Ergoloid Mesylates

Dementia is becoming an increasingly important health care problem as the U. S. population ages and health care costs continue to escalate. The first step in the management of dementia is an accurate assessment of its etiology by means of a complete physical and neurologic examination and a battery of tests designed to identify treatable causes.

Dementia is reversible in about 15 percent of cases. (1) Reversible dementia has a number of etiologies, including iatrogenic, infectious, metabolic, endocrine and psychiatric causes. The more common degenerative dementias include Alzheimer's disease, vascular dementias, Creutzfeldt-Jakob disease and Niemann-Pick disease. Alzheimer's disease is responsible for at least 50 percent of cases of dementia, (2) and although much has been learned about the biochemical changes in Alzheimer's disease, there are still no specific therapies for the management of the accompanying behavioral symptoms.

Clinicians treating patients with dementia are often faced with a variety of psychiatric symptoms, including depression, agitation and continued intellectual decline. Appropriate pharmacologic treatment of these symptoms can prevent premature hospitalization and provide significant relief to the patient and the caretakers. Depression

DIAGNOSIS

Blazer and Williams (3) have estimated that 15 percent of the elderly living in the community have substantial depressive symptoms. The term "pseudodementia" was coined by Kiloh (4) to describe patients who appeared to have dementia but who were in fact depressed. Subsequent research has shown that approximately 10 percent of patients presenting with symptoms of dementia actually have primary depression. (1,5,6) Such symptoms as apathy, decreased ability to think and concentrate, psychomotor agitation and diminished interest may lead the clinician to the incorrect diagnosis of dementia.

Patients with primary depression should be differentiated from those with dementia and a concurrent major depressive episode. Several authors (7-9) have shown that up to half of patients with degenerative dementia also have significant depressive symptoms, which usually occur only in the early stages of the dementia.

Neuropsychiatric and other psychologic tests are often helpful in distinguishing patients with primary depression alone from those with dementia. In patients with primary depression, different tests of the same cognitive function yield inconsistent results, and the results of the same tests become inconsistent over time. (10) Patients with dementia show a more global decline in cognitive function than do persons without dementia.

Laboratory tests for depression can be difficult to interpret. The dexamethasone suppression test loses much of its specificity in elderly patients with dementia. (11,12) The sleep electroencephalogram has been shown to distinguish depressed elderly patients from normal control subjects. (13,14) There is also consistent evidence that sleep parameters can be used to differentiate depression from dementia in the elderly. (15,16)

The diagnosis of major depression is also supported by a previous history of major depression, particularly if the depression responded to antidepressant or electroconvulsive therapy, or by a family history of depression. A patient with depression will also have a more abrupt onset of symptoms and a relatively short duration of symptoms.

In many cases, the mental status examination is the most important tool in differentiating dementia from depression. During the mental status examination, patients with dementia alone attempt to disguise their cognitive deficits with confabulation and make a real effort to answer correctly. (10) Social skills are often preserved. Patients also appear distressed when they make an error and admit to keeping notes and trying to compensate for their memory impairment.

In contrast, patients with primary depression and secondary cognitive deficits often show diminished effort during the mental status examination. They answer with "I don't know," and their responses emphasize their disability and low self-esteem. Depressed patients also show neurovegetative symptoms, including altered appetite (usually decreased), weight change (usually weight loss), decreased energy, fatigue, crying spells, anhedonia and hypersomnia or, more often, insomnia.

Patients with dementia, especially those with Alzheimer's disease, may exhibit intermittent depressive symptoms, lasting two to three days. This pattern is unlike the two-to three-week period of depressed mood or loss of interest that is a criterion for a major depressive episode, as outlined in the Diagnostic and Statistical Manual of Mental Disorders-IIIR (DSM-III-R). In patients with dementia, the episodes of depression usually include atypical somatic symptoms characterized by increased appetite, weight gain, a craving for sweets and chocolate, hypersomnia, lack of energy and marked anxiety.

Lazarus and co-workers (9) found that 40 percent of patients referred for neurologic evaluation of dementia had significant depressive symptoms. Compared with age-matched control subjects, patients with dementia had more intrapsychic feelings of depression, including depressed mood, anxiety, helplessness, hopelessness and worthlessness. Neurovegetative signs were notably absent. Depressive symptoms without a major depressive episode may therefore be a part of dementia.

The symptoms of intermittent and major depressive episodes respond to drug therapy. However, some depressive symptoms are more resistant to therapy. Kral (17) has described a type of depression resistant to antidepressant therapy in patients with Alzheimer's disease. The depression is characterized by a chronically depressed mood, irritability, aggressiveness and paranoid ideation.

Another type of depression that may occur in patients with dementia results from the loss of self-esteem and the difficulty in coping with the dementing process. This type of depression may be more responsive to supportive psychotherapy than to drug therapy.

The decision to treat depressive symptoms in patients with dementia depends on the possible benefits of therapy, the physician's philosophy of using medication and the potential risks of therapy, which mainly relate to side effects and the patient's physical health. In general, symptoms of a major depressive episode or intermittent depression are responsive to antidepressants. Table 1 lists dosage ranges of the common antidepressants available in the United States.

TRICYCLIC ANTIDEPRESSANTS

Antidepressants have long half-lives and are almost entirely metabolized by the liver and excreted by the kidney. Elderly patients should therefore be maintained on a dosage about one-half to two-thirds the usual adult dosage. Monitoring of plasma drug concentrations is also useful, particularly for amitriptyline (Elavil, Endep), imipramine (Tofranil), desipramine (Norpramin, Pertofrane), doxepin (Adapin, Sinequan) and nortriptyline (Aventyl, Pamelor), since most commercial laboratories can provide accurate blood level determinations for these drugs.

Table 2 lists the possible side effects of antidepressants, and Table 3 [omitted] (18,19) compares the side effect profiles of these drugs. Although most patients with dementia are at increased risk of side effects from antidepressants, patients with concurrent liver or kidney disease are at particular risk of drug accumulation and toxicity. Patients with dementia are sensitive to the competitive inhibition of muscarinic cholinergic receptors and alpha-adrenergic receptors. Since elderly patients often take a number of different medications, the side effects can be additive and dangerous. Central anticholinergic side effects may lead to memory loss and increased confusion, which may be followed by worsening of depression and an increased suicide potential. Antagonism of alpha-adrenergic receptors may cause orthostatic hypotension, with an accompanying risk of falls. Patients with coronary artery disease may be at risk of myocardial infarction if the heart attempts to compensate for the drop in blood pressure with a sudden increase in pulse rate.

Selection of the appropriate antidepressant drug is therefore dependent on the clinical condition of the patient and the side effect profile of the antidepressant. Nortriptyline and desipramine have a number of important qualities, including clinically meaningful blood levels and low anticholinergic and alpha-adrenergic effects.

MAO INHIBITORS

Although not generally used in elderly patients with dementia, the monoamine oxidase (MAO) inhibitors represent another class of potentially helpful antidepressants. The main problems with these drugs are the high incidence of orthostatic hypotension and anticholinergic side effects and the need to maintain a tyramine-free diet. Studies have shown that the MAO inhibitors are superior in the treatment of the atypical symptoms in intermittent depressive episodes. (20) Results of a recent study (21) also suggest that this class of drugs is particularly effective and relatively safe in elderly patients.

OTHER ANTIDEPRESSANTS

Fluoxetine (Prozac) and trazodone (Desyrel) are two drugs with little or no anticholinergic action. However, fluoxetine has an exceptionally long half-life (two days) and an active metabolite with a half-life greater than one week, which may lead to drug accumulation. Fluoxetine may cause anxiety and insomnia. Trazodone tends to be sedating and causes orthostatic hypotension.

OTHER THERAPIES

Other treatment approaches for depression in elderly patients with dementia include cognitive therapy and electroconvulsive therapy (ECT). Cognitive therapy has been shown to be as effective as tricyclic antidepressants in the treatment of endogenous depression. (22,23) However, patients with dementia may be unable to comprehend and participate in cognitive therapy. Supportive psychotherapy, behavior therapy and family therapy may be more useful.

ECT is a highly effective treatment for depression in the elderly, particularly when drug side effects have been difficult to manage. (24) However, ECT may temporarily worsen memory impairment and increase confusion. Moreover, data concerning the risks of ECT in the elderly are generally not available. (25)

Methylphenidate (Ritalin) has also been used to treat major depression in the elderly, particularly when psychomotor retardation is a significant problem or antidepressants and ECT are contraindicated. Potential side effects of this drug include hypertension, psychosis and increased agitation.

Agitation

Agitation and accompanying behavioral disturbances, such as emotional lability, belligerence, hostility, pacing and sleeplessness, are often the most significant problems in patients with dementia. Suspiciousness may develop when patients cannot find a misplaced object and then believe it was stolen. Hallucinations (both auditory and visual) and delusions may also occur.

NEUROLEPTICS

The medications used to treat agitation and psychosis in patients with dementia are listed in Table 4. The neuroleptics have traditionally been the mainstay of therapy. Risse and Barnes (26) describe seven behaviors that appear to benefit from neuroleptic therapy: hallucinations, suspiciousness (especially when not directly related to impaired memory), emotional lability, belligerence, hostility, excitement and sleeplessness. However, they point out that only a minority of patients show significant improvement. In general, the neuroleptics have little demonstrated clinical efficacy in patients with dementia, except when suspiciousness, hallucinations or hostility dominate the clinical picture and behavioral interventions have failed.

Moreover, behaviors such as pacing, talking to oneself, talking in front of the mirror and talking to loved ones who are not present (including a misperception of individuals as loved ones) are only partially responsive to treatment with neuroleptics. Other symptoms, including impaired memory, unsociability, poor self-care and indifference to surroundings, are unaffected by neuroleptics. (26)

The side effects of neuroleptic agents are listed in Table 5. The anticholinergic and antiadrenergic side effects (e.g., orthostatic hypotension) are similar to those associated with the antidepressants. Low-potency neuroleptics (e.g., chlorpromazine [Thorazine] and thioridazine [Mellaril]) are relatively sedating and are associated with a low incidence of extrapyramidal side effects. However, low-potency agents are more likely than high-potency agents to cause orthostatic hypotension and muscarinic anticholinergic symptoms. The high-potency neuroleptics (e.g., haloperidol [Haldol]) have little or no anticholinergic properties or blood pressure effects, but they do cause significant extrapyramidal symptoms and can actually increase agitation if akathisia develops. The pharmacologic characteristics of neuroleptics are summarized in Table 6 [omitted].

The most worrisome side effect of neuroleptics is tardive dyskinesia. Tardive dyskinesia may be devastating, further impairing the patient's ability to feed and dress himself and, perhaps, making ambulation difficult. Studies suggest that the elderly, particularly women, may be predisposed to tardive dyskinesia.

(27)

BENZODIAZEPINES

Benzodiazepines may be useful when the main behavioral problems are agitation, restlessness and insomnia related to anxiety. (26) However, benzodiazepines can increase confusion and memory impairment in patients with dementia, and may cause oversedation and ataxia. These side effects are minimized by using the benzodiazepines with short or intermediate half-lives. The benzodiazepines that are metabolized in the liver by conjugation are less likely to accumulate; metabolism by oxidation--but not by conjugation--is reduced in the elderly. (28) The benzodiazepines that are transformed to active metabolites are more likely to cause toxicity than are those metabolized to inactive compounds.

The commonly used benzodiazepines and their methods of biotransformation are listed in Table 7 [omitted]. The medications that fulfill the criteria of a relatively short halflife, few active metabolites and conjugation through the liver are oxazepam (Serax), lorazepam (Ativan) and temazepam (Restoril). Lorazepam and oxazepam are first-choice drugs for the short-term management of agitation related to anxiety; temazepam is reserved for the treatment of middle-of-the-night insomnia. When anxiety and agitation are accompanied by mild depressive symptoms, alprazolam (Xanax) is often effective.

One additional factor to consider when choosing a benzodiazepine for elderly patients with dementia is the propensity of these drugs to cause antegrade memory loss. This side effect is more common with the benzodiazepines that have a low volume distribution (low lipophilicity) and a high receptor binding affinity. Alprazolam, triazolam (Halcion) and lorazepam are probably the worst offenders.

OTHER THERAPIES

The other drugs used primarily to treat the aggressiveness and agitation associated with dementia are the anticonvulsants, lithium (Eskalith, Lithane, Lithobid) and propranolol (Inderal). However, there are few prospective controlled studies of the use of these drugs for this purpose.

The anticonvulsants, notably carbamazepine (Tegretol) and valproic acid (Depakene), have been shown to reduce aggressiveness in patients with psychiatric or neurologic diagnoses. (30) Although these drugs have not been evaluated for use in patients with dementia, there is evidence that carbamazepine may help control behavioral problems in patients with temporal lobe electroencephalographic abnormalities. (22) Potential side effects, including ataxia, cognitive impairment and bone marrow suppression, may limit the use of carbamazepine in this population.

Lithium has been shown to be effective in reducing aggressive and self-mutilating behaviors, (26,30-32) but no studies have been performed in patients with dementia. Lithium can also cause cognitive impairment and confusion, worsening dementia.

Propranolol has been used with some success in patients with aggressive behavior secondary to organic brain syndrome. (26,30,33,34) The dosage required may be as high as 500 mg per day, which can cause significant bradycardia and hypotension, particularly in elderly patients.

Hydroxyzine (Atarax), diphenhydmmine and chloral hydrate may be used to reduce sleeplessness. Hydroxyzine and diphenhydramine may also be given for mild anxiety. These two drugs are both antihistaminic and anticholinergic. The anticholinergic property may cause confusion, constipation and urinary retention. Chloral hydrate has a low therapeutic index and may cause insomnia or withdrawal symptoms. (35)

The treatment approach for the management of agitated patients with dementia is outlined in Figure 1 [omitted]. The basic approach is to identify the target symptom that is causing the agitation. The treatment is then designed to alleviate these symptoms. Cognitive Decline

The cognitive impairment that characterizes dementia may lead to depression and agitation, which may further compromise the patient's ability to function. Since there are few effective interventions, the primary management approach in patients with dementia is to determine if an underlying, treatable disorder is contributing to the cognitive impairment.

DRUG TREATMENT

In a review of the various pharmacologic treatments of cognitive decline in the elderly, Reisberg and colleagues (36) point out that ergoloid mesylates (Hydergine) and the smooth muscle relaxant papaverine are the medications most widely used for this problem. Some placebo-controlled studies of Hydergine in doses of 3.0 to 4.5 mg per day have shown at least a modest improvement in such variables as mental alertness, orientation, confusion, recent memory, emotional lability, anxiety, fears, motivation and depression. Papaverine has also been shown to be superior to placebo in increasing cognitive function, but the improvement is delayed and may take up to 16 to 24 months to occur.

In general, however, many clinicians question the efficacy of ergoloid mesylates and papaverine. (37,38) They argue that there is either no cognitive improvement with these drugs or the level of improvement is too small to be of any clinical significance.

EXPERIMENTAL THERAPIES

Other potentially useful treatments include the cholinomimetic medications, such as the centrally acting anticholinesterase tetrahydroamino acridine (THA). Cholinomimetic drugs remain experimental but hold some promise in the treatment of Alzheimer's disease. (The primary deficit in this disease is thought by some to be a relative cholinergic deficit.)

Experimentally, the neuropeptides (adrenocorticotropic hormone [ACTH], vasopressin and the enkephalins) and the nootropics (for example, piracetam, the cyclic derivative of gamma-aminobutyric acid [GABA]) have also shown promise but are not yet available for clinical use.

The clinician is left with few realistic choices for the treatment of the cognitive deficits of senile dementia. Although controversial, ergoloid mesylates remain the only medication with any proven efficacy. Consideration should be given to the fact that they pose little risk, have few side effects and, in selected cases, appear to be modestly beneficial.

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WILLIAM M. MCDONALD, M.D. is an associate in the Department of Psychiatry and assistant director of medical student education at Duke University Medical Center, Durham, N.C.

K. RANGA RAMA KRISHNAN, M.D. is assistant professor and medical director of the Department of Psychiatry and a consultant in the Pain Clinic at Duke University Medical Center.

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