Abstract
To the authors' knowledge there is as of yet no study demonstrating in vivo alterations in human serotonin transporters (SERT) during clomipramine treatment in patients with obsessive–compulsive disorder. The only study in which SERT binding has been investigated in obsessive–compulsive disorder (OCD) patients before and after treatment is a small pilot study by Stengler-Wenzke et al (2006), who treated five OCD patients with citalopram. In the study at hand, we measured transporter availability in the thalamus–hypothalamus with [123I] β-CIT single photon emission computed tomography (SPECT) in 24 patients with DSM-IV OCD. All patients displayed prominent behavioral checking compulsions (OC-checkers). At baseline and upon medication after 12 weeks of treatment with clomipramine (150 mg daily) 24 non-depressed OC-checkers underwent a SPECT measurement of brain SERT availability using [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane. For quantification of brain serotonin transporter availability, a ratio of specific to non-displaceable [123I] β-CIT brain binding was used (BPND=(thalamus and hypothalamus−cerebellum)/cerebellum). The SERT availability was compared between baseline and after treatment and correlated with severity of OC symptomatology and treatment response as assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). After treatment with clomipramine patients showed a 48% reduced brain serotonin transporter availability in the thalamus–hypothalamus, as compared with values at baseline (0.72±0.12 vs 1.39±0.18, p<0.001). Correlations between brain SERT availability and OC symptomatology (Y-BOCS scores) revealed significantly negative associations both at baseline and after treatment (r=−0.46; p<0.05 and r=−0.53; p<0.01 respectively). These data suggest that the SERT availability values could be considered a biological indicator of disease severity. Moreover, in search of predictors we found that higher pretreatment SERT availability significantly predicted better treatment response 12 weeks later (B=14.145±4.514; t=3.133; p=0.005). These results provide further support for an important role of alterations in serotonergic neurons in the pathophysiology of OCD.
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References
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders. 4th edn. American Psychiatric Press: Washington, DC.
Angst J, Gamma A, Endrass J, Goodwin R, Ajdacic V, Eich D et al. (2004). Obsessive-compulsive severity spectrum in the community: prevalence, comorbidity, and course. Eur Arch Psychiatry Clin Neurosci 254: 156–164.
Bäckström I, Bergström M, Marcusson J (1989). High affinity [3H] paroxetine binding to serotonin uptake sites in human brain tissue. Brain Res 486: 261–268.
Baumgarten HG, Grozdanovic Z (1998). Role of serotonin in obsessive-compulsive disorder. Br J Psychiatry 35 (suppl): 13–20.
Boja JW, Mitchell WM, Patel A, Kopajtic TA, Carroll FI, Lewin AH et al (1992). High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain. Synapse 12: 27–36.
Brücke T, Kornhuber J, Angelberger P, Asenbaum S, Frassine H, Podreka I (1993). SPECT imaging of dopamine and serotonin transporters with [123I] β-CIT. Binding kinetics in the human brain. J Neural Transm Gen Sect 94: 137–146.
De Keyser J, De Backer JP, Ebinger G, Vauquelin G (1989). [3H]GBR-12935 binding to dopamine uptake sites in the human brain. J Neurochem 53: 1400–1404.
First MB, Spitzer RL, Gibbon M, Williams JBW (1996). User's Guide for the Structured Clinical Interview for DSM-IV Axis 1 Disorders: SCID-1 Clinician Version. American Psychiatric Press: Washington, DC.
Fujita M, Takatoku K, Matoba Y, Nishiura M, Kobayashi K, Inoue O et al (1997). Enhancement of [123I] β-CIT binding in the striatum with clomipramine: is there a serotonin–dopamine interaction? Eur J Nucl Med 24: 403–408.
Goodman WK (1999). Obsessive–compulsive disorder: diagnosis and treatment. J Clin Psychiatry 60 (suppl 18): 27–32.
Goodman WK, McDougle CJ, Price LH (1992). The role of serotonin and dopamine in the pathophysiology of obsessive–compulsive disorder. Int Clin Psychopharmacol 7 (suppl 1): 35–38.
Goodman WK, Price LH, Delgado PL, Palumbo J, Krystal JH, Nagy LM et al (1990). Specificity of serotonin reuptake inhibitors in the treatment of obsessive–compulsive disorder. Comparison of fluvoxamine and desipramine. Arch Gen Psychiatry 47: 577–585.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR et al (1989b). The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 46: 1012–1016.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al (1989a). The Yale-Brown Obsessive Compulsive Scale. I. Development, Use, and Reliability. Arch Gen Psychiatry 46: 1006–1011.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62.
Heinz A, Knable MB, Wolf SS, Jones DW, Gorey JG, Hyde TM et al (1998a). Tourette's syndrome: [I-123]β-CIT SPECT correlates of vocal tic severity. Neurology 51: 1069–1074.
Heinz A, Ragan P, Jones DW, Hommer D, Williams W, Knable MB et al (1998b). Reduced central serotonin transporters in alcoholism. Am J Psychiatry 155: 1544–1549.
Hesse S, Müller U, Lincke T, Barthel H, Villmann T, Angermeyer MC et al (2005). Serotonin and dopamine transporter imaging in patients with obsessive–compulsive disorder. Psychiatry Res: Neuroimaging 140: 63–72.
Hollander E, DeCaria CM, Nitescu A, Gully R, Suckow RF, Cooper TP et al (1992). Serotonergic function in obsessive-compulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers. Arch Gen Psychiatry 49: 21–28.
Horwath E, Weissman M (2000). The epidemiology and cross-national presentation of obsessive–compulsive disorder. Psychiatr Clin North Am 23: 493–507.
Hyttel J (1977). Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu 10-171. Psychopharmacology 51: 225–233.
Hyttel J (1982). Citalopram: pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol Biol Psychiatry 6: 277.
Innis R, Baldwin R, Sybirska E, Zea Y, Laruelle M, Al-Tikriti M et al (1991). Single photon emission computed tomography imaging of monoamine reuptake sites in primate brain with [123I] β-CIT. Eur J Pharmacol 200: 369–370.
Innis R, Cunningham V, Delforge J, Fujita M, Gjedde A, Gunn R et al (2007). Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27: 1533–1539.
Insel TR (1992). Toward a neuroanatomy of obsessive–compulsive disorder. Arch Gen Psychiatry 49: 739–744.
Jacobsen LK, Staley JK, Malison RT, Zoghbi SS, Seibyl JP, Kosten TR et al (2000). Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients. Am J Psychiatry 157: 1134–1140.
Kasper S, Tauscher J, Willeit M, Stamenkovic M, Neumeister A, Küfferle B et al (2002). Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder—implications for psychopharmacology. World J Biol Psychiatry 3: 133–146.
Kent JM, Coplan JD, Lombardo I, Hwang DR, Huang Y, Mawlawi O et al (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.
Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison RT, Baldwin RM et al (2003). Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology 28: 413–420.
Kuikka JT, Bergström KA, Vanninen E, Laulumaa V, Hartikainen P, Länsiemies E (1993). Initial experience with single photon emission tomography using iodine-123-labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane in human brain. Eur J Nucl Med 20: 783–786.
Laruelle M, Wallace E, Seibyl JP, Zea-Ponce Y, Zoghbi SS, Neumeyer JL et al (1994). Graphical, kinetic, and equilibrium analyses of in vivo [123I]-β-CIT binding to dopamine transporters in healthy human subjects. J Cereb Blood Flow Metab 14: 982–994.
Leonard H, Swedo S, Rapoport JL, Coffey M, Cheslow D (1988). Treatment of childhood obsessive–compulsive disorder with clomipramine and desmethylimipramine: a double-blind crossover comparison. Psychopharmacol Bull 24: 93–95.
Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L et al (1998). Reduced brain serotonin transporter availability in major depression as measured by [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 44: 1090–1098.
McTavish D, Benfield P (1990). Clomipramine. An overview of its pharmacological properties and a review of its therapeutic use in obsessive–compulsive disorder and panic disorder. Drugs 39: 136–153.
Meyer JH (2007). Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 32: 86–102.
Meyer JH, Wilson AA, Ginovart N, Goulding V, Hussey D, Hood K et al. (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.
Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ et al (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.
Mintun M, Raichle M, Kolbourn M, Wooten G, Welch M (1984). A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15: 217–227.
Neumeyer JL, Wang S, Milius RA, Baldwin RM, Zea-Ponce Y, Hoffer PB et al (1991). [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT): high-affinity SPECT radiotracer of monoamine reuptake sites in brain. J Med Chem 34: 3144–3146.
Pirker W, Asenbaum S, Hauk M, Kandlhofer S, Tauscher J, Willeit M et al (2000). Imaging serotonin and dopamine transporters with 123I-β-CIT SPECT: binding kinetics and effects of normal aging. J Nucl Med 41: 36–44.
Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G et al (1995). β-CIT SPECT demonstrates blockade of 5-HT uptake sites by citalopram in the human brain in vivo. J Neural Transm Gen Sect 100: 247–256.
Pogarell O, Hamann C, Pöpperl G, Juckel G, Choukèr M, Zaudig M et al (2003). Elevated brain serotonin transporter availability in patients with obsessive–compulsive disorder. Biol Psychiatry 54: 1406–1413.
Prichep LS, Mas F, Hollander E, Liebowitz M, John ER, Almas M et al (1993). Quantitative electroencephalographic subtyping of obsessive–compulsive disorder. Psychiatry Res 50: 25–32.
Reimold M, Smolka M, Zimmer A, Batra A, Knobel A, Solbach C et al (2007). Reduced availability of serotonin transporters in obsessive–compulsive disorder correlates with symptom severity—a [11C] DASB PET study. J Neural Transm 114: 1603–1609.
Saxena S, Brody AL, Schwartz JM, Baxter LR (1998). Neuroimaging and frontal-subcortical circuitry in obsessive–compulsive disorder. Br J Psychiatry 35 (suppl): 26–37.
Saxena S, Rauch SL (2000). Functional neuroimaging and the neuroanatomy of obsessive–compulsive disorder. Psychiatr Clin North Am 23: 563–586.
Simpson HB, Lombardo I, Slifstein M, Huang HY, Hwang DR, Abi-Dargham A et al (2003). Serotonin transporters in obsessive–compulsive disorder: a positron emission tomography study with [11C] McN 5652. Biol Psychiatry 54: 1414–1421.
Stein DJ (2002). Obsessive–compulsive disorder. Lancet 360: 397–405.
Stein MB, Forde DR, Anderson G, Walker JR (1997). Obsessive–compulsive disorder in the community: an epidemiologic survey with clinical reappraisal. Am J Psychiatry 154: 1120–1126.
Stengler-Wenzke K, Müller U, Angermeyer MC, Sabri O, Hesse S (2004). Reduced serotonin transporter-availability in obsessive–compulsive disorder (OCD). Eur Arch Psychiatry Clin Neurosci 254: 252–255.
Stengler-Wenzke K, Müller U, Barthel H, Angermeyer MC, Sabri O, Hesse S (2006). Serotonin transporter imaging with [123I] β-CIT SPECT before and after one year of citalopram treatment of obsessive–compulsive disorder. Neuropsychobiology 53: 40–45.
Suhara T, Takano A, Sudo Y, Ichimiya T, Inoue M, Yasuno F et al (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.
Talairach J, Tournoux P (1988). Coplanar Stereotaxic Atlas of the Human Brain. Thieme Medical: New York, NY.
Tauscher J, Pirker W, Willeit M, de Zwaan M, Bailer U, Neumeister A et al (2001). [123I] β-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa. Biol Psychiatry 49: 326–332.
van der Wee NJ, Stevens H, Hardeman JA, Mandl RC, Denys DA, van Megen HJ et al (2004). Enhanced dopamine transporter density in psychotropic-naive patients with obsessive–compulsive disorder shown by [123I] β-CIT SPECT. Am J Psychiatry 161: 2201–2206.
Vythilingum B, Cartwright C, Hollander E (2000). Pharmacotherapy of obsessive-compulsive disorder: experience with the selective serotonin reuptake inhibitors. Int Clin Psychopharmacol 15 (suppl 2): S7–S13.
Willeit M, Praschak-Rieder N, Neumeister A, Pirker W, Asenbaum S, Tauscher J et al (2000). [123I]-β-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder. Biol Psychiatry 47: 482–489.
Zitterl W, Aigner M, Stompe T, Zitterl-Eglseer K, Gutierrez-Lobos K, Schmidl-Mohl B et al (2007). [123I]-β-CIT SPECT imaging shows reduced thalamus–hypothalamus serotonin transporter availability in 24 drug-free obsessive–compulsive checkers. Neuropsychopharmacology 32: 1661–1668.
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The authors declare that, except for income received from each respective primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Zitterl, W., Aigner, M., Stompe, T. et al. Changes in Thalamus–Hypothalamus Serotonin Transporter Availability during Clomipramine Administration in Patients with Obsessive–Compulsive Disorder. Neuropsychopharmacol 33, 3126–3134 (2008). https://doi.org/10.1038/npp.2008.35
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DOI: https://doi.org/10.1038/npp.2008.35
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