Abstract
Behavioral and psychological symptoms of dementia (BPSD) are common and debilitating problems, but current treatments are limited. Antipsychotic agents show some efficacy on BPSD, but their use is limited by the associated risk of cerebrovascular events and mortality. Reports have shown the efficacy of mood stabilizers on BPSD, but systemic reviews on this issue are scant. This article aims to review studies of the efficacy of mood stabilizers on BPSD, and the quality of the available evidence. We searched for articles published in English during the period 1990 to 2010 and included in the PubMed database that concerned treatment of BPSD with mood stabilizers, such as carbamazepine, valproate, gabapentin, topiramate, lamotrigine, 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 oxcarbazepine 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, oxcarbazepine 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.
Keywords: Behavioral and psychological symptoms of dementia (BPSD), Dementia, Mood stabilizers, Review
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 institutionalization [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 recommended 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), gabapentin (GPN), topiramate (TOP), lamotrigine (LTG), oxcarbazepine (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), Alzheimer'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 methodological quality of aclinical trial [[9], [10]]. Three main 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 available, 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 Recommendation 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, extrapolations 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, hallucination, 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 Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Scales developed specially for aggression 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 developed more specifically for assessing agitation is the Cohen–Mansfield Agitation Inventory (CMAI), and scales developed especially for manic syndrome are the Young Mania Rating Scale (YMRS) and the Bech–Rafaelsen 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.
Results
Carbamazepine (CBZ)
One meta‐analysis [13] and three RCTs [[14], [15], [16]] looked at 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 –7.7 ± 5.7 vs. –0.9 ± 6.3; p = 0.0003; 95% CI for the difference = 3.3∼10.2; effect size = 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 including 72 patients showed CBZ to be efficacious for global BPSD, using as measurements BPRS (mean difference –5.5, 95% CI –8.5∼ –2.5) and CGI (odds ratio (OR) 10.2, 95% CI 3.1∼ 33.1) [13]. With regard to hostility, two RCTs using a mean dosage of 304–400 mg per day CBZ for 6 weeks showed efficacy on the BPRS‐hostility factor (mean change –2.2 ± 1.2 vs. –0.67 ± 1.0; p = 0.009; effect size = 1.37 and –2.5 ± 2.4 vs. –0.3 ± 2.3; p = 0.0007; effect size = 0.92) [[14], [15]]. For aggression, two RCTs with a mean dosage of 304–600 mg per day of CBZ for 6–8 weeks showed efficacy on the OAS total score (mean change –6.7 ± 5.8 vs. –1.9 ± 6.6; p = 0.008; effect size = 0.76) [15] and RAGE (p < 0.05) [16]. For agitation, one RCT using a mean dosage of 304 mg per day CBZ for 6 weeks showed efficacy using the BPRS‐agitation factor (mean change –3.1 ± 2.4 vs. –0.3 ± 2.4; p = 0.0001; effect size = 1.15) [15].
Table 1.
Double‐blind, placebo‐controlled trials of carbamazepine monotherapy in dementia.
| Study | Study design | Diagnosis | n | Daily dose (mg) | Duration | Efficacy outcomes significantly improved with treatment over placebo | Efficacy outcomes not significantly improved with treatment over placebo | Jadad score |
|---|---|---|---|---|---|---|---|---|
| Olin et al., 2001 [14] | Double‐blind, RCT | AD | 21 | Fixed 400 | 6wk |
|
|
3 |
| Tariot et al., 1998 [15] | Double‐blind, RCT | AD VaD Dementia, NOS | 51 | Mean 304 | 6wk |
|
3 | |
| Cooney et al., 1996 [16] | Double‐blind, RCT | AD | 6 | Mean 600 | 8wk |
|
2 |
AD = Alzheimer's disease; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impressions; Dementia, NOS = Dementia, not otherwise specified; n = sample size; OAS = Overt Aggression Scale; RAGE = Rating scale for Aggressive behavior in the Elderly; RCT = Randomized‐controlled trial; VaD = Vascular dementia.
Common adverse effects of CBZ were diarrhea, sedation and dizziness but these were mostly tolerable. One small cross‐over, non‐RCT using a CBZ dosage of 100–300 mg per 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 even fatal skin reactions (Stevens–Johnson syndrome and toxic epidermal necrolysis), especially in patients with the HLA‐B 1502 allele, which is found almost exclusively in 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. Studies suggest that the effective dosage is 300–600 mg per over 6–8 weeks. However, the adverse effects of CBZ, especially Stevens–Johnson syndrome and drug–drug interaction, warrant closer attention, especially in elderly patients.
Valproate (VPA)
Uncontrolled open trials, case reports or case series have suggested the efficacy of VPA for variant BPSD [[19], [20], [21], [22], [23], [24], [25], [26]], although RCTs showed conflicting results. Five RCTs [[27], [28], [29], [30], [31]] looking at the effect of VPA monotherapy on BPSD are listed in Table 2. For global BPSD, three RCTs did not show significant efficacy [[27], [29], [31]] and a meta‐analysis merging two RCTs [[28], [31]] and including 202 patients in a 2009 Cochrane review [32] supported this negative result. For agitation, one RCT with a Jadad score of three, and including 172 patients with dementia on a median dosage of 1000 mg per day of VPA for 6 weeks, showed efficacy using the CMAI scale (mean change –14.3 ± 2.65 vs. –7.3 ± 2.72; p = 0.035; effect size = 2.60) [29]. This result was supported 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 = 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 inefficacy [31] and one RCT with a Jadad score of three and 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 216 patients did not support the efficacy for agitation either [32]. For aggression, treatment with VPA achieved no improvement in three RCTs [[28], [29], [30]] and even got worse in another RCT [27]. For hostility, VPA showed negative results in one RCT [28].
Table 2.
Randomized, double‐blind, placebo‐controlled trials of valproate monotherapy in dementia.
| Study | Diagnosis | n | Daily dose (mg) | Duration | Efficacy outcomes that significantly improved with treatment over placebo | Efficacy outcomes that did not significantly improve with treatment over placebo | Jaded score |
|---|---|---|---|---|---|---|---|
| Porsteinsson et al., 2001 [28] | AD VaD Dementia, NOS | 56 | Mean 826 (375∼1375) | 6wks | • Agitation: BPRS‐agitation factor |
|
3 |
| Tariot et al., 2001 [29] | AD VaD Dementia, NOS | 172 | Median 1000 | 6wks | • Agitation :CMAI |
|
3 |
| Sival et al., 2002 [30] | AD VaD | 42 | Fixed 480 | 3wks |
|
3 | |
| Tariot et al., 2005 [31] | AD | 153 | Mean 800 (500–1000) | 6wks |
|
4 | |
| Herrmann et al., 2007 [27] | AD | 14 | Mean 1135 | 6wks |
|
3 |
AD = Alzheimer's disease; BMRS = Bech–Rafaelsen Manic Scale; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impressions; CMAI = Cohen–Mansfield Agitation Inventory; Dementia, NOS = dementia, not otherwise specified; n = sample size; NPI = Neuropsychiatric Inventory; OAS = Overt Aggression Scale; SDAS‐9 = Social Dysfunction and Aggression Scale‐9; VaD = vascular dementia.
Agitation/aggression (NPI‐agitation/aggression factor, CMAI) were more severe on valproate than placebo.
Meta‐analysis in a Cochrane review showed VPA to have more overall adverse effects (n = 394; OR = 1.99; 95% CI = 1.29–3.08) than placebo; these included sedation (n = 241; OR = 2.48; 95% CI = 1.37–4.47), gastrointestinal upset (n = 208; OR = 7.09; 95% CI = 1.73–29.02), urinary tract infection (n = 227; OR = 3.02; 95% CI = 1.04–8.80) and thrombocytopenia (n = 186; OR = 7.91; 95% CI = 1.92–32.57). Although there was no significant difference with regard to severe adverse effects, overall, VPA has an unacceptable rate of adverse effects [32]. Two trials showed the tolerable dosage to be about 1000 mg per day or 15 mg/kg and the most common adverse effect was sedation [[29], [33]].
In summary, the higher quality study designs such as RCTs and meta‐analysis did not support the efficacy of VPA for managing global BPSD and its subdomains of agitation and aggression. Higher doses of VPA can lead to unacceptable adverse effects [32].
Gabapentin (GPN)
According to our search results, there are no meta‐analyses or RCTs looking at GPN in the management BPSD. Several 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 improvement in global BPSD [34]. However, two case series including 11 patients with AD in 300–1200 mg per day GPN showed four patients improved on global BPSD using NPI as measurement [[35], [36]]. Two uncontrolled open trials with, 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 positive 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 [[39], [40], [41], [42], [43], [44]]. 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 300–2400 mg per day of GPN, using OASS for evaluation [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 sedation. 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 (25–50 mg per day) of topiramate and risperidone 1.9 mg per day for 8 weeks, the TOP group showed improvement in global BPSD and agitation using CMAI, with no significant difference compared with risperidone [46]. Another case series including 15 patients with variant kinds of dementia using 25–150 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 [[48], [49], [50]]. 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.
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 100–300 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 (300–900 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, positive 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 intoxication 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 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 promising 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 drug–drug interactions, and the known tolerability problems expected with long‐term use, CBZ is not recommended 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 relatively 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 efficacious for BPSD, but the results were conflicting, with most trials being carried out more than 20 years ago, and lacking valid instruments.
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 | |
|---|---|---|---|---|---|
| CBZ a | (↑) One MA [13] of two RCTs | (↑) Two RCTs [[14], [15]] | (↑) Two RCTs [[15], [16]] | (↑) One RCT [15] | N/A |
| VPA | (↔) One MA [32] of two RCTs and two RCTs [[29], [30]] (↓) One RCT [27] (↑) Uncontrolled trials [[19], [22], [23]] | (↔) One RCT [28] | (↔) Three RCTs [[28], [29], [30]] (↓) One RCT [27] (↑) Uncontrolled trials [[21], [25], [26]] | (↔) One MA [32] of three RCTs (↑) One RCT [29] and uncontrolled trials [[20], [23], [24], [26]] | N/A |
| GPN | (↑) Two uncontrolled trials [[37], [38]] and case series [[35], [36]] (↔) One uncontrolled trial [34] | N/A | N/A | (↑) One uncontrolled trial [38] and case series [[39], [40], [41], [42], [43], [44], [45]] (↔) One uncontrolled trial [34] | (↑) One uncontrolled trial [38] looking at aggression, anxiety, apathy, wandering and sleep problems |
| TOP | (↑) One RCT [46], b | N/A | N/A | (↑) Case series [47] | N/A |
| LAM | N/A | N/A | (↑) Case series [[51], [52], [53]] | (↑) Case series [[51], [52], [54]] | (↑) One uncontrolled trial [56] about depression and case series [55] about manic symptoms |
| OXC | (↔) One RCT [57] | N/A | N/A | N/A | N/A |
| Li | (↑) Case reports [60] (↔) Case series [[61], [62]] | N/A | N/A | N/A | N/A |
CBZ = carbamazepine; GPN = gabapentin; LAM = lamotrigine; Li = lithium; MA = meta‐analysis; OXC = oxcarbazepine; RCT = randomized controlled trials; TOP = topiramate; VPA = valproate.
(↑) Significant effectiveness compared with placebo; (↔) no significant effectiveness compared with placebo or symptoms more severe than with placebo; (↓) symptoms significantly worse than with placebo.
For CBZ, only meta‐analyses or randomized controlled trials are listed.
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/A a | 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/A a | N/A | N/A | N/A | N/A | N/A |
| Li | III | N/A | N/A | N/A | N/A | N/A |
CBZ = carbamazepine; GPN = gabapentin; LAM = lamotrigine; Li = lithium; OXC = oxcarbazepine; TOP = topiramate; VPA = valproate.
Only one RCT showed nonsignificant efficacy compared with placebo; there is no evidence available to support the use of OXC.
There was some evidence supporting the use of mood stabilizers in the management of BPSD. However, antipsychotics have more robust evidence for efficacy, although they increase the risk of mortality [63]. Treatment guidelines published in 2007 by the American Psychiatric Association 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 findings 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 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 individuals who are sensitive or unresponsive to antipsychotics. However, drug–drug 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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