The Effects of Add-On Low-Dose Memantine on Cytokine Levels in Bipolar II Depression

Abstract

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.

The effect of mood-stabilizing drugs on cytokine levels in bipolar disorder: A systematic review

“…A non-significant reduction in sIL-6R and sIL-2R was observed, but IL-6 levels were unaltered despite significant improvement of clinical symptoms. A study in patients with bipolar depression could not find an effect of a 12-week valproate trial on the levels of IL-1β, IL-6, IL-8 and TNF-α (Lee et al, 2014). We found no studies reporting on the effect of carbamazepine or lamotrigine on cytokine levels in BD.…”

“…Two studies report on the effect of valproate on cytokine levels in patients with BD (Lee et al, 2014;Maes et al, 1995a). In 10 patients with mania, the effect of a 2-week trial with valproate on IL-6, sIL-2R and sIL-6R levels was evaluated (Maes et al, 1995a).…”

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…A number of agents do not have sufficient data to warrant specific recommendations for BDII depression, including cranial electrotherapy stimulation (CES),479 dextromethorphan + quinidine,480 light therapy,481, 482, 483, 484, 485 lisdexamfetamine (adjunctive),300 olanzapine,486 pioglitazone,302 adjunctive pregnenolone,306 celecoxib,297 levetiracetam,487 adjunctive lisdexamfetamine,300 s‐adenosylmethionine,488, 489, 490 acetyl‐ l ‐carnitine + alpha‐lipoic acid,491 adjunctive modafinil,268 rTMS,275, 492, 493 and memantine 494…”

A meta-analysis and systematic review of the comorbidity between irritable bowel syndrome and bipolar disorder

“…Some studies have reported that abnormal levels of cytokines such as tumor necrosis factor-α, IL-8, and IL-10 play an important role in the pathophysiology of BD. [7,8] Taken together, both IBS and BD may, at least partially, share a similar mechanism of pathophysiology. Therefore, it is hypothesized that they may have a similar comorbidity rate.…”