title: A clinical genetic method to identify mechanisms by which pain causes depression and anxiety.
abstract: BACKGROUND
  Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year.
  
  
  RESULTS
  We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood--the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery.
  
  
  CONCLUSIONS
  Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.
authors.affiliation: Clinical Pain Research Section, Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, Bethesda, MD, USA. mm77k@nih.gov
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Max
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Atlas
authors.forename: Robert R
authors.initials: RR
authors.lastname: Edwards
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Haythornthwaite
authors.forename: Antonella F
authors.initials: AF
authors.lastname: Bollettino
authors.forename: Heather S
authors.initials: HS
authors.lastname: Hipp
authors.forename: Colin D
authors.initials: CD
authors.lastname: McKnight
authors.forename: Inge A
authors.initials: IA
authors.lastname: Osman
authors.forename: Erin N
authors.initials: EN
authors.lastname: Crawford
authors.forename: Maryland
authors.initials: M
authors.lastname: Pao
authors.forename: Jemiel
authors.initials: J
authors.lastname: Nejim
authors.forename: Albert
authors.initials: A
authors.lastname: Kingman
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Aisen
authors.forename: Michele A
authors.initials: MA
authors.lastname: Scully
authors.forename: Robert B
authors.initials: RB
authors.lastname: Keller
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
mesh_terms: D001008:Anxiety Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D003866:Depressive Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D004351:Drug Resistance / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D007405:Intervertebral Disc Displacement / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D009154:Mutation / Q000235:genetics; D010146:Pain / Q000150:complications* / Q000235:genetics* / Q000523:psychology; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D011619:Psychotropic Drugs / Q000494:pharmacology; D044092:Receptor, Galanin, Type 2 / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics; D012585:Sciatica / Q000150:complications / Q000235:genetics / Q000523:psychology
chemical_list: D011619:Psychotropic Drugs; D044092:Receptor, Galanin, Type 2; D017450:Receptors, Opioid, mu