Skip to main content
SpringerLink
Log in

Molecular Imaging of Major Depressive Disorder with Positron Emission Tomography: Translational Implications for Neurobiology and Treatment

  • Protocol
  • First Online:
Translational Research Methods for Major Depressive Disorder

Part of the book series: Neuromethods ((NM,volume 179))

  • 571 Accesses

Abstract

Here we discuss the positron emission tomography (PET) method applied to research on the pathophysiology of major depressive disorder (MDD). The principles for PET quantification of radioligand binding are described together with its benefits and limitations. The concept of MDD, its historical development, and the consequences for research in the biology of depression are addressed. The most commonly applied radioligands are reviewed, as are the typical findings. A particular interest is given to the serotonin system as this represents the main focus of the research up to recently. The inherent challenge of small patient samples in PET studies of MDD is addressed. Finally, future perspectives are critically discussed. Here both current trends and areas of particular interest are reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. McArthur RA (2012) Translational neuroimaging: tools for CNS drug discovery, development and treatment. Academic Press, London

    Google Scholar 

  2. Farde L (1996) The advantage of using positron emission tomography in drug research. Trends Neurosci 19(6):211–214

    Article  CAS  PubMed  Google Scholar 

  3. Laruelle M (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20(3):423–451

    Article  CAS  PubMed  Google Scholar 

  4. Finnema SJ, Varrone A, Hwang TJ, Gulyas B, Pierson ME, Halldin C et al (2010) Fenfluramine-induced serotonin release decreases [11C]AZ10419369 binding to 5-HT1B-receptors in the primate brain. Synapse 64(7):573–577

    Article  CAS  PubMed  Google Scholar 

  5. Finnema SJ, Varrone A, Hwang TJ, Halldin C, Farde L (2012) Confirmation of fenfluramine effect on 5-HT(1B) receptor binding of [(11)C]AZ10419369 using an equilibrium approach. J Cereb Blood Flow Metab 32(4):685–695

    Article  CAS  PubMed  Google Scholar 

  6. Tedroff J, Pedersen M, Aquilonius SM, Hartvig P, Jacobsson G, Langstrom B (1996) Levodopa-induced changes in synaptic dopamine in patients with Parkinson’s disease as measured by [11C]raclopride displacement and PET. Neurology 46(5):1430–1436

    Article  CAS  PubMed  Google Scholar 

  7. Hartvig P, Torstenson R, Tedroff J, Watanabe Y, Fasth KJ, Bjurling P et al (1997) Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography. J Neural Transm (Vienna) 104(4–5):329–339

    Article  CAS  Google Scholar 

  8. Nord M, Finnema SJ, Halldin C, Farde L (2013) Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain. Int J Neuropsychopharmacol 16:1577–1586

    Article  CAS  PubMed  Google Scholar 

  9. Yang KC, Stepanov V, Amini N, Martinsson S, Takano A, Bundgaard C et al (2019) Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain. Neuropsychopharmacology 44(10):1706–1713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lundberg J, Christophersen JS, Buchberg Petersen K, Loft H et al (2007) PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram. Int J Neuropsychopharmacol 10:777–785

    Article  CAS  PubMed  Google Scholar 

  11. Arakawa R, Stenkrona P, Takano A, Svensson J, Andersson M, Nag S et al (2019) Venlafaxine ER blocks the norepinephrine transporter in the brain of patients with major depressive disorder: a PET study using [18F]FMeNER-D2. Int J Neuropsychopharmacol 22(4):278–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stenkrona P, Halldin C, Lundberg J (2013) 5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects. Eur Neuropsychopharmacol 23:1190

    Article  CAS  PubMed  Google Scholar 

  13. Lundberg J, Tiger M, Landen M, Halldin C, Farde L (2012) Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder. Int J Neuropsychopharmacol 15(8):1167–1172

    Article  CAS  PubMed  Google Scholar 

  14. Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122(5):509–522

    Article  CAS  PubMed  Google Scholar 

  15. Carlsson A, Corrodi H, Fuxe K, Hokfelt T (1969) Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-alpha-ethyl-meta-tyramine. Eur J Pharmacol 5(4):357–366

    Article  CAS  PubMed  Google Scholar 

  16. Carlsson A, Corrodi H, Fuxe K, Hokfelt T (1969) Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4,alpha-dimethyl-meta-tyramine. Eur J Pharmacol 5(4):367–373

    Article  CAS  PubMed  Google Scholar 

  17. Coppen A (1967) The biochemistry of affective disorders. Br J Psychiatry 113(504):1237–1264

    Article  CAS  PubMed  Google Scholar 

  18. Lapin IP, Oxenkrug GF (1969) Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1(7586):132–136

    Article  CAS  PubMed  Google Scholar 

  19. Tiger M (2014) PET studies of the serotonin system in depression and its treatment. PhD thesis, Karolinska Institutet

    Google Scholar 

  20. Feighner JP, Robins E, Guze SB, Woodruff RA Jr, Winokur G, Munoz R (1972) Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26(1):57–63

    Article  CAS  PubMed  Google Scholar 

  21. Belmaker RH, Agam G (2008) Major depressive disorder. N Engl J Med 358(1):55–68

    Article  CAS  PubMed  Google Scholar 

  22. Horwitz AV, Wakefield JC (2007) The loss of sadness - how psychiatry transformed normal sorrow into depressive disorder. Oxford University Press, Oxford

    Google Scholar 

  23. Ostergaard SD, Jensen SO, Bech P (2011) The heterogeneity of the depressive syndrome: when numbers get serious. Acta Psychiatr Scand 124(6):495–496

    Article  CAS  PubMed  Google Scholar 

  24. Savitz JB, Drevets WC (2013) Neuroreceptor imaging in depression. Neurobiol Dis 52:49–65

    Article  CAS  PubMed  Google Scholar 

  25. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K et al (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167(7):748–751

    Article  PubMed  Google Scholar 

  26. Woody ML, Gibb BE (2015) Integrating NIMH research domain criteria (RDoC) into depression research. Curr Opin Psychol 4:6–12

    Article  PubMed  PubMed Central  Google Scholar 

  27. Murrough JW, Czermak C, Henry S, Nabulsi N, Gallezot JD, Gueorguieva R et al (2011) The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding. Arch Gen Psychiatry 68(9):892–900

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tiger M, Svensson J, Liberg B, Saijo T, Schain M, Halldin C et al (2020) [(11) C]raclopride positron emission tomography study of dopamine-D2/3 receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects. Psychiatry Clin Neurosci 74(4):263–269

    Article  CAS  PubMed  Google Scholar 

  29. Gray NA, Milak MS, DeLorenzo C, Ogden RT, Huang YY, Mann JJ et al (2013) Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder. Biol Psychiatry 74(1):26–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schneck N, Tu T, Falcone HR, Miller JM, Zanderigo F, Sublette ME et al (2020) Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder. Mol Psychiatry 26:2393

    Article  PubMed  PubMed Central  Google Scholar 

  31. Tiger M, Veldman ER, Ekman CJ, Halldin C, Svenningsson P, Lundberg J (2020) A randomized placebo-controlled PET study of ketamine s effect on serotonin 1B receptor binding in patients with SSRI-resistant depression. Transl Psychiatry 10(1):159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tiger M, Farde L, Ruck C, Varrone A, Forsberg A, Lindefors N et al (2016) Low serotonin 1B receptor binding potential in the anterior cingulate cortex in drug-free patients with recurrent major depressive disorder. Psychiatry Res 253:36–42

    Article  Google Scholar 

  33. Tiger M, Ruck C, Forsberg A, Varrone A, Lindefors N, Halldin C et al (2014) Reduced 5-HT1B receptor binding in the dorsal brain stem after cognitive behavioural therapy of major depressive disorder. Psychiatry Res 223(2):164–170

    Article  PubMed  Google Scholar 

  34. Murrough JW, Henry S, Hu J, Gallezot JD, Planeta-Wilson B, Neumaier JF et al (2011) Reduced ventral striatal/ventral pallidal serotonin 1B receptor binding potential in major depressive disorder. Psychopharmacology 213(2–3):547–553

    Article  CAS  PubMed  Google Scholar 

  35. Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P (2006) Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907. Am J Psychiatry 163(9):1580–1587

    Article  PubMed  Google Scholar 

  36. Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ (2004) Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography. Biol Psychiatry 55(3):217–224

    Article  CAS  PubMed  Google Scholar 

  37. Ananth MR, DeLorenzo C, Yang J, Mann JJ, Parsey RV (2018) Decreased pretreatment amygdalae serotonin transporter binding in unipolar depression remitters: a prospective PET study. J Nucl Med 59(4):665–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Selvaraj S, Murthy NV, Bhagwagar Z, Bose SK, Hinz R, Grasby PM et al (2011) Diminished brain 5-HT transporter binding in major depression: a positron emission tomography study with [11C]DASB. Psychopharmacology 213(2–3):555–562

    Article  CAS  PubMed  Google Scholar 

  39. Miller JM, Kinnally EL, Ogden RT, Oquendo MA, Mann JJ, Parsey RV (2009) Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder. Synapse 63(7):565–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Baldinger-Melich P, Gryglewski G, Philippe C, James GM, Vraka C, Silberbauer L et al (2019) The effect of electroconvulsive therapy on cerebral monoamine oxidase A expression in treatment-resistant depression investigated using positron emission tomography. Brain Stimul 12(3):714–723

    Article  PubMed  Google Scholar 

  41. Moriguchi S, Wilson AA, Miler L, Rusjan PM, Vasdev N, Kish SJ et al (2019) Monoamine oxidase B total distribution volume in the prefrontal cortex of major depressive disorder: an [11C]SL25.1188 positron emission tomography study. JAMA Psychiatry 76(6):634–641

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dougherty DD, Bonab AA, Ottowitz WE, Livni E, Alpert NM, Rauch SL et al (2006) Decreased striatal D1 binding as measured using PET and [11C]SCH 23,390 in patients with major depression with anger attacks. Depress Anxiety 23(3):175–177

    Article  CAS  PubMed  Google Scholar 

  43. Saijo T, Takano A, Suhara T, Arakawa R, Okumura M, Ichimiya T et al (2010) Electroconvulsive therapy decreases dopamine D(2)receptor binding in the anterior cingulate in patients with depression: a controlled study using positron emission tomography with radioligand [(1)(1)C]FLB 457. J Clin Psychiatry 71(6):793–799

    Article  PubMed  Google Scholar 

  44. Moriya H, Tiger M, Tateno A, Sakayori T, Masuoka T, Kim W et al (2020) Low dopamine transporter binding in the nucleus accumbens in geriatric patients with severe depression. Psychiatry Clin Neurosci 74(8):424–430

    Article  CAS  PubMed  Google Scholar 

  45. Meyer JH, Kruger S, Wilson AA, Christensen BK, Goulding VS, Schaffer A et al (2001) Lower dopamine transporter binding potential in striatum during depression. NeuroReport 12(18):4121–4125

    Article  CAS  PubMed  Google Scholar 

  46. Moriguchi S, Yamada M, Takano H, Nagashima T, Takahata K, Yokokawa K et al (2017) Norepinephrine transporter in major depressive disorder: a PET study. Am J Psychiatry 174(1):36–41

    Article  PubMed  Google Scholar 

  47. Cannon DM, Carson RE, Nugent AC, Eckelman WC, Kiesewetter DO, Williams J et al (2006) Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder. Arch Gen Psychiatry 63(7):741–747

    Article  CAS  PubMed  Google Scholar 

  48. Klumpers UM, Veltman DJ, Drent ML, Boellaard R, Comans EF, Meynen G et al (2010) Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results. Eur J Nucl Med Mol Imaging 37(3):565–574

    Article  CAS  PubMed  Google Scholar 

  49. Abdallah CG, Hannestad J, Mason GF, Holmes SE, DellaGioia N, Sanacora G et al (2017) Metabotropic glutamate receptor 5 and glutamate involvement in major depressive disorder: a multimodal imaging study. Biol Psychiatry Cogn Neurosci Neuroimaging 2(5):449–456

    PubMed  PubMed Central  Google Scholar 

  50. Richards EM, Zanotti-Fregonara P, Fujita M, Newman L, Farmer C, Ballard ED et al (2018) PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects. EJNMMI Res 8(1):57

    Article  PubMed  PubMed Central  Google Scholar 

  51. Li H, Sagar AP, Keri S (2018) Translocator protein (18kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy. Prog Neuro-Psychopharmacol Biol Psychiatry 83:1–7

    Article  CAS  Google Scholar 

  52. Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM et al (2018) Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psychiatry 83(1):61–69

    Article  CAS  PubMed  Google Scholar 

  53. Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N et al (2019) Lower synaptic density is associated with depression severity and network alterations. Nat Commun 10(1):1529

    Article  PubMed  PubMed Central  Google Scholar 

  54. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA et al (1999) Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 156(5):675–682

    Article  CAS  PubMed  Google Scholar 

  55. Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT (2000) Differential limbic--cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychiatry 48(1):30–42

    Article  CAS  PubMed  Google Scholar 

  56. Veldman ER, Svedberg MM, Svenningsson P, Lundberg J (2017) Distribution and levels of 5-HT1B receptors in anterior cingulate cortex of patients with bipolar disorder, major depressive disorder and schizophrenia - an autoradiography study. Eur Neuropsychopharmacol 27(5):504–514

    Article  CAS  PubMed  Google Scholar 

  57. Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V (1976) “Serotonin depression”--a biochemical subgroup within the affective disorders? Science 191(4226):478–480

    Article  CAS  PubMed  Google Scholar 

  58. Asberg M (1997) Neurotransmitters and suicidal behavior. The evidence from cerebrospinal fluid studies. Ann N Y Acad Sci 836:158–181

    Article  CAS  PubMed  Google Scholar 

  59. Shrestha S, Hirvonen J, Hines CS, Henter ID, Svenningsson P, Pike VW et al (2012) Serotonin-1A receptors in major depression quantified using PET: controversies, confounds, and recommendations. NeuroImage 59(4):3243–3251

    Article  CAS  PubMed  Google Scholar 

  60. Gryglewski G, Lanzenberger R, Kranz GS, Cumming P (2014) Meta-analysis of molecular imaging of serotonin transporters in major depression. J Cereb Blood Flow Metab 34(7):1096–1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tiger M, Varnas K, Okubo Y, Lundberg J (2018) The 5-HT1B receptor - a potential target for antidepressant treatment. Psychopharmacology 235(5):1317–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Voineskos AN, Wilson AA, Boovariwala A, Sagrati S, Houle S, Rusjan P et al (2007) Serotonin transporter occupancy of high-dose selective serotonin reuptake inhibitors during major depressive disorder measured with [11C]DASB positron emission tomography. Psychopharmacology 193(4):539–545

    Article  CAS  PubMed  Google Scholar 

  63. Meyer JH, Wilson AA, Ginovart N, Goulding V, Hussey D, Hood K et al (2001) Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study. Am J Psychiatry 158(11):1843–1849

    Article  CAS  PubMed  Google Scholar 

  64. Meyer JH, Kapur S, Eisfeld B, Brown GM, Houle S, DaSilva J et al (2001) The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am J Psychiatry 158(1):78–85

    Article  CAS  PubMed  Google Scholar 

  65. Meyer. (2007) Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. Rev Psychiatr Neurosci 32(2):86–102

    Google Scholar 

  66. Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ et al (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161(5):826–835

    Article  PubMed  Google Scholar 

  67. Masuoka T, Tateno A, Sakayori T, Tiger M, Kim W, Moriya H et al (2020) Electroconvulsive therapy decreases striatal dopamine transporter binding in patients with depression: a positron emission tomography study with [(18)F]FE-PE2I. Psychiatry Res Neuroimaging 301:111086

    Article  PubMed  Google Scholar 

  68. Saijo T, Takano A, Suhara T, Arakawa R, Okumura M, Ichimiya T et al (2010) Effect of electroconvulsive therapy on 5-HT1A receptor binding in patients with depression: a PET study with [11C]WAY 100635. Int J Neuropsychopharmacol 13(6):785–791

    Article  CAS  PubMed  Google Scholar 

  69. Lanzenberger R, Baldinger P, Hahn A, Ungersboeck J, Mitterhauser M, Winkler D et al (2013) Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET. Mol Psychiatry 18(1):93–100

    Article  CAS  PubMed  Google Scholar 

  70. Yatham LN, Liddle PF, Lam RW, Zis AP, Stoessl AJ, Sossi V et al (2010) Effect of electroconvulsive therapy on brain 5-HT(2) receptors in major depression. Br J Psychiatry 196(6):474–479

    Article  PubMed  Google Scholar 

  71. Karlsson H, Hirvonen J, Kajander J, Markkula J, Rasi-Hakala H, Salminen JK et al (2010) Research letter: psychotherapy increases brain serotonin 5-HT1A receptors in patients with major depressive disorder. Psychol Med 40(3):523–528

    Article  CAS  PubMed  Google Scholar 

  72. Svenningsson P, Berg L, Matthews D, Ionescu DF, Richards EM, Niciu MJ et al (2014) Preliminary evidence that early reduction in p11 levels in natural killer cells and monocytes predicts the likelihood of antidepressant response to chronic citalopram. Mol Psychiatry 19(9):962–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Plaven-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD et al (2018) Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data. Biol Psychiatry 84(6):433–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Psychiatry Research, Department of Clinical Neuroscience, Region Stockholm and Karolinska Institutet, Stockholm, Sweden

    Mikael Tiger & Johan Lundberg

Authors
  1. Mikael Tiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johan Lundberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johan Lundberg .

Editor information

Editors and Affiliations

  1. Department of Psychiatry, Korea University Ansan Hospital, Ansan, Korea (Republic of)

    Yong-Ku Kim

  2. Deptartment of Speech Therapy, Isfahan University of Medical Sciences, Isfahan, Iran

    Meysam Amidfar

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Tiger, M., Lundberg, J. (2022). Molecular Imaging of Major Depressive Disorder with Positron Emission Tomography: Translational Implications for Neurobiology and Treatment. In: Kim, YK., Amidfar, M. (eds) Translational Research Methods for Major Depressive Disorder. Neuromethods, vol 179. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2083-0_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-2083-0_11

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2082-3

  • Online ISBN: 978-1-0716-2083-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation