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Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR

  • Svante Nyberg (a1) (a2), Aurelija Jucaite (a1), Akihiro Takano (a2), Matts Kågedal (a1), Zsolt Cselényi (a1), Christer Halldin (a2) and Lars Farde (a1) (a2)
  • DOI:
  • Published online: 01 July 2013

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[18F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6–8 d in nine healthy males (aged 21–33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.

Corresponding author
Address for correspondence: Dr S. Nyberg, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Tel.: +46 732 67 07 14Fax: +46 (8) 5177 17
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R Arakawa , M Okumura , H Ito , C Seki , H Takahashi , H Takano , R Nakao , K Suzuki , Y Okubo , C Halldin , T Suhara (2008) Quantitative analysis of norepinephrine transporter in the human brain using PET with (S,S)-18F-FMeNER-D2. J Nucl Med 49:12701276.

C Arango , J Bobes (2004) Managing acute exacerbations of schizophrenia: focus on quetiapine. Curr Med Res Opin 20:619626.

M Bauer , HW Pretorius , EL Constant , WR Earley , J Szamosi , M Brecher (2009) Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. J Clin Psychiatry 70:540549.

M Bauer , N El-Khalili , C Datto , J Szamosi , H Eriksson (2010) A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J Affect Disord 127:1930.

M Bergström , J Boethius , L Eriksson , T Greitz , T Ribbe , L Widen (1981) Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 5:136141.

A Bond , M Lader (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211218.

B Bortnick , N El-Khalili , M Banov , D Adson , C Datto , S Raines , W Earley , H Eriksson (2011) Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: a placebo-controlled, randomized study. J Affect Disord 128:8394.

PF Buckley (2004) Efficacy of quetiapine for the treatment of schizophrenia: a combined analysis of three placebo-controlled trials. Curr Med Res Opin 20:13571363.

A Chiesa , F Chierzi , RD De , A Serretti (2012) Quetiapine for bipolar depression: a systematic review and meta-analysis. Int Clin Psychopharmacol 27:7690.

AJ Cutler , SA Montgomery , D Feifel , A Lazarus , M Astrom , M Brecher (2009) Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study. J Clin Psychiatry 70:526539.

PC Davis , O Bravo , M Gehrke , CT Azumaya (2010) Development and validation of an LC-MS/MS method for the determination of quetiapine and four related metabolites in human plasma. J Pharm Biomed Anal 51:11131119.

JD Deupree , MD Montgomery , DB Bylund (2007) Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram. Eur J Pharmacol 576:5560.

CL DeVane , CB Nemeroff (2001) Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet 40:509522.

N El-Khalili , M Joyce , S Atkinson , RJ Buynak , C Datto , P Lindgren , H Eriksson (2010) Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol 13:917932.

L Farde , AL Nordstrom , FA Wiesel , S Pauli , C Halldin , G Sedvall (1992) Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 49:538544.

C Figueroa , M Brecher , JE Hamer-Maansson , H Winter (2009) Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release. Prog Neuropsychopharmacol Biol Psychiatry 33:199204.

S Ghose , M Fujita , P Morrison , G Uhl , DL Murphy , PD Mozley , M Schou , C Halldin , R Innis (2005) Specific in vitro binding of (S,S)-[3H]MeNER to norepinephrine transporters. Synapse 56:100104.

JM Goldstein (1999) Quetiapine fumarate (seroquel): a new atypical antipsychotic. Drugs Today (Barc) 35:193210.

NH Jensen , RM Rodriguiz , MG Caron , WC Wetsel , RB Rothman , BL Roth (2008) N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity. Neuropsychopharmacology 33:23032312.

S Kapur , R Zipursky , C Jones , G Remington , S Houle (2000a) Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157:514520.

S Kapur , R Zipursky , C Jones , CS Shammi , G Remington , P Seeman (2000b) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57:553559.

H Katila , I Mezhebovsky , A Mulroy , L Berggren , H Eriksson , W Earley , C Datto (2012) Randomized, double-blind study of the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder. Am J Geriatr Psychiatry. Advance online publication. doi:10.1097/JGP.0b013e3182545e50.

M Liebowitz , RW Lam , U Lepola , C Datto , D Sweitzer , H Eriksson (2010) Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Depress Anxiety 27:964976.

L Linner , C Wiker , ML Wadenberg , M Schalling , TH Svensson (2002) Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat. Neuropsychopharmacology 27:691698.

RS McIntyre , JZ Konarski , M Jones , B Paulsson (2007) Quetiapine in the treatment of acute bipolar mania: efficacy across a broad range of symptoms. J Affect Disord 100(Suppl. 1):S5S14.

D Mamo , S Kapur , CM Shammi , G Papatheodorou , S Mann , F Therrien , G Remington (2004) A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry 161:818825.

DC Mamo , H Uchida , I Vitcu , P Barsoum , A Gendron , J Goldstein , S Kapur (2008) Quetiapine extended-release vs. immediate-release formulation: a positron emission tomography study. J Clin Psychiatry 69:8186.

MM Marcus , K Jardemark , A Malmerfelt , C Bjorkholm , TH Svensson (2010) Reboxetine enhances the olanzapine-induced antipsychotic-like effect, cortical dopamine outflow and NMDA receptor-mediated transmission. Neuropsychopharmacology 35:19521961.

G Nikisch , P Baumann , G Wiedemann , B Kiessling , H Weisser , A Hertel , T Yoshitake , J Kehr , AA Mathe (2010) Quetiapine and norquetiapine in plasma and cerebrospinal fluid of schizophrenic patients treated with quetiapine: correlations to clinical outcome and HVA, 5-HIAA, and MHPG in CSF. J Clin Psychopharmacol 30:496503.

M Nord , L Farde (2011) Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther 17:97103.

M Nord , S Nyberg , J Brogren , A Jucaite , C Halldin , L Farde (2011) Comparison of D(2) dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects. Int J Neuropsychopharmacol 14:13571366.

S Nyberg , L Farde , C Halldin , ML Dahl , L Bertilsson (2007) PET-measured D2, 5-HT2, and norepinephrine transporter (NET) occupancy by quetiapine and N-desalkyl-quetiapine in non-human primates [abstract]. Eur Neuropsychopharmacol 17(Suppl. 4):S254S255. Abstract P.1.c.022.

H Olsson , L Farde (2001) Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy – a simulation study based on experimental data. Neuroimage 14, 936945.

M Sanford (2011) Quetiapine extended release: adjunctive treatment in major depressive disorder. CNS Drugs 25:803813.

M Schou , C Halldin , J Sovago , VW Pike , H Hall , B Gulyas , PD Mozley , D Dobson , E Shchukin , RB Innis , L Farde (2004) PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain. Synapse 53:5767.

M Schou , C Halldin , VW Pike , PD Mozley , D Dobson , RB Innis , L Farde , H Hall (2005) Post-mortem human brain autoradiography of the norepinephrine transporter using (S,S)-[18F]FMeNER-D2. Eur Neuropsychopharmacol 15:517520.

M Sekine , R Arakawa , H Ito , M Okumura , T Sasaki , H Takahashi , H Takano , Y Okubo , C Halldin , T Suhara (2010) Norepinephrine transporter occupancy by antidepressant in human brain using positron emission tomography with (S,S)-[18F]FMeNER-D2. Psychopharmacology (Berl) 210:331336.

N Seneca , B Andree , N Sjoholm , M Schou , S Pauli , PD Mozley , JB Stubbs , JS Liow , J Sovago , B Gulyas , R Innis , C Halldin (2005) Whole-body biodistribution, radiation dosimetry estimates for the PET norepinephrine transporter probe (S,S)-[18F]FMeNER-D2 in non-human primates. Nucl Med Commun 26:695700.

N Seneca , B Gulyas , A Varrone , M Schou , A Airaksinen , J Tauscher , F Vandenhende , W Kielbasa , L Farde , RB Innis , C Halldin (2006) Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2. Psychopharmacology (Berl) 188:119127.

T Suppes , C Datto , M Minkwitz , A Nordenhem , C Walker , D Darko (2010) Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord 121:106115.

A Takano , B Gulyas , A Varrone , P Karlsson , M Schou , AJ Airaksinen , F Vandenhende , J Tauscher , C Halldin (2008a) Imaging the norepinephrine transporter with positron emission tomography: initial human studies with (S,S)-[18F]FMeNER-D2. Eur J Nucl Med Mol Imaging 35:153157.

A Takano , A Varrone , B Gulyas , P Karlsson , J Tauscher , C Halldin (2008b) Mapping of the norepinephrine transporter in the human brain using PET with (S,S)-[18F]FMeNER-D2. Neuroimage 42:474482.

A Takano , S Nag , B Gulyas , C Halldin , L Farde (2011) NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo. Psychopharmacology (Berl) 216:279286.

A Takano , C Halldin , L Farde (2012) SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study. Psychopharmacology (Berl) 226:147153.

R Weisler , M Joyce , L McGill , A Lazarus , J Szamosi , H Eriksson (2009) Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study. CNS Spectr 14:299313.

HR Winter , WR Earley , JE Hamer-Maansson , PC Davis , MA Smith (2008) Steady-state pharmacokinetic, safety, and tolerability profiles of quetiapine, norquetiapine, and other quetiapine metabolites in pediatric and adult patients with psychotic disorders. J Child Adolesc Psychopharmacol 18:8198.

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