title: Familial risk for major depression is associated with lower striatal 5-HT₄ receptor binding.
abstract: BACKGROUND
  The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD.
  
  
  METHODS
  We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first-degree relatives treated for MDD.
  
  
  RESULTS
  We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a "risk-dose effect" on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012).
  
  
  CONCLUSIONS
  Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT4 receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment.
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Karine
authors.initials: K
authors.lastname: Madsen
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Eva
authors.initials: E
authors.lastname: Torstensen
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Klaus K
authors.initials: KK
authors.lastname: Holst
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Mette E
authors.initials: ME
authors.lastname: Haahr
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Ulla
authors.initials: U
authors.lastname: Knorr
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Vibe G
authors.initials: VG
authors.lastname: Frokjaer
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Malene
authors.initials: M
authors.lastname: Brandt-Larsen
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Pernille
authors.initials: P
authors.lastname: Iversen
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen).
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Fisher
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Torstensen, Holst, Haahr, Frokjaer, Fisher, and Knudsen); Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Drs Madsen, Holst, Haahr, Frokjaer, Iversen, Fisher, and Knudsen); Department of Biostatistics, University of Copenhagen, Denmark (Dr Holst); Psychiatric Centre Copenhagen, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Knorr); PET and Cyclotron Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (Dr Brandt-Larsen); Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (Dr Iversen). gmk@nru.dk.
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D010880:Piperidines; D019275:Radiopharmaceuticals; C534709:SB 207145; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D044422:Receptors, Serotonin, 5-HT4
keywords: 5-HT4 receptor; MDD; PET; depression; serotonin