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Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

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Abstract

Rationale

A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment.

Objectives

The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [11C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved.

Results

Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans.

Conclusions

Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

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References

  • Adell A, Artigas F (1991) Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo brain microdialysis study. Naunyn Schmiedeberg’s Arch Pharmacol 343:237–244

    Article  CAS  Google Scholar 

  • Andree B, Nyberg S, Ito H, Ginovart N, Brunner F, Jaquet F, Halldin C, Farde L (1998) Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain. J Clin Psychopharmacol 18:317–323

    Article  CAS  PubMed  Google Scholar 

  • Artigas F (1993) 5-HT and antidepressants: new views from microdialysis studies. Trends Pharmacol Sci 14:262

    Article  CAS  PubMed  Google Scholar 

  • Baldinger P, Kranz GS, Haeusler D, Savli M, Spies M, Philippe C, Hahn A, Hoflich A, Wadsak W, Mitterhauser M, Lanzenberger R, Kasper S (2014) Regional differences in SERT occupancy after acute and prolonged SSRI intake investigated by brain PET. Neuroimage 88:252–262

    Article  CAS  PubMed  Google Scholar 

  • Batis J, Barret O, Alagille D, Koren AO, Stehouwer JS, Cosgrove K, Goodman M, Seibyl J, Tamagnan G (2012) In vivo evaluation of [123I]mZIENT as a SPECT radioligand for the serotonin transporter. Nucl Med Biol 39:1137–1141

    Article  CAS  PubMed  Google Scholar 

  • Bel N, Artigas F (1992) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur J Pharmacol 229:101–103

    Article  CAS  PubMed  Google Scholar 

  • Catafau AM, Perez V, Plaza P, Pascual JC, Bullich S, Suarez M, Penengo MM, Corripio I, Puigdemont D, Danus M, Perich J, Alvarez E (2006) Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study. Psychopharmacology (Berlin) 189:145–153

    Article  CAS  Google Scholar 

  • Chalon S, Tarkiainen J, Garreau L, Hall H, Emond P, Vercouillie J, Farde L, Dasse P, Varnas K, Besnard JC, Halldin C, Guilloteau D (2003) Pharmacological characterization of N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a ligand of the serotonin transporter with high affinity and selectivity. J Pharmacol Exp Ther 304:81–87

    Article  CAS  PubMed  Google Scholar 

  • Cosgrove KP, Staley JK, Baldwin RM, Bois F, Plisson C, Al-Tikriti MS, Seibyl JP, Goodman MM, Tamagnan GD (2010) SPECT imaging with the serotonin transporter radiotracer [123I]p ZIENT in nonhuman primate brain. Nucl Med Biol 37:587–591

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cosgrove KP, Kloczynski T, Nabulsi N, Weinzimmer D, Lin SF, Staley JK, Bhagwagar Z, Carson RE (2011) Assessing the sensitivity of [11C]p943, a novel 5-HT1B radioligand, to endogenous serotonin release. Synapse 65:1113–1117

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Elfving B, Bjornholm B, Knudsen GM (2003) Interference of anaesthetics with radioligand binding in neuroreceptor studies. Eur J Nucl Med Mol Imaging 30:912–915

    Article  CAS  PubMed  Google Scholar 

  • Elfving B, Madsen J, Knudsen GM (2007) Neuroimaging of the serotonin reuptake site requires high-affinity ligands. Synapse 61:882–888

    Article  CAS  PubMed  Google Scholar 

  • Erichsen MN, Huynh TH, Abrahamsen B, Bastlund JF, Bundgaard C, Monrad O, Bekker-Jensen A, Nielsen CW, Frydenvang K, Jensen AA, Bunch L (2010) Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chrom ene-3-carbonitrile (UCPH-101). J Med Chem 53:7180–7191

    Article  CAS  PubMed  Google Scholar 

  • Farde L, Wiesel FA, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76

    Article  CAS  PubMed  Google Scholar 

  • Farde L, Wiesel FA, Nordstrom AL, Sedvall G (1989) D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology (Berlin) 99:S28–31

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Finnema SJ, Varrone A, Hwang TJ, Halldin C, Farde L (2012) Confirmation of fenfluramine effect on 5-HT1B receptor binding of [11C]AZ10419369 using an equilibrium approach. J Cereb Blood Flow Metab 32:685–695

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Garber JC, Barbee RW, Bielitzki JT, Clayton LA, Donovan JC, Hendriksen CFM, Kohn DF, Lipman NS, Locker PA, Melcher J, Quimby FW, Turner PV, Wood GA, Wurbel H (2011) Guide for the care and use of laboratory animals. The National Academies Press, Washington DC

    Google Scholar 

  • Halldin C, Lundberg J, Sovago J, Gulyas B, Guilloteau D, Vercouillie J, Emond P, Chalon S, Tarkiainen J, Hiltunen J, Farde L (2005) [11C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET. Synapse 58:173–183

    Article  CAS  PubMed  Google Scholar 

  • Herold N, Uebelhack K, Franke L, Amthauer H, Luedemann L, Bruhn H, Felix R, Uebelhack R, Plotkin M (2006) Imaging of serotonin transporters and its blockade by citalopram in patients with major depression using a novel SPECT ligand [123I]-ADAM. J Neural Transm 113:659–670

    Article  CAS  PubMed  Google Scholar 

  • Hinz R, Selvaraj S, Murthy NV, Bhagwagar Z, Taylor M, Cowen PJ, Grasby PM (2008) Effects of citalopram infusion on the serotonin transporter binding of [11C]DASB in healthy controls. J Cereb Blood Flow Metab 28:1478–1490

    Article  CAS  PubMed  Google Scholar 

  • Invernizzi R, Belli S, Samanin R (1992) Citalopram’s ability to increase the extracellular concentrations of serotonin in the dorsal raphe prevents the drug’s effect in the frontal cortex. Brain Res 584:322–324

    Article  CAS  PubMed  Google Scholar 

  • Jorgensen TN, Christensen PM, Gether U (2014) Serotonin-induced down-regulation of cell surface serotonin transporter. Neurochem Int 73:107–112

    Article  PubMed  Google Scholar 

  • Karlsson P, Farde L, Halldin C, Swahn CG, Sedvall G, Foged C, Hansen KT, Skrumsager B (1993) PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor. Psychopharmacology (Berlin) 113:149–156

    Article  CAS  Google Scholar 

  • Kent JM, Coplan JD, Lombardo I, Hwang DR, Huang Y, Mawlawi O, Van Heertum RL, Slifstein M, Abi-Dargham A, Gorman JM, Laruelle M (2002) Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with 11C McN 5652. Psychopharmacology (Berlin) 164:341–348

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lanzenberger R, Kranz GS, Haeusler D, Akimova E, Savli M, Hahn A, Mitterhauser M, Spindelegger C, Philippe C, Fink M, Wadsak W, Karanikas G, Kasper S (2012) Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas. Neuroimage 63:874–881

    Article  CAS  PubMed  Google Scholar 

  • Lundberg J, Christophersen JS, Petersen KB, Loft H, Halldin C, Farde L (2007) PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram. Int J Neuropsychopharmacol 10:777–785

    Article  CAS  PubMed  Google Scholar 

  • 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 15:1167–1172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Milak MS, Severance AJ, Prabhakaran J, Kumar JS, Majo VJ, Ogden RT, Mann JJ, Parsey RV (2011) In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer. J Cereb Blood Flow Metab 31:243–249

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mukaida K, Shichino T, Koyanagi S, Himukashi S, Fukuda K (2007) Activity of the serotonergic system during isoflurane anesthesia. Anesth Analg 104:836–839

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Nyberg S, Dencker SJ, Malm U, Dahl ML, Svenson JO, Halldin C, Naskashima Y, Farde L (1998) D2- and 5-HT2 receptor occupancy in high-dose neuroleptic-treated patients. Int J Neuropsychopharmacol 1:95–101

    Article  PubMed  Google Scholar 

  • Pinborg LH, Feng L, Haahr ME, Gillings N, Dyssegaard A, Madsen J, Svarer C, Yndgaard S, Kjaer TW, Parsey RV, Hansen HD, Ettrup A, Paulson OB, Knudsen GM (2012) No change in [(1)(1)C]CUMI-101 binding to 5-HT(1A) receptors after intravenous citalopram in human. Synapse 66:880–884

    Article  CAS  PubMed  Google Scholar 

  • Quelch DR, Parker CA, Nutt DJ, Tyacke RJ, Erritzoe D (2012) Influence of different cellular environments on [(3)H]DASB radioligand binding. Synapse 66:1035–1039

    Article  CAS  PubMed  Google Scholar 

  • Rao N (2007) The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet 46:281–290

    Article  CAS  PubMed  Google Scholar 

  • Redrobe JP, Jorgensen M, Christoffersen CT, Montezinho LP, Bastlund JF, Carnerup M, Bundgaard C, Lerdrup L, Plath N (2014) In vitro and in vivo characterisation of Lu AF64280, a novel, brain penetrant phosphodiesterase (PDE) 2A inhibitor: potential relevance to cognitive deficits in schizophrenia. Psychopharmacology (Berlin) 231:3151–3167

    Article  CAS  Google Scholar 

  • Ridler K, Plisson C, Rabiner EA, Gunn RN, Easwaramoorthy B, Abi-Dargham A, Laruelle M, Slifstein M (2011) Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: a positron emission tomography study in Papio anubis. Synapse 65:1119–1127

    Article  CAS  PubMed  Google Scholar 

  • Selvaraj S, Turkheimer F, Rosso L, Faulkner P, Mouchlianitis E, Roiser JP, McGuire P, Cowen PJ, Howes O (2012) Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study. Mol Psychiatry 17:1254–1260

    Article  CAS  PubMed  Google Scholar 

  • Smith GS, Kahn A, Sacher J, Rusjan P, van Eimeren T, Flint A, Wilson AA (2011) Serotonin transporter occupancy and the functional neuroanatomic effects of citalopram in geriatric depression. Am J Geriatr Psychiatr 19:1016–1025

    Article  Google Scholar 

  • Varrone A, Sjoholm N, Eriksson L, Gulyas B, Halldin C, Farde L (2009) Advancement in PET quantification using 3D-OP-OSEM point spread function reconstruction with the HRRT. Eur J Nucl Med Mol Imaging 36:1639–1650

    Article  PubMed  Google Scholar 

  • Yamamoto S, Ohba H, Nishiyama S, Harada N, Kakiuchi T, Tsukada H, Domino EF (2013) Subanesthetic doses of ketamine transiently decrease serotonin transporter activity: a PET study in conscious monkeys. Neuropsychopharmacology 38:2666–2674

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yamanaka H, Yokoyama C, Mizuma H, Kurai S, Finnema SJ, Halldin C, Doi H, Onoe H (2014) A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques. Transl Psychiatry 4, e342

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zeng Z, Chen TB, Miller PJ, Dean D, Tang YS, Sur C, Williams DL Jr (2006) The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites. Nucl Med Biol 33:555–563

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank all the members of the Karolinska Institutet PET group for their assistance and in particular Gudrun Nylén for excellent technical assistance.

Funding

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013). Sjoerd Finnema was partly supported by an International Postdoc grant from the Swedish Research Council.

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Author notes

  1. Sjoerd J. Finnema

    Present address: Department of Diagnostic Radiology, Yale University, New Haven, CT, USA

Authors and Affiliations

  1. Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Building R5:02, SE-17176, Stockholm, Sweden

    Sjoerd J. Finnema, Christer Halldin & Lars Farde

  2. H. Lundbeck A/S, Neuroscience Drug Discovery Denmark, Valby, Denmark

    Benny Bang-Andersen & Christoffer Bundgaard

  3. AstraZeneca, Translational Science Center at Karolinska Institutet, Stockholm, Sweden

    Lars Farde

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  1. Sjoerd J. Finnema
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  2. Christer Halldin
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  5. Lars Farde
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Correspondence to Sjoerd J. Finnema.

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Finnema, S.J., Halldin, C., Bang-Andersen, B. et al. Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study. Psychopharmacology 232, 4159–4167 (2015). https://doi.org/10.1007/s00213-015-3961-7

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  • DOI: https://doi.org/10.1007/s00213-015-3961-7

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