Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Dementia is a syndrome in which impairment of cortical or subcortical brain function leads to deterioration of cognitive processes or intellectual abilities, including memory, judgment, language, communication, and abstract thinking. Mild cognitive impairment (MCI) is characterized by subjective memory complaints, with objective evidence of non-age-related memory impairment from standardized tests, normal mental status, normal activities of daily living, and no evidence of global dementia (Dubois et al., 2010). Among individuals with MCI, the rate of transition to dementia (typically Alzheimer’s disease [AD]) is approximately 10% to 15% per year (Dubois et al., 2010).
Acetylcholinesterase inhibitor (AChI) drugs block the effects of cholinesterase enzymes that metabolize the neurotransmitter acetylcholine, and they are used clinically to boost cholinergic function. Currently available AChI drugs include tacrine (Cognex®), donepezil (Aricept®, Aricept Orally Disintegrating Tablets), rivastigmine (Exelon®, Exelon transdermal patch), and galantamine (Reminyl®, Razadyne®, Razadyne Extended Release). All are approved by the U.S. Food and Drug Administration (FDA) for the treatment of cognitive impairment in AD, which is characterized in part by the selective loss of cholinergic neurons in the brain. They also are commonly used in clinical practice for treating other dementing disorders, although there is little to no evidence of their efficacy and safety. Memantine (Namenda®) is an FDA-approved treatment for moderate to severe AD, and it has been investigated in other cognitive and neurodegenerative disorders. Memantine is not an AChI, but it weakly binds to and blocks activity at the N-methyl-D-aspartate (NMDA) glutamate receptor. The rationale for using memantine in AD is based on evidence that persistent glutamate activation of NMDA receptors contributes to neuronal cell death and the symptoms of dementia.
A meta-analysis of the effectiveness of the five drugs FDA approved for the treatment of dementia found that they produced statistically significant—but clinically marginal—improvement in cognition and global function (Raina et al., 2008). The AChI drugs and memantine are also not effective for the treatment of MCI. Because of the limited benefits of currently FDA-approved medications for dementia, other drug therapies have been used.
Drugs with vasodilator activity were originally tried in dementia when it was hypothesized that the condition was due to cerebrovascular insufficiency. Although these drugs have little evidence of benefit, are rarely used, and have not been further studied since the late 1980s, two are FDA approved for the treatment of dementia.
One FDA-approved drug is the peripheral vasodilator isoxsuprine (Vasodilan®), which is classified by the FDA as “possibly effective” for the relief of symptoms associated with senile dementia of the Alzheimer’s type and/or multiple infarct dementia. In an uncontrolled trial, isoxsuprine was reported to improve mental function and decrease memory loss in patients diagnosed as senile or pre-senile whose symptoms were in the absence of any previous psychiatric disorder (Elliott, Brown, & Smith, 1973). In a double-blind controlled study in which patients received isoxsuprine for 16 weeks, the active drug group showed a significantly greater improvement in mental performance than the placebo-treated group when assessed using a progressive picture-matching test (Hussain, Gedye, Naylor, & Brown, 1976). Adverse effects of isoxsuprine include rash, dizziness, hypotension, tachyarrhythmia, abdominal discomfort, nausea, and pulmonary edema.
Another FDA-approved drug is ergoloid mesylates (Hydergine®), which acts centrally to decrease vascular tone and slow heart rate and also acts peripherally to block alpha-adrenergic receptors (Hollister & Yesavage, 1984). Another possible mechanism is its effect on neuronal cell metabolism, possibly resulting in improved oxygen uptake and improved cerebral metabolism, which in turn may normalize depressed neurotransmitter levels. According to the product label, ergoloid mesylates has been used to treat symptoms of an idiopathic decline in mental capacity (such as cognitive and interpersonal skills, mood, self-care, and apparent motivation) related to aging or to an underlying dementing condition such as primary progressive dementia, Alzheimer’s dementia, or senile-onset multi-infarct dementia.
In a 24-week placebo-controlled study, ergoloid mesylates improved cognitive function, mood, and dizziness in patients described as having “senile mental deterioration” (van Loveren-Huyben et al., 1984, p. 584). The diagnostic criteria were unclear with regard to dementia. The deterioration of mental status was assessed using the Sandoz Clinical Assessment Geriatric Scale, which described 15 highly subjective signs and symptoms. Among the responders, marked individual differences were found in the degrees of improvement.
A double-blind study found that ergoloid mesylates improved mild impairment of recent memory compared with placebo among patients with mild dementia (Thienhaus, Wheeler, Simon, Zemlan, & Hartford, 1987). Ergoloid mesylates also showed significant improvement compared with placebo on the Inventory of Psychic and Somatic Complaints in the Elderly scale.
Ergoloid mesylates was superior to placebo in improving symptoms of mental deterioration during a 6-month double-blind study (Rouy, Douillon, Compan, & Wolmark, 1989). All patients had moderate mental deterioration secondary to cerebral aging. Following 6 months of treatment, ergoloid mesylates was superior to placebo with regard to improving cognitive deficits, anxiety, mood depression, unsociability, retardation, and irritability. Among patients treated with ergoloid mesylates and placebo, 85% and 4%, respectively, reported a very satisfactory response; 21% and 10% of patients, respectively, reported a satisfactory response.
Ergoloid mesylates was found to be ineffective in the treatment of AD in a 24-week randomized, double-blind, placebo-controlled trial (Thompson et al., 1990). Each group had significant deterioration in mental function, but patients taking ergoloid mesylates had a significantly greater decrease in mental function compared with placebo-treated patients.
Adverse effects of ergoloid mesylates include flushing, rash, nausea, vomiting, headache, blurred vision, nasal congestion, bradyarrhythmia, and orthostatic hypotension.
Anti-Oxidant and Anti-Inflammatory Drugs
The hypothesis that free radicals may initiate and maintain mechanisms responsible for neurodegeneration in AD has stimulated interest in investigating drugs such as ginkgo biloba, selegiline (Eldepryl®, Zelapar®), and vitamin E (e.g., alpha-tocopherol) as antioxidant therapies (Praticò & Delantry, 2000). Studies of ginkgo biloba in AD and MCI have failed to demonstrate significant benefit (Howland, 2010).
Selegiline is a selective inhibitor of monoamine oxidase type B that has potential neuroprotective properties. It is FDA approved for the treatment of Parkinson’s disease, and the transdermal patch formulation (Emsam®) is FDA approved for the treatment of depression (Howland, 2006a, 2006b). A meta-analysis of 17 placebo-controlled trials in AD found a statistically significant benefit on some measures of cognitive function, but the magnitude of the effect was not clinically meaningful (Birks & Flicker, 2003). In addition, no effects or only small effects were noted on other measures (i.e., mood symptoms, behavior, activities of daily living, and global assessment). Although well tolerated, the minimal benefits of selegiline do not justify its use for the treatment of dementia.
Vitamin E is a dietary compound with antioxidant properties involved in scavenging free radicals. Based on laboratory and animal studies that free radicals may contribute to the pathological processes underlying cognitive impairment, vitamin E has been of interest in the potential prevention and treatment of cognitive impairment. A randomized 2-year study compared vitamin E alone, selegiline alone, vitamin E plus selegiline, and placebo for the treatment of AD (Sano et al., 1997). In this study, the three active treatments each delayed a poor outcome (i.e., death, institutionalization, or significant functional decline) compared with placebo by an average of approximately 5 to 7 months, but no significant effect was found on cognition or on cognitive decline. A 3-year randomized, double-blind trial comparing donepezil, vitamin E, and placebo in patients with MCI showed no significant differences in the probability of progression from MCI to AD (Petersen et al., 2005). In the AD study, patients taking vitamin E had a greater number of falls. Vitamin E supplementation has also been associated with increased risks of bleeding and mortality (Rabins et al., 2007).
Some retrospective studies have found an inverse association between the use of anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the risk of developing AD (Launer, 2003). Of four randomized clinical trials, however, only one study found a small benefit at slowing cognitive decline in patients with AD (Rabins et al., 2007). The use of NSAIDs has been associated with an increased risk of cardiac toxicity, impaired renal function, and bleeding.
Statin drugs (e.g., lovastatin [Mevacor®], pravastatin [Pravachol®], simvastatin [Zocor®], and others) are used for treating hypercholesterolemia and have anti-inflammatory effects. Lowering cholesterol in experimental animal models slows the expression of AD neuropathology. Case-control clinical studies comparing the occurrence of AD between individuals taking statin drugs and those who are not suggest that the risk of AD is reduced among those taking the drug. Two randomized placebo-controlled trials found no benefit for statin drugs on reduction in occurrence of AD or dementia (McGuinness, Craig, Bullock, & Passmore, 2009). Statin drugs are associated with myopathies.
Omega-3 Fatty Acids
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that has been identified as a potential drug treatment for AD. Epidemiological studies have shown that omega-3 fatty acid consumption is associated with a reduced risk of cognitive decline or developing AD. Preclinical animal studies have found that DHA modifies the expression of AD-like neuropathologies. The most abundant fatty acid in the brain is DHA, and it is reduced in the brains of patients with AD. The other major omega-3 fatty acid found in fish, eicosapentaenoic acid (EPA), is virtually absent from the brain. A recent double-blind, placebo-controlled trial in patients with mild to moderate AD found no benefit for the use of DHA on slowing the rate of cognitive or functional decline in these patients (Quinn et al., 2010).
Hormone Replacement Therapy
Epidemiological studies in human and preclinical animal studies have suggested that estrogen therapy or combined estrogen and progestin therapy in postmenopausal women may protect against cognitive decline and dementia. Evidence reviews have found no evidence of sufficient efficacy and/or safety to justify the use of any of these drug therapies for the prevention or treatment of dementing disorders (O’Brien & Burns, 2010; Rabins et al., 2007). Indeed, these studies have suggested that their use is associated with an increased risk of cognitive decline, as well as an increased cancer risk in women.
Reduced levels of B vitamins (including folate and vitamin B12) have been associated with cognitive impairment and an increased risk of dementia. However, evidence reviews have found no evidence of sufficient efficacy to justify their use to prevent or treat dementing disorders (O’Brien & Burns, 2010).
Because of the limited benefits of FDA-approved standard treatments for dementia, many alternative drug therapies have been investigated. Isoxsuprine and ergoloid mesylates are FDA approved for the treatment of dementia, although they have limited evidence of benefit and are rarely used. There is no evidence that other drug therapies, including vitamin E, selegiline, NSAIDs, statin drugs, omega-3 fatty acids, estrogen or combined estrogen plus progestin therapy, or B vitamins, are sufficiently effective and safe to justify their clinical use for the treatment of MCI, AD, or other dementing disorders. Nurses should be familiar with these types of drugs, including their limited benefits and potential adverse effects, especially those drugs that are available to patients without a prescription.
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