ORIGINAL CONTRIBUTION

The Effects of Add-On Low-Dose Memantine on Cytokine

Levels in Bipolar II Depression
A 12-Week Double-Blind, Randomized Controlled Trial
Sheng-Yu Lee, MD,* Shiou-Lan Chen, PhD,* Yun-Hsuan Chang, PhD,* Po See Chen, MD, PhD,*
San-Yuan Huang, MD, PhD, Nian-Sheng Tzeng, MD, Yu-Shan Wang, MS, Liang-Jen Wang, MD, MPH,||
I Hui Lee, MD,* Tzu-Yun Wang, MD,* Tzung Lieh Yeh, MD,* Yen Kuang Yang, MD,*#
Jau-Shyong Hong, PhD,** and Ru-Band Lu, MD*#

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

Journal of Clinical Psychopharmacology

&

Key Words: bipolar II depression, memantine, treatment, cytokines

(J Clin Psychopharmacol 2014;34: 00Y00)

ipolar II disorder (BP-II), defined as recurrent episodes of

depression and hypomania, is frequently misdiagnosed in
clinical settings.1Y4 According to the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, Text Revision from
the American Psychiatric Association, depression prompts patients to seek treatment, whereas hypomania is often perceived as
egosyntonic, and patients tend to experience it as positive.2,5
Some scholars believe BP-II is greatly underdiagnosed in clinical practice and lacks in-depth research because BP-II has been
regarded as a milder form of bipolar I disorder (BP-I).5,6
Still, there has also been much criticism about psychiatrists
overdiagnosing and overmedicating people who do not have a
real mental disorder. These critics see BP-II as a conspiracy of
psychiatrists and pharmaceutical companies to increase prevalence rates to an unrealistic level.7 The lifetime prevalence rate
of BP-I is about 2.4%,8 and that of BP-II is about 3%.1,9Y11
Merikangas and Lamers12 reported that although the lifetime
prevalence rate of BP-II in adults is 0.4%, the lifetime rates in
adolescents approach 3% to 4%. Long-term follow-ups show
that patients with BP-II have a more chronic course, more mood
episodes, more major and minor depressive episodes, and
shorter interepisodes, all of which last longer than those of patients with BP-I.13Y15 However, the extent to which BP-II is
independent from BP-I remains unestablished, which still requires further investigation.12
Inflammation may be involved in the pathophysiology
of, phenomenology of, and treatment response to bipolar disorder (BP).16 It is reported that activation of the inflammatory
response system and increased activity of proinflammatory cytokines interleukin 1A (IL-1A), IL-6, IL-8, and tumor necrosis
factor > (TNF->) are expressed during acute manic and depressive states.17Y22 However, whether the expression of these
cytokines is state-dependent and normalizes when the patient
is in remission23,24 remains controversial. In addition, the association between cytokines and treatment is inconsistent.25Y27
These discrepancies might be explained by methodological differences, for example, heterogeneity in sample characteristics, modest sample size, and not controlling for known comorbidities.16
However, understanding the inflammatory mechanisms of BP
might reveal novel pathophysiology and treatment options and
benefit the investigation of using anti-inflammatory medications to
treat BP.28,29
Although the pharmacological guidelines for treatment are
well established,30,31 the treatment in practice remains less than
ideal. Most patients still have breakthrough episodes or significant

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Journal of Clinical Psychopharmacology

Lee et al

residual symptoms while on medication, and functional deficits

often remain even when patients are in remission.32 Because inflammation and neurodegeneration have been regarded as the
pathogenesis of BP,16,33 treatment combining anti-inflammatory
and neuprotective agents may provide more benefit than current
standard treatments without these agents. Memantine is an Nmethyl-D-aspartate (NMDA) receptor antagonist and medication for Alzheimers disease (usually 20 mg/d). It increases the
production of glial cellYderived neurotrophic factor,34 is antiinflammatory, and protects rodents against amphetamine derivativeinduced neurotoxic damage in vitro and in vivo.35 Memantine in
higher doses (7.5Y20 mg/kg, subcutaneously) is considered an
NMDA receptor antagonist and an inhibitor of morphine-induced
tolerance, physical dependence, and drug-seeking effects in animal models.36,37 However, we recently showed that using a low
dose of memantine (0.02 mg/kg) abolished morphine-induced
conditioned place preference behavior in rats because of its
IL-6Ymodulating effect in the medial prefrontal cortex.38 Our
preliminary clinical data showed that 5 mg (0.1 mg/kg) of oral
memantine added to methadone maintenance therapy given to
heroin-dependent patients significantly attenuated plasma cytokines, the methadone replacement dose, and combined opiate use
(Chen et al, unpublished data). Because the low dose of memantine
(5 mg; 0.1 mg/kg) we administered was not high enough to block
the NMDA receptors (50% inhibition concentration of memantine:
2Y3 HM),39 we propose that memantines anti-inflammatory effect
of reducing the activity of microglia and increasing in the release
of neurotrophic factors by astroglia are mechanistically remote
from an NMDA receptor. We hypothesized that a low dose of
add-on memantine would therapeutically benefit patients with
BP because of its reported anti-inflammatory and neuroprotective
effects, but not its glutamatergic effects.
We conducted a double-blind, placebo-controlled study of
add-on low-dose memantine (5 mg/d) plus valproic acid (VPA)
treatment in patients with BP-II to evaluate the efficacy of lowdose memantine as an augmenting agent in treating BP-II. To
investigate memantines possible anti-inflammatory effects in
BP-II, we monitored the changes in levels of cytokine expression during the course of treatment.
In this study, we investigated whether adding memantine to
VPA is more effective than VPA alone for treating BP-II depression and whether memantine at a dose of 5 mg/d has a
beneficial effect on plasma cytokine levels in depressed patients
with BP-II.

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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Although Diagnostic and Statistical Manual of Mental

Disorders, Fourth Edition, Text Revision criteria require a minimum duration of 4 days of hypomania, current epidemiologic
data suggest that a 2-day duration is more prevalent in community samples2,13,42Y45; therefore, we used the 2-day minimum for
hypomania in the diagnosis of BP-II.

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
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BDNF, Metabolic Profiles, and BP-II

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

(VPA + placebo; n = 117) for 12 weeks. All patients were first

diagnosed without a history of taking mood stabilizers or
memantine. One hundred fifty-seven (67.7%) of the 232 patients
completed the double-blind phase, and 75 (32.3%) dropped out
(placebo, n = 41; 35.0%; memantine, n = 34; 29.6%). Their
reasons for discontinuing the study were as follows: 1 attempted
suicide and 1 poor tolerance to adverse effect (dizziness) in the
placebo group and loss of follow-up for an unknown reason
(placebo, n = 23; memantine, n = 24), lack of efficacy (placebo,
n = 6; memantine, n = 4), refusal of treatment (placebo, n = 8;
memantine, n = 4), and violation of protocol (placebo, n = 2;
memantine, n = 1). All patients were treated with benzodiazepines (range, 2Y6 mg/d), and about 60% of the patients were
also treated with fluoxetine (range, 10Y20 mg/d). The percentage
of patients taking fluoxetine did not differ between the 2 treatment groups: placebo, n = 74 (63.2%); memantine, n = 68
(59.1%). The adverse events encountered were all in the placebo
group (n = 3): hair loss (n = 1), dizziness (n = 1), and a suicide
attempt by wrist laceration (n = 1).
None of the patients claimed to have taken antipsychotics
in the past. However, because pharmaceutical management is
not very stringent in Taiwan, benzodiazepines and antidepressants are relatively easily accessible without a physicians prescription. It was therefore difficult for us to confirm whether the

patients had actually ever used antipsychotics or antidepressant.

Tracing back their history, the average prior episodes were
4.2 T 6.6 times for the memantine group and 3.6 T 4.5 times
for the placebo group. Fifteen patients from each group had
attempted suicide. Only 2 patients from each group had ever been
hospitalized for depressive episodes. However, the exact number
of patients previously treated for depression could not be confirmed or independently determined.
The demographic and clinical characteristics, baseline
HDRS and YMRS scores, and cytokine levels of the patients
were similar in both patient groups at baseline (Table 1). There
were no significant differences in age, sex, or cytokine levels
between the 2 patient groups at baseline (Table 1). The improvement of the HDRS and YMRS scores from baseline after
12 weeks in the 2 treatment groups is plotted in Figures 1 and 2.
At end point, the VPA + memantine group had a significantly
lower IL-6 level than did the VPA + placebo group (P = 0.043).
We used multiple linear regression to analyze the treatment
effect of VPA + placebo and VPA + memantine in BP-II depression. In both patient groups, YMRS and HDRS scores were
significantly lower after 12 weeks of treatment, but not significantly different between the groups. For cytokines, there was a
significant difference in change of TNF-> levels in the VPA +
memantine group compared with the VPA + placebo group after

FIGURE 1. Improvement of the HDRS scores from baseline after

12 weeks of treatment in the valproate (VPA) + memantine and
VPA + placebo groups.

FIGURE 2. Improvement of the YMRS scores from baseline after

12 weeks of treatment in the valproate (VPA) + memantine and
VPA + placebo groups.

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Journal of Clinical Psychopharmacology

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

Volume 34, Number 3, June 2014

pathogens and resolving the inflammatory challenge.50 Tumor

necrosis factor > has several effects: cytotoxicity, antiviral activity, and regulation of the immune response51; it may also be a
potential biomarker for different stages of BP.52 Up-regulated
TNF-> expression may also be a sign of progression to the late
stages of BP,28 with its severe impairment, ongoing subsyndromal symptoms, shortened duration of euthymia between episodes, and resistance to treatment. Therefore, TNF-> modulation
may be involved in the pathophysiology of BP and regarded as
a molecular target for novel treatment development.28,53 In the
current study, we report significantly decreased TNF-> level in
the VPA + memantine group compared with the VPA + placebo
group. Our positive finding suggests that add-on memantine, a
hypothesis-driven treatment for BP, attenuates TNF-> levels in
BP-II depression. Because none of our participants had been
previously treated with VPA or memantine before being diagnosed
with BP-II depression, whether the improvement in their TNF->
level is associated with other clinical characteristics requires further investigation
Memantine, a noncompetitive NMDA receptor antagonist,
has an antidepressant-like effect in animal models in higher
doses (from 2.5Y5 to 20 mg/kg).54,55 As an add-on augmenting
agent at higher doses (10Y30 mg/d) in clinical studies, memantine
has a mood-stabilizing and an antimanic effect on treatmentresistant BP.56 Memantines antidepressant effect in humans still
remains controversial.57,58 Past studies attribute the antidepressant
and mood-stabilizing effect of memantine to the NMDA blocker
effect.59,60 In the current study, patients were given only 5 mg of
memantine per day, and their plasma memantine concentration was
about 10 to 50 ng/mL (0.05Y0.2 HM). Such a low dose of plasma
memantine was not high enough to block the NMDA receptors
(50% inhibition concentration of memantine: 2Y3 HM).39 We previously34 reported an alternative mechanism for memantine: an
anti-inflammatory effect by reducing the activity of microglia and
an increase in the release of neurotrophic factors by astroglia, which
are mechanistically remote from an NMDA receptor. We hypothesize that the declines in cytokine levels in the current study contributed to the anti-inflammatory effect of memantine, but not
through an NMDA blockade. Additional mechanistic studies are
necessary to confirm this hypothesis.
The dosage used in the current study was determined from
animal and human studies of addiction behavior. In a prior animal study (Chen et al, 2012), we found that using a low dose
of memantine (0.2Y1 mg/kg per day) may abolish morphineinduced conditioned place preference behavior in rats because
of its anti-inflammatory and neurotrophic effects in the addictionrelated brain area. We converted that to human equivalent dose
(0.03Y0.16 mg/kg) (US Department of Health and Human Services, 2005). By assuming the average human weight to be 60 kg,
we determined that the median daily dose for humans is 5 mg

TABLE 2. Changes in Symptoms and Cytokines From Baseline

After 12 Weeks of VPA + Memantine or VPA + Placebo
Treatment in Patients With BP-II Depression
Symptoms and Cytokines

&

Model 1: controlled for treatment course, sex, age. Reference group

is VPA + placebo group; model 2: controlled for treatment course, sex,
age, HDRS, and YMRS scores.
*P G 0.05
IL-1A indicates interleukin 1A; IL-6, interleukin 6; IL-8, interleukin
8; TNF->, tumor necrosis factor >.

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

Change of YMRS From Baseline After 12 wk

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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Volume 34, Number 3, June 2014

(range, 1.8Y9.6 mg/d). We have also used oral memantine (5 mg/d)

to treat opioid-dependent patients undergoing methadone maintenance therapy. We found that add-on memantine had more therapeutic benefit than did methadone alone in attenuating opioid
abuse, down-regulating inflammatory cytokine levels, and upregulating brain-derived neurotrophic factor levels (Chen et al,
unpublished data). We therefore used this dose to treat BP-II.
In treating neuropsychiatric disorders, being able to identify and quantify peripheral biomarkers for diagnosis or monitoring treatment response still remains a goal of many clinicians.
Studies suggested that changes in proinflammatory cytokines
may be related to the pathophysiology of BP and response to
pharmacological treatment.18,21 In the current study, we found
that adding memantine to VPA was not more effective than VPA
alone for improving IL-6, IL-8, and IL-1A levels. One explanation for these results may be that inflammatory status is irrelevant
to BP. Even in a systematic review,61 the positive correlation
between cytokine and BP was limited by heterogeneity, small
sample sizes, and not controlling for confounding factors. Unfortunately, this hypothesis of negative correlation is not well
supported by past studies because negative studies of inflammation are rarely published.
Changes in IL-6 levels according to mood state is one of
the most consistent findings in BP research.18,19 In the current
study, we report that changes of plasma IL-6 and IL-1A may be
associated with the severity of depressive symptoms, which is in
accordance with Brietzke et al,62 who reported that IL-6 was
positively correlated with HDRS. Our findings support the hypothesis that increased activity of proinflammatory cytokines
may be state-dependent.24 On the other hand, we report that
changes of TNF-> are associated with the severity of manic
symptoms, which is partially in accord with OBrien et al,21
who found that both mania and bipolar depression are associated with an increase in the production of TNF->, even with the
use of mood stabilizers or antipsychotic medication. Although
we found no association between TNF-> and depressive symptoms, we did find that the association of TNF-> and YMRS may
represent subclinical changes of manic symptoms in BP-II depression. Because TNF-> is critical in changes in neuroplasticity,
cell resilience, and neuronal survival,28 Kapczinski et al52 proposed TNF-> serum levels as staging biomarkers for BP. The
present study confirms the association between cytokines and BP;
however, whether the combination of these cytokines may be used
as biomarkers for the severity of BP-II depression still requires
further study.
We found that add-on memantine was not associated with
changes in HDRS and YMRS scores. However, the assessment
tool in the current study was only the summation of the scores
of the YMRS and HDRS, which makes it difficult to detect
specific improvement in individual symptoms. Additional factorial analysis for clustered symptoms is required to explore
specific differences in the effect of add-on memantine in patients with BP-II depression. Unlike studies that focused only
on the improvement of either manic or depressive symptoms,
we followed up our patients for over 12 weeks and closely
assessed both types of symptoms with the YMRS and HDRS.
Therefore, our evaluation of the clinical effectiveness of memantine
was more comprehensive than were other studies. Subsyndromal
manic symptoms were present in more than half of 1380 depressed patients with BP in 1 study,63 yet frequently they were not
assessed by psychiatrists. However, subsyndromal manic symptoms during bipolar depression are associated with greater lifetime illness severity, more frequent suicide attempts, and a greater
frequency of rapid cycling compared with pure BP.64 Our negative
finding partially replicated that of Zarate et al,58 who reported no
* 2014 Lippincott Williams & Wilkins

BDNF, Metabolic Profiles, and BP-II

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.

AUTHOR DISCLOSURE INFORMATION

The authors declare no conflicts of interest.

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