Skip to main content
SpringerLink
Log in

Safety, pharmacokinetic, and positron emission tomography evaluation of serotonin and dopamine transporter occupancy following multiple-dose administration of the triple monoamine reuptake inhibitor BMS-820836

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.

Objective

This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [11C]MADAM or [11C]PE2I, respectively.

Methods

Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1–4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4–8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions.

Results

Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0–5.5 h post-dose; estimated elimination half-life was 44–74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose.

Conclusions

Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Argyelan M, Szabo Z, Kanyo B, Tanacs A, Kovacs Z, Janka Z, Pavics L (2005) Dopamine transporter availability in medication free and in bupropion treated depression: a 99mTc-TRODAT-1 SPECT study. J Affect Disord 89:115–123

    Article  CAS  PubMed  Google Scholar 

  • Bodkin JA, Lasser RA, Wines JD Jr, Gardner DM, Baldessarini RJ (1997) Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatry 58:137–145

    Article  CAS  PubMed  Google Scholar 

  • Chalon S, Garreau L, Emond P, Zimmer L, Vilar MP, Besnard JC, Guilloteau D (1999) Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl) nortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J Pharmacol Exp Ther 291:648–654

    CAS  PubMed  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 

  • Comley RA, Salinas CA, Slifstein M, Petrone M, Marzano C, Bennacef I, Shotbolt P, Van der AJ, Neve M, Iavarone L, Gomeni R, Laruelle M, Gray FA, Gunn RN, Rabiner EA (2013) Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography. J Pharmacol Exp Ther 346:311–317

    Article  CAS  PubMed  Google Scholar 

  • Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A, Beyenburg S (2004) "Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry 65:1064–1068

    Article  CAS  PubMed  Google Scholar 

  • DeLorenzo C, Lichenstein S, Schaefer K, Dunn J, Marshall R, Organisak L, Kharidia J, Robertson B, Mann JJ, Parsey RV (2011) SEP-225289 serotonin and dopamine transporter occupancy: a PET study. J Nucl Med 52:1150–1155

    Article  PubMed  Google Scholar 

  • Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337

    Article  CAS  PubMed  Google Scholar 

  • Emond P, Garreau L, Chalon S, Boazi M, Caillet M, Bricard J, Frangin Y, Mauclaire L, Besnard JC, Guilloteau D (1997) Synthesis and ligand binding of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4′-iodophenyl)nortropane and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3′,4′-disubstituted phenyl)nortropane. New high-affinity and selective compounds for the dopamine transporter. J Med Chem 40:1366–1372

    Article  CAS  PubMed  Google Scholar 

  • Fava M (2003) Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 53:649–659

    Article  PubMed  Google Scholar 

  • Garlow SJ, Nemeroff CB (2004) The neurochemistry of depressive disorders: clinical studies. In: Charney DS, Nestler EJ (eds) Neurobiology of mental illness, 2nd edn. Oxford University Press, New York, pp 440–460

    Google Scholar 

  • Gough K, Hutchison M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J (1995) Assessment of dose proportionality: report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party. Drug Inf J 29:1039–1048

    Google Scholar 

  • Guilloteau D, Emond P, Baulieu JL, Garreau L, Frangin Y, Pourcelot L, Mauclaire L, Besnard JC, Chalon S (1998) Exploration of the dopamine transporter: in vitro and in vivo characterization of a high-affinity and high-specificity iodinated tropane derivative (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl)nortropane (PE2I). Nucl Med Biol 25:331–337

    Article  CAS  PubMed  Google Scholar 

  • Hall H, Halldin C, Guilloteau D, Chalon S, Emond P, Besnard J, Farde L, Sedvall G (1999) Visualization of the dopamine transporter in the human brain postmortem with the new selective ligand [125I]PE2I. Neuroimage 9:108–116

    Article  CAS  PubMed  Google Scholar 

  • Halldin C, Erixon-Lindroth N, Pauli S, Chou YH, Okubo Y, Karlsson P, Lundkvist C, Olsson H, Guilloteau D, Emond P, Farde L (2003) [(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain. Eur J Nucl Med Mol Imaging 30:1220–1230

    Article  CAS  PubMed  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) [(11)C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET. Synapse 58:173–183

    Article  CAS  PubMed  Google Scholar 

  • Hirschfeld RM, Montgomery SA, Aguglia E, Amore M, Delgado PL, Gastpar M, Hawley C, Kasper S, Linden M, Massana J, Mendlewicz J, Moller HJ, Nemeroff CB, Saiz J, Such P, Torta R, Versiani M (2002) Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry 63:826–837

    Article  CAS  PubMed  Google Scholar 

  • Hirvonen J, Johansson J, Teras M, Oikonen V, Lumme V, Virsu P, Roivainen A, Nagren K, Halldin C, Farde L, Hietala J (2008) Measurement of striatal and extrastriatal dopamine transporter binding with high-resolution PET and [11C]PE2I: quantitative modeling and test-retest reproducibility. J Cereb Blood Flow Metab 28:1059–1069

    Article  CAS  PubMed  Google Scholar 

  • James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL (2010) Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 363:905–917

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lane RM (1998) SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. J Psychopharmacol 12:192–214

    Article  CAS  PubMed  Google Scholar 

  • Larsen AK, Brennum LT, Egebjerg J, Sanchez C, Halldin C, Andersen PH (2004) Selectivity of (3)H-MADAM binding to 5-hydroxytryptamine transporters in vitro and in vivo in mice; correlation with behavioural effects. Br J Pharmacol 141:1015–1023

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lavretsky H, Kim MD, Kumar A, Reynolds CF III (2003) Combined treatment with methylphenidate and citalopram for accelerated response in the elderly: an open trial. J Clin Psychiatry 64:1410–1414

    Article  CAS  PubMed  Google Scholar 

  • Learned-Coughlin SM, Bergstrom M, Savitcheva I, Ascher J, Schmith VD, Langstrom B (2003) In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry 54:800–805

    Article  CAS  PubMed  Google Scholar 

  • Li Y-W, Lelas S, Liu S, Raybon J, Pieschl R, Langdon S, Orie A, Wright R, Molski T, Lodge N, Molino B, Sinz M, Adams S, Olson R, Macor J, Sargent B, Houston J, Zaczek R (2012) Preclinical pharmacological characterization of BMS-820836, a novel triple monoamine reuptake inhibitor. Biol Psychiatry 71:299S

    Google Scholar 

  • Lundberg J, Odano I, Olsson H, Halldin C, Farde L (2005) Quantification of 11C-MADAM binding to the serotonin transporter in the human brain. J Nucl Med 46:1505–1515

    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 

  • Marshall RD, Liebowitz MR (1996) Paroxetine/bupropion combination treatment for refractory depression. J Clin Psychopharmacol 16:80–81

    Article  CAS  PubMed  Google Scholar 

  • Meyer JH (2007) Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 32:86–102

    PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Meyer JH, Goulding VS, Wilson AA, Hussey D, Christensen BK, Houle S (2002) Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology (Berl) 163:102–105

    Article  CAS  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 

  • Millan MJ (2009) Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs. Neurotherapeutics 6:53–77

    Article  CAS  PubMed  Google Scholar 

  • Morelli E, Moore H, Rebello TJ, Gray N, Steele K, Esposito E, Gingrich JA, Ansorge MS (2011) Chronic 5-HT transporter blockade reduces DA signaling to elicit basal ganglia dysfunction. J Neurosci 31:15742–15750

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nemeroff CB (2007) Prevalence and management of treatment-resistant depression. J Clin Psychiatry 68(Suppl 8):17–25

    CAS  PubMed  Google Scholar 

  • Nikolaus S, Hautzel H, Heinzel A, Muller HW (2012) Key players in major and bipolar depression—a retrospective analysis of in vivo imaging studies. Behav Brain Res 232:358–390

    Article  PubMed  Google Scholar 

  • Risinger R, Bhagwagar Z, Luo F, Cahir M, Miler L, Mendonza A, Meyer JH, Zheng M, Hayes W (2014) Evaluation of safety and tolerability, pharmacokinetics and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled, ascending single-dose study. Psychopharmacology 231:2299–2310

  • Tarkiainen J, Vercouillie J, Emond P, Sandell J, Hiltunen J, Frangin Y, Guilloteau D, Halldin C (2001) Carbon-11 labelling of MADAM in two different positions: a highly selective PET radioligand for the serotonin transporter. J Labelled Comp Radiopharm 44:1013–1023

    Article  CAS  Google Scholar 

  • Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ (2006a) Medication augmentation after the failure of SSRIs for depression. N Engl J Med 354:1243–1252

    Article  CAS  PubMed  Google Scholar 

  • Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M (2006b) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40

    Article  PubMed  Google Scholar 

  • Voineskos AN, Wilson AA, Boovariwala A, Sagrati S, Houle S, Rusjan P, Sokolov S, Spencer EP, Ginovart N, Meyer JH (2007) Serotonin transporter occupancy of high-dose selective serotonin reuptake inhibitors during major depressive disorder measured with [11C]DASB positron emission tomography. Psychopharmacology (Berl) 193:539–545

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The current staff at the PET Centre, as well as the former staff at GE Healthcare Uppsala Imanet and Quintiles AB (Phase I), Uppsala, Sweden, are acknowledged for their various contributions related to this study. Special thanks to Wolfgang Kühn, MD, and Jakob Björk, PhD, Quintiles AB, Uppsala, Sweden, for their contributions as principal investigator and project manager, respectively. The authors are grateful to Brian Atkinson, PhD, a former employee of Bristol-Myers Squibb, for providing writing and editorial support.

Author information

Authors and Affiliations

  1. Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, 08534, USA

    Ming Zheng, Feng Luo, Robert Risinger, Matthew Cahir, Sanjay Keswani & Wendy Hayes

  2. PET Centre, Department of Medical Imaging, Uppsala University Hospital, 751 85, Uppsala, Sweden

    Lieuwe Appel & Gunnar Antoni

  3. Section of Nuclear Medicine and PET, Department of Radiology, Oncology and Radiation Sciences, Uppsala University, 751 85, Uppsala, Sweden

    Lieuwe Appel

  4. Global Clinical Research, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, 06492, USA

    Roger Lane & Zubin Bhagwagar

  5. Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, 08534, USA

    David Burt

  6. Department of Psychiatry, Yale University, New Haven, CT, 06511, USA

    Zubin Bhagwagar

Authors
  1. Ming Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lieuwe Appel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roger Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Burt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert Risinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gunnar Antoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matthew Cahir
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sanjay Keswani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wendy Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zubin Bhagwagar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming Zheng.

Additional information

Drs. M. Zheng and L. Appel contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 661 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, M., Appel, L., Luo, F. et al. Safety, pharmacokinetic, and positron emission tomography evaluation of serotonin and dopamine transporter occupancy following multiple-dose administration of the triple monoamine reuptake inhibitor BMS-820836. Psychopharmacology 232, 529–540 (2015). https://doi.org/10.1007/s00213-014-3688-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3688-x

Keywords

Search

Navigation