Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-19T00:15:31.144Z Has data issue: false hasContentIssue false
  • English
  • Français

Altered serotonin transporter binding potential in patients with obsessive-compulsive disorder under escitalopram treatment: [11C]DASB PET study

Published online by Cambridge University Press:  01 October 2015

E. Kim ,
O. D. Howes ,
J. W. Park ,
S. N. Kim ,
S. A Shin ,
B.-H. Kim ,
F. E. Turkheimer ,
Y.-S. Lee  and
J. S. Kwon
E. Kim
Affiliation:
Department of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Korea
O. D. Howes
Affiliation:
Psychiatric Imaging, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London, UK King's College London, Institute of Psychiatry, London, UK
J. W. Park
Affiliation:
Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
S. N. Kim
Affiliation:
Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
S. A Shin
Affiliation:
Department of Biomedical Sciences, Seoul National University, Seoul, Korea
B.-H. Kim
Affiliation:
Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine and Hospital, Seoul, Korea
F. E. Turkheimer
Affiliation:
King's College London, Institute of Psychiatry, London, UK
Y.-S. Lee
Affiliation:
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
J. S. Kwon*
Affiliation:
Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea
*
* Address for correspondence: Professor J. S. Kwon, Department of Psychiatry,Seoul National University College of Medicine & Department of Brain & Cognitive Sciences, College of Natural Science, Seoul National University, 28 Yeongon-dong, Chongno-gu, Seoul 110-744, Korea. (Email: kwonjs@snu.ac.kr)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Obsessive-compulsive disorder (OCD) is a chronic, relapsing mental illness. Selective serotonin reuptake inhibitors block serotonin transporters (SERTs) and are the mainstay of treatment for OCD. SERT abnormalities are reported in drug-free patients with OCD, but it is not known what happens to SERT levels during treatment. This is important as alterations in SERT levels in patients under treatment could underlie poor response, or relapse during or after treatment. The aim of the present study was first to validate a novel approach to measuring SERT levels in people taking treatment and then to investigate SERT binding potential (BP) using [11C]DASB PET in patients with OCD currently treated with escitalopram in comparison with healthy controls.

Method

Twelve patients and age- and sex-matched healthy controls were enrolled. The patients and healthy controls underwent serial PET scans after administration of escitalopram and blood samples for drug concentrations were collected simultaneously with the scans. Drug-free BPs were obtained by using an inhibitory Emax model we developed previously.

Results

The inhibitory Emax model was able to accurately predict drug-free SERT BP in people taking drug treatment. The drug-free BP in patients with OCD currently treated with escitalopram was significantly different from those in healthy volunteers [Cohen's d = 0.03 (caudate), 1.16 (putamen), 1.46 (thalamus), −5.67 (dorsal raphe nucleus)].

Conclusions

This result extends previous findings showing SERT abnormalities in drug-free patients with OCD by indicating that altered SERT availability is seen in OCD despite treatment. This could account for poor response and the high risk of relapse in OCD.

Keywords

Anxiety disordermolecular imagingobsessive-compulsive disorderserotonin transporterSSRI
Type
Original Articles
Information
Psychological Medicine , Volume 46 , Issue 2 , January 2016 , pp. 357 - 366
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aylward, EH, Harris, GJ, Hoehn-Saric, R, Barta, PE, Machlin, SR, Pearlson, GD (1996). Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging. Archives of General Psychiatry 53, 577–584.CrossRefGoogle ScholarPubMed
Barnes, NM, Sharp, T (1999). A review of central 5-HT receptors and their function. Neuropharmacology 38, 1083–1152.CrossRefGoogle ScholarPubMed
Baumgarten, HG, Grozdanovic, Z (1998). Role of serotonin in obsessive-compulsive disorder. British Journal of Psychiatry 35, (Suppl.), 13–20.CrossRefGoogle Scholar
Bech, P, Lonn, SL, Overo, KF (2010). Relapse prevention and residual symptoms: a closer analysis of placebo-controlled continuation studies with escitalopram in major depressive disorder, generalized anxiety disorder, social anxiety disorder, and obsessive-compulsive disorder. Journal of Clinical Psychiatry 71, 121–129.CrossRefGoogle ScholarPubMed
Bel, N, Artigas, F (1992). Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. European Journal of Pharmacology 229, 101–103.CrossRefGoogle ScholarPubMed
Cadeddu, R, Ibba, M, Sadile, A, Carboni, E (2014). Antidepressants share the ability to increase catecholamine output in the bed nucleus of stria terminalis: a possible role in antidepressant therapy? Psychopharmacology 231, 1925–1933.CrossRefGoogle ScholarPubMed
Collu, M, Poggiu, AS, Devoto, P, Serra, G (1997). Behavioural sensitization of mesolimbic dopamine D2 receptors in chronic fluoxetine-treated rats. European Journal of Pharmacology 322, 123–127.CrossRefGoogle ScholarPubMed
Dziedzicka-Wasylewska, M, Rogoz, Z, Skuza, G, Dlaboga, D, Maj, J (2002). Effect of repeated treatment with tianeptine and fluoxetine on central dopamine D(2)/D(3) receptors. Behavioural Pharmacology 13, 127–138.CrossRefGoogle Scholar
Egerton, A, Mehta, MA, Montgomery, AJ, Lappin, JM, Howes, OD, Reeves, SJ, Cunningham, VJ, Grasby, PM (2009). The dopaminergic basis of human behaviors: a review of molecular imaging studies. Neuroscience and Biobehavioral Reviews 33, 1109–1132.CrossRefGoogle ScholarPubMed
Fernandez Cordoba, E, Lopez-Ibor Alino, J (1967). Use of monochlorimipramine in psychiatric patients who are resistant to other therapy. Actas Luso-Españolas de Neurología y Psiquiatría 26, 119–147.Google ScholarPubMed
Fineberg, NA, Tonnoir, B, Lemming, O, Stein, DJ (2007). Escitalopram prevents relapse of obsessive-compulsive disorder. European Neuropsychopharmacology 17, 430–439.CrossRefGoogle ScholarPubMed
Gartside, SE, Umbers, V, Hajos, M, Sharp, T (1995). Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT. British Journal of Pharmacology 115, 1064–1070.CrossRefGoogle Scholar
Giovacchini, G, Lang, L, Ma, Y, Herscovitch, P, Eckelman, WC, Carson, RE (2005). Differential effects of paroxetine on raphe and cortical 5-HT1A binding: a PET study in monkeys. Neuroimage 28, 238–248.CrossRefGoogle Scholar
Goodman, WK, Price, LH, Rasmussen, SA, Mazure, C, Fleischmann, RL, Hill, CL, Heninger, GR, Charney, DS (1989). The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Archives of General Psychiatry 46, 1006–1011.CrossRefGoogle ScholarPubMed
Hajos-Korcsok, E, McTavish, SF, Sharp, T (2000). Effect of a selective 5-hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine. European Journal of Pharmacology 407, 101–107.CrossRefGoogle ScholarPubMed
Hesse, S, Muller, U, Lincke, T, Barthel, H, Villmann, T, Angermeyer, MC, Sabri, O, Stengler-Wenzke, K (2005). Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry Research 140, 63–72.CrossRefGoogle ScholarPubMed
Hesse, S, Stengler, K, Regenthal, R, Patt, M, Becker, GA, Franke, A, Knupfer, H, Meyer, PM, Luthardt, J, Jahn, I, Lobsien, D, Heinke, W, Brust, P, Hegerl, U, Sabri, O (2011). The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder. International Journal of Neuropsychopharmacology 14, 606–617.CrossRefGoogle ScholarPubMed
Ichise, M, Liow, JS, Lu, JQ, Takano, A, Model, K, Toyama, H, Suhara, T, Suzuki, K, Innis, RB, Carson, RE (2003). Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. Journal of Cerebral Blood Flow and Metabolism 23, 1096–1112.CrossRefGoogle ScholarPubMed
Innis, R, Baldwin, R, Sybirska, E, Zea, Y, Laruelle, M, al-Tikriti, M, Charney, D, Zoghbi, S, Smith, E, Wisniewski, G, Hoffer, P, Wang, S, Milius, R, Neumeyer, J (1991). Single photon emission computed tomography imaging of monoamine reuptake sites in primate brain with [123I]CIT. European Journal of Pharmacology 200, 369–370.CrossRefGoogle ScholarPubMed
Kang, KW, Lee, DS, Cho, JH, Lee, JS, Yeo, JS, Lee, SK, Chung, JK, Lee, MC (2001). Quantification of F-18 FDG PET images in temporal lobe epilepsy patients using probabilistic brain atlas. Neuroimage 14, 1–6.CrossRefGoogle ScholarPubMed
Karno, M, Golding, JM, Sorenson, SB, Burnam, MA (1988). The epidemiology of obsessive-compulsive disorder in five US communities. Archives of General Psychiatry 45, 1094–1099.CrossRefGoogle ScholarPubMed
Kim, E, Howes, OD, Yu, KS, Jeong, JM, Lee, JS, Jang, IJ, Shin, SG, Kapur, S, Kwon, JS (2011). Calculating occupancy when one does not have baseline: a comparison of different options. Journal of Cerebral Blood Flow and Metabolism 31, 1760–1767.CrossRefGoogle ScholarPubMed
Kwon, JS, Jang, JH, Choi, JS, Kang, DH (2009). Neuroimaging in obsessive-compulsive disorder. Expert Review of Neurotherapeutics 9, 255–269.CrossRefGoogle ScholarPubMed
Laruelle, M, Baldwin, RM, Malison, RT, Zea-Ponce, Y, Zoghbi, SS, al-Tikriti, MS, Sybirska, EH, Zimmermann, RC, Wisniewski, G, Neumeyer, JL, Milius, RA, Wang, S, Smith, EO, Roth, RH, Charney, DS, Hoffer, PB, Innis, RB (1993). SPECT imaging of dopamine and serotonin transporters with [123I]beta-CIT: pharmacological characterization of brain uptake in nonhuman primates. Synapse 13, 295–309.CrossRefGoogle ScholarPubMed
Lee, JS, Lee, DS (2005). Analysis of functional brain images using population-based probabilistic atlas. Current Medical Imaging Reviews 1, 81–87.CrossRefGoogle Scholar
Malagie, I, Trillat, AC, Jacquot, C, Gardier, AM (1995). Effects of acute fluoxetine on extracellular serotonin levels in the raphe: an in vivo microdialysis study. European Journal of Pharmacology 286, 213–217.CrossRefGoogle ScholarPubMed
Matsumoto, R, Ichise, M, Ito, H, Ando, T, Takahashi, H, Ikoma, Y, Kosaka, J, Arakawa, R, Fujimura, Y, Ota, M, Takano, A, Fukui, K, Nakayama, K, Suhara, T (2010). Reduced serotonin transporter binding in the insular cortex in patients with obsessive-compulsive disorder: a [11C]DASB PET study. Neuroimage 49, 121–126.CrossRefGoogle ScholarPubMed
McDougle, CJ, Goodman, WK, Leckman, JF, Lee, NC, Heninger, GR, Price, LH (1994). Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. a double-blind, placebo-controlled study in patients with and without tics. Archives of General Psychiatry 51, 302–308.CrossRefGoogle ScholarPubMed
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. American Journal of Psychiatry 161, 826–835.CrossRefGoogle ScholarPubMed
Neumeyer, JL, Tamagnan, G, Wang, S, Gao, Y, Milius, RA, Kula, NS, Baldessarini, RJ (1996). N-substituted analogs of 2 beta-carbomethoxy-3 beta- (4′-iodophenyl)tropane (beta-CIT) with selective affinity to dopamine or serotonin transporters in rat forebrain. Journal of Medicinal Chemistry 39, 543–548.CrossRefGoogle ScholarPubMed
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. International Journal of Neuropsychopharmacology 16, 1577–1586.CrossRefGoogle ScholarPubMed
Overbeek, T, Schruers, K, Vermetten, E, Griez, E (2002). Comorbidity of obsessive-compulsive disorder and depression: prevalence, symptom severity, and treatment effect. Journal of Clinical Psychiatry 63, 1106–1112.CrossRefGoogle ScholarPubMed
Pallanti, S, Hollander, E, Bienstock, C, Koran, L, Leckman, J, Marazziti, D, Pato, M, Stein, D, Zohar, J, International Treatment Refractory OCDC (2002). Treatment non-response in OCD: methodological issues and operational definitions. International Journal of Neuropsychopharmacology 5, 181–191.CrossRefGoogle ScholarPubMed
Pauls, DL, Alsobrook, JP II, Goodman, W, Rasmussen, S, Leckman, JF (1995). A family study of obsessive-compulsive disorder. American Journal of Psychiatry 152, 76–84.Google ScholarPubMed
Pogarell, O, Hamann, C, Popperl, G, Juckel, G, Chouker, M, Zaudig, M, Riedel, M, Moller, HJ, Hegerl, U, Tatsch, K (2003). Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder. Biological Psychiatry 54, 1406–1413.CrossRefGoogle ScholarPubMed
Praschak-Rieder, N, Wilson, AA, Hussey, D, Carella, A, Wei, C, Ginovart, N, Schwarz, MJ, Zach, J, Houle, S, Meyer, JH (2005). Effects of tryptophan depletion on the serotonin transporter in healthy humans. Biological Psychiatry 58, 825–830.CrossRefGoogle ScholarPubMed
Rauch, SL, Savage, CR (1997). Neuroimaging and neuropsychology of the striatum. Bridging basic science and clinical practice. Psychiatric Clinics of North America 20, 741–768.CrossRefGoogle ScholarPubMed
Reimold, M, Smolka, MN, Zimmer, A, Batra, A, Knobel, A, Solbach, C, Mundt, A, Smoltczyk, HU, Goldman, D, Mann, K, Reischl, G, Machulla, HJ, Bares, R, Heinz, A (2007). Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity – a [11C]DASB PET study. Journal of Neural Transmission 114, 1603–1609.CrossRefGoogle ScholarPubMed
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. Molecular Psychiatry 17, 1254–1260.CrossRefGoogle ScholarPubMed
Stein, DJ (2000). Neurobiology of the obsessive-compulsive spectrum disorders. Biological Psychiatry 47, 296–304.CrossRefGoogle ScholarPubMed
Stengler-Wenzke, K, Muller, U, Angermeyer, MC, Sabri, O, Hesse, S (2004). Reduced serotonin transporter-availability in obsessive-compulsive disorder (OCD). European Archives of Psychiatry and Clinical Neuroscience 254, 252–255.CrossRefGoogle ScholarPubMed
Takano, A, Suzuki, K, Kosaka, J, Ota, M, Nozaki, S, Ikoma, Y, Tanada, S, Suhara, T (2006). A dose-finding study of duloxetine based on serotonin transporter occupancy. Psychopharmacology 185, 395–399.CrossRefGoogle ScholarPubMed
Talbot, PS, Frankle, WG, Hwang, DR, Huang, Y, Suckow, RF, Slifstein, M, Abi-Dargham, A, Laruelle, M (2005). Effects of reduced endogenous 5-HT on the in vivo binding of the serotonin transporter radioligand 11C-DASB in healthy humans. Synapse 55, 164–175.CrossRefGoogle ScholarPubMed
van der Wee, NJ, Stevens, H, Hardeman, JA, Mandl, RC, Denys, DA, van Megen, HJ, Kahn, RS, Westenberg, HM (2004). Enhanced dopamine transporter density in psychotropic-naive patients with obsessive-compulsive disorder shown by [123I]β-CIT SPECT. American Journal of Psychiatry 161, 2201–2206.CrossRefGoogle ScholarPubMed
Vythilingum, B, Cartwright, C, Hollander, E (2000). Pharmacotherapy of obsessive-compulsive disorder: experience with the selective serotonin reuptake inhibitors. International Clinical Psychopharmacology 15 (Suppl. 2), S7–S13.CrossRefGoogle ScholarPubMed
Wang, Z, Maia, TV, Marsh, R, Colibazzi, T, Gerber, A, Peterson, BS (2011). The neural circuits that generate tics in Tourette's syndrome. American Journal of Psychiatry 168, 1326–1337.CrossRefGoogle ScholarPubMed
Weissman, MM, Bland, RC, Canino, GJ, Greenwald, S, Hwu, HG, Lee, CK, Newman, SC, Oakley-Browne, MA, Rubio-Stipec, M, Wickramaratne, PJ (1994). The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. Journal of Clinical Psychiatry 55 (Suppl.), 5–10.Google ScholarPubMed