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Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study

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Abstract

Rationale

To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo 123I-ADAM SPECT.

Objectives

123I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc.

Materials and methods

Measures of SERT availability by means of 123I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day. 123I-ADAM SPECT measures of SERT availability from a group of ten previously studied age-matched healthy volunteers were used for comparison. The relationship between percentages of SERTocc and paroxetine Cp was studied using an E max model.

Results

Mean SERTocc values were 66.4 ± 9.5% in midbrain, 63.0 ± 9.6% in thalamus, and 61.3 ± 10.9% in striatum. No significant differences in SERTocc were found among these three regions. No significant differences in mean SERT availability were found in any region between drug-free MDD patients (midbrain = 1.14 ± 0.15; thalamus = 0.85 ± 0.13; striatum = 0.70 ± 0.07) and healthy volunteers (midbrain = 1.19 ± 0.22; thalamus = 0.96 ± 0.14; striatum = 0.67 ± 0.15). The E max model returned a SERToccmax = 70.5% and a Cp50 = 2.7 ng/ml.

Conclusions

Using 123I-ADAM SPECT, treatment with paroxetine 20 mg/day leads to more than 60% SERTocc on average in cerebral regions with known high SERT density. Data from this study do not support the existence of SERT availability differences between drug-free MDD patients and healthy volunteers. Finally, the E max model is suitable for the study of paroxetine Cp relationship to 123I-ADAM SPECT-measured SERTocc. This approach may be useful for pharmacokinetic–pharmacodynamic relationships in drug development.

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References

  • Ahonen A, Heikman P, Kauppinen T, Koskela A, Bergström K (2004) Serotonin transporter availability in drug free depression patients using a novel SERT ligand. Eur J Nucl Med 31:S227

    Google Scholar 

  • Brett MA, Dierdorf HD, Zussman BD, Coates PE (1987) Determination of paroxetine in human plasma, using high-performance liquid chromatography with fluorescence detection. J Chromatogr 419:438–444

    PubMed  CAS  Google Scholar 

  • Catafau AM, Pérez V, Penengo MM, Bullich S, Danús M, Puigdemont D, Pascual JC, Corripio I, Llop J, Perich J, Álvarez E (2005) SPECT of serotonin transporters using 123I-ADAM: optimal imaging time after bolus injection and long-term test–retest in healthy volunteers. J Nucl Med 46:1301–1309

    PubMed  CAS  Google Scholar 

  • Cavanagh J, Patterson J, Pimlott S, Dewar D, Eersels J, Dempsey MF, Wyper D (2006) Serotonin transporter residual availability during long-term antidepressant therapy does not differentiate responder and nonresponder unipolar patients. Biol Psychiatry 59:301–308

    Article  PubMed  CAS  Google Scholar 

  • Dahlstrom M, Ahonen A, Ebeling H, Torniainen P, Heikkila J, Moilanen I (2000) Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents. Mol Psychiatry 5:514–522

    Article  PubMed  CAS  Google Scholar 

  • Dresel S, Mager T, Rossmüller B, Meisenzahl E, Hahn K, Möller H-J, Tatsch K (1999) In vivo effects of olanzapine on striatal dopamine D2/D3 receptor binding in schizophrenic patients: an iodine-123 iodobenzamide single-photon emission tomography study. Eur J Nucl Med 26:862–868

    Article  PubMed  CAS  Google Scholar 

  • Erlandsson K, Sivananthan T, Lui D, Spezzi A, Townsend CE, Mu S, Lucas R, Warrington S, Ell PJ (2005) Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM: a SPECT validation study. Eur J Nucl Med Mol Imaging 32:1329–1336

    Article  PubMed  CAS  Google Scholar 

  • Figueras G, Pérez V, San Martino O, Álvarez E, Grupo de Trastornos Afectivos, Artigas F (1999) Pretreatment platelet 5-HT concentration predicts the short-term response to paroxetine in major depression. Biol Psychiatry 46:518–524

    Article  PubMed  CAS  Google Scholar 

  • Gefvert O, Bergström M, Långström B, Lundberg T, Lindström L, Yates R (1998) Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel®) in patients with schizophrenia. Psychopharmacology 135:119–126

    Article  PubMed  CAS  Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    Article  PubMed  CAS  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(5):659–670

    Article  PubMed  CAS  Google Scholar 

  • Ichimiya T, Suhara T, Sudo Y, Okubo Y, Nakayama K, Nankai M, Inoue M, Yasuno F, Takano A, Maeda J, Shibuya H (2002) Serotonin transporter binding in patients with mood disorders: a PET study with [11C](+)McN5652. Biol Psychiatry 51:715–722

    Article  PubMed  CAS  Google Scholar 

  • Kapur S, Zipursky RB, Remington G (1999) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone and olanzapine in schizophrenia. Am J Psychiatry 156:286–293

    PubMed  CAS  Google Scholar 

  • Knable MB, Heinz A, Raedler T, Weinberger DR (1997) Extrapyramidal side effects with risperidone and haloperidol at comparable D2 receptor occupancy levels. Psychiatry Res 75:91–101

    PubMed  CAS  Google Scholar 

  • Kent JM, Coplan JD, Lombardo I, Hwang D, 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 164:341–348

    Article  PubMed  CAS  Google Scholar 

  • Kugaya A, Sanacora G, Staley JK, Malison RT, Bozkurt A, Khan S, Anand A, Van Dyck CH, Baldwin RM, Seibyl JP, Charney D, Innis RB (2004) Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors. Biol Psychiatry 56:497–502

    Article  PubMed  CAS  Google Scholar 

  • Laruelle M, Baldwin RM, Malisson RT, Zea-Ponce Y, Zoghbi SS, al-Tikriti MS, Sybirska EH (1993) SPECT imaging of dopamine and serotonin transporter with 123I-β-CIT pharmacological characterization of brain uptake in nonhuman primates. Synapse 13(4):295–309

    Article  PubMed  CAS  Google Scholar 

  • Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G, Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS (1998) Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 44(11):1090–1098

    Article  PubMed  CAS  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 [11C]DASB PET imaging study. Am J Psychiatry 158:1843–1849

    Article  PubMed  CAS  Google Scholar 

  • Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004a) 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 

  • Meyer JH, Houle S, Sagrati S, Carella A, Hussey D, Ginovart N, Goulding V, Kennedy J, Wilson AA (2004b) Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61:1271–1279

    Article  PubMed  CAS  Google Scholar 

  • Newberg AB, Amsterdam JD, Wintering N, Ploessl K, Swanson RL, Shults J, Alavi A (2005) 123I-ADAM binding to serotonin transporters in patients with major depression and healthy controls: a preliminary study. J Nucl Med 46:973–977

    PubMed  CAS  Google Scholar 

  • Nyberg S, Chou YH, Halldin C (2002) Saturation of striatal D2 dopamine receptors by clozapine. Int J Neuropsychopharmacol 5(1):6–11

    Article  PubMed  CAS  Google Scholar 

  • Normann C, Horn M, Hummel B, Grunze H, Walden J (2004) Paroxetine in major depression correlating plasma concentration and clinical response. Pharmacopsychiatry 37(3):123–126

    Article  PubMed  CAS  Google Scholar 

  • Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295

    PubMed  CAS  Google Scholar 

  • Parsey RV, Hastings RS, Oquendo MA, Huang Y, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ (2006) Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry 163:52–58

    Article  PubMed  Google Scholar 

  • Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G, Pozzera A, Deecke L, Podreka I, Brücke T (1995) β-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo. J Neural Transm 100:247–256

    Article  CAS  Google Scholar 

  • Rits (1964) Declaration of Helsinki. Recommendations guiding doctors in clinical research. World Med J 11:281

    PubMed  CAS  Google Scholar 

  • Staley JK, Sanacora G, Tamagnan G, Maciejewski PK, Malison RT, Berman RM, Vythilingam M, Kugaya A, Baldwin RM, Seibyl JP, Charney D, Innis RB (2005) Sex differences in diencephalons serotonin transporter availability in major depression. Biol Psychiatry 59:40–47

    Article  PubMed  CAS  Google Scholar 

  • Stockmeier CA (2003) Involvement of serotonin in depression: evidence from post-mortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 37:357–373

    Article  PubMed  Google Scholar 

  • Talvik M, Nordström A-L, Larsen N-E, Jucaite A, Cervenka S, Halldin C, Farde L (2004) A cross-validation study on the relationship between central D2 receptor occupancy and serum perphenazine concentration. Psychopharmacology 175:148–153

    Article  PubMed  CAS  Google Scholar 

  • Tauscher J, Küfferle B, Asenbaum S, Fischer P, Pezawas L, Barnas C, Tauscher-Wisniewski S, Brücke T, Kasper S (1999a) In vivo 123I IBZM SPECT imaging of striatal dopamine-2 receptor occupancy in schizophrenic patients treated with olanzapine in comparison to clozapine and haloperidol. Psychopharmacology 141:175–181

    Article  PubMed  CAS  Google Scholar 

  • Tauscher J, Pirker W, De Zwaan M, Asenbaum S, Brücke T, Kasper S (1999b) In vivo visualization of serotonin transporters in the human brain during fluoxetine treatment. Eur Neuropsychopharmacol 9:177–179

    Article  PubMed  CAS  Google Scholar 

  • Williams RB (1994) Neurobiology, cellular and molecular biology, and psychosomatic medicine. Psychosom Med 56:308–315

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Vincent J. Cunningham and Roger N. Gunn for the useful discussions, Kim Bergstrom for the appropriate 123I-ADAM availability, Nuria Merino for the technical assistance, Joaquim Soler for his contribution with patient recruitment, and all the patients who participated in this study. This study was funded by Marató TV3 exp. 011410 and supported by the Psychiatry Centre of Excellence for Drug Discovery (Psychiatry CEDD), GlaxoSmithKline.

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Authors and Affiliations

  1. Experimental Medicine, Clinical Pharmacology Discovery Medicine, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Torre Mapfre. Villa olimpica, La Marina, 16–18, Pl. 9 B y C, 08005, Barcelona, Spain

    Ana M. Catafau

  2. Centre for Imaging in Psychiatry, CRC-Mar, Hospital del Mar, Barcelona, Spain

    Ana M. Catafau, Pedro Plaza, Santiago Bullich, Marina Suarez, Maria M. Penengo & Monica Danus

  3. Psychiatry Department, Hospital Sant Pau, Barcelona, Spain

    Victor Perez, Juan-Carlos Pascual, Iluminada Corripio, Dolors Puigdemont & Enric Alvarez

  4. Magnetic Resonance Department, CRC-MAR, Hospital del Mar, Barcelona, Spain

    Javier Perich

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  1. Ana M. Catafau
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  2. Victor Perez
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  3. Pedro Plaza
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  4. Juan-Carlos Pascual
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  5. Santiago Bullich
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  10. Monica Danus
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  11. Javier Perich
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  12. Enric Alvarez
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Correspondence to Ana M. Catafau.

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Catafau, A.M., Perez, V., Plaza, P. et al. Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study. Psychopharmacology 189, 145–153 (2006). https://doi.org/10.1007/s00213-006-0540-y

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  • DOI: https://doi.org/10.1007/s00213-006-0540-y

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