title: Therapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder.
abstract: Changes in inflammatory cytokines and dysfunction of the neurotrophic system are thought to be involved in the pathology of bipolar disorder (BP). We investigated whether inflammatory and neurotrophic factors were changed in BP. We also investigated whether treating BP with valproic acid (VPA) plus low-dose (30 or 60 mg/day) dextromethorphan (DM) is more effective than treating it with VPA only, and whether DM affects plasma cytokines and brain derived neurotrophic factor (BDNF) levels. In a 12-week, randomized, double-blind study, patients were randomly assigned to the VPA+DM30, VPA+DM60, or VPA+Placebo groups. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate symptom severity, and ELISA to analyze plasma cytokine and BDNF levels. We recruited 309 patients with BP and 123 healthy controls. Before treatment, patients with BP had significantly higher plasma cytokine and lower plasma BDNF levels than did healthy controls. After treatment, HDRS and YMRS scores in each group showed significant improvement. Plasma cytokine levels tended to decline in all groups. Changes in plasma BDNF levels were significantly greater in the VPA+DM60 group than in the VPA+Placebo group.
  
  
  CONCLUSIONS
  patients with BP have a certain degree of systemic inflammation and BDNF dysfunction. Treatment with VPA plus DM (60 mg/day) provided patients with BP significantly more neurotrophic benefit than did VPA treatment alone.
authors.affiliation: Department of Neurology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shiou-Lan
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Kaohsiung Veteran׳s General Hospital, Kaohsiung, Taiwan.
authors.forename: Sheng-Yu
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yun-Hsuan
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Po-See
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Department of Neurology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Behavioral Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: I-Hui
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Tzu-Yun
authors.initials: TY
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Kao-Ching
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yen-Kuang
authors.initials: YK
authors.lastname: Yang
authors.affiliation: Laboratory of Toxicology and Pharmacology, NIH/NIEHS, Research Triangle Park, NC, USA.
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.affiliation: Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Behavioral Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Addiction Research Center, National Cheng Kung University, Tainan, Taiwan; Center for Neuropsychiatric Research, National Health Research Institute, Miaoli, Taiwan. Electronic address: rblu@mail.ncku.edu.tw.
authors.forename: Ru-Band
authors.initials: RB
authors.lastname: Lu
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood; D016207:Cytokines / Q000097:blood*; D003915:Dextromethorphan / Q000008:administration & dosage* / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage* / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D018696:Neuroprotective Agents; D014635:Valproic Acid; D003915:Dextromethorphan
keywords: BDNF; Bipolar disorder; Cytokine; HDRS; YMRS