title: Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction.
abstract: BACKGROUND
  Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile.
  
  
  METHODS
  In this double-blind, placebo-controlled clinical trial, 140 individuals who met the DSM-IV criteria for methamphetamine dependence were randomized to receive either TPM or placebo, of whom 99 consented to participate in our genome-wide expression study. The RNA samples were collected from whole blood for 50 TPM- and 49 placebo-treated participants at three time points: baseline and the ends of weeks 8 and 12. Genome-wide expression profiles and pathways of the two groups were compared for the responders and non-responders at Weeks 8 and 12. To minimize individual variations, expression of all examined genes at Weeks 8 and 12 were normalized to the values at baseline prior to identification of differentially expressed genes and pathways.
  
  
  RESULTS
  At the single-gene level, we identified 1054, 502, 204, and 404 genes at nominal P values < 0.01 in the responders vs. non-responders at Weeks 8 and 12 for the TPM and placebo groups, respectively. Among them, expression of 159, 38, 2, and 21 genes was still significantly different after Bonferroni corrections for multiple testing. Many of these genes, such as GRINA, PRKACA, PRKCI, SNAP23, and TRAK2, which are involved in glutamate receptor and GABA receptor signaling, are direct targets for TPM. In contrast, no TPM drug targets were identified in the 38 significant genes for the Week 8 placebo group. Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups. These pathways are involved in relevant physiological functions such as neuronal function/synaptic plasticity, signal transduction, cardiovascular function, and inflammation/immune function.
  
  
  CONCLUSIONS
  Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA. Ming_Li@virginia.edu.
authors.forename: Ming D
authors.initials: MD
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA. wangjujw@gmail.com.
authors.forename: Ju
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA. tniu.hsph01@gmail.com.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Niu
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA. jzm4h@eservices.virginia.edu.
authors.forename: Jennie Z
authors.initials: JZ
authors.lastname: Ma
authors.affiliation: Department of Psychiatry, University of Maryland, Baltimore, USA. csenvi@psych.umaryland.edu.
authors.forename: Chamindi
authors.initials: C
authors.lastname: Seneviratne
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, USA. nat7b@virginia.edu.
authors.forename: Nassima
authors.initials: N
authors.lastname: Ait-Daoud
authors.affiliation: Information Management Consultants, Reston, USA. JSaadvandi@imc.com.
authors.forename: Jim
authors.initials: J
authors.lastname: Saadvandi
authors.affiliation: Information Management Consultants, Reston, USA. RMorris@imc.com.
authors.forename: Rana
authors.initials: R
authors.lastname: Morris
authors.affiliation: Department of Veterans Affairs Cooperative Studies Program Coordination Center, Perry Point, USA. fordavew@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Weiss
authors.affiliation: Department of Psychiatry, University of Missouri, Kansas City, USA. jcampbell@kc.rr.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Pacific Addiction Research Center, Honolulu, USA. haning@hawaii.edu.
authors.forename: William
authors.initials: W
authors.lastname: Haning
authors.affiliation: South Bay Treatment Center, San Diego, USA. drmawhinney@sbcglobal.net.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mawhinney
authors.affiliation: Lutheran Hospital Office of Research, Des Moines, USA. weisda@ihs.org.
authors.forename: Denis
authors.initials: D
authors.lastname: Weis
authors.affiliation: Matrix Institute on Addictions, West Los Angeles, USA. mickex@aol.com.
authors.forename: Michael
authors.initials: M
authors.lastname: McCann
authors.affiliation: Department of Veterans Affairs, Salt Lake City Health Care System, Salt Lake City, USA. christopher.stock@va.gov.
authors.forename: Christopher
authors.initials: C
authors.lastname: Stock
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, NIDA, Bethesda, USA. rkan@nida.nih.gov.
authors.forename: Roberta
authors.initials: R
authors.lastname: Kahn
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, NIDA, Bethesda, USA. iturriae@nida.nih.gov.
authors.forename: Erin
authors.initials: E
authors.lastname: Iturriaga
authors.affiliation: Veterans Administration Medical Center, Philadelphia, USA. yu_e@mail.trc.upenn.edu.
authors.forename: Elmer
authors.initials: E
authors.lastname: Yu
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, NIDA, Bethesda, USA. aelkashe@nida.nih.gov.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elkashef
authors.affiliation: Department of Psychiatry, University of Maryland, Baltimore, USA. bjohnson@psych.umaryland.edu.
authors.forename: Bankole A
authors.initials: BA
authors.lastname: Johnson
mesh_terms: D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000209:etiology; D016739:Behavior, Addictive / Q000188:drug therapy; D015415:Biomarkers / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D016208:Databases, Factual; D004311:Double-Blind Method; D005632:Fructose / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020869:Gene Expression Profiling; D006801:Humans; D008694:Methamphetamine / Q000009:adverse effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects*; D000077236:Topiramate
chemical_list: D015415:Biomarkers; D000697:Central Nervous System Stimulants; D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose; D008694:Methamphetamine