Skip to main content
SpringerLink
Log in

NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo

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

Abstract

Rationale

Norepinephrine transporter (NET) is one of the key targets for antidepressants such as combined serotonin and norepinephrine reuptake inhibitors as well as some of the tricyclic antidepressants. Clomipramine, a tricyclic antidepressant, has been reported to have an active metabolite, desmethylclomipramine, which has high affinity for NET in vitro. However, the NET occupancy of clomipramine and desmethylclomipramine has not fully been evaluated in vivo.

Objectives

In this positron emission tomography (PET) study, we investigate NET occupancy by clomipramine and desmethylclomipramine, respectively, in non-human primates with a selective radioligand for NET, (S,S)-[18F]FMeNER-D2.

Methods

PET measurements were performed with (S,S)-[18F]FMeNER-D2 at baseline and after the intravenous administration of clomipramine and desmethylclomipramine, respectively. NET binding was calculated with the simplified reference tissue model using the caudate as reference region. NET occupancy was calculated as the difference in NET binding between the baseline and pretreatment condition. The relationship between NET occupancy and dose/plasma concentration was evaluated using hyperbolic functions.

Results

NET occupancy by both clomipramine and desmethylclomipramine increased in a dose and plasma concentration-dependent manner. The mean Kd values, expressed as the dose or plasma concentration at which 50% of NET was occupied, were 0.44 mg/kg and 24.5 ng/ml for clomipramine and 0.11 mg/kg and 4.4 ng/ml for desmethylclomipramine.

Conclusions

Not only desmethylclomipramine but also clomipramine was demonstrated to occupy NET in the non-human primate in vivo. It can thus be assumed that NET occupancy during clinical treatment with clomipramine is a combined effect of unchanged clomipramine and its main metabolite desmethylclomipramine.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aitchison K, Datla K, Rooprai H, Fernando J, Dexter D (2009) Regional distribution of clomipramine and desmethylclomipramine in rat brain and peripheral organs on chronic clomipramine administration. J Psychopharmacol 24:1261–1268

    Article  PubMed  Google Scholar 

  • Altemus M, Swedo SE, Leonard HL, Richter D, Rubinow DR, Potter WZ, Rapoport JL (1994) Changes in cerebrospinal fluid neurochemistry during treatment of obsessive-compulsive disorder with clomipramine. Arch Gen Psychiatry 51:794–803

    PubMed  CAS  Google Scholar 

  • Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT (2001) Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 25:871–880

    Article  PubMed  CAS  Google Scholar 

  • Davies MA, Compton-Toth BA, Hufeisen SJ, Meltzer HY, Roth BL (2005) The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine's actions? Psychopharmacology (Berl) 178:451–460

    Article  CAS  Google Scholar 

  • Eriksson E, Westberg P, Alling C, Thuresson K, Modigh K (1991) Cerebrospinal fluid levels of monoamine metabolites in panic disorder. Psychiatry Res 36:243–251

    Article  PubMed  CAS  Google Scholar 

  • Faravelli C, Ballerini A, Ambonetti A, Broadhurst AD, Das M (1984) Plasma levels and clinical response during treatment with clomipramine. J Affect Disord 6:95–107

    Article  PubMed  CAS  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 (Berl) 99:S28–S31

    Article  Google Scholar 

  • Fineberg NA, Gale TM (2005) Evidence-based pharmacotherapy of obsessive-compulsive disorder. Int J Neuropsychopharmacol 8:107–129

    Article  PubMed  CAS  Google Scholar 

  • Gillman PK (2007) Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 151:737–748

    Article  PubMed  CAS  Google Scholar 

  • Giuliano F, Hellstrom WJ (2008) The pharmacological treatment of premature ejaculation. BJU Int 102:668–675

    Article  PubMed  CAS  Google Scholar 

  • Hendset M, Haslemo T, Rudberg I, Refsum H, Molden E (2006) The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs. Pharmacopsychiatry 39:121–127

    Article  PubMed  CAS  Google Scholar 

  • Hyttel J (1982) Citalopram—pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol Biol Psychiatry 6:277–295

    Article  PubMed  CAS  Google Scholar 

  • Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL (2008) N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity. Neuropsychopharmacology 33:2303–2312

    Article  PubMed  CAS  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 (Berl) 113:149–156

    Article  CAS  Google Scholar 

  • Koch S, Hemrick-Luecke SK, Thompson LK, Evans DC, Threlkeld PG, Nelson DL, Perry KW, Bymaster FP (2003) Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats. Neuropharmacology 45:935–944

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Martensson B, Wagner A, Beck O, Brodin K, Montero D, Asberg M (1991) Effects of clomipramine treatment on cerebrospinal fluid monoamine metabolites and platelet 3H-imipramine binding and serotonin uptake and concentration in major depressive disorder. Acta Psychiatr Scand 83:125–133

    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 (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 

  • Nagy A, Johansson R (1977) The demethylation of imipramine and clomipramine as apparent from their plasma kinetics. Psychopharmacology (Berl) 54:125–131

    Article  CAS  Google Scholar 

  • Pilkington GJ, Parker K, Murray SA (2008) Approaches to mitochondrially mediated cancer therapy. Semin Cancer Biol 18:226–235

    Article  PubMed  CAS  Google Scholar 

  • Schou M, Halldin C, Sovago J, Pike VW, Hall H, Gulyas B, Mozley PD, Dobson D, Shchukin E, Innis RB, Farde L (2004) PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain. Synapse 53:57–67

    Article  PubMed  CAS  Google Scholar 

  • Schou M, Halldin C, Pike VW, Mozley PD, Dobson D, Innis RB, Farde L, Hall H (2005) Post-mortem human brain autoradiography of the norepinephrine transporter using (S,S)-[18F]FMeNER-D2. Eur Neuropsychopharmacol 15:517–520

    Article  PubMed  CAS  Google Scholar 

  • Sekine M, Arakawa R, Ito H, Okumura M, Sasaki T, Takahashi H, Takano H, Okubo Y, Halldin C, Suhara T (2010) Norepinephrine transporter occupancy by antidepressant in human brain using positron emission tomography with (S,S)-[18F]FMeNER-D2. Psychopharmacology (Berl) 210:331–336

    Article  CAS  Google Scholar 

  • Seneca N, Gulyas B, Varrone A, Schou M, Airaksinen A, Tauscher J, Vandenhende F, Kielbasa W, Farde L, Innis RB, Halldin C (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) 188:119–127

    Article  CAS  Google Scholar 

  • Suhara T, Takano A, Sudo Y, Ichimiya T, Inoue M, Yasuno F, Ikoma Y, Okubo Y (2003) High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography. Arch Gen Psychiatry 60:386–391

    Article  PubMed  CAS  Google Scholar 

  • Swanson LW, Hartman BK (1975) The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol 163:467–505

    Article  PubMed  CAS  Google Scholar 

  • Takano A, Gulyas B, Varrone A, Maguire RP, Halldin C (2009) Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[18F]FMeNER-D2. Eur J Nucl Med Mol Imaging 36:1308–1314

    Article  PubMed  CAS  Google Scholar 

  • Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249–258

    Article  PubMed  CAS  Google Scholar 

  • Trimble MR (1990) Worldwide use of clomipramine. J Clin Psychiatry 51:51–54, discussion 55–58

    PubMed  Google Scholar 

  • Vandel B, Vandel S, Jounet JM, Allers G, Volmat R (1982) Relationship between the plasma concentration of clomipramine and desmethylclomipramine in depressive patients and the clinical response. Eur J Clin Pharmacol 22:15–20

    Article  PubMed  CAS  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 

Download references

Acknowledgements

The authors thank Gudrun Nylen and all the members of the Karolinska PET group for their assistance in the PET experiments. This study was supported in part by Karolinska Institutet Foundation and the Swedish Science Council (41804).

Author information

Authors and Affiliations

  1. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, 171 76, Stockholm, Sweden

    Akihiro Takano, Sangram Nag, Balázs Gulyás, Christer Halldin & Lars Farde

Authors
  1. Akihiro Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sangram Nag
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Balázs Gulyás
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christer Halldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lars Farde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akihiro Takano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takano, A., Nag, S., Gulyás, B. et al. NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo. Psychopharmacology 216, 279–286 (2011). https://doi.org/10.1007/s00213-011-2212-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2212-9

Keywords

Search

Navigation