Kaohsiung Journal of Medical Sciences (2012) 28, 185e193

Available online at www.sciencedirect.com

journal homepage: http://www.kjms-online.com

REVIEW ARTICLE

Mood stabilizers for the treatment of behavioral and

psychological symptoms of dementia: An update review
Yi-Chun Yeh a, Wen-Chen Ouyang b,c,*

a
Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
b
Jianan Mental Hospital, Tainan, Taiwan
c
College of Medical and Life Science, Chung Hwa University of Medical Technology, Taiwan

Received 13 May 2011; accepted 28 July 2011

Available online 14 February 2012

KEYWORDS Abstract Behavioral and psychological symptoms of dementia (BPSD) are common and debil-
Behavioral and itating problems, but current treatments are limited. Antipsychotic agents show some efficacy
psychological on BPSD, but their use is limited by the associated risk of cerebrovascular events and mortality.
symptoms of Reports have shown the efficacy of mood stabilizers on BPSD, but systemic reviews on this issue
dementia (BPSD); are scant. This article aims to review studies of the efficacy of mood stabilizers on BPSD, and
Dementia; the quality of the available evidence. We searched for articles published in English during the
Mood stabilizers; period 1990 to 2010 and included in the PubMed database that concerned treatment of BPSD
Review with mood stabilizers, such as carbamazepine, valproate, gabapentin, topiramate, lamotri-
gine, oxcarbazepine and lithium. The quality of the studies was assessed by considering the
trial designs, analyses, subjects and results. We found one meta-analysis and three randomized
controlled trials (RCTs) supporting the efficacy of carbamazepine in managing global BPSD,
particularly aggression and hostility. With regard to valproate, current evidence from one
meta-analysis and five RCTs did not strongly support its efficacy for global BPSD, including
agitation and aggression. Only open trials or case series showed some efficacy of gabapentin,
topiramate and lamotrigine in controlling BPSD. The single RCT investigating the effect of ox-
carbazepine on agitation and aggression showed negative results. Case series reports on
lithium tended to show it to be ineffective. Thus far, among mood stabilizers, carbamazepine
has the most robust evidence of efficacy on BPSD. More RCTs are needed to strengthen
evidence regarding the efficacy of gabapentin, topiramate and lamotrigine. Valproate, oxcar-
bazepine and lithium showed low or no evidence of efficacy. Large and well designed RCTs
focusing on specific symptoms of BPSD are needed to deal with the issue.
Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved.

* Corresponding author. Jianan Mental Hospital, No. 80, Lane 870, Jhung-Shan Road, Rende District, Tainan City 71742, Taiwan.
E-mail address: d88904@gmail.com (W.-C. Ouyang).

1607-551X/$36 Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved.

doi:10.1016/j.kjms.2011.10.025
186
Background
With an increasing and aging population, dementia has
become an important problem in public health. Behavioral
and psychological symptoms of dementia (BPSD) are
common and distressing problems. BPSD encompasses signs
and symptoms regarding behavior, mood, and perception or
thought content that frequently occur in patients with
dementia. Up to 97% of patients with dementia have
experienced BPSD [1]. BPSD may not only increase the
burden of caregivers [1] and accelerate early institution-
alization [2] but also increases social costs [3].
In a survey of clinical expert opinion on psychotropic
medicines used for dementia in clinical practice, the strongly
suggested first-line treatment for agitated delusion in
dementia was monotherapy with an antipsychotic; the rec-
ommended second-line treatment was a combination of
antipsychotics with a mood stabilizer. For patients with
agitation alone (without delusion), monotherapy with an
antipsychotic was still the first option, but fewer experts
(60%) suggested it for these patients than did for those with
delusion. The mood stabilizer alone was also the second
option (rated first-line by 35%) [4]. However, there is no
treatment approved by the US Food and Drug Administration
(FDA).
Evidence shows atypical antipsychotics are efficacious
for BPSD [5], but recent findings emphasized the risks of
cerebrovascular events and mortality associated with
atypical antipsychotics, which would limit their use in
dementia [6,7]. Therefore other medicine options are
needed and it is important to have a comprehensive review
of their safety and efficacy. Clinically, mood stabilizers
including carbamazepine (CBZ), valproate (VPA), gaba-
pentin (GPN), topiramate (TOP), lamotrigine (LTG), oxcar-
bazepine (OXC) and lithium (Li) were used in treatment for
bipolar disorders or epilepsy, and a few studies have shown
their efficacy for BPSD. However, systemic reviews looking
at this issue are scant. In the present study, we reviewed
the relevant published studies in order to ascertain whether
mood stabilizers are efficacious for BPSD. In addition, we
hoped to find evidence to differentiate the efficacy of
different mood stabilizers on specific domains of BPSD.
Methods
We used the PubMed database to make a comprehensive
search of the medical literature from 1990 to February
2010. Keywords included Alzheimer disease (AD), Alz-
heimer’s disease or dementia combined with drug names.
Emphasis was placed on relevant systemic reviews and
randomized controlled trials (RCTs) relating to BPSD;
however, nonrandomized trials and case series were
included if there were insufficient or inadequate RCTs.
Bibliographies from all papers and recent reviews were
manually cross-referenced.
The quality of studies was assessed by taking the trial
designs, analyses, and participants into account. We used
the Jadad scale [8] to evaluate the quality of RCT design.
The Jadad scale, one of the most widely used assessment
tools, is a procedure to independently assess the method-
ological quality of aclinical trial [9,10]. Three main
Y.-C. Yeh, W.-C. Ouyang
questions ask whether the authors adequately describe
their randomization, double blinding and withdrawals/
dropouts. One point is scored for each “yes”. Two further
questions ask if the methods of randomization and double
blinding are appropriate; again, a “yes” answer secures one
point. Finally, a point is deducted if the methods of
randomization are inappropriate, and another if the
methods of double blinding are inappropriate. So the Jadad
score can range from 0 to 5 points, with a higher score
indicating a better quality study. Where data were avail-
able, we also calculated the effect size using Hedge’s g for
RCTs with positive results [11].
The first author carried out the literature review and
assessed the quality of studies. Then the second author led
a core group discussion; the strengths and weaknesses
of the methodological design of each study justified
a consensus view. The conclusions of the core group were
then circulated to experts for additional professional
comment on the consensus. The core group members and
the experts were certificated psychiatrists or neurologists
in dementia care or geriatric psychiatry in Taiwan. We
made recommendations based on Strength of Recommen-
dation Taxonomy (SORT) as set out below [12].
Assessing the quality of the study
Level I: good-quality patient-oriented evidence (A-strength
recommendation).
Level II: limited-quality patient-oriented evidence (B-
strength recommendation).
Level III: other evidence: consensus, usual practice,
opinion, disease-oriented evidence, or case series for
studies of diagnosis, treatment, prevention, or screening
(C-strength recommendation).
Strength of recommendation
A: based on consistent and good-quality patient-oriented
evidence: systemic review/meta-analysis of RCTs with
consistent findings or high-quality individual RCT or all-
or-none study.
B: based on inconsistent or limited-quality patient-oriented
evidence: systemic review/meta-analysis of lower-
quality clinical trials or of studies with inconsistent
findings or lower-quality clinical trial or cohort study or
case-control study.
C: based on other evidence: consensus guidelines, extrap-
olations from bench research, usual practice, opinion,
disease-oriented evidence (intermediate or physiologic
outcomes only), or case series for studies of diagnosis,
treatment, prevention, or screening.
Measurements of BPSD
BPSD includes symptoms of agitation, aggression, aberrant
behaviors, anxiety, depression, apathy, euphoria, halluci-
nation, delusion, eating problems and sleep problems. In
patients with BPDS, condition severity and treatment
response are often evaluated by means of scales. Three
scales commonly used in trials for measurement of global
BPSD are the Neuropsychiatric Inventory (NPI), the Brief
Review of mood stabilizers for BPSD 187

Psychiatric Rating Scale (BPRS), and Clinical Global

AD Z Alzheimer’s disease; BPRS Z Brief Psychiatric Rating Scale; CGI Z Clinical Global Impressions; Dementia, NOS Z Dementia, not otherwise specified; n Z sample size; OAS Z Overt
Jadad
score
Impression (CGI). Scales developed specially for aggression

2
are the Overt Aggression Scale (OAS), Rating Scale for
Aggressive Behavior in the Elderly (RAGE) and the Social
Dysfunction and Aggression Scale-9 (SDAS-9) A scale

significantly improved with

developed more specifically for assessing agitation is the

treatment over placebo

Efficacy outcomes not
CoheneMansfield Agitation Inventory (CMAI), and scales

 Global BPSD: BPRS

 Global BPSD: CGI
developed especially for manic syndrome are the Young
Mania Rating Scale (YMRS) and the BecheRafaelsen Manic
Scale (BMRS).
We described the results that we found for the efficacy
of different mood stabilizers by sorting them with respect
to the various symptoms of BPSD, and noting in the text or
tables which scales the study used.

Aggression Scale; RAGE Z Rating scale for Aggressive behavior in the Elderly; RCT Z Randomized-controlled trial; VaD Z Vascular dementia.
Results

Efficacy outcomes significantly

Agitation: BPRS-agitation
improved with treatment

 Hostility: BPRS-hostility

Hostility: BPRS-hostility
Carbamazepine (CBZ)

Global BPSD: BPRS

over placebo

Aggression: RAGE
One meta-analysis [13] and three RCTs [14e16] looked at

Aggression: OAS
CBZ monotherapy for BPSD (Table 1). With regard to global
BPSD, one RCT using a dose of 304  119 mg per day of CBZ
for 6 weeks showed efficacy (mean change on BPRS score
e7.7  5.7 vs. e0.9  6.3; p Z 0.0003; 95% CI for the dif-
ference Z 3.3w10.2; effect size Z 1.12) [15] but another
RCT using 400 mg per day CBZ did not [14]. A further meta-






analysis study merging the above two RCTs [14,15] and
Double-blind, placebo-controlled trials of carbamazepine monotherapy in dementia.

including 72 patients showed CBZ to be efficacious for

global BPSD, using as measurements BPRS (mean difference
Duration

e5.5, 95% CI e8.5w e2.5) and CGI (odds ratio (OR) 10.2, 95%
6wk

6wk

8wk
CI 3.1w 33.1) [13]. With regard to hostility, two RCTs using
a mean dosage of 304e400 mg per day CBZ for 6 weeks
showed efficacy on the BPRS-hostility factor (mean change
e2.2  1.2 vs. e0.67  1.0; p Z 0.009; effect size Z 1.37
Daily dose

Fixed 400

Mean 304

Mean 600
and e2.5  2.4 vs. e0.3  2.3; p Z 0.0007; effect size Z
(mg)

0.92) [14,15]. For aggression, two RCTs with a mean dosage

of 304e600 mg per day of CBZ for 6e8 weeks showed efficacy
on the OAS total score (mean change e6.7  5.8 vs.
e1.9  6.6; p Z 0.008; effect size Z 0.76) [15] and RAGE
(p < 0.05) [16]. For agitation, one RCT using a mean dosage
21

51
n

of 304 mg per day CBZ for 6 weeks showed efficacy using the
BPRS-agitation factor (mean change e3.1  2.4 vs. e0.3 
2.4; p Z 0.0001; effect size Z 1.15) [15].
Dementia,
Diagnosis

Common adverse effects of CBZ were diarrhea, sedation

and dizziness but these were mostly tolerable. One small
NOS
VaD

cross-over, non-RCT using a CBZ dosage of 100e300 mg per

AD

AD

AD

day for 4 weeks showed that CBZ induced deterioration in

intellectual function [17] but this adverse effect was not
supported by two RCTs [14,15]. CBZ can cause dangerous or
Double-blind,

Double-blind,

Double-blind,
Study design

even fatal skin reactions (StevenseJohnson syndrome and

toxic epidermal necrolysis), especially in patients with the
HLA-B 1502 allele, which is found almost exclusively in
RCT

RCT

RCT

Asians [18]. Before starting treatment with CBZ, genetic

testing for HLA-B 1502 is necessary.
In summary, CBZ is effective for global BPSD and its
subdomains of aggression, hostility and (possibly) agitation.
Cooney et al.,
Tariot et al.,

Studies suggest that the effective dosage is 300e600 mg per

2001 [14]

1998 [15]

1996 [16]
Olin et al.,

over 6e8 weeks. However, the adverse effects of CBZ,

Table 1

especially StevenseJohnson syndrome and drugedrug

Study

interaction, warrant closer attention, especially in elderly

patients.
188 Y.-C. Yeh, W.-C. Ouyang

Valproate (VPA)

Dementia, NOS Z dementia, not otherwise specified; n Z sample size; NPI Z Neuropsychiatric Inventory; OAS Z Overt Aggression Scale; SDAS-9 Z Social Dysfunction and Aggression
AD Z Alzheimer’s disease; BMRS Z BecheRafaelsen Manic Scale; BPRS Z Brief Psychiatric Rating Scale; CGI Z Clinical Global Impressions; CMAI Z CoheneMansfield Agitation Inventory;
Jaded
score

3
3

4
Uncontrolled open trials, case reports or case series have
suggested the efficacy of VPA for variant BPSD [19e26],

Efficacy outcomes that did not significantly

although RCTs showed conflicting results. Five RCTs [27e31]

Aggression: CMAI-aggressive behavior

Agitation/aggressiona: NPI-agitation/
improve with treatment over placebo
looking at the effect of VPA monotherapy on BPSD are listed
in Table 2. For global BPSD, three RCTs did not show

Hostility: BPRS-hostility factor

significant efficacy [27,29,31] and a meta-analysis merging
two RCTs [28,31] and including 202 patients in a 2009

aggression factor, CMAI

Cochrane review [32] supported this negative result. For
agitation, one RCT with a Jadad score of three, and

Aggression: SDAS-9
Global BPSD: BPRS

Global BPSD: BPRS

including 172 patients with dementia on a median dosage of

Global BPSD: CGI

Global BPSD: CGI

Global BPSD: NPI
Aggression: OAS
Agitation: CMAI

Agitation: CMAI
1000 mg per day of VPA for 6 weeks, showed efficacy using

Mania: BRMS
the CMAI scale (mean change e14.3  2.65 vs. e7.3  2.72;
p Z 0.035; effect size Z 2.60) [29]. This result was sup-
ported by that of another RCT with a Jadad score of three
and including 56 patients on 826  216 mg per day of VPA,
using the BPRS-agitation factor (p Z 0.05) [28]. However,














another RCT with a Jadad score of four and including 153
patients on a mean dosage of 800 mg per day of VPA showed

improved with treatment over placebo

Efficacy outcomes that significantly
inefficacy [31] and one RCT with a Jadad score of three and

 Agitation: BPRS-agitation factor

including 14 patients on a mean dose of 1135 mg per day of
VPA showed inefficacy in aggravation compared with
placebo, using the CMAI scale [27]. A meta-analysis study
recruiting the above three RCTs [27,28,31] and including

Agitation/aggression (NPI-agitation/aggression factor, CMAI) were more severe on valproate than placebo.
Randomized, double-blind, placebo-controlled trials of valproate monotherapy in dementia.

216 patients did not support the efficacy for agitation

 Agitation :CMAI
either [32]. For aggression, treatment with VPA achieved no
improvement in three RCTs [28e30] and even got worse in
another RCT [27]. For hostility, VPA showed negative results
in one RCT [28].
Meta-analysis in a Cochrane review showed VPA to have
more overall adverse effects (n Z 394; OR Z 1.99; 95%
CI Z 1.29e3.08) than placebo; these included sedation
(n Z 241; OR Z 2.48; 95% CI Z 1.37e4.47), gastrointestinal
Duration

upset (n Z 208; OR Z 7.09; 95% CI Z 1.73e29.02), urinary

6wks

6wks

3wks

6wks

6wks
tract infection (n Z 227; OR Z 3.02; 95% CI Z 1.04e8.80)
and thrombocytopenia (n Z 186; OR Z 7.91; 95%
CI Z 1.92e32.57). Although there was no significant
(375w1375)

(500e1000)
Daily dose

difference with regard to severe adverse effects, overall,

(mg)

VPA has an unacceptable rate of adverse effects [32]. Two

Median

Fixed
Mean

Mean

Mean

trials showed the tolerable dosage to be about 1000 mg per

1000

1135
826

480

800

day or 15 mg/kg and the most common adverse effect was

sedation [29,33].
172

153
n

56

42

14

In summary, the higher quality study designs such as

RCTs and meta-analysis did not support the efficacy of VPA
Dementia, NOS

Dementia, NOS

for managing global BPSD and its subdomains of agitation

Diagnosis

and aggression. Higher doses of VPA can lead to unaccept-

able adverse effects [32].
VaD

VaD

VaD
AD

AD

AD

AD

AD

Scale-9; VaD Z vascular dementia.

Gabapentin (GPN)
Porsteinsson et al., 2001 [28]

Herrmann et al., 2007 [27]

According to our search results, there are no meta-analyses

or RCTs looking at GPN in the management BPSD. Several
Tariot et al., 2001 [29]

Tariot et al., 2005 [31]

Sival et al., 2002 [30]

open trials and case series showed the efficacy of GPN for
BPSD as follows. One uncontrolled open trial in 12 patients
with variant types of dementia on a mean dose of 900 mg
per day GPN for 4 weeks did not show significant improve-
ment in global BPSD [34]. However, two case series
Table 2

including 11 patients with AD in 300e1200 mg per day GPN

Study

showed four patients improved on global BPSD using NPI as

a

measurement [35,36]. Two uncontrolled open trials with,

Review of mood stabilizers for BPSD
respectively, 20 patients and four patients with AD and
using a mean dosage of 980 mg per day and 300 mg per day
for 15 months and 4 weeks respectively also showed posi-
tive results [34,37,38].
Several open trials and case series also showed efficacy
of GPN for agitation. Seven case reports including nine
demented patients with agitation showed that five patients
with AD, one with vascular dementia (VaD) and one with
another type of dementia responded subjectively to GPN;
those patients remaining unresponsive had Lewy body
dementia [39e44]. Later positive reports of efficacy using
objective measurements included a case series of three
patients with AD and one with mixed-type dementia on
a dose of 300e2400 mg per day of GPN, using OASS for eval-
uation [45] and an uncontrolled open trial with 20 patients
with AD on a mean dosage of 980 mg per day for 15 months,
using the NPI-agitation factor for evaluation [38]. Only one
uncontrolled open trial, with 12 patients with variant type
dementia on 900 mg per day of GPN, showed negative results
[34]. The uncontrolled open trial in 2003 also showed
that GPN was efficacious for aggression, anxiety, apathy,
wandering, and sleep problems, using NPI-subdomains [38].
The reports of the above trials stated that GPN was well
tolerated and the most common adverse effect was seda-
tion. In summary, limited evidence supported the efficacy
of GPN for global BPSD, especially for agitation. A little
evidence showed that it was also efficacious for aggression,
anxiety, apathy, wandering and sleep problems. However,
to date there is no RCT of the efficacy of GPN in BPSD. The
only negative trial above [34] included many variant types
of dementia such as AD, VaD, frontotemporal dementia
and alcohol-related dementia. Accordingly, a further RCT
focusing on specific types of dementia is needed.
Topiramate (TOP)
According to our search results, few studies have assessed
the efficacy of topiramate (TOP) in BPSD. In one RCT with
48 AD patients on 44 mg per day (25e50 mg per day) of
topiramate and risperidone 1.9 mg per day for 8 weeks, the
TOP group showed improvement in global BPSD and agita-
tion using CMAI, with no significant difference compared
with risperidone [46]. Another case series including 15
patients with variant kinds of dementia using 25e150 mg
per day of TOP showed improvement in agitation using CMAI
[47]. However, adverse effects could not be ignored. One
case report showed an elderly patient with depressive
disorder taking 200 mg per day TOP over 3 months turned
out to be demented, and recovered after stopping TOP
treatment. TOP has been reported to cause cognitive
deficit in young adults or epilepsy patients [48e50]. Though
the above RCTs in older patients with dementia did not
show change in the scores for the mini-mental state
examination in the TOP group [46], this is possibly because
of the shorter duration of treatment and lower dosage.
In summary, there has to date been a lack of RCTs to
investigate the efficacy of TOP. However, the existing
literature illustrates that a deleterious adverse effect on
cognition compromises its efficacy, especially in fragile
populations. So we do not suggest the use of TOP to manage
BPSD.
189
Lamotrigine (LTG)
Two case series including 46 demented patients, and using
LTG with a mean dosage of 191 mg per day and 192.5 mg
per day respectively showed that 42 patients were
improved with respect to agitation and aggression, as
evaluated by CGI [51,52]. Two other case reports also
showed improvement by subjective judgment [53,54]. One
case series including five patients with dementia and using
a dose of 100e300 mg per day of LTG showed improvement
in manic symptoms, as assessed on the YMRS [55]. One
uncontrolled trial including 11 patients with AD showed LTG
was not effective for behavior symptoms but was effective
for depressive symptoms, using the Alzheimer Disease
Assessment Scale [56]. Among the above case reports,
common adverse effects of LTG included somnolence, rash
and tremor.
In summary, LTG may be effective for agitation,
aggression, and manic and depressive symptoms but RCTs
using an objective scale for evaluation are needed. Adverse
effects, especially rash, should be considered.
Oxcarbazepine (OXC)
OXC is the keto-derivative of CBZ but is better tolerated
than CBZ. However, according to our search results, only
one RCT looked at OXC for global BPSD and it showed
negative results. The trial studied 103 patients with AD on
537 mg per day (300e900 m/day) of OXC for 8 weeks; it did
not show any significant difference in efficacy in agitation,
using the Brief Agitation Rating Scale, or aggression, using
the NPI-agitation factor, compared with placebo [57].
Common adverse effects of OXC include nausea, vomiting,
dizziness and drowsiness [58]. Although OXC is better
tolerated, one study in patients with epilepsy showed the
risk of hyponatremia to be higher than with CBZ, especially
for individuals older than 40 years [59]. In summary, posi-
tive evidence for OXC in BPSD is lacking. Larger and better
designed RCTs are needed. Hyponatremia should be paid
attention to, especially in the elderly.
Lithium (Li)
Several case reports described the use of lithium in BPSD
but lacked objective evaluation of outcome. One case
report showed the efficacy of Li for BPSD in dementia [60].
Another three case reports or case series did not show
efficacy [61,62]. Common adverse effects of Li include
confusion and ataxia. Because the volume of Li distribution
and renal function both decrease in the elderly, their
higher risk of Li intoxication should also be considered. In
summary, clinical use of Li is limited because there is
insufficient evidence on its efficacy and the risk of intoxi-
cation in older patients with dementia.
Discussion
We summarize the results of our study in Table 3. The levels
of recommendation and related evidence levels with regard
to mood stabilizers in variant BPSD are presented in
 190
Table 3 Summary of published study results and observations on the efficacy of mood stabilizers in managing the variant behavior and psychological symptoms of dementia (BPSD).
Global BPSD Hostility Aggression Agitation Others
a
CBZ ([) One MA [13] of two RCTs ([) Two RCTs [14,15] ([) Two RCTs [15,16] ([) One RCT [15] N/A
VPA (4) One MA [32] of two RCTs and two RCTs [29,30] (4) One RCT [28] (4) Three RCTs [28e30] (4) One MA [32] of three RCTs N/A
(Y) One RCT [27] (Y) One RCT [27] ([) One RCT [29] and uncontrolled
([) Uncontrolled trials [19,22,23] ([) Uncontrolled trials [21,25,26] trials [20,23,24,26]
GPN ([) Two uncontrolled trials [37,38] and case N/A N/A ([) One uncontrolled trial [38] ([) One uncontrolled trial [38] looking
series [35,36] and case series [39e45] at aggression, anxiety, apathy, wandering
(4) One uncontrolled trial [34] (4) One uncontrolled trial [34] and sleep problems
TOP ([) One RCT [46]b N/A N/A ([) Case series [47] N/A
LAM N/A N/A ([) Case series [51e53] ([) Case series [51,52,54] ([) One uncontrolled trial [56] about
depression and case series [55] about
manic symptoms
OXC (4) One RCT [57] N/A N/A N/A N/A
Li ([) Case reports [60] N/A N/A N/A N/A
(4) Case series [61,62]

CBZ Z carbamazepine; GPN Z gabapentin; LAM Z lamotrigine; Li Z lithium; MA Z meta-analysis; OXC Z oxcarbazepine; RCT Z randomized controlled trials; TOP Z topiramate; VPA Z valproate.
([) Significant effectiveness compared with placebo; (4) no significant effectiveness compared with placebo or symptoms more severe than with placebo; (Y) symptoms significantly worse than with placebo.
a
For CBZ, only meta-analyses or randomized controlled trials are listed.
b
Significant improvement in symptoms compared with pre-medication; no significant difference when compared with risperidone.

Table 4 Levels of recommendation of mood stabilizers on variant behavior and psychological symptoms of dementia (BPSD).
Global BPSD Hostility Aggression Agitation Manic symptoms Depressive symptoms
CBZ II II II II N/A N/A
VPA III N/Aa III III N/A N/A
GPN III N/A III III N/A N/A
TOP III N/A N/A III N/A N/A
LAM N/A N/A III III III III
OXC N/Aa N/A N/A N/A N/A N/A

Y.-C. Yeh, W.-C. Ouyang

Li III N/A N/A N/A N/A N/A
CBZ Z carbamazepine; GPN Z gabapentin; LAM Z lamotrigine; Li Z lithium; OXC Z oxcarbazepine; TOP Z topiramate; VPA Z valproate.
a
Only one RCT showed nonsignificant efficacy compared with placebo; there is no evidence available to support the use of OXC.
Review of mood stabilizers for BPSD
Table 4. Overall, there is to date a lack of large and well
designed RCTs investigating the use of mood stabilizers in
BPSD. Of all the mood stabilizers, CBZ has the most prom-
ising evidence of efficacy for global BPSD, especially for
aggression and hostility. However, given the relatively
small body of clinical trial evidence, the high risk of
drugedrug interactions, and the known tolerability prob-
lems expected with long-term use, CBZ is not recom-
mended for the routine treatment of agitation in patients
with dementia [63]. Early studies indicated that VPA was
possibly effective in agitation and aggression but RCTs in
recent years have not supported this finding. Use of VPA to
treat BPSD in dementia is not recommended, on the basis
of current evidence [63]. Open trials tended to support the
use of GPN for global BPSD and agitation; however, further
RCTs are expected to strengthen evidence for its efficacy.
We do not recommend the use of TOP for BPSD, because of
its adverse effect on cognition. LTG showed efficacy in
agitation, aggression, and manic and depressive symptoms
on open trials and further RCTs are needed. OXC is a rela-
tively well tolerated drug but we found only one RCT,
which showed negative results. More trials of OXC are
anticipated. Some case series have shown Li to be effica-
cious for BPSD, but the results were conflicting, with most
trials being carried out more than 20 years ago, and lacking
valid instruments.
There was some evidence supporting the use of mood
stabilizers in the management of BPSD. However, antipsy-
chotics have more robust evidence for efficacy, although
they increase the risk of mortality [63]. Treatment guide-
lines published in 2007 by the American Psychiatric Asso-
ciation advise that nonpharmacological management
should be initiated before medicine is administrated, and
that if medications are considered, antipsychotics are the
first option for psychosis or agitation, with mood stabilizers
a second-line choice [63]. Our update review adds new
information to the current treatment guidelines. Our find-
ings suggest that CBZ is the most promising mood stabilizer
in dementia with BPSD, especially for patients showing
aggression and hostility. CBZ can be considered for patients
who are sensitive or unresponsive to antipsychotics, who
have significant cardiovascular risk factors and who are
aggressive or hostile, but not delusional.
Our review of published studies has some limitations.
First, there are few published large RCTs in this area.
Second, the use in studies of different outcome measures
makes it difficult to compare and integrate their findings
for analysis. Third, many instruments lack validity and
reliability. Some studies used subjective measurements
such as CGI or subjective judgment, which decreases the
reliability of their findings. Some instruments used for
assessment in adults, such as BPRS, OAS and YMRS, lack
validity for older patients with dementia. Fourth, many
trials include variant types of dementia, which increases
the heterogeneity of the data. Past review articles on the
efficacy of anticonvulsants in BPSD have focused on either
overall BPSD [64,65] or only one symptom (e.g., aggression
or agitation) [66,67]. Fifth, trials focusing on safety were
scant and our article lacks systematic evaluation of the
safety data. This is the first review article encompassing
the whole of BPSD and its individual symptoms. However,
there is a need for larger and better designed RCTs focusing
191
on specific symptoms and dementia and using instruments
with better validity, to be carried out.
Conclusion
Thus far, not enough evidence supports the efficacy of
mood stabilizers in BPSD. Among all the mood stabilizers,
CBZ has shown the most promise, on the basis of current
evidence. It can be used as second-line treatment in indi-
viduals who are sensitive or unresponsive to antipsychotics.
However, drugedrug interaction or side effects should be
watched for.
Acknowledgments
The authors thank the Taiwan Dementia Society and the
Taiwanese Society of Geriatric Psychiatry for their financial
support. We also acknowledge the contributions of experts
including Jen-Ping Huang, Jong-Ling Fuh, Cheng-Sheng
Chen and Chia-Fen Tsai.
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