . Hippocampal volume reduction in major depression. Am J Psychiatry 2000; 157: 115–118.

    Article  CAS  Google Scholar 

  30. Bremner JD, Vythilingam M, Vermetten E et al. Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry 2002; 51: 273–279.

    Article  Google Scholar 

  31. MacQueen GM, Campbell S, McEwen BS et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA 2003; 100: 1387–1392.

    Article  CAS  Google Scholar 

  32. Gross C, Zhuang X, Stark K et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 2002; 416: 396–400.

    Article  CAS  Google Scholar 

  33. Kendler KS, Gardner CO, Prescott CA . Toward a comprehensive developmental model for major depression in women. Am J Psychiatry 2002; 159: 1133–1145.

    Article  Google Scholar 

  34. Azmitia EC, Gannon PJ, Kheck NM, Whitaker-Azmitia PM . Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology 1996; 14: 35–46.

    Article  CAS  Google Scholar 

  35. Cohen Z, Bouchelet I, Olivier A et al. Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacologic characterization. J Cereb Blood Flow Metab 1999; 19: 908–917.

    Article  CAS  Google Scholar 

  36. Burnet PW, Eastwood SL, Lacey K, Harrison PJ . The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain. Brain Res 1995; 676: 157–168.

    Article  CAS  Google Scholar 

  37. Harrison PJ . The neuropathology of primary mood disorder. Brain 2002; 125: 1428–1449.

    Article  Google Scholar 

  38. Holsboer F . Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 2001; 62: 77–91.

    Article  CAS  Google Scholar 

  39. Sapolsky RM . Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 2000; 57: 925–935.

    Article  CAS  Google Scholar 

  40. López JF, Chalmers DT, Little KY, Watson SJ . Regulation of serotonin1A, glucocorticoid, and mineralcorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998; 43: 547–573.

    Article  Google Scholar 

  41. Holsboer F, von Bardeleben U, Wiedemann K, Müller OA, Stalla GK . Serial assessment of corticotropin-releasing hormone response after dexamethasone in depression: implications for pathophysiology of DST nonsuppression. Biol Psychiatry 1987; 22: 228–234.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the volunteers without whom this study would not be possible. Thanks are also due to Andrew Blythe, Joanne Holmes, David Turton, Ray Khan, Safiye Osman, Jasbir Grewal, Vijaykumar Vaja, Keith Poole, Leonard Schnorr, Abdellah Haida, Ann Peers and others at the MRC Cyclotron Unit, London, for expert technical assistance. The study was supported by an MRC Co-operative Group grant. ZB was a MRC Clinical Training Fellow.

Author information

Authors and Affiliations

  1. University Department of Psychiatry, Warneford Hospital, Oxford, UK

    Z Bhagwagar, P A Sargent & P J Cowen

  2. Medical Research Council Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK

    E A Rabiner & P M Grasby

Authors
  1. Z Bhagwagar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E A Rabiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P A Sargent
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P M Grasby
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P J Cowen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P J Cowen.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bhagwagar, Z., Rabiner, E., Sargent, P. et al. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 9, 386–392 (2004). https://doi.org/10.1038/sj.mp.4001401

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001401

Keywords

  • serotonin
  • 5-HT1A receptor
  • depression
  • ligand PET

This article is cited by

Search

Advanced search

Quick links