Of dementia, depression and drugs.

Clinical pearls on the drugs that cause dementia, drugs intended to "cure it

Modern drug therapy of the elderly has been intimately associated with dementia for some years now -- as a cause, as an attempted cure, and as an adjunct to treatment. Here are a few reflections on each of these manifestations.

As Cause

Those who are experienced in clinical management of the elderly know that, often, what seems to be senile dementia of the Alzheimer's type (DAT) really isn't. Rather, the resident is experiencing a transient dementia caused by a reversible pathology or outside factor. The most common reversible causes of what appears to be DAT can be diseases of the central nervous or cardiovascular system; metabolic disorders including hypothyroidism; infection; sensory deprivation; trauma; body temperature changes -- and, perhaps most common of all, drugs.

The most common drag causes of pseudodementia are central nervous system-active medications, including anxiolytics, anti-depressants, sedatives and hypnotics, narcotic analgesics, sedating antihistamines, and antipsychotics. Even the H-2 blocking agent cimetidine, when used in doses not adjusted for decreased renal function found in the older patient, may cause delirium which can be misdiagnosed as dementia.

Misdiagnosis is a common and serious problem. In a 1977 study reported in the Journal of the American Geriatrics Society, Miller and Elliott reported on examining the primary and secondary diagnoses of 100 consecutive nursing facility admissions; 64% of the patients' primary diagnoses were inaccurate, and 84% of the patients' secondary diagnoses were either lacking or inaccurate. The predominance of the diagnostic errors concerned mislabeling patients with dementia or missing depression.

A type of case that is all too frequently observed serves to illustrate this. J.B., a 78-year-old male who was diagnosed as having early-to-middle DAT, was started on thioridazine 50 mg BID. Within a week, he became more disoriented to time and place, and could not remember his wife's name even though she was his caregiver in the home environment. His dose was increased to TID, then 50 mg QID over successive weeks, and he became even more disoriented, began "sundowning," became incontinent of his urine and could not be easily aroused.

After 4 falls and a fractured hip, his thioridazine was tapered gradually by 10 to 15% per week. He recovered continence and orientation to place and person, but not to time. Once he had been tapered to 25 mg per day of the thioridazine, he was changed to a less sedating and anticholinergic neuroleptic, haloperidol 0.5 mg daily, with ultimate resolution of his apparent dementia.

As Cure

With the presumption that at least 50 to 60% of dementia is of the Alzheimer's type, much drug research has been developed to attempt to reverse or halt the progression of the disease, with its cortical neurofibrillary tangles and clusters of degenerating nerve endings known as neuritic plaques that are found on autopsy. The presumed pathophysiologic changes in DAT revolve around a deficit in acetylcholine. Cholinergic-oriented approaches have included presynaptic, synaptic and postsynaptic agents. The two most promising agents in early-to-middle dementia are Cognex and Mentane.

In a recent study, T.L. Thompson, et al (N Engl J Med 1990; 323:445-8) found that Hydergine, the only drug currently FDA-approved for Alzheimer's, had no significant benefit in dementia, and may actually worsen dementia in a sub-set of patients. This is not surprising, considering that the drug is structurally related to the hallucinogenic agent LSD.

Noncholinergic approaches that at one time appeared to offer the most promise were the nootopics or memory enhancers. Unfortunately, both toxicity and a substantial-placebo effect were seen. The Table lists some agents that are in various stages of clinical trials and their proposed methods of action.

Illustrative of the difficulties involved in this research, this investigator had very promising results in the first phase of a nootopic trial. Ten of twelve patients screened from 156 candidates for the trial showed marked improvement in their orientation, memory and ability to perform activities of daily living (ADLs). The first phase of this trial was placebo "washout," in which all prior neuroactive drugs were to be discontinued and extensive tests of cognition that took 4 to 6 hours per patient were performed over one month. The most obvious conclusion from the early success of the drug was that when prior drugs are stopped and much time is spent with the patient, a substantial improvement might be noted. All but one patient returned to their placebo medicine on termination of the trial due to liver toxicity of the active drug. One patient believed that the placebo was a "wonder drug" and planned to take one capsule a week to sustain her remarkable "recovery" from her dementia.

As Adjunctive Therapy

As noted in this space in previous issues of NURSING HOMES, depression is the most frequently underrecognized problem of older adults. In long-term care facilities, 10 to 20% of patients with no cognitive impairment have major depression and 30 to 40% with cognitive impairment (e.g. dementia) have depressive symptoms. Pseudodementia patients treated for depression recover most of their cognitive impairment. The more common finding in the nursing home, however, is the patient who has both mild-to-moderate dementia (GDS scale stages 3 to 5 above) and co-existing depression; these patients are most likely to benefit from antidepressant medication, although the cognitive impairment remains.

Removal of drugs that contribute to depression is essential; these include commonly used antihypertensives, such as methyldopa, beta blockers, reserpine, and the other sympatholytics. For hypertension in nursing home patients, therapeutic substitution of a calcium channel blocker or angiotensin converting enzyme inhibitor (ACEI) may be appropriate to avoid worsening mental dysfunction.

Bibliography

Blazer D. Depression in the elderly. New Engl J Med 1989; 310:164-6. Bredenkamp VL. Alzheimer's Research Update. The ACCP Report 1993; 13(8):3.

Differential diagnosis of dementing diseases. NIH Consensus Development Conference Statement. Vol. 6, No. 11, 6-8 Jul 1987. US Govt Printing Office, No. 1987-161-296:61128.

Reisberg B. A global deterioration scale for assessment of cognitive decline in older patients. Am J Psych 1982; 139:1136-9.

Tornatore FL Researchers look at promising new drugs to combat Alzheimer's Disease. LTC Pharmacist 1993; 1(9):3-4.

Williams DB, Copelan DN. New drugs for 1993. The Consultant Pharmacist 1993; 8:208-26.

James W. Cooper, Pharm. PhD., is Professor and Head, Department of Pharmacy Practice, The University of Georgia College of Pharmacy, Athens, GA.