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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 >
(TNF->), 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 > 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-> (P = 0.005) level changes. Treating bipolar II depression with
VPA + memantine may improve the plasma TNF-> level. However,
adding-on memantine may not improve clinical symptoms or cytokine
levels other than TNF->. 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, TriService 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.
Received May 2, 2013; accepted after revision November 4, 2013.
Reprints: Ru-Band Lu, MD, Institute of Behavioral Medicine, Department
of Psychiatry, Addiction Center, College of Medicine and Hospital,
National Cheng Kung University, 138 Sheng-Li Rd, Tainan 70428,
Taiwan (e<mail: rblu@mail.ncku.edu.tw).
This work was supported in part by grant NSC98-2314-B-006-022-MY3
(to R.-B.L.) and NSC100-2314-B-006-048-MY3
(to S.-Y.L.) from the Taiwan National Science Council, grant DOH
95-TD-M-113-055 (to R.-B.L.) from the Taiwan Department of Health, grant
NHRI-EX-97-9738NI (to R.-B.L.) from the Taiwan National Health Research
Institute, and the National Cheng Kung University Project for Promoting
Academic Excellence and Developing World Class Research Centers.
Copyright * 2014 by Lippincott Williams & Wilkins
ISSN: 0271-0749
DOI: 10.1097/JCP.0000000000000109
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Lee et al
METHODS
Patient Selection
The research protocol was approved by the institutional
review board for the Protection of Human Subjects at TriService General Hospital and at National Cheng Kung University Hospital. After the study had been completely described to
the participants, they all signed written informed consent forms.
Patients with BP-II were recruited from outpatient and inpatient settings. All were initially evaluated in an interview
by an attending psychiatrist and followed up with a more detailed interview by a clinical psychologist using the Chinese
Version of the Modified Schedule of Affective Disorder and
SchizophreniaYLife Time,40 which has a good interrater reliability,41 to determine Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition diagnoses. Patients with major mental illnesses, borderline personality disorder, drug
dependence, and cognitive disorders other than BP-II were
excluded. Patients who had taken memantine within 1 week
before the first dose of the double-blind medication were
excluded.
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Study Design
One week after a baseline assessment, patients were assigned
randomized add-on treatment with low-dose memantine (5 mg/d)
or a placebo for 12 weeks while they continued their open-label
VPA treatment (500 and 1000 mg daily [50Y100 Hg/mL in plasma]), which had begun when they joined the study. Symptom
severity was assessed at baseline, the starting day of memantine
(1 week after baseline; day 0 of week 1) followed by measurements of treatment responses on day 7 of weeks 1, 2, 4, 8, and 12.
The severity of mood symptoms was assessed using the Hamilton
Depression Rating Scale (HDRS)46,47 and the Young Mania Rating
Scale (YMRS).48 Only patients in depressed state (HDRSR18)
were recruited. Concomitant benzodiazepine medication (lorazepam G8 mg) was used for nighttime sedation and to treat agitation
and insomnia during the study. Up to 20 mg daily of fluoxetine
was permitted for associated depressive symptoms.
Ten milliliters of whole blood was withdrawn from the
antecubital vein of each patient. Plasma, which was isolated
from the whole blood after it had been centrifuged at 3000g for
15 minutes at 4-C, was immediately stored at j80-C. Cytokine
levels were quantified using an antibody pair assay system
(Flexia; BioSource Intl, Camarillo, CA). Sample processing and
data analysis were done according to the manufacturers instructions. The immunological parameters (TNF->, IL-1A, IL-6,
and IL-8) were measured at baseline and at each visit when
symptom severity was assessed.
Statistical Analysis
The demographic and clinical characteristics of the patients, their baseline YMRS and HDRS scores, and their baseline cytokine levels were compared between groups using 1way analysis of variance for continuous variables and W2 tests
for categorical variables. Data are mean T SD. All cytokine
levels were distributed erratically and showed a significant level
of positive skew (Table 1). Arithmetic transformations were
used to produce approximately normal distributions for further
analysis; log (x + 1) was used for cytokine levels. The YMRS
and HDRS total scores were used as measures of response to addon memantine. Potential prognostic factors included the treatment duration (weeks 0Y12), use of memantine, baseline YMRS
and HDRS scores, sex, and age. To evaluate the possible effects
of the prognostic factors on the response values, a multiple linear
regression model capable of controlling for other prognostic
factors was used. Because there were repeated assessments, multiple linear regressions with the generalized estimating equation
method49 were used to control for time effects, baseline psychopathology, and other patient-related variables. The association of
memantine treatment and changes in cytokine levels was also
evaluated using multiple linear regressions with the generalized
estimating equation method after controlling for time effects, severity of mood symptoms, and other patient-related variables.
SPSS 16.0 for Windows (SPSS Inc, Chicago, IL) was used for
statistical computations. Significance was set at P G 0.05.
RESULTS
Two hundred thirty-two depressed patients with BP-II were
recruited and randomly assigned to groups given either add-on
memantine (5 mg/d) (VPA + memantine; n = 115) or placebo
* 2014 Lippincott Williams & Wilkins
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TABLE 1. Characteristics at Baseline and End Point of Patients With BP-II Depression Taking VPA + Memantine or VPA + Placebo
Baseline
n
Sex (male/female), n
Age, mean (SD), y
HDRS1 score, mean (SD)
YMRS2score, mean (SD)
TNF->, mean (SD), pg/mL
IL-6, mean (SD), pg/mL
IL-8, mean (SD), pg/mL
IL-1A, mean (SD), pg/mL
VPA level, mean (SD), mg/L
End Point
VPA + Memantine
VPA + Placebo
VPA + Memantine
VPA + Placebo
115
53/62
32.90 T 12.02
19.20 T 5.60
8.56 T 4.33
1.89 T 2.32
1.40 T 1.31
2.34 T 2.40
1.32 T 1.47
0
117
65/52
30.66 T 11.11
19.22 T 5.39
9.48 T 4.59
1.74 T 1.70
1.51 T 1.75
1.79 T 1.97
1.29 T 1.19
0
0.149
0.088
0.987
0.132
0.892
0.606
0.072
0.863
V
81
42/39
32.40 T 11.78
8.76 T 6.47
4.86 T 3.04
1.74 T 2.42
0.96 T 0.69
1.89 T 2.68
1.37 T 1.24
66.0 T 27.5
76
47/31
29.80 T 10.55
9.44 T 6.51
5.80 T 3.90
1.63 T 1.80
1.46 T 2.01
1.72 T 2.25
1.18 T 0.89
67.5 T 23.5
0.286
0.163
0.521
0.102
0.772
0.043
0.677
0.343
0.76
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Lee et al
Model 1
HDRS score
YMRS score
Model 2
TNF->
IL-6
IL-8
IL-1A
Wald W2
j0.062
0.004
0.11
0.001
0.739
0.972
j0.044
j0.018
j0.023
j0.004
6.24
1.95
1.69
0.069
0.013*
0.16
0.19
0.793
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12 weeks of treatment (P = 0.013) (Table 2). There was no significant difference in change of other cytokines in the 2 groups
(Table 2). In addition, the change in HDRS scores was significantly associated with the changes in IL-6 (P = 0.012) and
IL-1A (P = 0.005) levels, and the change in YMRS score was
significantly associated with change in TNF-> (P = 0.005)
levels (Table 3).
DISCUSSION
There are no published reports on using VPA plus add-on
low-dose memantine (5 mg/d) to treat BP-II depression while
closely monitoring patients cytokine levels during treatment.
We found that VPA plus add-on memantine was significantly
more effective than VPA alone for improving TNF-> levels, but
not for IL-6, IL-8, and IL-1A levels, for drug-naive patients with
BP-II depression. However, adding memantine to VPA was not
more effective than VPA alone improving IL-6, IL-8, or IL-1A
levels; nor was it more effective than VPA alone for improving
total HDRS and YMRS scores. Regardless of the treatment
used, decreases in the HDRS score were associated with decreases in IL-6 and IL-1A levels, and decreases in the YMRS
score were associated with decreases in the TNF-> level. Our
study provides initial evidence that changes in plasma cytokines
may be associated with the severity of mood symptoms in patients with BP-II depression.
Tumor necrosis factor > is a potent proinflammatory cytokine that augments the immune response to assist in eliminating
TABLE 3. Correlation of Changes in Clinical Symptoms With Cytokine in Patients With BP-II Depression
Change of HDRS From Baseline After 12 wk
TNF->
IL-6
IL-8
IL-1A
Wald W2
Wald W2
0.003
0.005
0.001
0.005
1.19
6.27
0.12
7.73
0.275
0.012
0.731
0.005*
0.010
0.000
0.005
0.007
7.87
0.008
1.69
3.50
0.005*
0.928
0.194
0.061
Controlled for treatment course, sex, age, HDRS, and YMRS scores.
*P G 0.01.
P G 0.05.
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antidepressant effect of memantine in the treatment of major depression. However, because fewer patients in the VPA +
memantine group dropped out compared with the VPA + placebo
group, an indistinct advantage of add-on memantine may require
additional assessment tools.
Our study has some limitations. First, we measured plasma
cytokines because previous studies suggested that changes in
peripheral cytokine secretion may partly reflect the changes in
peripheral levels. However, like other studies, we were unable to
arrive at a definitive conclusion about this.65 Second, if we correct for multiple comparisons, only significance (P G 0.0125)
remains significant. Therefore, our positive finding for memantines
effect on TNF-> may not hold up. In addition, we did not explore
other factors, such as smoking and weight, which could affect the
correlation between symptoms and proinflammatory factors. Furthermore, it is possible that other medications permitted in the
study obscured the mood-stabilizing effect of memantine. We did
not take a ceiling effect into consideration when planning the
study; however, it does appear that the patients recruited were not
severely depressed. Therefore, combining a mood stabilizer with
memantine may, in some way, have masked the antidepressant
effect of memantine. In additional studies, it will be important for
us to include patients with more severe depressive symptoms
to avoid a ceiling effect. Although we tried to limit concomitant treatment medication to only 3 drugs, the possible antiinflammatory effect of memantine interpreted from our finding
should still be taken with caution. Moreover, because none of the
patients in the current study had a history of taking mood stabilizers or memantine before being diagnosed with BP-II depression, our result is not applicable to patients who underwent
previous psychiatric treatment. Finally, because the present study
was a fixed-dose comparison without dose-assessment trials, the
definitive effects of add-on memantine and their clinical efficacy
require additional studies.
In conclusion, we found that treating BP-II depression with
add-on memantine may improve the plasma TNF-> level, but
that it had little effect on other cytokines. In addition, VPA +
memantine may not be more effective for clinical symptoms
than is VPA + placebo. We also report that clinical symptoms
may be correlated with certain cytokines. Whether plasma cytokine levels can be used as biomarkers of BP may warrant
further studies.
ACKNOWLEDGMENTS
The authors thank Dr. Shih-Hsien Lin for his statistical
advices and Ms Shen-Chun Yang and Hong-Yi Chang for their
assistance in preparing the manuscript.
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Lee et al
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