Abstract
There is an increasing interest in the underlying mechanisms of the antidepressant and anxiolytic treatment effect associated with changes in serotonergic neurotransmission after treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) in humans. The 5-HT1A receptor is known to play a crucial role in the pathophysiology of affective disorders, and altered 5-HT1A receptor binding has been found in anxiety patients. SSRI treatment raises the 5-HT level in the synaptic cleft and might change postsynaptic receptor densities. Therefore, our study in patients suffering from anxiety disorders investigated the effects of long-term treatment with escitalopram on the 5-HT1A receptor. A longitudinal positrone emission tomography (PET) study in 12 patients suffering from anxiety disorders was conducted. Two dynamic PET scans were performed applying the selective 5-HT1A receptor antagonist [carbonyl-11C]WAY-100635. Eight regions of interest were defined a priori (orbitofrontal cortex, amygdala, hippocampus, subgenual cortex, anterior and posterior cingulate cortex, dorsal raphe nucleus and cerebellum as reference). After the baseline PET scan, patients were administered escitalopram (average dose of 11.2±6.0 mg day−1) for a minimum of 12 weeks. A second PET scan was conducted after 109±27 days. 5-HT1A receptor binding potentials in 12 patients were assessed by PET applying the Simplified Reference Tissue Model.There was a significant reduction in the 5-HT1A receptor binding potential after a minimum of 12 weeks of escitalopram treatment in the hippocampus (P=0.006), subgenual cortex (P=0.017) and posterior cingulate cortex (P=0.034). The significance of the hippocampus region survived the Bonferroni-adjusted threshold for multiple comparisons. These PET data in humans in vivo demonstrate a reduction of the 5-HT1A binding potential after SSRI treatment.
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References
Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 2002; 416: 396–400.
Gross C, Hen R . The developmental origins of anxiety. Nat Rev Neurosci 2004; 5: 545–552.
Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ et al. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999; 46: 1375–1387.
Meltzer CC, Price JC, Mathis CA, Butters MA, Ziolko SK, Moses-Kolko E et al. Serotonin 1A receptor binding and treatment response in late-life depression. Neuropsychopharmacology 2004; 29: 2258–2265.
Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J et al. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000; 57: 174–180.
Neumeister A, Bain E, Nugent AC, Carson RE, Bonne O, Luckenbaugh DA et al. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci 2004; 24: 589–591.
Lanzenberger R, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien LK et al. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 2007; 61: 1081–1089.
Lesch KP, Hoh A, Schulte HM, Osterheider M, Muller T . Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive–compulsive disorder. Psychopharmacology (Berl) 1991; 105: 415–420.
Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ . Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 2004; 9: 386–392.
Lerer B, Gelfin Y, Gorfine M, Allolio B, Lesch KP, Newman ME . 5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge. Neuropsychopharmacology 1999; 20: 628–639.
Bosker FJ, Cremers TI, Jongsma ME, Westerink BH, Wikstrom HV, den Boer JA . Acute and chronic effects of citalopram on postsynaptic 5-hydroxytryptamine(1A) receptor-mediated feedback: a microdialysis study in the amygdala. J Neurochem 2001; 76: 1645–1653.
Bundgaard C, Larsen F, Jorgensen M, Gabrielsson J . Mechanistic model of acute autoinhibitory feedback action after administration of SSRIs in rats: application to escitalopram-induced effects on brain serotonin levels. Eur J Pharm Sci 2006; 29: 394–404.
Varnas K, Halldin C, Hall H . Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 2004; 22: 246–260.
Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA et al. Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635. Brain Res 1997; 745: 96–108.
Sprouse J, Braselton J, Reynolds L, Clarke T, Rollema H . Activation of postsynaptic 5-HT(1A) receptors by fluoxetine despite the loss of firing-dependent serotonergic input: electrophysiological and neurochemical studies. Synapse 2001; 41: 49–57.
Le Poul E, Laaris N, Doucet E, Laporte AM, Hamon M, Lanfumey L . Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine. Naunyn Schmiedebergs Arch Pharmacol 1995; 352: 141–148.
Le Poul E, Laaris N, Hamon M, Lanfumey L . Fluoxetine-induced desensitization of somatodendritic 5-HT1A autoreceptors is independent of glucocorticoid(s). Synapse 1997; 27: 303–312.
Blier P, de Montigny C, Chaput Y . A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence. J Clin Psychiatry 1990; 51 (Suppl:): 14–20; discussion 21.
Blier P, de Montigny C . Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994; 15: 220–226.
Pineyro G, Blier P . Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 1999; 51: 533–591.
Ceglia I, Acconcia S, Fracasso C, Colovic M, Caccia S, Invernizzi RW . Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors. Br J Pharmacol 2004; 142: 469–478.
Li Q, Muma NA, van de Kar LD . Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: reductions in hypothalamic and midbrain Gi and G(o) proteins and in neuroendocrine responses to a 5-HT1A agonist. J Pharmacol Exp Ther 1996; 279: 1035–1042.
Li Q, Muma NA, Battaglia G, Van de Kar LD . A desensitization of hypothalamic 5-HT1A receptors by repeated injections of paroxetine: reduction in the levels of G(i) and G(o) proteins and neuroendocrine responses, but not in the density of 5-HT1A receptors. J Pharmacol Exp Ther 1997; 282: 1581–1590.
El Mansari M, Blier P . Responsiveness of 5-HT(1A) and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition. J Psychiatry Neurosci 2005; 30: 268–274.
Pandey SC, Isaac L, Davis JM, Pandey GN . Similar effects of treatment with desipramine and electroconvulsive shock on 5-hydroxytryptamine1A receptors in rat brain. Eur J Pharmacol 1991; 202: 221–225.
Beck SG, Birnstiel S, Choi KC, Pouliot WA . Fluoxetine selectively alters 5-hydroxytryptamine1A and gamma-aminobutyric acidB receptor-mediated hyperpolarization in area CA1, but not area CA3, hippocampal pyramidal cells. J Pharmacol Exp Ther 1997; 281: 115–122.
Nishi M, Azmitia EC . Agonist- and antagonist-induced plasticity of rat 5-HT1A receptor in hippocampal cell culture. Synapse 1999; 31: 186–195.
Klimek V, Zak-Knapik J, Mackowiak M . Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain. J Psychiatry Neurosci 1994; 19: 63–67.
David SP, Murthy NV, Rabiner EA, Munafo MR, Johnstone EC, Jacob R et al. A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 2005; 25: 2586–2590.
Patel TD, Azmitia EC, Zhou FC . Increased 5-HT1A receptor immunoreactivity in the rat hippocampus following 5,7-dihydroxytryptamine lesions in the cingulum bundle and fimbria-fornix. Behav Brain Res 1996; 73: 319–323.
Sanchez C . The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of s-citalopram*. Basic Clin Pharmacol Toxicol 2006; 99: 91–95.
Sanchez C, Bergqvist PB, Brennum LT, Gupta S, Hogg S, Larsen A et al. Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology (Berl) 2003; 167: 353–362.
Culpepper L . Escitalopram: A New SSRI for the Treatment of Depression in Primary Care. Prim Care Companion J Clin Psychiatry 2002; 4: 209–214.
Murdoch D, Keam SJ . Escitalopram: a review of its use in the management of major depressive disorder. Drugs 2005; 65: 2379–2404.
Stein DJ, Kasper S, Andersen EW, Nil R, Lader M . Escitalopram in the treatment of social anxiety disorder: analysis of efficacy for different clinical subgroups and symptom dimensions. Depress Anxiety 2004; 20: 175–181.
Kasper S, Stein DJ, Loft H, Nil R . Escitalopram in the treatment of social anxiety disorder: randomised, placebo-controlled, flexible-dosage study. Br J Psychiatry 2005; 186: 222–226.
Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence AD et al. A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables. Neuroimage 2002; 15: 620–632.
Parsey RV, Oquendo MA, Simpson NR, Ogden RT, Van Heertum R, Arango V et al. Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635. Brain Res 2002; 954: 173–182.
Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533–1539.
Parsey RV, Hastings RS, Oquendo MA, Huang YY, Simpson N, Arcement J et al. Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry 2006; 163: 52–58.
Rabiner EA, Bhagwagar Z, Gunn RN, Cowen PJ, Grasby PM . Preferential 5-HT1A autoreceptor occupancy by pindolol is attenuated in depressed patients: effect of treatment or an endophenotype of depression? Neuropsychopharmacology 2004; 29: 1688–1698.
Riad M, Zimmer L, Rbah L, Watkins KC, Hamon M, Descarries L . Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in the nucleus raphe dorsalis of rat. J Neurosci 2004; 24: 5420–5426.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59 (Suppl 20): 22–33; quiz 34–57.
Spielberger CD, Vagg PR . Psychometric properties of the STAI: a reply to Ramanaiah, Franzen, and Schill. J Pers Assess 1984; 48: 95–97.
Bantick RA, Rabiner EA, Hirani E, de Vries MH, Hume SP, Grasby PM . Occupancy of agonist drugs at the 5-HT1A receptor. Neuropsychopharmacology 2004; 29: 847–859.
Wadsak W, Mien L, Ettinger D . Simple and fully automated preparation of [carbonyl-11C]WAY-100635. Radiochimica Acta 2007; 95: 417–422.
Mikolajczyk K, Szabatin M, Rudnicki P, Grodzki M, Burger C . A JAVA environment for medical image data analysis: initial application for brain PET quantitation. Med Inform (Lond) 1998; 23: 207–214.
Meyer JH, Gunn RN, Myers R, Grasby PM . Assessment of spatial normalization of PET ligand images using ligand-specific templates. Neuroimage 1999; 9: 545–553.
Friston K, Holmes A, Worsley K, Poline J-B, Frith C, Frackowiak R . Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Map 1995; 2: 189–210.
Adolphs R . Neural systems for recognizing emotion. Curr Opin Neurobiol 2002; 12: 169–177.
Pine DS, Fyer A, Grun J, Phelps EA, Szeszko PR, Koda V et al. Methods for developmental studies of fear conditioning circuitry. Biol Psychiatry 2001; 50: 225–228.
Schneider F, Weiss U, Kessler C, Muller-Gartner HW, Posse S, Salloum JB et al. Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia. Biol Psychiatry 1999; 45: 863–871.
Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT . Differential limbic—cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychiatry 2000; 48: 30–42.
Tillfors M, Furmark T, Marteinsdottir I, Fischer H, Pissiota A, Langstrom B et al. Cerebral blood flow in subjects with social phobia during stressful speaking tasks: a PET study. Am J Psychiatry 2001; 158: 1220–1226.
Tauscher J, Bagby RM, Javanmard M, Christensen BK, Kasper S, Kapur S . Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers. Am J Psychiatry 2001; 158: 1326–1328.
Bremner JD, Bronen RA, De Erasquin G, Vermetten E, Staib LH, Ng CK et al. Development and Reliability of a Method for Using Magnetic Resonance Imaging for the Definition of Regions of Interest for Positron Emission Tomography. Clin Positron Imaging 1998; 1: 145–159.
Baker KG, Halliday GM, Tork I . Cytoarchitecture of the human dorsal raphe nucleus. J Comp Neurol 1990; 301: 147–161.
Lammertsma AA, Hume SP . Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4 (3 Part 1): 153–158.
Burnet PW, Eastwood SL, Harrison PJ . [3H]WAY-100635 for 5-HT1A receptor autoradiography in human brain: a comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia. Neurochem Int 1997; 30: 565–574.
Lesch KP . 5-HT1A receptor responsivity in anxiety disorders and depression. Prog Neuropsychopharmacol Biol Psychiatry 1991; 15: 723–733.
Newman ME, Shapira B, Lerer B . Regulation of 5-hydroxytryptamine1A receptor function in rat hippocampus by short- and long-term administration of 5-hydroxytryptamine1A agonist and antidepressants. J Pharmacol Exp Ther 1992; 260: 16–20.
Varrault A, Leviel V, Bockaert J . 5-HT1A-sensitive adenylyl cyclase of rodent hippocampal neurons: effects of antidepressant treatments and chronic stimulation with agonists. J Pharmacol Exp Ther 1991; 257: 433–438.
Hume S, Hirani E, Opacka-Juffry J, Myers R, Townsend C, Pike V et al. Effect of 5-HT on binding of [(11)C] WAY 100635 to 5-HT(IA) receptors in rat brain, assessed using in vivo microdialysis nd PET after fenfluramine. Synapse 2001; 41: 150–159.
Udo de Haes JI, Cremers TI, Bosker FJ, Postema F, Tiemersma-Wegman TD, den Boer JA . Effect of increased serotonin levels on [18F]MPPF binding in rat brain: fenfluramine vs the combination of citalopram and ketanserin. Neuropsychopharmacology 2005; 30: 1624–1631.
Zimmer L, Riad M, Rbah L, Belkacem-Kahlouli A, Le Bars D, Renaud B et al. Toward brain imaging of serotonin 5-HT1A autoreceptor internalization. Neuroimage 2004; 22: 1421–1426.
Meyer JH, Kapur S, Eisfeld B, Brown GM, Houle S, DaSilva J et al. The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am J Psychiatry 2001; 158: 78–85.
Leysen JE, Pauwels PJ . 5-HT2 receptors, roles and regulation. Ann N Y Acad Sci 1990; 600: 183–191; discussion 192–3.
Tauscher J, Verhoeff NP, Christensen BK, Hussey D, Meyer JH, Kecojevic A et al. Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET. Neuropsychopharmacology 2001; 24: 522–530.
Acknowledgements
This work was supported by an unrestricted investigator-initiated research grant from H Lundbeck A/S. We are grateful to C Windischberger, E Moser, A Becherer, A Erfurth, N Praschak-Rieder, M Willeit, J Kanaan, N Klein, T Geiss-Granadia, D Ettlinger, T Attarbaschi, S Friedreich and R Dudczak for their scientific, medical or administrative support.
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S Kasper has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, Servier, Sepracor, GlaxoSmithKline, Organon, has served as a consultant or on advisory boards for AstraZeneca, Austrian Sick Found, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lily, Lundbeck, Pfizer, Organon, Sepracor, Janssen, and Novartis, and has served on speakers’ bureaus for AstraZeneca, Eli Lilly, Lundbeck, Servier, Sepracor and Janssen. K Kletter has received several grants from the pharmaceutical industry in the area of nuclear medicine. L Pezawas, C Spindelegger, R Lanzenberger, U Moser, W Wadsak and M Mitterhauser received travel grants from several companies in CNS research.
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Spindelegger, C., Lanzenberger, R., Wadsak, W. et al. Influence of escitalopram treatment on 5-HT1A receptor binding in limbic regions in patients with anxiety disorders. Mol Psychiatry 14, 1040–1050 (2009). https://doi.org/10.1038/mp.2008.35
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DOI: https://doi.org/10.1038/mp.2008.35
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