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5. Fry PS: Depression, Stress, and Adaptations in the Elderly. Rockville, MD, Aspen, 1986,pp 323-347.

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8. Meston CM: Aging and sexuality.West J Med 167:285-290, 1997.

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Nemiroff RA, Colarusso CA: The Race Against Time. New York, Plenum Press, 1985. Pearlman CK: Frequency of intercourse in males at different ages. Med Aspects Hum Sex 6:92, 1972. Pipher M: Another Country: Navigating the Emotional Terrain of Our Elders. Riverhead Books, 1999.

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66. PSYCHOPHARMACOLOGY FOR ELDERLY PATIENTS

RoGerta M. Richardson, M.D

1. How do changes in body composition that occur with aging affect your choice of psy-

chotropicmedication?

The aging body shows a significant decrease in lean body mass, corresponding increase in total body fat, and decrease in total body water. Thus, water-soluble drugs have a greater concen- tration per unit dose because of the apparent decrease in the size of the reservoir. The blood alcohol level per drink rises with age, and the usual two martinis a day can’t be tolerated at age 70. Fat-soluble drugs have a greater volume of distribution. They are stored in fat and released grad- ually, and therefore show a longer half-life in the elderly. The highly fat-soluble benzodiazepines, such as diazepam, have a greatly increased half-life in older individuals, and typical antipsychotics are affected by this phenomenon as well. Remember, too, that the brain is a very fatty organ.

2. Why is it essential to know the route of metabolism of any drug prescribed?

Most drugs are metabolized primarily in the liver. In general, hepatic blood flow and size decrease significantly with aging. However, individual variation in activity of liver enzymes is vast. For this reason, there can be a 20-fold difference in appropriate dose of some antidepressants among patients of the same advanced age. Ignorance of this fact leads to two common prescribing mistakes: overdosing and underdosing. Remember to start low, go slow-but don’t stop too soon. Also take into account metabolic interac- tions with other medications. This is especially crucial for older patients who may be taking a number of different medications, and who are more vulnerable to adverse effects of blood levels that climb too high, or drop too low. Medications with renal metabolism are more predictable. Creatinine clearance decreases steadily and predictably with age. Age and body weight are factors, such that the older and smaller a person is, the lower his or her creatinine clearance will be. Lithium is the psychotropic medication most influenced by this phenomenon. Dosages must be drastically reduced in the elderly to avoid toxicity. Some of the benzodiazepines also are metabolized renally and have a slower clearance in elderly patients.

3. How are changes in receptor sensitivity and neurotransmittersrelevant?

Aging brings reduced sensitivity to some pharmacologic agents and increased sensitivity to others. The most important consideration in prescribing psychotropics, however, is the cholinergic neurotransmitter system. Several of the commonly used psychotropic agents have significant

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anticholinergic properties. But in the aging brain, cholinergic binding sites are decreased; choline acetyltransferase, vital for making acetylcholine, is decreased; and acetylcholine is even more de- creased in the brains of patients with Alzheimer’s disease. Therefore, the elderly are predisposed to central anticholinergic toxicity in the form of confusion, delirium, and psychosis. Whenever prescribing psychotropic medications for the elderly, therefore, choose the least anti- cholinergic agent in each class and avoid combining two or more highly anticholinergic medica- tions. For example, among the tricyclic antidepressants (TCAs), the secondary amines nortriptyline and desipramine are preferred. Amitriptyline is highly anticholinergic and should be avoided. Among the antipsychotics, the high-potency agents such as haloperidol are preferred over the more anticholinergic thioridazine or chlorpromazine. Clozapine also is highly anticholinergic. Avoid over- the-counter sleep medications and antihistamines. Note: Central anticholinergic toxicity may occur without peripheral manifestations in older pa- tients.

Summary of Changes in the Aging Body and Their Effect on Psychotropic Drugs

CHANGE

EFFECT

EXAMPLE

Increased body fat

Fat-soluble drugs stored longer, releasing slowly

Diazepam

Decreasedbody water

Water-solubledmgs show higher concentration

Ethanol

Decreased liver size and blood flow

Drugs metabolized in liver cleared more slowly, but individual variation is great

Antidepressants

Decreased creatinine clearance

Drugs metabolizedrenally cleared more slowly;predictable

Lithium, gabapentin

Decreased acetylcholine in brain

Anticholinergic drugs more likely to cause

Amitriptyline

central toxicity

Chlorpromazine

4. What are the major considerationsin choosing an antidepressantfor older patients?

All treatments for depression are potentially useful for elderly patients (see Chapter 47). As in any patient, the many available agents carry various risks, side effects, and costs. Consider the indi- vidual patient’s health, other medications, tolerance of particular side effects, cognitive abilities, social resources, and financial means. Comorbid psychiatric conditions such as anxiety, psychosis, and substance abuse also may affect the choice. Most importantly, be thoroughly familiar with con-

traindications to specific agents, major drug interactions, and common side effects of agents

being prescribed.

5. Why should I always check the electrocardiogrambefore prescribing a TCA in patients

over the age of 40?

The TCAs have quinidine-like effects on cardiac conduction; they slow conduction across the atrioventricular node. Clinically relevant problems at therapeutic blood levels are limited to patients with preexisting conduction disease. However, only severe disease absolutely contraindicates use of TCAs. Stoudamire and Atkinson reported that “asymptomatic patients with right bundle branch block, isolated left anterior fascicular block, and left posterior fascicular block usually can be treated safely with TCAs if dosage is increased gradually and ECGs obtained following each dosage in- crease.”” Note the word asymptomatic. Syncopal attacks suggest an intermittently higher degree of block, and TCAs should not be used unless a pacemaker is in place. The same applies to patients with bifascicular or trifascicular block. TCAs also are contraindicated for at least 6 weeks after an acute myocardial infarction. In pa- tients who develop persistently long Q-Tc intervals, the risk for fatal ventricular fibrillation is in- creased. If TCAs must be used, they should be used cautiously, in association with ECG monitoring and consultation with a cardiologist about the acceptable upper limit of Q-Tc intervals for the partic- ular patient.

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6. List other contraindicationsto the use of TCAs.

Other contraindications to TCAs are due to their anticholinergic effects and include: (1) narrow- angle glaucoma, (2) significantly enlarged prostate, (3) marginally compensated congestive heart failure (because tachycardia may precipitate failure). Also consider the possibility of (4) orthostatic hypotension, which increases the risk of falling.

7. Is it safe to prescribe monoamine oxidase inhibitors (MAOIs) to elderly patients? MAOIs can be tricky in elderly patients. The biggest concern is the need for compliance with dietary restrictions, because ingestion of foods high in tyramine may cause a hypertensive crisis. MAOIs should not be prescribed for patients who cannot be relied on to understand and follow this diet. Certain concurrent medications also must be avoided. Most significant are the sympathomimet- ics, which include medications used to treat asthma; therefore, patients with asthma should not re- ceive MAOIs. The same applies to patients with a history of anaphylaxis, because the epinephrine required for treatment may precipitate a hypertensive crisis in the presence of MAOIs. Orthostatic hypotension also is a common side effect.

8. Aren’t the newer antidepressants preferable?

To date, the selective serotonin reuptake inhibitors (SSRIs) appear to be the safest of the antidepres- sants. There are no data to suggest that nefazodone, venlafaxine, or mirtazapine are unsafe, but fewer data have been collected about the use of these relatively newer agents in the geriatric population. SSRIs should be started at low doses, and increased more gradually in the elderly. In rare in- stances, they can cause parkinsonism and, less rarely, an akathisia-like syndrome. Therefore, use them cautiously in those with Parkinson’s disease. Older patients frequently experience postural in- stability early in the course of treatment with SSRls; although this resolves within a few weeks, it may cause falls, with serious consequences for an older person. Other significant and common side effects include nausea, anorexia, diarrhea, headache, tremor, insomnia, and sedation. Because of the extraordinarily long half-life of fluoxetine, the shorter acting ones might be preferable. Sertraline and citalopram also are less likely to interfere with the metabolism of commonly prescribed medica- tions such as coumadin, phenytoin, and cimetadine.

9. How can the other, newer antidepressants be used?

Bupropion is a useful antidepressant in a class by itself. It can be used safely and effectively in the elderly, always with a consideration toward seizure risk. It should not be used in anyone with a history of seizures, or significant brain lesions that might predispose to seizures. Dosing guidelines must be strictly followed. An advantage over other antidepressants is its mildly stimulating effect, rather than sedation which accompanies most of the others. A disadvantage is that two to three times a day dosing is necessary, increasing the likelihood of mistakes, missed dosages, and noncompliance. Nefazodone and mirtazapine may be especially helpful for the person with high anxiety andor insomnia. Vanlafaxine has many similarities to the SSRIs, but may be effective when an SSRI is not. It also has been approved recently for the treatment of generalized anxiety disorder, based on con- trolled studies of its effectiveness.

10. What are the treatment options if none of the above antidepressants is safe, tolerated,

and/or effective?

Psychostimulants,such as methylphenidate, may be helpful in very old, frail patients with apa- thetic depression; for example, medically ill patients who are not participating in their care or reha- bilitation or not eating. In spite of their reputation for suppressing appetite, in this setting the stimulants generally increase appetite, energy, and interest. The stimulants are rarely contraindi- cated; even patients with heart disease usually tolerate them. A careful approach, beginning with a low dose and monitoring vital signs after each dose until stabilized, is recommended. Electroconvulsive therapy is another possibility for frail elderly persons who are depressed. Despite its scary reputation, ECT is one of the safest treatments for certain older people. Intracranial

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heart disease. In addition, patients with a history of retinal detachment should have a consultation with a knowledgeable ophthalmologist, because the sudden increase in blood pressure may cause problems.

11. How should I approach the treatment of anxiety in elderly patients?

First, make a careful diagnosis. In many older people who present with anxiety as their chief complaint, the actual diagnosis is major depression. Anxiolytics do not treat such patients ade-

quately. In fact, the sedative-hypnotics may worsen depression. The appropriate response is to pre-

scribe an antidepressant, which often provides sufficient

waiting for the antidepressant to take full effect. Venlafaxine may be a good choice, as it has recently obtained FDA approval for treatment of generalized anxiety disorder.

If an anxiolytic medication is needed, consider low doses of the benzodiazepines lorazepam and oxazepam, both of which are metabolized in the blood through oxidation. Because this process does not change appreciably with aging, lorazepam and oxazepam, unlike other anxiolytic agents, do not accumulate in the aging body as a result of slowed metabolism. This unique method of me- tabolism, however, does not mean that older people should receive the same dosages as younger people. Older people are much more susceptible to postural instability and memory loss. In all cases, the lowest possible dosage should be used, and signs of toxicity should be monitored carefully. Buspirone is not a substitute for benzodiazepines, because the patient will feel no immediate relief. Buspirone may be helpful with generalized anxiety over time, and some evidence suggests that it may have antidepressant effects. However, it is not very helpful as an early treatment of de- pression nor as treatment for situational anxiety. Do not neglect nonpharmacologic means of anxiety control, such as relaxation exercises, deep breathing, and manipulation of the environment.

treatment even in the short term while

12. Which agents are preferred in the treatment of psychosis in elderly patients?

As always, the first consideration is diagnosis. Elderly schizophrenics need and usually tolerate higher doses than demented or delirious patients. Patients with affective illness show a wide range of need and tolerance. The high-potencyagents are preferred for geriatric patients because of their side-effect profile. The minimal advantage of increased sedation with the low-potency medications, such as chlorpro- mazine and thioridazine, is far outweighed by the disadvantages of increased anticholinergic side ef- fects and higher incidence of orthostatic hypotension. The second-generation antipsychotics risperidone, olanzapine, and perhaps quetiapine are preferred because of their lower risk of ex- trapyramidal symptoms. Olanzapine, especially, combines the benefits of sedation with low risk of EPS. The high cost of these agents should be considered, however.

13. What is the main problem with high-potencyantipsychotics?

The main problem with haloperidol and other high-potency antipsychotics is the likely occurrence of extrapyramidal symptoms.Acute dystonia is extremely uncommon in the elderly. Parkinsonism, however, is quite common and contributes significantly to the risk for falling. Its onset may be insidi- ous. One month after hospital discharge, for example, the patient may be found to be stooped, shuf- fling, stiff, and possibly tremulous. For these reasons, the physician must be very cautious, using the lowest effective dose and monitoring the patient closely for a few months if he or she is to stay on the antipsychotic medication. Prophylactic anticholinergic medications such as benztropine are no substi- tute; they increase the risk of mental confusion and other side effects of anticholinergics. Evaluate elderly patients for symptoms of parkinsonism before starting an antipsychotic. Patients with Parkinson’s disease or similar syndromes may deteriorate clinically, and antipsychotics should be avoided in such patients if at all possible. The only currently available antipsychotic that has definitely been proven not to worsen Parkinson’s disease symptoms is clozapine, which is quite useful in treating psychosis associated with Parkinson’s disease. The required dosages are much lower than those used to treat schizophrenia-25-50 mg/day is often sufficient. Weekly blood counts are needed because of the risk of agranulocytosis. Quetiapine, the newest antipsychotic at this writ- ing, also looks quite promising for use in Parkinson’s patients.

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14. What is the risk of tardive dyskinesia in antipsychotic treatment?

The risk of tardive dyskinesia increases with age. A recent study showed that among those over age 65 treated with a typical antipsychotic, one-third developed tardive dyskinesia at 12 months:

one-half at 2 years: and two-thirds at 3 years. The incidence is higher in women and in patients with mood disorders. Thus elderly women with psychotic depression are at particular risk for developing tardive dyskinesia; antipsychotic medications should be prescribed only with informed consent and close follow-up. Use newer agents if at all possible. With frequent and careful examination for early signs, tardive dyskinesia can be detected and the offending agent stopped before a debilitating con- dition develops.

15. Name one of the most common and serious, yet overlooked, complications of psychotropic

medication in elderly patients.

Most of the psychotropics in current use increase the risk of falling in older patients. Osteoporosis is endemic among elderly women; thus, it does not take much to cause serious frac- tures. A fractured hip may lead to all of the morbidity and mortality associated with prolonged im- mobility and possible surgery, including pulmonary embolus, pneumonia, urosepsis, decubitus ulcers, and lengthy and expensive rehabilitation efforts after the bone has healed. Subdural hematomas may result from relatively minor blows to the head in older people. The elder who lives alone and cannot get up after a fall may develop muscular necrosis and even dehydration if not found for some time. For many elderly people the prospect of falling is so frightening that, especially after one fall has occurred, activity may be significantly limited. Such limitation may lead to increasing depres- sion and declining health. Psychotropic medications can contribute to falling through various mechanisms, and the physi- cian must be alert for symptoms in several areas. TCAs, MAOIs, and some of the antipsychotics commonly cause orthostatic hypotension. Patients must be warned and then asked about a feeling of faintness upon rising from a lying or sitting position. If the reply is positive, blood pressure should be measured in recumbent and standing positions. A drop of 20 points or more in systolic pressure usually is considered significant. Asymptomatic findings may be tolerated; symptomatic findings should not. Fainting is one of the most dangerous reasons for a fall, because the victim has no con- trol over the landing.

16. True or false: The SSRIs do not cause risk of falling.

False. Unfortunately, the SSRIs are not foolproof in this regard. SSRIs can cause significant postural instability in many older people early in the course of treatment. Fortunately, this symptom seems to resolve within a few weeks, and the risk may be minimized by more gradual titration of the dose. Dizziness is a relatively common side effect of the new antidepressant venlafaxine at all ages. Elderly patients taking these medications should be asked if they feel dizzy or unsteady on their feet. If so, the dosage should be lowered or special precautions taken to increase safety, depending on the frailty and dependability of the patient as well as the seventy of the depression and dizziness.

17. Discuss the effects of benzodiazepineson fall risk in the elderly.

Benzodiazepines also cause postural instability. The effect may be subtle, but the risks are not. When geriatric patients are prescribed doses that are too high or a long-acting agent that accumu- lates over time, frank intoxication may lead to a fall as long as 2 weeks after the drug is started. The classic example is the patient who is prescribed flurazepam in the hospital and discharged with in- structions to continue the drug at home. Two weeks later, when this particularly long-acting medica- tion reaches peak blood level, the patient falls-or falls asleep at the wheel of a car! Nystagmus is a sign of excessive levels of benzodiazepine and indicates cerebellar dysfunction.

18. How might antipsychoticscause falls?

Antipsychotics also are commonly associated with falls among elderly persons because of the induction of parkinsonism. One of the cardinal features of this syndrome is postural instability. If the

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more obvious signs of parkinsonism are present (i.e., pill-rolling tremor, cogwheel rigidity, shuffling gait, masked facies, inhibited arm swing), postural instability is present too. Steps should be taken either to decrease, discontinue, or change the medication or to treat the parkinsonism with anti- cholinergic agents (with attention to possible attendant complications).

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