Reply from John Morris, M.D., Washington University, St. Louis (posted 2 September 1998).

The caveat about mental status tests is that they should be used primarily to confirm the presence of cognitive deficits, to help demonstrate an AD-consistent pattern of deficits (e.g., impairments in aspects of memory (especially new memory and learning, as in recall tasks) and in "executive functions), and to monitor dementia progression over time (through serial testing). They also can be used to monitor variations in the expected rates of decline, such as with antidementia drug therapy. Mental status tests should not be "diagnostic" in the sense that they cannot, certainly at the intital time of testing, indicate whether the individual has declined from previous levels of cognitive abilities (the hallmark of AD) nor whether there is impairment sufficient to interfere with performance of accustomed activities. This information must be collected by other means (e.g., informant interview). The most widely used brief mental status test is the Mini-Mental State Examination (MMSE); others include the Short Blessed Test. More comprehensive batteries of tests measure performance in multiple domains (episodic/declarative memory, semantic memory, nonverbal memory, visuospatial abilities, speeded psychomotor performance, executive tasks, etc). At least in mild or even moderate AD, neurologic abnormalities are infrequent so that the neurologic examination is performed to evaluate the presence of features that may indicate another dementing illness. For example, the presence of extrapyramidal signs may indicate diffuse Lewy body disease or Parkinson's dementia; focal neurological deficits may suggest corticobasal degeneration or strokes; myoclonus may indicate Creutzfeldt-Jakob disease. All these findings must be placed in the proper clinical context, however.

Reply from John Morris, M.D., Washington University, St. Louis (posted 2 September 1998).

The "standard" tests are not to "rule in" AD but rather to find possible indications of other dementing illnesses that may co-exist with AD or perhaps be responsible for the dementia. In this regard, these tests are weighted to discovering potentially correctable causes of dementia: thyroid function tests, vitamin B12 level, serum biochemistries, complete blood counts, etc. Other tests are used in the proper clinical context: VDRL for syphilis, HIV or Lyme titres, EEG when Creutzfeldt-Jakob is under consideration, and so forth. None of these tests have been studied sufficiently to know whether they are cost-effective - does their expense justify the (rare) detection of a potentially correctable dementia? The answer is not known but surely will depend in part on what populations are to be screened for non-AD causes. The "test battery for non-AD dementia" controversy perhaps is greatest for neuroimaging - is it appropriate for every person with dementia? The answer is "probably not," but a noncontrast head CT scan generally gets done in most dementia work-ups (if not a head MRI to better evaluate possible vascular disease). Of note, the most common "non-AD" causes of dementia probably are overmedication and depressive illness, neither of which is detected by laboratory tests but rather by the clinical history. In my opinion, 90% or more of the information needed to diagnose dementia and to perform a differential diagnosis comes from the clinical information (again, using informants as well as interviewing and examination of the patient). This isn't to say that laboratory tests shouldn't be performed, just that we don't know what the exact role should be (particularly given the cost-effectiveness issues). My practice is to tailor the tests depending on the results of the history and examination (e.g., if I suspect Creutzfeldt-Jakob disease, I will get a lumbar puncture for the 14.3.3 cerebrospinal fluid test and probably also get an EEG, whereas I would not obtain either of these tests when typical AD is suspected). It should be recalled that AD patients are not immune to other illnesses and that these co-existent illnesses can contribute to overall dementia severity, so that if there is hypothyroidism in addition to AD, correction of the thyroid status may at least partially benefit the dementia.

Reply from John Morris, M.D., Washington University, St. Louis (posted 2 September 1998).

"Cutting-edge" tests look to provide a reliable biomarker of AD. At this time, my opinion is that none has been shown to serve this role. The tests under investigation that may contribute at least partially to dementia diagnosis include structural neuroimaging (e.g., hippocampal volumetry), functional neuroimaging (PET, SPECT, fMRI - these may be useful for finding patterns of unusual cerebral involvement, such as in frontal lobe dementia), cerebrospinal fluid studies (for AD, this is focused on levels of amyloid beta peptide and tau), and genetic markers or risk factors, such as apolipoprotein E. Again, none presently is "diagnostic" for AD.

Reply from John Morris, M.D., Washington University, St. Louis (posted 2 September 1998).

I do NOT obtain genetic tests (including ApoE) for AD. In rare familial cases (such as pedigrees with familial Creutzfeldt-Jakob disease that suggest mutations in the PrP gene) I will obtain the tests when the family so desires. This is a very important and rapidly developing area with new mutations and polymorphisms constantly being identified. It is clear that family members (affected and unaffected) should receive genetic counseling BEFORE and AFTER any genetic testing is performed, but it is difficult to keep abreast of all developments and we are also facing new issues regarding consent, confidentiality of results (important for insurance, employment, etc), and related concerns.

Reply from John Morris, M.D., Washington University, St. Louis (posted 2 September 1998).

I virtually always tell the patient their diagnosis, generally at the first visit if I am confident of clinical AD, in the presence of the family. They have a right to know what the diagnosis is, and also I want their assistance in disease management: planning for the future (e.g., durable power of attorney; driving issues) and drug and nondrug therapy if indicated. Of course, I note the obvious: the diagnosis cannot be absolutely known without examination of brain tissue and thus I will monitor the clinical course and inform them if the initial diagnosis needs to be revised; the lay image of AD (often someone in advanced stages, ready for nursing home and without much quality of life) does not apply to them and indeed our role will be to optimize quality of life to allow them to function as long as possible in their usual activities (as long as they are not a danger to themselves or to others), although some modification or supervision may be necessary; and AD now is a treatable disorder and I will be working with them to initiate drug therapy as appropriate. The other aspect of conveying the diagnosis to the patient and the family is to identify up front the family as an essential component of the care process (and indeed to be aware that the caregivers themselves may need care). Support from other sources (i.e., the Alzheimer Association) is encouraged.

Reply from ARF (posted 13 August 2001). We just located this article which suggests that your grandmother could be having a toxic reaction to donepezil. I advise you to consult her physician immediately to investigate this possibility.

Calvo-Romero JM. Ramos-Salado JL. Symptomatic sinus bradycardia associated with donepezil.[Spanish] Revista de Neurologia. 28(11):1070-2, 1999 Jun 1-15.

Reply from Norman Relkin, M.D. Ph.D. Cornell Weill Cornell Medical).

My sympathies go out to the patient and caregiver for having to deal with two devastating illnesses at once. Regardless of the affected individual's cancer status, however, hormone replacement would not be recommended. 'Hormone replacement therapy' (HRT) usually refers combined use of estrogen and progesterone, versus 'ERT' which is estrogen replacement alone. A recently published, multicenter, placebo-controlled prospective study of estrogen replacement therapy as a treatment for AD in hysterectomized women showed no benefit after one year of estrogen treatment. Until further data becomes available, neither ERT or HRT are being recommended as primary treatments for individuals already diagnosed with AD.

Estrogen replacement is under study as a possible means of preventing of Alzheimer's disease, and for symptomatic therapy as an adjunct to acetylcholinesterase inhibitors. The use of testosterone as a possible treatment for AD is also under investigation in men, but there is not adequate data to support its clinical use at the present time.

Reply from Norman Relkin, M.D. Ph.D. Cornell Weill Cornell Medical).

I need to preface my statements by saying I have been a consultant for Pfizer and Eisai, that I am a principal investigator in a study they are sponsoring and serve on their speaker's bureaus. From that completely unbiased standpoint, I would speak to this issue as follows:

Acute adverse effects after withdrawal of donepezil (Aricept®) are uncommon owing to the relatively long half-life of the medication. Discontinuation of donepezil may be accompanied by a decline in cognitive and/or behavioral status over a 4-6 week period, analogous to the washout phenomena seen in the E2020 pivotal studies. This washout effect sometimes occurs in patients who never overtly improved on donepezil or seemed to worsen while on the medication as a result of progression of the underlying illness. This being the case, unless the patient is experiencing side effects or has progressed to a stage of illness in which they are unable to ingest pills or benefit from treatment, I tend to discourage discontinuation of donepezil.

Reply from John Morris, M.D., Washington University, St. Louis.
There are no firm guidelines regarding donepezil (Aricept) withdrawal. My approach has been to maintain therapy (assuming that the patient tolerates the medicine safely and that there are no unusual considerations, such as cost issues or concerns that the patient is not taking the medicine in compliance with instructions) as long as a) the family/caregiver have not noticed overt WORSENING of the patient's cognitive/behavioral/functional abilities; and b) there is no overt WORSENING of the patient's cognitive test scores (e.g., Mini-mental State). It is true that with time some deterioration occurs during donepezil therapy but this varies in duration and severity with the patient. Only when there is clear worsening do I suggest that treatment be discontinued; this may be after 2 years in some cases. I just simply stop the drug (no slow dose reduction). In general, there has not been sudden deterioration once the drug is stopped. If there is, it is a simple matter to just resume therapy at the previous dose.

Reply from Norman Relkin, M.D. Ph.D. Cornell Weill Cornell Medical).

The incidence of depression is increased among AD patients and adds significantly to the overall burden of disease when left untreated. Appropriate use of antidepressants can improve the quality of life of depressed AD patients considerably. In most cases, antidepressants can be safely administered in combination with acetylcholinesterase (AChE) inhibitors such as donepezil (Aricept).

My colleagues and I commonly prescribe AChE inhibitors in combination with antidepressants in the SSRI class such as sertraline (Zoloft) and paroxetine (Paxil). We've observed a comparable spectrum of side effects to those that occur when the two classes of drugs are used independently. I tend to avoid using tricyclic antidepressants in the AD population because of their potential to adversely affect cognition. I likewise shy away from the use of MAO inhibitors because of the difficulty in imposing dietary restrictions on patients with dementia. Consequently, I cannot comment from personal experience on the safety of using tricyclics or MAO inhibitors in combination with drugs like Aricept. However, we recently reported data on the safety and efficacy of donepezil obtained from the study of more than 800 patients enrolled in open-label Aricept trials throughout the United States. (McRae T, Relkin N and Knopman D (1998) " A Large Scale Open Label Trial of Donepezil in the Treatment of Alzheimer's Disease" Neurology Vol 50 (4) supplement 4, p A90.) More than a quarter of those treated with donepezil in these trials were on concomitant medications, including a variety of antidepressants. Nevertheless, the adverse events profile and clinical efficacy of donepezil in open-label use proved to be quite comparable to that observed in the more restrictive Phase 3 clinical trials that excluded patients receiving antidepressants. Clinically significant interactions between donepezil and the commonly prescribed antidepressants appear to be quite rare.

I usually stagger the time of initiation of AChE inhibitors and antidepressants so that the source of any treatment-related side effects can be more readily determined. If the patient is already on a stable dose of Aricept, I add the antidepressant at the recommended geriatric starting dose. If the patient is currently untreated with either agent, I usually initiate the antidepressant first and adjust the dose after 4 to 6 weeks if necessary. Once the dose of the antidepressant is stable and there are early signs of remitting depression, I will initiate donepezil.

I generally continue antidepressant therapy in dementia patients for at least 6 months, and reassess the patient at three to six month intervals. Since both SSRIs and AChE inhibitors can be psycho-activating, I am particularly vigilant for signs of newly emergent restlessness, anxiety, insomnia, mania and agitation. In my experience, these are relatively rare complications and usually respond fairly rapidly to reductions in dosage and/or a brief drug holiday.

Comment by John P Blass, MD, PhD. Cornell Weill Cornell Medical). (jpblass@mail.med.cornell.edu).

Apart from the clinical rationale for and experience with the use of antidepressants in AD, excellently summarized by Dr. Relkin, there is also neuropharmacological rationale for using Zoloft or other SSRIs in AD patients who act depressed. Perhaps a third of AD patients show damage to serotonergic systems at autopsy. In them, treatment with a serotonergic agonist is quite as rational as treatment with a cholinergic agonist. Whether it is more useful to refer to such patients as suffering from "depression" or from "central cholinergic deficiency" is a matter of choice, since depressive symptoms have been shown to be relatively common in patients with central adrenergic and serotonergic damage.