The effects of add-on low-dose memantine on cytokine levels in bipolar II depression: a 12-week double-blind, randomized controlled trial.
Memantine, a noncompetitive N-methyl-d-aspartate receptor antagonist with a mood-stabilizing effect, and an association between bipolar disorder and proinflammatory cytokine levels have been reported. Whether adding-on memantine would reduce cytokine levels and is more effective than valproic acid (VPA) alone in bipolar II disorder was investigated. A randomized, double-blind, controlled, 12-week study was conducted. Patients undergoing regular VPA treatments were randomly assigned to a group: VPA + memantine (5 mg/d) (n = 106) or VPA + placebo (n = 108). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical response. Symptom severity, plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-8, and IL-1 levels were examined during weeks 0, 1, 2, 4, 8, and 12. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Tumor necrosis factor α levels were significantly lower in the VPA + memantine group than in the VPA + placebo group (P = 0.013). Posttreatment HDRS and YMRS scores decreased significantly in both groups, but not significant, nor was the other between-group cytokine level difference pretreatment and posttreatment. The HDRS score changes were significantly associated with IL-6 (P = 0.012) and IL-1 (P = 0.005) level changes and changes in YMRS score changes with TNF-α (P = 0.005) level changes. Treating bipolar II depression with VPA + memantine may improve the plasma TNF-α level. However, adding-on memantine may not improve clinical symptoms or cytokine levels other than TNF-α. Clinical symptoms may be correlated with certain cytokines.
From the *Department of Psychiatry, †Institute of Behavioral Medicine, and ‡Institute of Allied Health Sciences, College of Medicine and Hospital, National Cheng Kung University, Tainan; §Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei; ∥Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung; ¶Department of Psychiatry, Tainan Hospital, Department of Health, Executive Yuan, Tainan; #Addiction Research Center, National Cheng Kung University, Tainan, Taiwan; and **Laboratory of Toxicology and Pharmacology, NIH/NIEHS, Research Triangle Park, NC.
Sheng-Yu
SY
Lee
Shiou-Lan
SL
Chen
Yun-Hsuan
YH
Chang
Po See
PS
Chen
San-Yuan
SY
Huang
Nian-Sheng
NS
Tzeng
Yu-Shan
YS
Wang
Liang-Jen
LJ
Wang
I Hui
IH
Lee
Tzu-Yun
TY
Wang
Tzung Lieh
TL
Yeh
Yen Kuang
YK
Yang
Jau-Shyong
JS
Hong
Ru-Band
RB
Lu
D000328:Adult; D018692:Antimanic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy*; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D055815:Young Adult
D018692:Antimanic Agents; D016207:Cytokines; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014635:Valproic Acid; D008559:Memantine