Archives for January 2012

Effective Pharmacological Management of Alzheimer’s Disease

Am J Manag Care. 2011 Nov;17 Suppl 13:S346-55.

Effective pharmacological management of Alzheimer’s disease.

Atri A.


Alzheimer’s dementia represents organ failure of the brain. It denotes a clinical milestone that is the result of a pathological process, Alzheimer’s disease (AD), which over 1 or more decades has wrought insidious destruction, and finally overwhelmed the brain’s capacities to compensate. It is incurable, progressive, and follows an individual pace and course. AD is particularly demanding and devastating to family and caregivers, and patients, all of whom suffer psychologically and emotionally.

The cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine and the N-methyl- D-aspartate receptor antagonist memantine are approved by the US Food and Drug Administration for AD; they are often used in combination once the disease reaches moderate stages. The relatively good safety profile of these medications, along with their efficacy in alleviating symptoms, is supported by several level-I evidence-grade, short-term, randomized, placebo-controlled trials (RCTs).

However, these studies are of limited value in assessing the real-world clinical and economic impact of AD therapies. Long-term, observational studies can provide complementary information to results from short-term clinical trials and more accurately assess practical long-term benefits, risks, costs, and effects on clinically meaningful end points.

There is now accumulating and convergent evidence from short- and long-term RCTs, longer-term open-label extensions of RCTs, and long-term observational studies that ChEIs and memantine reduce decline in cognition and daily function, and delay nursing home placement.

Optimal care in AD is multifactorial; it includes early diagnosis and multidisciplinary care with educational and nonpharmacological interventions, while ensuring safety, treating comorbidities, caring for caregivers, and appropriate initiation and maintenance of combination therapy.



Predicting Progression of Alzheimer’s Disease

Alzheimer’s Research & Therapy 2010, 2:2  doi:10.1186/alzrt25

Predicting Progression of Alzheimer’s Disease

Rachelle S Doody1*, Valory Pavlik1,2, Paul Massman3,1, Susan Rountree1, Eveleen Darby1 and Wenyaw Chan4



Clinicians need to predict prognosis of Alzheimer’s disease (AD), and researchers need models of progression to develop biomarkers and clinical trials designs. We tested a calculated initial progression rate to see whether it predicted performance on cognition, function and behavior over time, and to see whether it predicted survival.


We used standardized approaches to assess baseline characteristics and to estimate disease duration, and calculated the initial (pre-progression) rate in 597 AD patients followed for up to 15 years. We designated slow, intermediate and rapidly progressing groups. Using mixed effects regression analysis, we examined the predictive value of a pre-progression group for longitudinal performance on standardized measures. We used Cox survival analysis to compare survival time by progression group.


Patients in the slow and intermediate groups maintained better performance on the cognitive (ADAScog and VSAT), global (CDR-SB) and complex activities of daily living measures (IADL) (P values < 0.001 slow versus fast; P values < 0.003 to 0.03 intermediate versus fast). Interaction terms indicated that slopes of ADAScog and PSMS change for the slow group were smaller than for the fast group, and that rates of change on the ADAScog were also slower for the intermediate group, but that CDR-SB rates increased in this group relative to the fast group. Slow progressors survived longer than fast progressors (P = 0.024).


A simple, calculated progression rate at the initial visit gives reliable information regarding performance over time on cognition, global performance and activities of daily living. The slowest progression group also survives longer. This baseline measure should be considered in the design of long duration Alzheimer’s disease clinical trials.


© 2015 BioMed Central Ltd unless otherwise stated. Part of Springer Science+Business Media.


Effect of Plant Extracts on Alzheimer’s Disease

J Neurosci Rural Pract. 2011 Jan;2(1):56-61. doi: 10.4103/0976-3147.80102.

Effect of plant extracts on Alzheimer’s disease: An insight into therapeutic avenues

M Obulesuand  Dowlathabad Muralidhara Rao1

Capital College, Garden City Group of Institutions, Bangalore, India.

Srikrishnadevaraya University, Anantapur, India.


Alzheimer’s disease (AD) is a devastative neurodegenerative disorder which needs adequate studies on effective treatment options. The extracts of plants and their effect on the amelioration of AD symptoms have been extensively studied.

This paper summarizes the mechanisms like acetylcholinesterase (AChE) inhibition, modification of monoamines, antiamyloid aggregation effect, and antioxidant activity which are actively entailed in the process of amelioration of AD symptoms.

These effects are induced by extracts of a few plants of different origin like Yizhi Jiannao, Moringa oleifera (Drumstick tree), Ginkgo Biloba (Ginkgo/Maidenhair tree), Cassia obtisufolia (Sicklepod), Desmodium gangeticum (Sal Leaved Desmodium), Melissa officinalis (Lemon Balm), and Salvia officinalis (Garden sage, common sage).


Alzheimer’s association estimated that one in eight Americans above age of 65 years and half of the Americans above age of 85 years have been presently suffering from this devastative neurodegenerative disorder. According to this estimation, the number of patients may reach 16 million by 2050 thus augmenting the economic cost of Alzheimer’s disease (AD) health care system, which is 80-100 billion dollars presently.

Loss of cholinergic synapses in hippocampus and neocortex has been a consistent finding in AD, thus accentuating the need to employ a substantial strategy that regulates the AChE function to combat this defect. Tacrine, donepezil, and rivastigmine are a few AChE inhibitors approved by U.S. Food and Drug Administration for the amelioration of AD symptoms.

Although advent of such inhibitors has been effective in function yet there has been augmenting need to quest for new drugs. In the light of this fact, polyphenolic compounds from fruits and vegetables have been exploited because of their potential antioxidative properties. There has been growing focus on traditional herbal medicines presently since the failure of existing treatments. The first neurotransmitter found to be involved in AD is acetylcholine. Therefore, there have been manifold studies to employ AChE inhibitors.

Plants provide wealth of bioactive compounds, which exert a substantial strategy for the treatment of neurological disorders such as Alzheimer’s disease. It has been recently shown that a Chinese herb, Yizhi Jiannao Granules is effective in improving AD symptoms, and it also aggravates such amelioration when combined with acupuncture. Zeatin has been found to have a protective role against Aβ-induced neurotoxicity in PC12 cells and ameliorate scopolamine-induced amnesia in ICR mice.

Cholinesterase Inhibition

Growing lines of evidence suggests that among 73 native and naturalized plants collected from the central region of Argentina, organic fractions obtained from extracts of Achyrocline tomentosa (Marcela) (Asteraceae), Eupatorium viscidum (Common boneset) (Asteraceae), Ruprechtia apetala (manzano del campo) (Polygonaceae), Trichocline reptans (arnica) (Asteraceae), and Zanthoxylum coco (cochucho, coco) (Rutaceae) demonstrated substantial inhibition of AChE (higher than 80%).

Poncirus trifoliate (Trifoliate Orange) extract has been shown to inhibit AchE considerably. Methoxsalen isolated from medicinal herbs Treculia obovoidea (Catterall) and Angelica archangelica (Garden Angelica), shows antimicrobial and anti-AchE activities in vitro.

Studies on the seeds of Cassia obtisufolia proved their neuroprotective role in mice via attenuation of secondary Ca2+ dysregulation and mitochondrial toxin 3-NP. Moreover, they can improve memory impairment via AChE inhibition. Flavonoids, a group of phenolic compounds which demonstrate antimutagenic, anticarcinogenic, and antiageing properties may be responsible for neuroprotective role of Cassia obtusifolia extracts. Dried ginger has been shown to induce Ca2+ antagonistic activity and butylcholinesterase inhibitory activity which are effective in AD treatment.

Modification of Monoamines

Moringa oleifera (MO) which belongs to the family Moringaceae, is prevalent almost all over the Asian and African countries. Its fruit and leaves which show anti-inflammatory and hypotensive effect are consumed as food by the people. It has been found recently that Moringa oleifera leaf extract which is not toxic even at higher concentration levels, enhances memory via nootropics activity and provides substantial antioxidants like vitamin C and E to combat oxidative stress in AD.

Wealth of studies substantiated that monoamines entailed in the memory loss are altered by Moringa oleifera leaf extracts. Several lines of evidence also suggest that colchicines-induced AD can be ameliorated by ethanolic extract of Moringa oleifera by modifying the brain monoamines (norepinephrine, dopamine, and serotonin) and electrical activity in a rat model.

Antiamyloid Aggregation Effect

Ginkgo biloba being a potential store house of antioxidants offers ample of health benefits to AD patients like antiamyloid aggregation effect. Extensive studies on Ginkgo biloba revealed that 240 mg of Ginkgo biloba per day can decrease the incidence of AD. Although there are a few substantial studies on Ginkgo biloba to ameliorate AD symptoms and worldwide sales of it exceed $249 million annually in the United States, yet there has been augmenting need to initiate more promising clinical trials in this direction.

It has been found that the Ginkgo biloba extracts ameliorate cognitive defects in a mouse model of AD (Tg2576). Manifold clinical trials proved amelioration of AD symptoms and the clinical evaluation of EGb 761 that is widely used for dementia in many countries and an extensively used dietary supplement in the United States for memory enhancement, is presently in progress.

Although in vivo mechanism for EGb 761 is elusive yet it has been found to ameliorate AD symptoms both in vivo (AD mice Tg 2576) and in vitro. Upregulation of a small APP release, a nontoxic, nonamyloidogenic metabolite of APP, via a PKC-independent manner in hippocampi and cortices of EGb761-treated rats has been studied.


Desmodium gangeticum generally known as Salparni, is prevalent in India and has significant medicinal use as a bitter tonic, febrifuge, digestive, anticatarrhal, antiemetic, and anti-inflammatory conditions. Moreover, it has been extensively used in ayurveda for the amelioration of neurological symptoms.

Its extracts employed in mice to evaluate the efficacy in amelioration of AD symptoms via nootropic activity and deterioration of AChE activity yielded considerable outcome. It also possesses antioxidative property.

Rosmarinic acid isolated from Salvia officinalis, attenuates a number of events provoked by Aβ-like reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Despite a few pharmacological activities of sage attributed to AD include antioxidant activity, anti-inflammatory effects and cholinesterase inhibition, yet the mode of sage-protective action is unclear.

Rosmarinic acid has been known to initiate antioxidant, anti-inflammatory, antimutagen, antibacterial, and antiviral properties. Rosmarinic acid effectively inhibits hall mark events of AD-like formation of fibrils from Aβ, destabilization preformed Aβ fibrils in vitro and tau hyperphosphorylation.

Neuroprotective Effect of Traditional Japanese-Chinese, Korean, and European Plant Extracts

Kihi-to, a traditional Japanese-Chinese traditional medicine, shows significant amelioration of Aβ(25–35)-induced impairments in memory acquisition, memory retention, and object recognition memory in mice. It also attenuates neuritic, synaptic, and myelin losses in the cerebral cortex, hippocampus and striatum. Kihi-to also effectively attenuates the calpain augmentation in the cerebral cortex and hippocampus.

Abundance of research revealed that among several traditional Chinese medicines, Ginseng Radix Astragali Radix and Polygalae Radix demonstrated potential axonal extension activity against amyloid β (Aβ) (25–35)-induced axonal atrophy.

Among the 90 traditional Korean tea plants, methanolic extracts of Pueraria thunbergiana (Kudzu) rich in Daidzein (4,7 dihydroxy isoflavone), are actively entailed in the amelioration of scopolamine induced amnesia in mice. Abundance of research unraveled the neuroprotective effect of Gossypium Herbaceam extracts against ibotenic acid induced learning and memory impairment in rats.

Melissa officinalis extract has been proven to ameliorate mild to moderate AD. Among the European herbs M. officinalis and another herb in the labiatae family, S. officinalis, might present a natural treatment for AD by amelioration of cognition.

This herb actively amends mood and cognitive ability during acute administration in healthy young volunteers and has no side effects or symptoms of toxicity. S. triloba (Greek Sage) and Teucrium polium (Cat Thyme) are also effective in amelioration of AD symptoms.

Ayurvedic Plants and AD

Formulation of some Indian medicinal plants classified in Ayurveda, the classic Indian system of medicine, as Medhyarasayanas or drugs considerably ameliorates memory and intellect. Studies on rats demonstrated that the oral administration of Trasina, a herbal formulation, once daily for 21 days can effectively ameliorate colchicine induced effects like reduced frontal, cortical and hippocampal acetylcholine (Ach) concentrations, choline acetyltransferase (ChAT) activity, and muscarinic cholinergic receptor (MCR) binding.

It has been reported recently that alcoholic extract of Bacopa monnieri (Water Hyssop) significantly improves escape latency time in Morris water maze test and ameliorates reduction of neurons and cholinergic neuron densities in Wistar rats which are employed as AD animal models. Anwala churna (Emblica officinalis Gaertn.), an Ayurvedic preparation showed an exemplary improvement in memory and brain cholinesterase activity, thus ameliorating the scopolamine induced amnesia in young and aged mice.


Curcuma longa (Turmeric) has been the source of Curcumin (diferuloylmethane), an orange–yellow component of turmeric or curry powder. This being a potential polyphenol natural product has been predominantly used in some medicinal preparation or used as a food-coloring agent. Wealth of studies in vitro and in vivo substantiated that curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties.

The molecular underpinnings of these effects have been found to involve the regulation of diverse molecular targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase).

Its ability to regulate multiple targets and its safety for human use, made curcumin an amenable therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, AD, and other inflammatory illnesses.

Recent studies on cultured astrocytes obtained from pregnant Sprague-Dawley (SD) rat and neonatal 0–2-day-old SD rats showed improved neuronal survival by curcumin treatment in NMDA toxicity through the activation of PI3K/MAPK signaling pathways.

Studies employing surface plasmon resonance experiments, unraveled that the liposomes exposing the curcumin derivative (maintaining the planarity) demonstrate considerable affinity for Aβ1-42 fibrils (1–5 nM), through the exhibition of multivalent interactions, thus opening an amenable therapeutic avenue unlike the nonplanar curcumin.


There have been manifold studies to combat this dreadful neurodegenerative disorder for a few decades. Although a few drugs are available today for the management of AD and many plants and their extracts are extensively employed in animal studies and AD patients, yet no substantial drug or plant extract is able to reverse the AD symptoms adequately.

The intervention of phytotherapy, which entails the use of herbal medicines may be a potential corner stone based on which treatment strategies can be streamlined. It is tangible that there has been augmenting need for such therapeutic intervention.


Copyright © Journal of Neurosciences in Rural Practice


Relationship between Depression and Dementia

Arch Gen Psychiatry. 2011 Sep;68(9):970-7.

Temporal relationship between depression and dementia: findings from a large community-based 15-year follow-up study

Li G, Wang LY, Shofer JB, Thompson ML, Peskind ER, McCormick W, Bowen JD, Crane PK, Larson EB.


Departments of Psychiatry andBehavioral Sciences, University of Washington, Seattle, USA.



Late-life depression is associated with increased risk of dementia, but the temporal relationship between depression and development of dementia remains unclear.


To examine the association between risk of dementia and baseline depressive symptoms; history of depression, particularly early-life (<50 years) vs late-life depression (≥50 years); and individual domains of the Center for Epidemiologic Studies Depression Scale.


A large cohort with initially nondemented participants was followed up biennially for up to 15 years. Baseline depressive symptoms were assessed using the 11-item version of the Center for Epidemiologic Studies Depression Scale; presence of significant depressive symptoms was defined as a score of 11 or greater. Self-reported history of depression was collected at the baseline interview. Cox proportional hazards regression was used to assess the association between depression and dementia risk.


Population-based cohort drawn from members of the Group Health Cooperative in Seattle, Washington.


A cohort of 3410 participants without dementia aged at least 65 years.


During a mean of 7.1 years of follow-up, 658 participants (19.3%) developed dementia. At baseline, 9.4% of participants had presence of significant depressive symptoms, and 21.2% reported a history of depression. The adjusted hazard ratio for dementia associated with baseline depressive symptoms was 1.71 (95% confidence interval, 1.37-2.13), after adjusting for age at entry, sex, educational level, and wave of enrollment.

Compared with participants without depression history, those with late-life depression were at increased dementia risk (adjusted hazard ratio, 1.46; 95% confidence interval, 1.16-1.84), but early-life depression had no association with dementia risk (1.10 [0.83-1.47]).

Depressed mood (adjusted hazard ratio, 1.48; 95% confidence interval, 1.25-1.76) and perceived performance difficulty (1.39 [1.15-1.67]) were independently associated with dementia.


This study confirmed that late-life depression is associated with increased risk of dementia and supplied evidence that late-life depression may be an early manifestation of dementia rather than increasing risk for dementia.


Early Onset Alzheimer’s Disease Linked to Rapid Cognitive Decline

Psychol Med. 2009 Nov;39(11):1907-11. doi: 10.1017/S0033291709005492. Epub 2009 Apr 1.

Most rapid cognitive decline in APOE epsilon4 negative Alzheimer’s disease with early onset.

van der Vlies AE1, Koedam EL, Pijnenburg YA, Twisk JW, Scheltens P, van der Flier WM.



We aimed to compare the rate of cognitive decline in patients with early and late onset Alzheimer’s disease (AD) and to investigate the potentially modifying influence of the apolipoprotein E (APOE) genotype.


We included 99 patients with early onset AD (age 65 years) and 192 patients with late onset AD (age >65 years) who had at least two scores on the Mini-Mental State Examination (MMSE) (range 2-14) obtained at least 1 year apart. Linear mixed models were performed to investigate the rate of cognitive decline dependent on age at onset (AAO) and APOE genotype.


The mean (S.D.) age for patients with early onset AD was 57.7 (4.5) years, and 74.5 (5.1) years for patients with late onset AD. AAO was not associated with baseline MMSE [beta (S.E.)=0.8 (0.5), p=0.14]. However, patients with early onset showed a faster decline on the MMSE [beta (S.E.)=2.4 (0.1) points/year] than those with late onset [beta (S.E.)=1.7 (0.1) points/year, p=0.00]. After stratification according to APOE genotype, APOE epsilon4 non-carriers with early onset showed faster cognitive decline than non-carriers with late onset [2.4 (0.3) v. 1.3 (0.3) points/year, p=0.01]. In APOE epsilon4 carriers, no difference in rate of cognitive decline was found between patients with early and late onset [beta (S.E.)=0.2 (0.2), p=0.47].


Patients with early onset AD show more rapid cognitive decline than patients with late onset, suggesting that early onset AD follows a more aggressive course. Furthermore, this effect seems to be most prominent in patients with early onset who do not carry the genetic APOE epsilon4 risk factor for AD.


Relationship between Antidepressants and Falls in Dementia Nursing Home Residents

Br J Clin Pharmacol. 2012 May; 73(5): 812–820. 10.1111/j.1365-2125.2011.04124.x

Dose-response relationship between selective serotonin re-uptake inhibitors and injurious falls: a study in nursing home residents with dementia.

Sterke CS1, Ziere G, van Beeck EF, Looman CW, van der Cammen TJ.



The contribution of selective serotonin re-uptake inhibitors (SSRIs) to injurious fall risk in patients with dementia has not been quantified precisely until now. Our objective was to determine whether a dose-response relationship exists for the use of SSRIs and injurious falls in a population of nursing home residents with dementia.


Daily drug use and daily falls were recorded in 248 nursing home residents with dementia from 1 January 2006 until 1 January 2008. For each resident and for each day of the study period, data on drug use were abstracted from the prescription database, and information on falls and subsequent injuries was retrieved from a standardized incident report system, resulting in a dataset of 85,074 person-days.


We found a significant dose-response relationship between injurious falls and the use of SSRIs. The risk of an injurious fall increased significantly with 31% at 0.25 of the Defined Daily Dose (DDD) of a SSRI, 73% at 0.50 DDD, and 198% at 1.00 DDD (Hazard ratio = 2.98; 95% confidence interval 1.94, 4.57). The risk increased further in combination with a hypnotic or sedative.


Even at low doses, SSRIs are associated with increased risk of an injurious fall in nursing home residents with dementia. Higher doses increase the risk further with a three-fold risk at 1.00 DDD. New treatment protocols might be needed that take into account the dose-response relationship between SSRIs and injurious falls.


© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society


Pharmacological and Non-Pharmacological Treatments for Depression in Dementia

Ann Longterm Care. 2009 February 2; 17(2): 29–36.

Treatments for Depression in Older Persons with Dementia

Dr. Zvi D. Gellis, Associate Professor and Director,1 Dr. Kimberly P. McClive-Reed, Research Assistant Professor,2 and Dr. Ellen Brown, Director of Education and Education Research3

Depression in Dementia

Dementia itself is not a disease, but a constellation of symptoms caused by diseases and disorders that affect the brain, including Alzheimer’s disease (AD), Parkinson’s disease (PD), diffuse Lewy body disease (DLBD), strokes, and others. Dementia involves progressive loss of memory and other cognitive functions such as problem-solving and emotional control.

The earliest diagnosable stage of dementia is referred to as mild cognitive impairment (MCI). Although MCI does not always lead to dementia, for those who do develop dementia, abilities to independently perform instrumental and basic activities of daily living are generally impaired as the condition progresses.

Behavioral and psychological symptoms of dementia (BPSD), also frequently referred to as neuropsychiatric symptoms of dementia, affect up to 95% of those with dementia during the course of the illness 1. Symptoms of depression are especially common in mild cognitive impairment and throughout the course of dementia.

Reported prevalence of depression or depressive symptoms in persons with dementia ranges from 0 to 96% 25, while moderate to high rates of depression or its symptoms are consistently reported for persons with MCI (i.e., 36% by Palmer and colleagues6; 63.3% by Sofrizzi and colleagues7; 39% by Hwang and colleagues8).

The wide range of prevalence for depression in dementia is due to several factors, including differences in researchers’ focus on symptoms versus specifically defined depressive disorders, diverse study samples varying in causes of dementia, stage of illness, country of residence, and placement of patient, and variation in the instruments used to assess depressive symptoms and disorders.

Outcomes of Depression in Dementia

The occurrence of depression occurring in people with MCI or dementia can lead to a number of negative outcomes. For example, pre-existing depression has been identified as a predictor of, or risk factors for, subsequent dementia. One meta-analysis9 estimated that persons experiencing depression have approximately double the risk of developing dementia than those without a prior history of depression, and more recent study findings concur 6, 10. Depression may also be a risk factor for progression from MCI to dementia. Several studies report an association between baseline depressive symptoms in participants with MCI and later progression to dementia 1115.

Comorbidity of cognitive impairment and depression has been associated with increased mortality16 reduced quality of life 1720 and increases in caregiver burden and distress 17, 21, 22. Possibly due to the negative impact on caregivers, co-morbid depression and cognitive impairment are associated with higher rates of institutionalization of the demented care recipient 2325.

Pharmacological Treatment of Depression in Dementia

Both pharmacologic and nonpharmacologic treatment approaches have been found to be helpful in reducing depression in cognitive impairment and dementia. Pharmacological treatment of depression in patients with dementia, although common, presents some unusual difficulties.

Patients with dementia have more comorbid illnesses than non-demented peers, with approximately 60% of those with AD having 3 or more medical conditions. This heightened level of comorbidity results in the use of multiple medications. Therefore, drug interactions and polypharmacy may help provoke BPSD in some patients with dementia, or may play a part in driving these patients’ sometimes atypical responses to the drugs used to treat BPSD26.

Given their physical and cognitive frailty, persons with dementia may also be particularly susceptible to adverse effects. Since dementia patients may be less able to communicate, clinicians and caretakers must carefully observe patent’s behavior for evidence of adverse events when new medications are introduced. Prescription of new medications intended to treat depression or other BPSD in dementia patients should always be made using the familiar adage originated for dosing the elderly, “Start low and go slow” 27.


Antidepressants are frequently prescribed for treatment of depression in dementia. A recent meta-analysis 27 covered treatment of depression with tricylic antidepressants (TCA; imipramine and clomipramine), and selective serotonin reuptake inhibitors (SSRI; sertraline and fluoxetine) in five studies on patients with dementia. Treatment response and remission was superior to placebo in the combined sample, but significant declines in cognitive scores occurred during the use of TCAs in both studies employing them.

Reviews of research on the pharmacological treatment of BPSD in general 2830 indicate positive effects of various antidepressants (including sertraline, fluoxetine, citalopram, trazodone, and moclobemide) on depression in dementia, with citalopram and sertraline being the most commonly prescribed 3133. Case reports and small pilot studies indicate that other antidepressants, including trazadone, buspirone, and mirtazapine, may improve depression in patients with dementia, but no large trials have been performed in persons with dementia to date 28, 29, 34.

The practice guidelines recently issues by the Work Group on Alzheimer’s Disease and Other Dementias of the American Psychiatric Association 35 currently support SSRIs as the first pharmacological treatment of choice for depression in dementia, as SSRIs tend to be better tolerated than other antidepressants. However, the Work Group suggests that if patients with dementia cannot tolerate higher dosages when needed for remission of depression, trials of alternative antidepressants such as bupropion, venlafaxine, and mirtazapine may be considered.


Newer medications that show potential promise in the treatment of depression in dementia include anticholinergics, anticonvulsants, and memantine. Decreased cholinergic activity, primarily resulting from decreased acetylcholine concentrations caused by dementia-related neurological changes, has been associated with decreased cognitive ability in dementia, as well as increases in BPSD, including anxiety and depression 36.

Cholinesterase inhibitors have been used to successfully target these problems by increasing levels of acetylcholine in patients with mild to moderate dementia 37. In particular, a recent randomized controlled trial demonstrated improvement in depression scores of patients with dementia, as measured on the Hamilton Depression Scale, for patients given rivastigmine or a combined regimen of rivastigmine and fluoxetine, compared to placebo 38.


Anticonvulsants, through their modulation of GABA, may be another class of agents for treating BPSD. GABA concentrations are often decreased in cortical regions of the brain of patients with dementia, and medications that increase GABA levels have been shown to improve mood disorders 28. However, trials of the anticonvulsant carbamazepine to treat BPSD have yielded contradictory results 39, or have not reported data on depression.

At least one clinical trial of valproate, another anticonvulsant, resulted in significant improvement in melancholic, sorrowful and anxious behaviors40, but the results of other small trials of valproate are contradictory30. Preliminary trials of the anticonvulsant lamotrigine in elderly patients with dementia also noted improvement symptoms of agitation and depression41.


Memantine, a drug that reduces excessive glutamate receptor signaling, has also been studied in patients with dementia. Glutamate signaling is important for learning and memory, but in some patients with dementia it may increase to “oversignalling” levels that destroy neurons.

A recent review and meta-analysis of the research on memantine for the treatment of psychological symptoms of dementia showed small but significant improvements on the Neuropsychiatric Inventory, with limited adverse effects42.
In summary, a variety of pharmacological treatments have some efficacy in the treatment of depression in dementia, but care must be exercised in their use with this population of generally frail older persons to avoid adverse effects. Alexopoulous and colleagues constructed an expert consensus response after surveying 50 experts in dementia from North America on preferred, alternate, and unacceptable treatment choices for BPSD43.

The general consensus was that SSRIs were the preferred pharmacological treatment for depression in patients with dementia. Further research appears to be needed to establish the effects of both older and newer pharmacological options on depression in dementia patients.

Non-Pharmacological Treatments for Depression in Dementia

Clinical guidelines specify the use of non-pharmacological treatments for BPSD before pharmacological treatments are tried 28, 44. Nonpharmacological therapies that specifically target depression or its symptoms fall roughly into three categories: emotion-oriented therapies, brief psychotherapies, and sensory stimulation therapies.

Emotion-Oriented Therapies

The primary aim of emotion-oriented therapies is to fit the therapy to emotional needs of people with dementia, and by doing so, improve their quality of life, social functioning, and ability to cope with the cognitive, emotional and social consequences of the disease as they subjectively experience them 45. Examples of emotion-oriented approaches include reminiscence, reality, validation, and simulated presence therapy.

Reminiscence therapy encourages persons with dementia to talk about their pasts, generally using memory aids such as old family photos and personal objects 46. Reality orientation therapy is based on the theory that inability to orient themselves reduces the ability of those with dementia to function, and that confusion can be reduced by giving repeated orientation clues, such as the time of day, date, season, or names.

Validation therapy assumes that the person with dementia may choose to retreat to an inner reality based on emotions, rather than trying to wrestle with failing intellectual powers.

The therapist accepts the resulting disorientation of a person with dementia and validates his or her presumed feelings, providing a background for meaningful conversations addressing their emotions 47. Simulated presence therapy involves exposing an individual with dementia to audio or videotaped recordings of loved ones 48.

Unfortunately, the limited literature available on emotion-oriented therapies in patients with dementia includes few studies with depression as a measured outcome. Even when these outcomes are reported, findings on the effects of emotion-oriented therapies on these and other BPSD are inconsistent and based on limited or methodologically questionable studies4955.

Despite several positive clinical reports of efficacy for these interventions, there is currently insufficient evidence for their effectiveness in reducing any BPSD, and almost no research providing data on their effects on depression. However, numerous anecdotal and research reports of clinical effectiveness, and the client-centered nature of these individualized therapies, suggest that they might yet prove to be of value.

More methodologically sound, larger, and well-controlled randomized trials are urged by their supporters (e.g., Finnema and colleagues45).

Brief Psychotherapies

Brief psychotherapies that have been used with some success in persons with depression in dementia include behavior therapy and cognitive-behavioral therapies. Behavioral therapies are more commonly applied in the later stages of dementia, while modified cognitive-behavioral strategies appear to be more successful with those in the earlier stages of cognitive decline.

Behavior therapy requires a period of detailed assessment in which the triggers, behaviors and reinforcers (also known as the ABC: antecedents, behaviors and consequences) are identified, and their relationships made clear to the patient. Interventions are then based on an analysis of these findings.

There are several interventions for patients with dementia based on behavior theory, including token economy, progressive muscle relaxation, imaging, and social skills training, to name a few54. However, most trials of such therapies do not focus on depression as an outcome. An exception is behavioral programming based on Lewinsohn’s Pleasant Events model56. The model has three core components: (a) explaining the approach to the patient, emphasizing that a person’s behavior is related to how he or she feels; (b) identifying pleasant and negative events in the patient’s daily life, and assisting patients to work on increasing the first and decreasing the second; and (c) explaining that relaxation and mood monitoring are tools to assist the client in improving.

Logsdon and Teri57 constructed and validated a Pleasant Events Schedule—Alzheimer’s Disease (PES-AD) to assist caregivers in implementing an intervention for patients with dementia. Teri and colleagues 58 applied this model to people with dementia, and found that depression scores improved in those who participated in a home-based program combining exercise with behavioral management training for caregivers, but the effects of the behavioral management component alone were not studied.

Lichtenberg and colleagues59 also examined the effect of a program based on this model on depression in nursing home residents with dementia. They found no differences on depression scores on either of two standard scales used, although statistically significant positive mood increases were noted.

Although cognitive-behavioral therapy (CBT) is more commonly used with caregivers of patients with dementia than with the patients themselves, a few studies have tested the effects individual or group CBT on BPSD, and on depression in particular. Teri and colleagues60, 61 reported clinical improvements in depression scores on standardized measures following CBT, using two strategies for treating Alzheimer’s patients.

Cognitive therapy was used with mildly demented adults to challenge the patient’s negative cognitions in order to reduce distortions and enable the patient to generate more adaptive ways of viewing specific situations and events. Behavioral intervention, based on the Lewinsohn’s Pleasant Events model described in the previous section of this paper, was used with more moderately or severely demented adults. Koder62 also addressed the use of CBT techniques to treat anxiety in two cases of older patients with cognitive impairment, and reported positive results.

Other modifications to CBT, besides targeting cognitive strategies to early-stage dementia and behavioral strategies to later stages, involve reducing the cognitive load on the demented person by increasing repetition, utilizing concrete examples, and providing memory aids, such as cue cards.

Implementing CBT with persons suffering from dementia also requires a highly structured format and continuous monitoring of the person’s understanding of the therapeutic material. Also, most CBT programs for persons with dementia involve their caregivers, both as CBT “coaches” for the care recipient, and as treatment partners who often benefit from the intervention as well53, 60, 62.

Early efforts have also been made to examine the efficacy of a related strategy, Problem-Solving Therapy (PST)63, in treating depression in persons with cognitive deficits. Specially, Alexopolous and colleagues64 observed improvements in depression following PST in persons with executive dysfunction, although persons with MMSE scores indicating MCI or dementia were screened out of the sample.

A single case study65 found that PST significantly improved the depression scores and clinical profile of an older patient with PD and MCI, both short and long-term (6 months post-treatment). However, further research on the implementation of PST in depressed persons with diagnosed MCI or dementia is needed.

Although there have been no methodologically rigorous trials of CBT or PST to treat depression in persons with dementia, interest in this topic has recently revived 66. Stanley and colleagues67 have recently received funding from NIMH to conduct a randomized controlled trial of the impact of CBT on anxiety in persons with mild to moderate dementia, and plan to measure depression using the Geriatric Depression Scale68 as a secondary outcome, with results expected in 2010.

In addition, Kiosses69 is currently conducting an NIMH-funded trial of PST to treat depressed, cognitively impaired older adults, with results anticipated in 2011.

Sensory Stimulation Therapies

Sensory stimulation therapies that have been used to treat BPSD include art/music therapy, aromatherapy, animal-assisted/pet therapy, activity therapies, massage/touch therapies, and multisensory approaches (such as snoezelen).

The goals of these therapies range from improvement of mood to increased health and improvement of memory. Similar to the emotion-oriented therapies, few rigorous studies have been performed, and results of efficacy are mixed, although reports from clinical observers are generally very positive. The impact of sensory stimulation therapies on depression in dementia has received limited attention, but their potential for efficacy appears positive.

Art therapy is theorized to provide people with dementia with meaningful stimulation, improved social interaction, and a chance to exercise personal choice52. Clinical observation of patients with dementia engaging in art therapy has indicated that it can provide pleasure and improve mood (REF).

However, participants in an art therapy program recently studied by Rusted and colleagues70 actually exhibited increased depression scores on two standardized measures over the course of a forty-week program, possibly due to feelings of failure in achieving a pleasing work of art. Reviews on art therapy in dementia71 suggest that further and more rigorous research is needed to assess its potential benefits on depression in this population.

Several clinical reports have described benefits gained by people with dementia from music therapy involving either listening or performing, although most involve listening72. Lord and Garner73 found that a group of nursing home residents who regularly had music played to them, compared to a comparison group who did not, experienced higher levels of well-being, better social interaction, and improvements in autobiographical memory.

More recently, Holmes and colleagues74 randomized patients with moderate to severe dementia and diagnosed apathy to conditions of silent periods, prerecorded music, or live interactive music, and found much higher levels of positive engagement in the live music condition than the silence or recorded condition. Other studies support the beneficial effects of music therapy on various BPSD other than depression 7581, indicating that this mode of intervention deserves further attention.

Aromatherapy is one of the fastest growing of all the complementary therapies 82. It appears to have several advantages over the pharmacological treatments widely used for dementia, especially limitation of adverse effects from traditional pharmacotherapy. There have been some positive results from recent controlled trials which have shown statistically significant reductions in agitation, with excellent compliance and tolerability8385.

However, the type of aromatherapy oils tested, method of administration and outcome measures used varied widely across the few available studies, and depression has not been studied as an outcome. Further trials are needed before conclusions can be drawn on the effectiveness of aromatherapy for depression or other BPSD.

Animal-assisted therapy (AAT) has been reported to lessen agitation and improve socialization in patients with dementia in several small, uncontrolled trials86, 87. Two small studies 88, 89 reported reductions of apathy and withdrawal in dementia patients exposed to therapy dogs in a nursing home setting. However, in the only study that employed a measurement of depression88, no significant changes in depression occurred. Further studies with larger samples and expanded measurement are needed.

In their review of the limited literature available on AAT and dementia, Filan and Llewellyn-Jones90 concluded that AAT may have positive effects on BPSD, but the duration of these effects is unknown, and studies are needed to disentangle the relative benefits gained from “visiting” animals versus “resident” animals. Possible interaction effects from dual exposure of patient and staff/caregivers to the animals during therapy also require further exploration.

Activity therapies include structured physical and recreational activities. A review of 27 studies by Eggermont and Scherder91 concluded that physical activity programs can improve mood in patients with dementia, with a recent study92 indicating that whole-body movement programs have a greater positive impact than walking alone.

One study found that depression scores improved in people with dementia who participated in a home-based program combining exercise with behavioral management training for caregivers58; unfortunately, it is not possible to disentangle the effects of one intervention from the other.

Another study with depression as an outcome93 found that a biweekly exercise program improved ADL function in AD patients compared to controls over a one-year period, but had no impact on depression scale scores. These mixed results indicated that activity therapy may be beneficial for depression in dementia, but studies need to focus closely on the effects of specific types of activities.

A review of massage and touch interventions for dementia94 found that the very limited amount of reliable evidence available supported massage and touch interventions for anxiety associated with dementia, especially hand massage for the immediate or short-term reduction of agitated behavior.

Cohen-Mansfield95 reported decreases in anxiety in two small trials, one involving daily hand massage and therapeutic touch, and the other hand massage with essential oils. Unfortunately, no massage trials appear to have considered depression as an outcome variable. Massage therapy, like other CAM for dementia, requires further research to establish its efficacy in BPSD, including depression.

Multisensory approaches usually involve using a room designed to provide several types of sensory stimulation such as light (frequently in the form of moving flexible fiber optics), texture (cushions and vibrating pads), smell, or sound. The use of these resources is tailored to the individual and therefore not all of the available forms of stimulation may be used in one session.

One such approach, Snoezelen, provides sensory stimuli to stimulate the primary senses of sight, hearing, touch, taste and smell, through the use of lighting effects, tactile surfaces, meditative music and the odor of relaxing essential oils. A review by Vervaik and colleagues96 provides some evidence that Snoezelen/Multisensory stimulation in a multisensory room is effective in reducing apathy in late-stage dementia patients.

A recent randomized controlled trial by Staal and colleagues97 also found that patients on a geriatric psychiatric unit receiving Snoezelen and standard psychiatric care had reduced apathy and agitation scores, as well as increased activities of daily living, compared to patients receiving standard care alone.

Although multisensory approaches to treatment of BPSD appear quite promising, there is a need for more research-based evidence to inform and justify the use of snoezelen and similar multisensory approaches in dementia care98.


A wide range of pharmacological and nonpharmacological treatments have been used to relieve depression in persons with cognitive impairment and dementia. Clinical consensus and research appear to support SSRIs as a first choice for the treatment of depression in dementia.

In nonresponsive or special needs patients, other drugs have been used, including antipsychotics, anticholinergics, anticonvulsants, memantine, and complementary/alternative medications. Extra care is required in prescribing to this population, due to the generally high level of medical and psychiatric comorbidity and potential difficulty in assessing the cognitively impaired patient’s response.

Nonpharmacologic interventions including emotion-oriented therapies, behavioral and cognitive-behavioral modification programs, and structured activity programs demonstrate initial support for treating depression, anxiety, and other BPSD.

Sensory stimulation therapies such as art/music therapy, aromatherapy, animal-assisted/pet therapy, activity therapies, massage/touch therapies, and multisensory approaches show some promise for successful treatment of depression in dementia, but further and more rigorous research is needed to establish their validity.