eMedicine Specialties > Neurology > Behavioral Neurology and Dementia
Dementia Pharmacotherapy
Updated: Jan 22, 2010
Introduction
Dementia may be defined as an acquired syndrome of severe impairment in intellectual abilities including memory sufficient to interfere in social or occupational functioning. It affects about 1% of adults aged 60-64 years and 30-40% of those over 85 years.1 Alzheimer disease (AD) is estimated to account for about 60-70% of dementia in the elderly with prevalence in the United States estimated at 4.5 million.2 When mild cases are included, the prevalence of AD may be as high as 10.3% in institutionalized white persons older than 65 years3 and potentially higher in black and Hispanic persons.4 The annual cost of Alzheimer disease to the US economy is estimated to be greater than $141 billion (1997 dollars)5 , and the health care burden is estimated to more than double from 2000 to 2050 due to the aging demographics of the US population.6
Alzheimer disease is the focus of this overview due to its frequency and importance. Other clinically important etiologies of dementia including Parkinson disease dementia and vascular dementia are also discussed since specific pharmacological approaches have been studied. The treatment of dementia due to specific neurodegenerative diseases such as Huntington disease, Wilson disease, Creutzfeldt-Jakob disease, Pick disease, frontotemporal dementia, and the Parkinson-Plus syndromes is discussed in individual chapters devoted to these diseases.
Approach to the Treatment of Dementia
A definitive diagnostic test for Alzheimer disease is not available and it is important to exclude potentially reversible causes of dementia such as vitamin B12 deficiency, hypothyroidism, and neurosyphilis before making a clinical diagnosis, although the latter is recommended only when clinical suspicion is high.7 A thorough medication review is also a prerequisite in eliminating medication side effects that can mimic dementia. An important cause of dementia that may improve with surgical treatment is normal pressure hydrocephalus. Imaging studies in the form of CT or MRI brain are helpful in evaluating this disorder as well as vascular dementia. The role of functional imaging studies such as PET, SPECT and fMRI as a diagnostic tool for dementia is increasing but a discussion is outside the scope of this chapter.
Basis of Pharmacotherapy and the Amyloid Hypothesis
The amyloid hypothesis suggests that progression in Alzheimer disease results from a cascade beginning with amyloid plaque formation, followed by inflammation, abnormal tau phosphorylation, and free radical toxicity.8 This results in synaptic loss, disturbed calcium homeostasis, and cholinergic dysfunction as well as neuronal loss. Dysfunction of other neurotransmitter systems including glutamate, norepinephrine, and serotonin follow in the late stages. While the amyloid hypothesis remains unproven, current treatment options in Alzheimer disease address aspects of this cascade. Investigational therapies aim to affect earlier steps in the cascade and include γ and β secretase inhibitors and vaccines against the amyloid beta (Aβ) protein.
Recent clinical trials including active and passive Aβ42 immunization, decreasing production of Aβ42 with tarenflurbil (Flurizan), and blocking Aβ aggregation with tramiprosate (Alzhemed) were geared toward testing this hypothesis.9 Their failure, at least on primary outcome measures, was disappointing and has lead to questions regarding the amyloid hypothesis. It is felt that while the serial dysfunction beginning with Aβ formation does well at explaining the relatively rare genetic forms of early-onset Alzheimer disease, alternative mechanisms must be invoked in the more common late-onset Alzheimer disease. Small and Duff hypothesize a dual pathway with Aβ and tau linked by separate mechanisms driven by a common upstream driver as a possible explanation and offer a detailed review of the pathophysiology of Alzheimer disease.10
The Cholinergic Hypothesis and the Role of Glutamate
The diagonal band and the nucleus basalis of Meynert, which has a widely distributed cholinergic projection to the cerebral cortex, undergo degeneration in Alzheimer disease. Anticholinergic medications had also been observed to cause memory impairment and confusion. The cholinergic hypothesis postulates that the destruction of basal forebrain cholinergic neurons results in a deficit in central cholinergic transmission, which is the basis for Alzheimer disease symptomatology.11 This hypothesis provides the rationale for the development of the acetylcholinesterase (AChE) inhibitors for Alzheimer disease therapy. AChE inhibition is believed to increase the acetylcholine concentration in the synaptic cleft with enhanced cholinergic transmission and a reduction of the cholinergic deficit.
Glutamate excitotoxicity mediated through excessive activation of N -methyl-D-aspartate (NMDA) receptors may also play a role in the neuronal death observed in Alzheimer disease.12 Excessive activation of NMDA receptors leads to an increase in intracellular Ca++, triggering downstream events and ultimately leading to neuronal death.13 Thus, NMDA receptor antagonists may protect neurons from glutamate-mediated excitotoxic cell death, although a direct neuroprotective effect remains to be demonstrated.
The Specific Pharmacotherapy of Alzheimer Disease
Current FDA-approved medications for the treatment of Alzheimer disease include the AChE inhibitors galantamine, donepezil, and rivastigmine for mild-to-moderate cases, and memantine, an NMDA receptor partial antagonist, for moderate-to-severe Alzheimer disease. Modest symptomatic improvements are seen with all these drugs.14,15
Tacrine (tetrahydroaminoacridine) was the earliest drug in this category, but the high likelihood of liver toxicity lead to its abandonment in practice.16 In double-blinded, placebo-controlled studies, donepezil, rivastigmine, and galantamine have been shown to mildly slow the rate of cognitive decline and improve activities of daily living (ADLs) and behavior in mild-to-moderate Alzheimer disease for a period of 6-18 months. Donepezil has higher selectivity for AChE. Rivastigmine also inhibits butyrylcholinesterase, and galantamine also has a modifying effect on nicotinic receptors. The clinical significance of these differences is difficult to demonstrate.17
In randomized controlled trials (RCTs) with a cumulative enrollment of more than 1000 patients, donepezil was superior to placebo over a period ranging from 12-24 weeks both on composite neuropsychological testing and a clinician's global evaluation. Efficacy was demonstrated at doses of 5 and 10 mg/d. Side effects occurred in 17% of patients, but no hepatotoxicity was reported.18,19
Rivastigmine tartrate, in doses of 6-12 mg/d was superior to placebo over 26 weeks on a clinician's global assessment and ADL scale. Side effects occurred in 50% of patients with discontinuation required in 25%.20 The rivastigmine transdermal patch improves the tolerability of the drug while maintaining efficacy.
In the IDEAL study, patients with Alzheimer disease were randomized to placebo or 1 of 3 active treatment target dose groups: rivastigmine patch 9.5 mg/24 hours; rivastigmine 17.4 mg/24 hours; or 6 mg BID rivastigmine capsules. Primary efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). All rivastigmine treatment groups were superior to placebo. The 9.5 mg/24 hours patch showed similar efficacy to capsules, with approximately two-thirds fewer reports of nausea (7.2% vs 23.1%) and vomiting (6.2% vs17.0%). The 17.4 mg/24 hour patch showed earlier improvement and numerically superior cognitive scores patch but tolerability was similar to capsules. Local skin tolerability was good for all patch strengths.21
Galantamine was studied in 2 RCTs with a cumulative enrollment of more than 1600 subjects with mild-to-moderate Alzheimer disease. Treatment with galantamine resulted in significant improvement on the ADAS-Cog, the clinician's global assessment, the ADL scale, and a behavior scale. Side effects occurred in up to 13% of subjects at 16 mg/d and up to 17% on 24 mg/d.22
Memantine is a noncompetitive NMDA receptor antagonist. Its specific mechanism of action in Alzheimer disease has not been defined but it is believed to selectively block the excessive release of glutamate that contributes to neurodegeneration in Alzheimer disease. In patients with moderate-to-severe Alzheimer disease on stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, ADL, global outcome, and behavior. Treatment discontinuations because of adverse events for memantine versus placebo were 15 (7.4%) versus 25 (12.4%), respectively.23 However, in a similar study of patients with mild-to-moderate Alzheimer disease, the addition of memantine to a concurrent stable use of AChE inhibitors (donepezil, rivastigmine, galantamine) did not show an advantage over placebo.24
The modest efficacy of these medications in dementia should be balanced against the potential for serious side effects. A recent, large-scale, population-based, cohort study documented increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia on AChE inhibitors.25
Few clinical trials have examined the efficacy of ginkgo biloba in long-term cognitive improvement.
A recent study called The Ginkgo Evaluation of Memory by Snitz et al assessed how ginkgo biloba decreased the progression of cognitive decay that comes with age. Adults aged 72-96 years with normal or mild cognitive impairment (n=3069) received either ginkgo biloba extract, 120 mg twice daily, or placebo. The median follow-up time was 6.1 years, and researchers measured cognitive decline using the Modified Mini-Mental State Examination (3MSE), the cognitive section of the Alzheimer Disease Assessment Scale (ADAS-Cog), and z scores of neuropsychological tests on memory, attention, visual-spatial construction, language, and executive function. There was a noted rate of change based on baseline cognitive function, but no difference was noted in slowing the progression of cognitive decline between the treatment groups in any of the tests used to measure cognition. Ginkgo biloba was not more efficacious than placebo in slowing cognitive decline.26
Neuroprotective Strategies in Alzheimer Disease
Neuroprotective strategies for dementia remain an unmet need. Lowering free radical formation and oxidative stress in the brain is a generic neuroprotective strategy in neurodegenerative disease including Alzheimer disease and Parkinson disease. In early studies, vitamin E was felt to have the potential to delay decline in moderate-to-severe Alzheimer disease for an endpoint that included death, nursing home placement, or conversion to severe dementia. However, the Alzheimer’s Disease Cooperative Study Group-MCI study did not reveal superiority to placebo.27 The potential for thrombosis with the 2000 IU dose is also a source of concern against recommending vitamin E.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and estrogens have been explored as alternatives but have failed to meet the burden of proof in RCTs. AD pathology includes microscopic evidence of inflammation, and epidemiological studies suggest a protective effect of NSAIDs. However, clinical trials with prednisone, diclofenac, rofecoxib, and naproxen were negative.28 In animal models, estrogen restores neural synapses, increases solubility of Aβ and increases activity of choline acetyl transferase. However, recent RCTs failed to show that estrogen reduced the risk of dementia in postmenopausal women. In fact, combination therapy with estrogen and progesterone could increase the risk of Alzheimer disease.29
Recent studies suggest that statins may play a beneficial role. In a population-based study, Horsdal et al found a reduced risk of hospitalization with dementia among users of statins.30 They hypothesize the role of multiple mechanisms, including stimulation of α-secretase activity; modulation of amyloid precursor protein metabolism; and Aβ production, immunomodulation leading to attenuation of inflammatory markers, and reduction of lipoprotein oxidation and free radical injury. In the Rotterdam Study, 6992 individuals without dementia aged 55 years or older were observed for a mean of 9 years. A total of 582 participants developed Alzheimer disease. The use of statins (but not nonstatin, cholesterol-lowering drugs) was associated with a reduced risk of Alzheimer disease (hazard ratio, 0.57) regardless if the statin's lipophilicity.31
Dimebolin, used as an antihistaminic in Russia since 1983, showed significant improvement over placebo at 12 months in early phase II studies.32 It has multiple mechanisms of action that include modulating the action of AMPA and NMDA glutamate receptors, blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels. In addition, it may block a novel target that involves mitochondrial pores that play a role in apoptotic cell death.33
Treatment of Dementia With Parkinsonism and Vascular Dementia
Estimates of Parkinson disease dementia vary based on populations and ascertainment methods. However, most estimates place the range at 20-40% of patients with Parkinson disease, thus conferring a 2- to 6-fold increased risk compared with controls.34
AChE inhibitors have been shown to be of modest benefit. Currently, rivastigmine is the only drug with FDA approval for the treatment of Parkinson disease dementia. In a 24-week RCT, absolute responses to rivastigmine on the ADAS-Cog were comparable over 6 months, although rivastigmine-placebo differences tended to be larger in those with visual hallucinations (4.27; P =0.002) than in those without hallucinations (2.09; P =0.015). On the ADCS-CGIC, differences between rivastigmine and placebo were 0.5 in those with visual hallucinations (P =0.030) and 0.3 in those without hallucinations (P =0.111). Visual hallucinations appeared to predict more rapid decline and possibly greater therapeutic benefit from rivastigmine treatment in Parkinson disease dementia.35
AChE inhibitors and memantine produce small benefits in cognition of uncertain clinical significance in patients with mild-to-moderate vascular dementia. However, the results do not support widespread use of these drugs in vascular dementia.36
Treatment of Behavioral Symptoms
With disease progression, behavioral and psychological symptoms become an increasing source of disability. These include agitation, psychosis (delusions and hallucinations), aggression, and apathy. In addition to the effect on the patient, they significantly increase caregiver burden and may pose a threat to safety both for the patient and the caregiver.
The first step in treating behavioral symptoms, including agitation and psychosis, must be a search for a provocative factor. Intercurrent infection, especially in the form of pneumonia or urinary tract infection, can trigger an abrupt change in behavior. Metabolic disturbances and new medications are also common precipitants. Drugs with anticholinergic side effects, such as bladder agents and tricyclic antidepressants, have the potential to markedly worsen symptoms. The possibility of an acute stroke, transient ischemic attack, or seizure should be kept in mind.
Nonpharmacological approaches, including behavior therapy for depression and psychomotor therapy for agitation, should be considered. Sustained benefit has been difficult to demonstrate in evidence-based studies with such interventions. Education and support programs for caregivers and staff also have an important role.
General principles in pharmacotherapy of behavioral symptoms include avoiding drugs with higher anticholinergic effects, a "start low and go slow" approach to titrating medications, and an attempt at early dose reduction or withdrawal when symptoms are controlled. A thorough review of medications, reducing polypharmacy where possible, is also crucial.
Agitation is common, occurring in about 20% of patients at home and 50% of patients in a nursing home setting. Atypical neuroleptics are most commonly used, although caution must be exercised both with regard to metabolic disturbances, especially hyperglycemia, and the increased risk of stroke. Long-term use of these drugs should therefore be avoided. The addition of cholinesterase inhibitors and/or memantine may reduce the incidence and severity of behavioral symptoms. SSRIs, benzodiazepines and valproic acid may also be used as adjunct medications if neuroleptics alone do not control symptoms. Sedation and increased fall risk limit their use as first-line therapy.
In the CATIE-AD study of outpatients with Alzheimer disease, clinical symptoms, such as anger, aggression, and paranoid ideas, improved with atypical antipsychotics. However, impact on overall functioning, care needs, and quality of life was less impressive.37 The DART-AD study on inpatients highlights the need to minimize long-term use. Patients who continued to receive typical and atypical antipsychotics showed reduced survival compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI, 58-80%) in the continued treatment group versus 77% (64-85%) in the placebo group.38 In general, careful consideration must be given to weaning patients off antipsychotics after 3 months of behavioral therapy.
Treatment of Depression
The prevalence of depression in Alzheimer disease, Parkinson disease, and stroke may be as high as 87%, 75%, and 79%, respectively.39 Identifying depression can be difficult as verbal ability declines. The diagnostic criteria for major depression in Alzheimer disease have therefore been modified by the National Institute of Mental Health.40 In the event of a clinical suspicion of depression, the selective serotonin reuptake inhibitors (SSRIs) are used as first-line therapy. These have been shown to be both safe and efficacious in mild-to-moderate Alzheimer disease.41
Treatment of Sleep Disorders
Sleep disorders, including insomnia, REM behavior disorders, and reversal of sleep-wake cycles, are frequently associated with dementia. Poor sleep architecture can worsen cognitive symptoms. However, caution must be exercised in pharmacotherapy of sleep disorders in this group because of a greater tendency to side effects such as hallucinations, paradoxical agitation, and confusion. A careful combination of pharmacotherapy combined with nonpharmacological measures is required.42 Alzheimer disease is often associated with low endogenous levels of melatonin. However, no significant effects of exogenous melatonin on sleep, circadian rhythms, or agitation were observed when compared with placebo.43
Keywords
dementia treatment, dementia medications, dementia management, Alzheimer’s disease treatment, cognitive impairment management, Parkinson disease treatment
The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Roy Sucholeiki, MD and Richard J Caselli, MD to the development and writing of this article.
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References
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Keywords
dementia treatment, dementia medications, dementia management, Alzheimer’s disease treatment, cognitive impairment management, Parkinson disease treatment
