|Year : 2016 | Volume
| Issue : 1 | Page : 66-79
Pharmacotherapy of dementia
Ajit Avasthi, Gourav Gupta, Sandeep Grover
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||6-May-2016|
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
This review aims to evaluate the existing evidence for pharmacotherapy for management of dementia. Data search strategies included electronic databases of relevant publications or cross-references. The searches were limited to acetyl cholinesterase inhibitors (AChEIs), memantine, antipsychotics, antidepressants, mood stabilizers, and benzodiazepines. Data in the form of meta-analysis and systemic reviews for treatment in five main types of dementia (Alzheimer's, frontotemporal, Parkinson's, Lewy body disease, and vascular type) were extracted. If a meta-analysis or systemic review was not available, then the searches included evaluation of data in the form of double-blind, randomized controlled trials or open-label studies. Various studies suggest that compared to placebo, AChEIs and memantine are associated with better outcome in all domains of Alzheimer's disease. In addition, combination therapy of AChEIs and memantine is superior to monotherapy with AChEIs in terms of behavioral disturbances, activities of daily living, and global assessment. In patients with dementia associated with Parkinson's disease or Lewy body dementia, use of donepezil, rivastigmine, and memantine is associated with significant efficacy on the global outcome measures when compared with placebo. Compared to placebo, AChEIs, but not memantine, have also been shown to have better cognitive outcomes in patients with dementia associated with Parkinson's disease or Lewy body dementia. Data are limited for the role of pharmacotherapy in management of frontotemporal dementia. In patients of vascular dementia, all AChEIs and memantine show some beneficial effects on cognition. Antidepressants and antipsychotics have been shown to be beneficial in management of behavioral symptoms and agitation. However, it is important to remember that there is black box warning for use of antipsychotics among patients with dementia. One of the major limitations of the research is variability in assessment instruments used for rating various symptoms encountered in patients of dementia. However, it can be concluded that in recent times, quality of studies has improved and many studies have included adequate sample sizes.
Keywords: Dementia, efficacy, pharmacotherapy
|How to cite this article:|
Avasthi A, Gupta G, Grover S. Pharmacotherapy of dementia. J Geriatr Ment Health 2016;3:66-79
| Introduction|| |
Dementia is a group of chronic diseases characterized by a constant decline in the function of multiple cognitive domains comprising memory impairment, behavioral problems, loss of initiative, loss of independence in daily activities, and loss of participation in social activities.  In the fifth revision of Diagnostic and Statistical Manual (DSM-5),  dementia is subsumed under the category of major neurocognitive disorder.
In general, it is suggested that the prevalence of dementia is increasing. The global prevalence of dementia is as high as 24 million and has been predicted to quadruple by the year 2050.  It is also now well recognized that it is associated with significant financial and caregiver burden.  Subtypes of degenerative dementias include Alzheimer's, frontotemporal, Parkinson's, Lewy body dementia More Details, and vascular type. Alzheimer's disease (AD) is the most common form of dementia, accounting for an estimated 50-75% of cases. 
Unfortunately, at this moment, there is no cure for dementia, and management of dementia involves use of strategies which merely delay the cognitive deterioration process or reduce the behavioral problems present as part of the broad clinical picture of dementia. Accordingly, multiple classes of medications are used in the management of dementia. These can be broadly categorized as cognitive enhancers, antipsychotics, antidepressants, mood stabilizers, and sedative hypnotics.
Over the last few decades, the evidence base for management of dementia has broadened with the availability of numerous randomized controlled trials (RCTs) for various medications in different type of dementia. Similarly, multiple reviews and meta-analyses are also available according to the specific medication, specific class of medication, type of dementia, or type of symptom of dementia.
This article provides a broad overview of the existing data. The data search strategies for this review included electronic databases of relevant publications or cross-references. The electronic searches included PubMed and other search engines (e.g. Google Scholar, PsychINFO). Cross-searches of electronic database and hand search of review articles yielded other relevant material. The electronic and hand searches focused on pharmacological treatment of dementia, and the keywords were used to locate the meta-analysis and systemic reviews for treatment in five main types of dementia (Alzheimer's, frontotemporal, Parkinson's, Lewy body disease, and vascular type). If a meta-analysis or systemic review was not available, then the searches included evaluation of data in the form of double-blind, randomized controlled trials (DBRCTs) or open-label studies. Terms for dementias (Alzheimer's, frontotem electronic search poral, Parkinson's, Lewy body disease, and vascular type) were combined with various class of medications and specific drugs used in dementia (acetyl cholinesterase inhibitors [AChEIs], donepezil, galantamine, rivastigmine, metrifonate, tacrine, antipsychotics, haloperidol, thioridazine, thiothixene, chlorpromazine, acetophenazine, clozapine, olanzapine, risperidone, quetiapine, aripiprazole, antidepressants, sertraline, fluoxetine, citalopram, trazodone, mood stabilizers, valproate, carbamazepine, lithium, anticonvulsants, benzodiazepines, memantine, or psychotropic drugs), along with symptoms of dementia (cognitive symptoms, behavioral and psychological symptoms of dementia [BPSD], neuropsychiatric symptoms, behavior). An attempt has been made to provide a broad overview of the available data.
| Outcome measures|| |
Many outcome measures have been used in evaluating the treatment response among patients with dementia. The commonly used primary outcome measures include mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), activities of daily living (ADL), neuropsychiatric inventory (NPI), and Clinician's Interview-Based Assessment of Change-Plus (CIBIC-plus) as the measure of cognition, function, behavior, and global assessment of change, respectively [Table 1]. Commonly used secondary outcome measures include adverse events and dropout rates during the drug treatment. Some of the trials, which primarily assessed the safety of drugs, took incidence of adverse events as the primary outcome measure while NPI, MMSE, and caregiver burden (e.g. as measured by the Zarit scale) were taken as secondary outcome measure.
|Table 1: Commonly used instruments to assess the efficacy/effectiveness of pharmacotherapy among patients with dementia|
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| Alzheimers Disease|| |
AD is an irreversible and progressive neurodegenerative disorder and is the most common cause of dementia worldwide.  The incidence of AD is increasing in line with population aging throughout the world. As per estimates of 2010, 35.6 million people were living with dementia, and this is expected to double to 65.7 million by 2030 and 115.4 million by 2050. Approximately half of the patients with AD have moderate or severe disease.  The primary feature of AD is progressive cognitive decline, characterized by episodic memory loss and impairments in attention/concentration, orientation, judgment, visuospatial ability, executive function, and language.  Severe AD is characterized by reduced communication and mobility. Patients may have apraxia, agnosia, and neuropsychiatric symptoms and increasingly require specialized care.  AD is therefore associated with a substantial burden for patients, families, caregivers, and society. However, successful treatment can substantially improve quality of life for patients. 
In terms of etiology, it is hypothesized that the cognitive decline observed among patients with AD is due to the loss of cholinergic tone, along with reduction in acetylcholine (ACh) levels in the brain. Further, it is hypothesized that neuronal loss in AD is related to glutamatergic over-stimulation. Accordingly, medications used for management of AD involve molecules which enhance the cholinergic signaling.  The nicotinic ACh receptor family and the muscarinic ACh receptor family are the targets of ACh in the brain. 
The commonly used molecules which act on the Ach system are AChEIs. The AChEIs increase cholinergic neurotransmission in forebrain by preventing the breakdown of ACh. Four AChEIs have been developed over the years. These include tacrine, donepezil, rivastigmine, and galantamine. Tacrine, first AChEIs approved for the treatment of AD in 1993. However, soon, it was found to be associated with high incidence of hepatotoxicity. , Accordingly, this molecule is not used for management of dementia. Donepezil is approved for complete spectrum of AD while other two are approved for mild to moderate AD only. 
Donepezil is a selective reversible AChEI, which has been licensed for management of all stages (mild, moderate, and severe) of AD. Many DBRCTs have evaluated the efficacy of donepezil and it has been shown to be better than placebo studies. ,,, A recent review included 6 recent trials of donepezil which evaluated its efficacy in patients with moderate to severe AD.  Many of these studies included patients from more than one center and evaluated the patients for a duration of 24 weeks. The studies have been done among patients of Asia, Europe, Australia, North America, South Africa, and South America. The sample size of these studies varied from 290 to 1434 and on an average, the mean age of the study sample has been more than 70 years. As discussed earlier, the studies have varied in terms of primary and secondary outcome measures. In general, data suggest that compared to placebo, donepezil is associated with improvement in MMSE scores and other cognitive measures donepezil has also been shown to lead to reduction in caregiver burden. There is some evidence to suggest that there is a dose-response relationship among patients with severe AD.  Donepezil has also been tried in patients with severe AD. Efficacy data from 3 large, prospective, RCTs and a post hoc analysis show that initiation of donepezil treatment in patients with severe AD can provide small, but significant, benefits in terms of short-term improvement and/or maintenance of cognition and function. ,,,
Donepezil has been approved at daily doses of 5 or 10 mg/day for more than a decade  and in 2010, a new high-dose once-daily 23 mg tablet was approved for treatment of patients with moderate to severe AD.  Cholinergic deficits are greater in patients with more severe disease, suggesting a need for higher AChEI doses to increase the efficacy of existing ACh activity in the brain. The donepezil 23 mg tablet is a sustained release formulation (donepezil 5 and 10 mg/day are immediate-release formulations) that provides a higher once-daily dose without a sharp daily rise in peak concentration. Studies which have evaluated the efficacy and safety of 23 mg/day compared with 10 mg/day suggest the predictable tolerability profile for the higher dose. ,
Rivastigmine is an inhibitor of both acetylcholinesterase and butyrylcholinesterase. Usual oral dose for rivastigmine is 1.5 mg twice daily, and it can be increased gradually over weeks to 6 mg twice daily. It is also available in patches which may decrease side effects and increase compliance. , Studies have shown the efficacy of both oral formulations and also patches. A recent meta-analysis included 13 DBRCTs which evaluated the efficacy of rivastigmine (6-12 mg/day orally or 9.5 mg/day transdermally) in contrast to placebo in trials of 12 weeks or longer.  Patients were diagnosed with probable AD according to internationally accepted criteria. The available evidence suggested that compared to placebo, rivastigmine was associated with better outcomes for cognitive function (assessed by using ADAS-cog score [n = 3232; 6 studies] and the MMSE score [n = 3205; 6 studies]), ADL (n = 3230; 6 studies) and clinician-rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (n = 3338; 7 studies).  Studies have also evaluated the usefulness of rivastigmine on behavioral change, and these studies suggest no significant differences compared to placebo. Studies which have evaluated the effect of rivastigmine on caregiver distress have not reported any significant beneficial effect when compared to placebo. Studies which have evaluated the tolerability of rivastigmine suggest that patients on rivastigmine were about twice as likely to withdraw from the trials (n = 3569, 7 studies) or to experience an adverse event during the trials (n = 3587, 7 studies) compared to placebo. 
Galantamine can stimulate nicotinic ACh receptors, in addition to ChEI activity.  It is usually recommended in the doses of 4 mg twice daily and can be increased gradually up to 12 mg twice daily. Extended release formulations are also available. In terms of its efficacy in management of AD, a meta-analysis included 11 RCTs involving patients with a diagnosis of probable or possible AD without any other psychiatric or neurological disorder receiving galantamine ≥16 mg daily for minimum duration of 8 weeks. A total of 4074 participants were included, with 2515 in the galantamine group and 1559 in the placebo group. The doses of galantamine ranged from 16 to 40 mg daily, and the durations of trials ranged from 8 to 28 weeks. Evidence suggests that compared to placebo, galantamine was associated with significantly better cognitive outcome (as assessed by ADAS-cog score or MMSE scores), improvement in behavioral symptoms (as assessed by using NPI), and global outcome (as assessed by using CIBIC plus scale). However, in terms of functional outcome, galantamine was not associated with significant beneficial effect on the level of functioning as assessed by mean change in ADL score. Compared to placebo, more number of patients on galantamine experienced adverse effects. Main adverse effects were gastrointestinal and nervous system side effects such as nausea, vomiting, diarrhea, anorexia, dizziness, depression, and headache. 
| N-Methyl-D-Aspartate Receptor Antagonist|| |
Memantine is a noncompetitive N-methyl-D-aspartate receptor antagonist. Memantine is thought to protect neurons from excessive glutamate activity that results in excitotoxicity. , Other properties of memantine that may also be relevant in management of AD include its ability to enhance long-term potentiation  and decrease tau hyperphosphorylation. , Clinical studies and meta-analyses show that treatment with memantine improves cognition, neuropsychiatric and behavioral symptoms, and clinical global impression ,,, among patients with AD. A recent meta-analysis evaluated the efficacy of memantine compared to placebo.  The meta-analysis included 9 RCTs involving 2433 patients with AD. The mean duration for the studies included in the meta-analysis was 31 weeks (range 24-52 weeks), and the mean age of the study population was 76 years. Three studies were conducted in the United States, 2 in Japan, 1 in Austria, 1 in the United Kingdom, 1 in China, and 1 in multiple countries (Austria, Belgium, Denmark, Finland, France, Greece, Lithuania, The Netherlands, Poland, Spain, Sweden, and the United Kingdom). This meta-analysis showed compared to placebo, memantine monotherapy was associated with improvement in cognitive function, behavioral disturbance, ADL, assessment of global function, and stage of dementia assessment scores. Discontinuation rates because of all causes and adverse events were similar between pooled memantine monotherapy and placebo groups. Memantine was associated with significantly lower rate of discontinuation because of inefficacy in the pooled memantine monotherapy group. No significant differences were found between groups in the incidence of all adverse events, serious adverse events, insomnia, anxiety, depression, falls, influenza-like symptoms/upper respiratory infections, dizziness, headache, urinary tract infection, peripheral edema, diarrhea, constipation, rhinitis, and death. 
| Combination acetyl cholinesterase plus memantine|| |
Studies have also evaluated the efficacy of combination of AChEIs and memantine. The combination which has been evaluated in RCTs includes donepezil and memantine. A meta-analysis included three trials which evaluated the efficacy of combination when compared to donepezil alone. Out of the three trials, the first trial showed a significant benefit of combination therapy (memantine plus AChEIs) compared with AChEI monotherapy on cognition, ADL, global outcome, and behavior. Combination therapy was also well tolerated. However, the second trial did not find any advantage of combination therapy compared with AChEI monotherapy in any domain in patients with mild as well as moderate disease. The third trial depicted statistically significant benefit of combination compared to AChEI monotherapy extended release (ER) on cognition, global improvement, and behavior, but not on function, after 6 months of treatment. Memantine ER was well tolerated. This systematic review and meta-analysis suggest a small but significant benefit of memantine combination therapy on cognitive, global, and behavior measures, but not on function/ADL, when data from all included trials, including one trial of ER memantine, were pooled. This effect size is comparable to that seen for memantine monotherapy. However, since the impact on clinical global impression depends on exactly which studies are included and there is no benefit on function, the clinical relevance of combination therapy is not robustly demonstrated.  Another review included 7 RCTs, 3 of which evaluated AChEI plus memantine, 3 evaluated donepezil and memantine, and 1 evaluated rivastigmine patch and memantine.  The mean study duration of these trials was 27 weeks, with four trials of 24 weeks and one trial each of 52 weeks and 16 weeks. In one trial, the study duration ranged from 6 months to 4 years. The sample sizes ranged from 43 to 677 patients in each study, and the mean age of the study population was 76 years. The studies were conducted in 1 or multiple countries: 3 were conducted in the United States, 1 in South Korea, 1 in the United Kingdom, 1 in Romania, and 1 in Argentina, Chile, Mexico, and the United States. Evidence from these trials suggests that combination of AChEI and memantine was superior to monotherapy with AChEI in terms of behavioral disturbances, ADL, and global assessment; however, the effect size was small. For cognitive functions, there was a trend for beneficial effect of combination therapy when compared to AChEI alone. 
From the above review, it can be concluded that AChEI when given alone or in combination with memantine are beneficial in management of AD.
| Parkinson's Disease Dementia And Lewy Body Dementia|| |
There is significant overlap in the clinical features of Lewy body dementia (DLB) and dementia of Parkinson's disease (PDD).  The diagnosis of PDD rests on the occurrence of formally diagnosed Parkinson's disease (PD) followed at least 12 months later by dementia (with no other apparent cause identified). The diagnosis of "probable DLB" is more complex than that for PDD. It depends on the presence of two of the following symptoms, i.e., persistent visual hallucinations, fluctuations in cognitive and functional ability, and Parkinsonism More Details. If parkinsonian symptoms are part of the picture, dementia should have occurred within 12 months of the onset of the parkinsonian symptoms. It is suggested that 15-38% patients with PD develop dementia at 4-5 years follow-up and 50-78% develop dementia at 8-10 years follow-up. ,,,,,,, It is known that occurrence of dementia doubles the mortality risk of PD and dramatically increases the level of care needed by the PD patient. 
The mechanisms underlying PDD is not delineated fully. The involvement of central cholinergic systems in PDD is supported by several observations. The ascending cholinergic system arising from the nucleus basalis of Meynert is damaged in PDD, which causes decreased cholinergic activity both in cortical areas and in basal telencephalon.  Second, cholinergic deficits are more marked in PD patients with dementia compared with those without. ,,, Other theory suggests that symptoms of dementia in PD may be due to dopamine deafferentation of prefrontal-striatal loops, but the absence of a significant effect of L-dopa on cognition argues against a major role for dopaminergic-driven cognitive decline.  Studies also suggest an association between the timing of appearance of Lewy bodies (LBs) in the cortex and the development of dementia. , The diagnosis of PDD rests on the occurrence of formally diagnosed PD followed at least 12 months later by dementia (with no other apparent cause identified).
Most of the studies which have evaluated the efficacy of various pharmacological agents due to lack of distinction between PDD and DLB have included patients with both the disorders. However, occasional studies have evaluated patient with only one diagnosis.
Cholinesterase inhibitor in Parkinson's disease
A recent meta-analysis evaluated the 4 DBRCTs of patients with diagnosis of PD based on the UK Brain Bank criteria, taking any dosage of rivastigmine and donepezil were included. ,,,, One RCT compared rivastigmine with placebo and 3 RCTs compared donepezil with placebo. No RCTs were found for galantamine. Evidence from these studies suggests that AChEIs significantly slow cognitive decline as assessed by MMSE and ADAS-cog and improved behavioral disturbance and global functioning. Death rate was reduced in treated patients as compared with placebo.
Memantine in DLB and Parkinson's disease dementia
A recent review included 7 RCTs involving 431 patients with DLB. Within the 7 RCTs, two included patients with DLB and PDD, two included patients with PDD, and three included patients with PD. In 5 out of 7 studies, memantine was used along with L-dopa, and remaining 2 studies did not mention whether the patients were on L-dopa or not. The mean study duration was 15.8 weeks, and the mean age of the study population was 71.2 years. Six of seven studies were double-blind, placebo-controlled trials. Overall data from these trials suggest that memantine was not associated with any significant beneficial effect on motor function, MMSE, NPI, and ADL scores. However, memantine was superior to placebo in terms of AD Cooperative Study-Clinical Global Impression of Change (CGI-C) scores. Memantine was well tolerated in patients with DLB, with no significant differences in serious adverse events in the form of somnolence/tiredness, stroke, dizziness/vertigo, and confusion were found between the groups. 
A recent meta-analysis assessed efficacy and safety of treatment among patients with cognitive impairment in PD, PDD, and dementia with LBs. It included ten trials (5 donepezil, 2 rivastigmine, and 3 memantine trials), sample size of which varied from 14 to 550 patients and the treatment duration of which ranged from 10 weeks to 24 weeks. This meta-analysis concluded that the therapeutic benefits of drugs were observed with donepezil 5 mg/day, donepezil 10 mg/day, rivastigmine 12 mg/day, and memantine 20 mg/day. AChEIs (donepezil and rivastigmine), but not memantine, significantly improved the cognitive function (MMSE and ADAS-cog). Donepezil and rivastigmine produced significant effects on NPI-10, but memantine 20 mg did not improve NPI-12. One rivastigmine and two memantine trials used ADL or disability assessment for dementia scale (DAD) to assess ADL, and the findings suggested significant effect with rivastigmine 12 mg/day on ADL. Studies which assessed the caregiver burden with Zarit caregiver burden interview (ZBI) showed that donepezil 10 mg/day produced significant effects over placebo, but donepezil 5 mg/day and memantine 20 mg/day did not lead to improvement on ZBI scale. The common adverse events were cholinergic in nature (anorexia, nausea, vomiting, diarrhea, etc.); other side effects included aggravation of Parkinson and psychiatric symptoms (tremor, fall, somnolence, insomnia, pain, hallucination, confusion state, etc.), dizziness, urinary tract infection, and respiratory tract infection. Most adverse events were mild or moderate. Inconsistent with dropout risk, rivastigmine groups experienced significantly more adverse events than placebo groups. However, donepezil and memantine did not produce significant difference on adverse events compared to placebo. The number of dropouts for adverse events was not significantly greater in rivastigmine, donepezil, or memantine and those with placebo. Donepezil and memantine did not significantly change the mortality compared to placebo. However, subjects with rivastigmine 12 mg/day were significantly less likely to die than those with placebo in rivastigmine trials. 
Hence, overall, it could be concluded that AChEIs are better than memantine in management of DLB and PDD.
| Frontotemporal dementia|| |
Frontotemporal dementia (FTD) is a clinical term for a cluster of syndromes resulting from degeneration of the frontal and temporal lobes. ,,,, FTD is the third leading cause of dementia, prevalence of which in epidemiological studies from European countries and the United States ranges from 4 to 15/100,000 among people aged <65 years of age.  Although historically regarded as a disorder with presenile onset (prior to 65 years of age), perhaps 25% of pathologically confirmed cases present after the age of 65 years. , There are three variants of FTD which often overlap, particularly at later stages of disease as atrophy becomes more widespread. ,, About half of cases present with behavioral change (behavioral variant FTD), and the remainder present with language decline (primary progressive aphasia) characterized either by impaired speech production (progressive nonfluent aphasia) or by impaired word comprehension and semantic memory (semantic dementia).
There have been relatively few RCTs in FTD, and those that have been done and included small number of participants and have been inconclusive, particularly with regard to cognition.
In terms of neurotransmitter involvement, FTD is not associated with specific cholinergic deficiency, so there is no clear rationale to use anticholinesterase agents in FTD. However, in some patients, these agents may help in memory, but these may worsen behavior in others.  Studies which have evaluated the role of donepezil suggest that donepezil is associated with greater worsening on the FTD Inventory (Four treated patients had increased disinhibited or compulsive acts, which abated with discontinuation of the medication). However, there were no changes in global cognitive performance or dementia severity.  Use of memantine in FTD is also not supported by available evidence. A RCT which included 39 patients on memantine and 42 patients on placebo for 26 weeks did not show any benefit of memantine on NPI, CGI-C, neuropsychological battery, and other cognitive, global, and ADL measures. 
| Vascular dementia|| |
Vascular dementia (VaD) is an outcome of ischemic, ischemic-hypoxic, or hemorrhagic brain tissue lesions due to cardiovascular disease and cardiovascular pathological changes. , It is suggested that prevalence of VaD is increasing, doubling every 5 years to the age of 90. Currently, it is estimated that 1-4 of every 100 individuals by age of 65 are affected by VaD.  Studies have evaluated the role of donepezil in management of dementia.
A Cochrane review included two large-scale, DBRCTs which included 1219 subjects with mild to moderate cognitive decline due to probable or possible VaD (according to the NINCDS/AIREN criteria and the Hachinski Ischemia Scale). In these trials, 5 or 10 mg/day of donepezil was compared with placebo for 24 weeks. These studies suggested that donepezil was associated with significantly better performance than the placebo on the ADAS-cog scale and MMSE at 12 and 24 weeks, respectively. The sum of the boxes of the clinical dementia rating showed statistically significant benefit of 10 mg donepezil daily over both placebo and 5 mg daily dosage of donepezil at 24 weeks. Global function as assessed using Clinician's Interview-Based Impression of Change-plus (CIBIC-plus) showed improved global function of participants taking 5 mg of donepezil daily compared with the placebo group, but this was not seen in the higher dose group. On the instrumental ADL scale, there was no statistically significant difference between the groups taking donepezil 5 mg/day and placebo; however, donepezil 10 mg/day was found to be better than placebo. There was statistically significant benefit for donepezil at either dosage compared with placebo on the AD Functional Assessment and Change Scale. In terms of tolerability, donepezil was well tolerated, and most of the side effects were transient and these resolved by stopping the medication. Some of the adverse events, especially nausea, diarrhea, anorexia, and cramp, were more commonly seen with 10 mg/day and were significant more compared with placebo. The dropout rate was similar between the groups, with completion rate of 84.2%. The withdrawal rate was low and due mainly to side effects. 
Available studies also suggest that rivastigmine is not useful in the management of VaD. A Cochrane review, which included 2 small trials (n = 40 and n = 50), did not find any significant difference on any outcome measure relevant to cognition, neuropsychiatric symptoms, function or global rating over 24-26 weeks.  However, a large sample size trial which included 710 participants with VaD showed statistically significant advantage in cognitive response (but not with global impression of change or noncognitive measures) with rivastigmine (mean dose of 9.4 mg/day). However, in this trial, significantly higher number of patients on rivastigmine arm withdrew from the study due to adverse events.  Overall, it can be concluded that rivastigmine is not beneficial in management of VaD.
Studies which have evaluated the efficacy of galantamine among patients with VaD suggest that it may have beneficial effect on cognition among patients with VaD. A Cochrane review which included 2 DBRCTs, evaluating galantamine dose of 16-24 mg/day in two divided doses of 6 months duration in 1378 participants. It was seen that compared to placebo, galantamine was associated with the favorable cognitive outcome as assessed on ADAS-cog. In one of these studies, authors also reported statistically significant beneficial effect of galantamine on ADL (DAD) and behavior (NPI); however, in another trial (GAL-INT-26, n = 788 patients), placebo group did well compared with galantamine for behavior (NPI). In both the trials, significantly higher numbers of patients on galantamine dropped out from treatment. 
Another review included trials of 6-month duration with similar VaD criteria and outcome measures. This review included eight trials, i.e., 3 for donepezil, 2 for galantamine, 1 for rivastigmine, and 2 for memantine. In total, 3093 patients received study drugs and 2090 patients were on placebo. The available data suggested cognitive effects of all medications; however, only 5 mg daily donepezil had an effect on the Clinicians' Global Impression of Change scale. All the AChEI treatment groups were associated with more dropouts and adverse events (anorexia, nausea, vomiting, diarrhea, and insomnia) compared to placebo, but the same was not true with memantine. 
| Pharmacological management of behavioral symptoms associated with dementia|| |
Patients with dementia often manifest neuropsychiatric symptoms such as agitation, psychosis, depression, and apathy. Management of these symptoms is equally important as these symptoms can lead to dangerousness to self or others and these can have impact on the caregivers. Management of these symptoms involves use of psychotropic medications although these uses are considered to be off-label as use of these medications is not approved by the Food and Drug Administration (FDA).
Studies which have evaluated the efficacy/effectiveness of various psychotropic medications have used different rating scales. Studies which have evaluated the efficacy/effectiveness of antidepressants in the management of depression among people with dementia have used Hamilton Depression Rating Scale (HDRS), Montgomery Asberg Depression Rating Scale (MADRS), or Cornell Scale for Depression in Dementia (CSDD), CGI, and modified AD Cooperative Study - CGI-C. Response to antidepressants is defined as 50% or more reduction in the rating of these scales, and remission rates were defined as HDRS score of 7 or less, CSDD score of 6 or less, or MADRS score of 10 or less or global rating of very much improved. Studies which have evaluated antipsychotics in management of various behavioral and psychological symptoms associated with dementia include scales such as agitated behavior mapping instrument, behavioral and emotional activities manifested in dementia, behavior rating scale for dementia, behavioral pathology in AD (BEHAVE-AD), behavioral activities in demented geriatric patients, brief agitation rating scale, Cambridge mental disorders of the elderly examination, caretaker obstreperous behavior rating assessment, clinical rating scale for symptoms of psychosis in AD, Cohen-Mansfield agitation scale, Columbia University scale for psychopathology in AD, Consortium to establish a registry for AD, CSDD, dementia behavior disturbance scale, dementia mood assessment scale, disruptive behavior rating scale, dysfunctional behavior rating instrument, harmful behaviors scale, irritability, aggression, and apathy scale, Manchester and Oxford Universities scale for the psychopathological assessment of dementia, neurobehavioral rating scale (NBRS), NPI, Nurses' Observation Scale for inpatient evaluation, nursing home behavior problem scale, observed agitation in patients with DAT (SOAPD), overt aggression scale, Pittsburgh agitation scale, present behavioral examination, rating anxiety in dementia, rating scale for aggression in the elderly, resistiveness to care scale (DAT), Ryden aggression scale, agitated behavior in dementia scale, California dementia behavior questionnaire, caregiver and clinical assessment of behavioral disturbance, and challenging behavior scale.
| Management of neuropsychiatric symptoms with cholinesterase inhibitors and memantine|| |
Wang et al.  carried out a meta-analysis to quantify the efficacy and safety of pharmacological treatment on neuropsychiatric symptoms in AD patients. They included DBRCT with parallel or crossover design in patients diagnosed with probable or possible AD as per DSM-IV criteria or criteria of the National Institute of Neurological and Communicative Disorders and Stroke/AD and Related Disorders Association. Studies included in this meta-analysis compared any medication at any dose with placebo, with any treatment durations. Neuropsychiatric outcomes were measured with NPI-10 or NPI-12 or NPI-Nursing Home Version. The meta-analysis included 32 trials, i.e., 15 AChEIs trials (eight for donepezil, four for galantamine, and three for metrifonate), eight trials of memantine, six trials which evaluated atypical antipsychotics, 2 antidepressant trials, and 1 mood stabilizer trial. All trials were placebo controlled DBRCT, conducted mainly in North American and European countries. Total study population in these trials included 6812 patients in the active treatment group and 4844 participants in placebo arm. The mean age of patients ranged from 73.3 to 85.6 years. The mean baseline MMSE score ranged from 4.5 to 21.2. Out of the 15 trials for various AChEIs, seven trials reported statistically significant benefit. However, there was substantial heterogeneity (I2 = 67%) among the studies. In sensitivity analyses excluding studies that did not use intention to treat analysis method or the only one long-term trial, the beneficial effect of AChEIs on NPI was still noted. However, when studies that used estimated standard deviations were excluded, the significant beneficial effect of AChEIs disappeared. When the specific AChEIs were evaluated, galantamine was associated with significant improvement in behavioral disturbances of AD patients, but the same was not true for donepezil. The eight trials of memantine included in the meta-analysis, involving 1496 patients in the active treatment group and 1333 patients in placebo group, did not reveal beneficial effect of memantine on the behavioral symptoms as assessed by NPI. As with AChEIs studies, there was large heterogeneity in studies; however, no publication bias was observed. Sensitivity analysis showed that exclusion of trials which estimated standard deviations did not alter outcome.
| Management of neuropsychiatric symptoms with antipsychotics|| |
Atypical antipsychotics are the most widely used class of psychotropic medications in the treatment of BPSD as conventional antipsychotics use is associated with serious cardiovascular and anticholinergic adverse effects and extrapyramidal symptoms which may lead to decreased mobility, increased risk for falls, increased need for personal care, nursing home admission, and increased mortality risk. Most of the evidence for use of antipsychotics favors the use of risperidone and olanzapine  and to a lesser extent for the use of quetiapine,  aripiprazole,  ziprasidone,  and haloperidol.  However, in patients with DLB or PDD, quetiapine or clozapine is the preferred option, given the risk of worsening motor symptoms with other antipsychotics,  but the use of clozapine is restricted in many countries due to the risk of serious adverse effects.
Various meta-analyses have evaluated the efficacy of antipsychotics for management of neuropsychiatric symptoms in patients with dementia. A meta-analysis by Wang et al.  which included six trials of antipsychotics showed significant improvement on NPI total score in patients with AD treated with atypical antipsychotics compared with placebo. There was mild heterogeneity among the pooled studies and improvement on NPI scale remained significant in sensitivity analysis after excluding studies that used estimated standardized mean differences. There was no significant publication bias. Subgroup analysis for specific antipsychotics showed beneficial effect of olanzapine and aripiprazole. A recent meta-analysis included 23 RCTs involving 5819 participants and showed that compared to placebo, aripiprazole and risperidone have superior efficacy in terms of management of psychiatric symptoms. Aripiprazole, risperidone, olanzapine, and quetiapine were also associated with improvement in cognitive symptoms as assessed by CGI-C. Overall use of atypical antipsychotics was not found to be associated with risk for injuries or falls, significantly higher risks for somnolence, urinary tract infection, edema, and abnormal gait. However, there was no significant evidence for death reported.  Another meta-analysis, which included 9 placebo-controlled trials of atypical antipsychotics for aggression and psychosis in AD assessed on the BEHAVE-AD and NPI subscores, reported beneficial effects for risperidone and olanzapine.  Risperidone also improved psychosis. However, both risperidone and olanzapine were associated with higher rates of serious cardiovascular events and extrapyramidal symptoms.  The Clinical Antipsychotic Trials of Intervention Effectiveness-AD study (CATIE-AD) showed benefits of risperidone and olanzapine on the NPI total score. However, there was high rate of discontinuation due to adverse effects.  Quetiapine was shown to have limited efficacy on symptoms which may have been related to the low doses prescribed. Overall, treatment in the CATIE-AD study did not result in improvement in functioning, care needs, or quality of life. Atypical antipsychotics were also associated with worsening of cognitive function compared with placebo. 
Studies which have evaluated the efficacy of quetiapine in management of various symptoms seen among patients with dementia suggest that quetiapine in doses of 100 mg/day is not beneficial for management of psychotics symptoms among patients with dementia;  however, it has been shown to be beneficial in the management of agitation in the doses of 200 mg/day.  Studies which have compared the efficacy of low doses of quetiapine and risperidone (mean doses quetiapine 77 ± 40 mg/day, risperidone 0.9 ± 0.3 mg/day) suggest that both the molecules are equally effective.  Quetiapine has been found to have negligible extrapyramidal symptom risk, minimal anticholinergic effects, and fewer metabolic adverse effects.  The main concerns include sedation and orthostatic hypotension.
Studies which have evaluated aripiprazole have concluded that compared to placebo, aripiprazole is associated with modest improvements in psychosis and agitation. , It is generally well-tolerated with the most common reported adverse event being mild somnolence. The somnolence was not associated with falls or accidental injury. No clinically significant electrocardiogram abnormalities or weight changes have been noted with aripiprazole.  A placebo-controlled study of the short-acting formulation of 10 mg to 15 mg in divided doses in dementia patients suggests that it is efficacious for acute agitation. 
There are no controlled trials of clozapine for patients with behavioral and psychological symptoms of AD. Similarly, efficacy of the newer atypical antipsychotics including ziprasidone, paliperidone, asenapine, and lurasidone has not been established in controlled trials for patients with behavioral and psychological symptoms of AD.
However, it is important to note that the food and drug administration of the United States of America issued a black box warning in 2005 for use of atypical antipsychotics in patients with dementia due to increased risk of mortality. Later with the available of further evidence, the black box warning was also extended to conventional antipsychotics too.
| Management of neuropsychiatric symptoms with antidepressants|| |
A few meta-analyses have evaluated the beneficial effects of antidepressants among patients with dementia. A meta-analysis of seven trials involving 330 patients having depression in dementia reported an odds ratio (OR) of 2.12 for response and OR 1.97 for remission outcomes.  Another meta-analysis included nine trials of various selective serotonin reuptake inhibitors (SSRIs), involving 692 patients, for management of agitation and psychosis in dementia.  The meta-analysis concluded that there was a significant difference between antidepressants and placebo on measures of agitation as reported on the change in Cohen-Mansfield Agitation Inventory (CMAI) score. However, there were no significant differences in change in behavioral symptoms of dementia with SSRIs compared to placebo in one study that reported on changes in the NPI and Behavioral Pathology in Dementia scales. One study compared citalopram to placebo found a significant difference in NPS as measured on the NBRS after controlling for baseline severity NBRS score although the unadjusted mean difference was not statistically significant. One study compared citalopram to the atypical antipsychotic risperidone and found no difference in NBRS scores. Three studies compared SSRIs to haloperidol, of which 2 studies reported no statistically significant differences in changes in CMAI total scores. There was also no difference in trial withdrawals due to any cause or due to adverse events for SSRIs compared to typical antipsychotics. Studies which have evaluated trazodone have not found it to be more efficacious than placebo and other studies have shown trazodone to be as efficacious as haloperidol in terms of CMAI scores. A meta-analysis by Wang et al.  included two RCTs on sertraline that met inclusion criteria. Neither of the two trials showed superiority of sertraline to placebo on changes of NPI scales. A systematic review which included 9 DBRCTs showed that SSRIs and trazodone and amphetamines may be effective in reducing some behavioral symptoms, but none of these medications had an impact on cognition.  A few open-label trials have evaluated that buspirone for agitation and aggression in dementia suggests some benefit. ,, A pilot placebo-controlled study on trazodone and buspirone suggested benefits for trazodone but not buspirone in behaviorally disturbed AD patients.  Open-label trials have also shown beneficial effect of mirtazapine for agitation among patients with AD found significant reduction in the CMAI-Short form and CGI-Severity scales (P < 0.001) between pre- and post-treatment.  A multicentric trial evaluated the role of mirtazapine, sertraline, and placebo in management of depression among patients with AD and reported no significant difference in the depressive symptoms between different treatment groups at 13 and 39 weeks. In fact, participants in the active treatment groups reported higher adverse reactions. 
Treatment of depression in FTD with SSRIs has shown these to be helpful although one study of paroxetine was positive  and another negative.  Trazodone has also been reported to be helpful for sleep as well as for "frontal" behavioral aberrations. 
| Management of Neuropsychiatric Symptoms with Mood Stabilizers/Antiepileptics|| |
Wang et al.  included one trial for mood stabilizers in their meta-analysis and this trial showed that valproate might worsen the NPI total score compared with placebo.
| Management of Neuropsychiatric Symptoms with Sedative-Hypnotics|| |
Some of the RCTs have evaluated the role of benzodiazepines such as oxazepam, alprazolam, diazepam, and lorazepam in management of BPSD. These studies have compared benzodiazepines with other active drugs such as haloperidol, olanzapine, and diphenhydramine and suggest no significant difference between the active drugs.  One study indicated that thioridazine may have better efficacy than diazepam for treating symptoms of BPSD. 
| Conclusion|| |
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Conflicts of interest
There are no conflicts of interest.
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