title: Segregating the cerebral mechanisms of antidepressants and placebo in fibromyalgia.
abstract: Antidepressant drugs are commonly used to treat fibromyalgia, but there is little knowledge about their mechanisms of action. The aim of this study was to compare the cerebral and behavioral response to positive treatment effects of antidepressants or placebo. Ninety-two fibromyalgia patients participated in a 12-week, double-blind, placebo-controlled clinical trial with milnacipran, a serotonin-norepinephrine reuptake inhibitor. Before and after treatment, measures of cerebral pain processing were obtained using functional magnetic resonance imaging. Also, there were stimulus response assessments of pressure pain, measures of weekly pain, and fibromyalgia impact. Following treatment, milnacipran responders exhibited significantly higher activity in the posterior cingulum compared with placebo responders. The mere exposure to milnacipran did not explain our findings because milnacipran responders exhibited increased activity also in comparison to milnacipran nonresponders. Stimulus response assessments revealed specific antihyperalgesic effects in milnacipran responders, which was also correlated with reduced clinical pain and with increased activation of the posterior cingulum. A short history of pain predicted positive treatment response to milnacipran. We report segregated neural mechanisms for positive responses to treatment with milnacipran and placebo, reflected in the posterior cingulum. The increase of pain-evoked activation in the posterior cingulum may reflect a normalization of altered default mode network processing, an alteration implicated in fibromyalgia pathophysiology.
  
  
  CONCLUSIONS
  This study presents neural and psychophysical correlates to positive treatment responses in patients with fibromyalgia, treated with either milnacipran or placebo. The comparison between placebo responders and milnacipran responders may shed light on the specific mechanisms involved in antidepressant treatment of chronic pain.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Boston, Massachusetts. Electronic address: karinj@nmr.mgh.harvard.edu.
authors.forename: Karin B
authors.initials: KB
authors.lastname: Jensen
authors.affiliation: Center for Anesthesiology, Emergency and Intensive Care Medicine, University Hospital, Göttingen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Petzke
authors.affiliation: National Clinical Guideline Centre, Royal College of Physicians, London, United Kingdom.
authors.forename: Serena
authors.initials: S
authors.lastname: Carville
authors.affiliation: School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Ernest
authors.initials: E
authors.lastname: Choy
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Fransson
authors.affiliation: Center for Neurosensory Disorders, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Gracely
authors.affiliation: Pierre Fabre, Boulogne, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Vitton
authors.affiliation: Department of Anesthesiology and Postoperative Intensive Care Medicine, University of Cologne, Germany.
authors.forename: Hanke
authors.initials: H
authors.lastname: Marcus
authors.affiliation: Centre for Neuroimaging Science, Institute of Psychiatry, King's College, London, United Kingdom.
authors.forename: Steven C R
authors.initials: SC
authors.lastname: Williams
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingvar
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Kosek
mesh_terms: D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D003521:Cyclopropanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005356:Fibromyalgia / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D000078764:Milnacipran; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement; D058748:Pain Perception / Q000187:drug effects* / Q000502:physiology; D015990:Placebo Effect; D011312:Pressure; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D003521:Cyclopropanes; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Antidepressive agents; fibromyalgia; magnetic resonance imaging; milnacipran; placebos