Drug Therapy in Elderly Patients:

December 1, 2006

ABSTRACT: Age-related changes that affect drug distribution, such as increased total body fat, decreased muscle mass, and decreased total body water, necessitate reduction in the dosage of water- and lipid-soluble agents. Because creatinine clearance declines with age, the dosage of agents that are excreted primarily by the kidney must also be lowered to prevent toxicity. Examples include aminoglycosides, fluoroquinolones, penicillins, procainamide, lithium, angiotensin-converting enzyme inhibitors, and digoxin. A good rule of thumb to follow until creatinine clearance can be calculated is to reduce the total dose by half in frail elderly persons or in those with established renal disease. Anticholinergic agents should be used with caution because they are associated with urinary retention, heart block, constipation, dry mouth, blurred vision, sedation, and acute or chronic confusion in elderly patients.

Elderly patients, particularly those aged 85 years or older (the "oldest old"), take an average of 5 to 8 drugs each day. This is attributable principally to the number of chronic conditions that affect this age group. Polypharmacy heightens the risk of significant drug-drug interactions and other adverse events, particularly in frail elderly persons. Moreover, many drugs that are used safely by younger persons are inappropriate for older ones because of age-related changes and comorbid conditions that affect absorption, distribution, metabolism, and elimination.

A number of reports have shown that the risk of adverse drug events in elderly patients rises with comorbidity; increasing numbers of medications; inappropriate medications; the use of antipsychotics, anticoagulants, diuretics, and antiepileptics; and the use of multiple prescribers and pharmacies by patients and caregivers.1-4

Here I review the principal considerations that affect prescribing practices for elderly patients and offer strategies that will help prevent or minimize adverse drug reactions.

AGE-RELATED PHARMACOKINETIC CHANGES
The normal aging processes that affect the major organ systems should prompt a reduction in the dosages of specific classes of drugs, particularly those eliminated mainly by the kidney or metabolized by the liver or whose effect is primarily on the CNS. Basic guidelines for prescribing that take into account normal changes of aging are reviewed in Table 1. The principal drugs that are considered potentially inappropriate in elderly patients are listed in Table 2.

 Table 1 - Principles of prescribing for elderly patients
Recommendation ExamplesAdvantages

Maximize the dose of 1 agent for a specific disease process before adding a second agent Antihypertensive and antidiabetic agentsLess confusion and cost, less risk of adverse drug reaction

Use 1 agent to treat 2 conditions Drugs used to treat hypertension and benign prostatic hyperplasia, hypertension and angina, hypertension and paroxysmal atrial tachycardia or other atrial arrhythmiaLess confusion and cost, less risk of adverse events

Use an agent no more than once or twice daily Antihypertensive agents, such as ACE inhibitors, calcium channel blockers, ß-blockersBetter compliance

Avoid inappropriate drugs See Table 2Less risk of adverse events

Minimize use of anticholinergic agents and discontinue when possible Phenothiazine major tranquilizers, atypical antipsychotics, narcotics, antispasmodics, sedating cold and cough medications, OTC sleep agents, muscle relaxantsLess risk of adverse events

Ask patient to bring medications and review at every visit All medications, including OTC agentsLess confusion, better compliance

ACE, angiotensin-converting enzyme; OTC, over-the-counter.

Distribution. Changes related to aging, such as increased total body fat, decreased muscle mass, and decreased total body water, necessitate dosage reductions in elderly persons.5,6 These changes dramatically reduce the volume of distribution for water-soluble compounds and for compounds distributed only in lean tissue, such as digoxin and lithium. Moreover, the age-related rise in body fat increases the volume of distribution of lipid-soluble compounds, such as diazepam. The clearance of such compounds is significantly prolonged, which increases the risk of adverse events.

Elimination. Because aging of the kidney is associated with decreased creatinine clearance, the dosage of agents that are excreted primarily by the kidney must be reduced in order to prevent toxicity. This is especially true in the oldest patients, in whom creatinine clearance slows dramatically.

A frequently used formula for determining creatinine clearance in men is ([140 2 age]) 3 lean body weight [kg]/72 3 serum creatinine level [mg/dL]).7 For women, the total is multiplied by 0.85. Blood urea nitrogen and serum creatinine levels may be in the normal range despite significant reductions in creatinine clearance. One study of nursing home residents indicated that 1 of 3 renally excreted drugs was inappropriately dosed based on the calculated creatinine clearance.8

Agents that require dosage reduction in patients with reduced creatinine clearance include the aminoglycosides, fluoroquinolones, penicillins, procainamide, lithium, angiotensin-converting enzyme (ACE) inhibitors, digoxin, metformin, fluconazole, bisphosphonates, thiazides, nizatidine, atenolol, and clofibrate.9 Once-daily dosing of aminoglycosides is associated with a decreased risk of morbidity (ototoxicity and renal failure) in patients with reduced creatinine clearance (usually below 50 mL/min). It also alleviates the need for expensive peak and trough testing.10 A good rule of thumb to follow until creatinine clearance can be calculated is to reduce the total dose of the agent by half in frail elderly persons or in the presence of established renal disease (when blood urea nitrogen and serum creatinine levels are typically elevated).

Metabolism. Changes in the liver related to age include reduced blood flow and decreased phase I metabolism (oxidation, reduction, and hydroxylation). Agents that use pathways involved in phase I reactions include long-acting benzodiazepines (eg, diazepam, chlordiazepoxide, and flurazepam). These agents must be avoided in elderly persons because of the risk of sedation, hypotension, falls, and confusion. Short-acting benzodiazepines are preferred because they do not have to be metabolized by phase I and otherwise are deactivated though conjugation, sulfation, methylation, or acetylation (phase II).6

Other agents that require hepatic metabolism includeNSAIDs, aspirin, calcium channel blockers, acetaminophen, b-blockers, erythromycin, statins, ketoconazole, phenytoin, tetracyclines, valproic acid, lidocaine, carbamazepine, metoprolol, tricyclic antidepressants, selective serotonin reuptake inhibitors, neuroleptics, cimetidine, ranitidine, famotidine, terfenadine, and proton pump inhibitors.9 Some of these agents use components of the cytochrome system (CYP1A2, CYP2C, CYP2D, and CYP3A) that may involve interactions between model compounds, drug substrates, inducers, and inhibitors. This may result in toxic levels of one agent or inadequate levels of another and what may appear as noncompliance with drug therapy or lack of efficacy. In cases where 2 specific agents are necessary but the potential for adverse interaction exists, attention to specific time of administration, dosage, and requirement to ingest the agent with or without food or beverage is critical.9,11 Pharmacology texts provide information about agents to be avoided for specific cytochrome pathways. Consultation with a pharmacist may also be helpful.

Liver disease (cirrhosis, hepatitis, or malignancy) or malnutrition typically results in decreased serum albumin and total protein levels that directly affect protein binding for highly bound agents. This may be associated with an increase in the free active fraction of the specific agent and a heightened risk of toxicity. Examples of such agents include barbiturates, phenytoin, carbamazepine, and warfarin.12

AGE-RELATED PHARMACODYNAMIC CHANGES

Aging of the CNS results in reduction in and sensitivity to the number of receptor sites, especially in the brain. The anticholinergic and, to a lesser extent, antimuscarinic agents must be used with caution because they are associated with urinary retention, heart block, constipation, dry mouth, blurred vision, sedation, and acute or chronic confusion. Classes of drugs that have significant anticholinergic activity include the phenothiazine major tranquilizers, the newer atypical antipsychotics, tricyclic antidepressants, narcotics, antispasmodics, and prescription or over-the-counter sedating antihistamines and sleep remedies.13,14 The pathophysiology of delirium is related to higher serum anticholinergic activity; development of acute confusion is particularly common with higher doses of anticholinergics in frail elderly patients, in those with dementia, and postoperatively. Higher doses may also be responsible for mild cognitive impairment or a "dementia syndrome," which may be reversed with discontinuation of the agent. This phenomenon is attributable to the subtle structural and physiologic changes consistent with Alzheimer disease that may be present even before symptoms emerge, and to the fact that the pathophysiology of Alzheimer disease involves anticholinergic disruption of nerve fibers.

 Table 2 - Potentially inappropriate drugs for elderly patients*
Pharmacologic agent ClassRationale

Diazepam, chlordiazepoxide, flurazepam Long-acting benzodiazepinesRequire phase I metabolism; cause sedation, acute confusion, cognitive dysfunction, hypotension, falls, injury

Amitriptyline Tricyclic antidepressantsSedation, acute confusion, cognitive dysfunction, hypotension, falls, injury, urinary retention, blurred vision, constipation, heart block

Dipyridamole AntithromboticsMay cause orthostatic hypotension

Propranolol ß-BlockersCognitive dysfunction, depression, heart block; worsens or precipitates congestive heart failure; masks hypoglycemia; worsens hyperglycemia; precipitates or worsens bronchospasm (COPD, asthma)

Methyldopa AntihypertensivesBradycardia, exacerbation of depression

Reserpine, guanethidine Ganglionic blockersDepression, impotence, sedation, hypotension

Dicyclomine, hyoscyamine, belladonna alkaloids AnticholinergicsSedation, acute confusion, cognitive dysfunction, blurred vision, constipation, heart block, hypotension

Propoxyphene, pentazocine NarcoticsSedation, acute confusion, hallucinations

Trimethobenzamide AntiemeticsExtrapyramidal side effects; weakly effective for nausea

Meprobamate AnxiolyticsAddicting, sedating

Digoxin Cardiovascular; arrhythmia controlAcute confusion, depression, anxiety, heart block, anorexia, visual changes

Disopyramide AntiarrhythmicsNegative inotropic effect, may cause congestive heart failure

Doxepin AntidepressantsSedation, acute confusion, cognitive dysfunction, hypotension, falls, injury, urinary retention, blurred vision

Ticlopidine AntithromboticsNo more effective than aspirin, requires routine monitoring of hemogram and liver function studies

Meperidine NarcoticsShort-acting, addicting, poor pain control requiring frequent dosing

Barbiturates  Addicting, sedating, cognitive dysfunction, hypotension, falls, injury

COPD, chronic obstructive pulmonary disease. *This list is not exhaustive. Adapted from Fick DM et al. Arch Intern Med. 2003.

Age-related changes of the GI tract include decreased motility and blood flow and an increased incidence of constipation. There is little change in gastric acidity with aging. Disease processes such as gastritis, malignancy, and malabsorption syndrome may increase or decrease the resorption of specific agents.15

Reduced thirst and appetite, which are common in elderly persons, are exacerbated in patients with depression and dementia.16 Agents that may be associated with the development of anorexia or nausea include nitrofurantoin, procainamide, digoxin, thyroxine, and the selective serotonin reuptake inhibitors (especially long-acting fluoxetine). These drugs are best avoided, particularly in frail elderly persons or those in long-term-care facilities.17

EFFECTS OF SPECIFIC AGENTS

H2 blockers. Rarely, these agents are associated with confusion at high doses--possibly because of anticholinergic effects--especially at creatinine clearances below 50 mL/min. At this level, a reduction in dosage by half may be prudent.13 The exception to this rule is famotidine, for which dosage adjustment is unnecessary until a creatinine clearance of 10 mL/min or lower is reached.18 For this reason, famotidine is widely used in long-term-care facilities.

The nonspecific use of H2 blockers has been associated with inadequate healing of gastric and duodenal ulcerations and a greater likelihood of recurrence. These agents have also been used for prophylaxis with NSAIDs, although they are indicated for such use only in the ICU to prevent GI bleeding in patients with respiratory failure or coagulopathy.19 Controversy exists about whether long-standing H2-blocker therapy in the presence of dysphagia and subsequent aspiration results in increased morbidity and mortality from pneumonia.

Antihypertensives. The long-acting b-blocker propranolol has been associated with such adverse events in elderly patients as precipitation or exacerbation of heart failure; masking of hypoglycemia; hypotension; masking of symptoms of endocrine disease (hypothyroidism); reduction in exercise capacity; exacerbation of chronic lung disease or bronchospasm; depression; cognitive dysfunction and, rarely, arthropathy.20,21

Because b-blockers reduce all-cause and cardiovascular morbidity and mortality in high-risk patients and in patients undergoing noncardiac surgery, the use of selective agents, such as atenolol, metoprolol, or carvedilol, is recommended.22 These agents have a better side-effect profile than propranololand are associated with better compliance because they are taken only once or twice daily.

Another high-risk group of antihypertensive agents that is contraindicated in elderly patients includes methyldopa, reserpine, guanethidine, and hydralazine. Methyl- dopa, an agent that must be taken 4 times a day, may cause depression, sedation, hemolytic anemia, and drug-induced systemic lupus erythematosus. Although the ganglionic blocking agents reserpine and guanethidine are inexpensive and can be dosed once daily, they may cause hypotension, dizziness, syncope, sedation, and depression. Newer agents, such as calcium channel blockers and ACE inhibitors,are associated with better compliance and fewer side effects.23 The inotropic effect of hydralazine may cause heart failure.24

The sudden discontinuation of clonidine may cause rebound hypertension. Although the patch formulation provides better compliance because of a once-weekly dosing regimen, sedation is a worrisome side effect in some older patients.24

The a-blockers--such as doxazosin, prazosin, and terazosin--are best used in low to moderate doses in elderly persons because higher doses may be associated with postural hypotension and first-dose syncope. They may be used as dual-action therapy for elderly men with hypertension and symptoms of benign prostatic hyperplasia because they decrease the incidence of frequency, urgency, and nocturia.25

The thiazide diuretics are considered first-line agents for the management of hypertension in elderly patients because they reduce the risk of stroke and myocardial infarction (MI) in these patients.26 They are also relatively inexpensive and can be administered once daily, thereby increasing the likelihood of compliance. Their use in older white women is associated with a reduced risk of hip fracture, possibly because these agents block the urinary elimination of calcium.27 Doses higher than 50 mg are ineffective in achieving blood pressure control and are not recommended in patients with renal insufficiency.

Rare side effects include hypercalcemia, hypokalemia, and postural hypotension.5 However, continued use of thiazide diuretics in frail elderly patients and those in long-term-care facilities may contribute to dehydration, especially during the summer months. These agents may also contribute to or cause urinary incontinence. Their use is not associated with adverse lipid effects.28

Antipsychotic agents. The risk of such side effects as sedation and postural hypotension varies among the major tranquilizers. Generally, the response is dose-related; thus, low-potency agents carry a greater risk of adverse events.29 Because of their anticholinergic effects, antipsychotic agents may cause or contribute to cognitive dysfunction and delirium. Their hypotensive effects may increase the incidence of falls and subsequent hip fracture.30 Although early clinical studies indicate that the newer atypical antipsychotic agents are associated with a lower incidence of tardive dyskinesia,31 a recent study found no difference in the risk of involuntary movements between older and newer agents.32

Digitalis glycosides. Few indications exist for the use of digoxin in elderly patients, other than for active heart failure or rate control. Because digoxin is excreted primarily in the urine, dosage reduction is necessary for frail elderly patients or those with chronic renal insufficiency or renal failure. Doses higher than 0.125 mg should be used with caution. Side effects include confusion, anorexia, nausea, yellow-green vision, agitation, and depression.23,33

Analgesics. The traditional NSAIDs nonspecifically inhibit both of the cyclooxygenase (COX) enzymes responsible for inflammation and therefore effectively relieve chronic pain. However, their nonspecific inhibition of these sites may cause side effects that prevent their safe use in elderly patients. Because of their effect on the renal tubules in inhibiting prostaglandin-mediated vasodilation, they may contribute to or cause hypertension, fluid retention, reversible renal insufficiency, heart failure and, rarely, renal failure. High doses may also be associated with the development of acute confusion or cognitive dysfunction.34 Preliminary studies initially indicated that these agents slowed the progression of or prevented Alzheimer disease. However, other reports contradict this finding.35,36

Helpful rules of thumb for the use of the traditional NSAIDs include the following:

  • When possible, substitute acetaminophen (dosed around the clock) for an NSAID and titrate to maximal dosing.
  • Use NSAIDs as needed and, when possible, in combination with around-the-clock dosing of acetaminophen.
  • Use the lowest dose possible.
  • Use NSAIDs for an acute flare of inflammation for 7 to 10 days and then discontinue.
  • When long-term NSAID therapy is necessary, order renal function studies and a hemogram every 2 to 3 months to identify early signs of GI bleeding or renal dysfunction.

Although some studies indicate that the newer COX-2 agents are less likely to cause GI bleeding than traditional NSAIDs,37 the COX-2 agents have been implicated in the development of hypertension and MI.38

The narcotic analgesics (oxycodone, codeine, meperidine, and morphine derivatives) have anticholinergic properties and therefore are associated with anticholinergic side effects. Their use postoperatively in elderly patients may result in other serious complications, such as acute confusion or delirium, fecal impaction, respiratory depression, and reduced physical function. Pentazocine, a narcotic antagonist, may cause sedation or addiction. Meperidine provides poor pain relief because of its short half-life and requirement for frequent dosing.23 The use of adjunctive acetaminophen around the clock or a low-dose NSAID may allow the use of the lowest possible dose of the narcotic for pain relief, thus reducing the potential for side effects.

Other agents. Theophylline is an acceptable alternative for treatment of asthma or stable chronic lung disease; long-acting formulations are recommended in elderly patients. Side effects, which occur primarily with the short-acting formulations, include anorexia, nausea, hypotension, arrhythmias, and drug-drug interactions, especially when theophylline is used concomitantly with erythromycin, cimetidine, diazepam, or phenytoin.39

Muscle relaxants pose a significant risk for elderly persons because they may cause sedation, hypotension, and falls. Some muscle relaxants also have anticholinergic activity. They should be used with extreme caution or not at all in frail elderly persons.23

Methylphenidate has been associated with anxiety, arrhythmias, worsening hypertension, precipitation of angina, insomnia, nausea, and anorexia; it is best avoided in frail elderly persons. In the hospital setting, it is used to help differentiate patients with dementia from those with chronic confusion secondary to depression or pseudodementia, because it leads to immediate improvement in patients in the latter group.40

References:

REFERENCES:1. Field TS, Gurwitz JH, Harrold LR, et al. Risk factors for adverse drug events among older adults in the ambulatory setting. J Am Geriatr Soc. 2004;52: 1349-1354.
2. Simon SR, Chan KA, Soumerai SB, et al. Potentially inappropriate medication use by elderly persons in US Health Maintenance Organizations, 2000-2001. J Am Geriatr Soc. 2005;53:227-232.
3. Gurwitz JH, Field TS, Judge J, et al. The incidence of adverse drug events in two large academic long-term care facilities. Am J Med. 2005;118:251-258.
4. Schwartz JB. Clinical pharmacology. In: Hazzard WR, Blass JP, Ettinger WH, et al, eds. Principles of Geriatric Medicine and Gerontology. 4th ed. New York: McGraw-Hill; 1999:326-330.
5. Cefalu CA. Clinical pharmacology. In: Burke MM, Laramie JA, eds. Primary Care of the Older Adult: A Multidisciplinary Approach. St Louis: Mosby; 2000: 90.
6. Pharmacotherapy. In: Cobb E, Duthie EH Jr, Murphy JB, eds. Geriatrics Review Syllabus: A Core Curriculum in Geriatric Medicine. 5th ed. New York: Blackwell Publishing; 2002:37-39.
7. Cefalu CA. Clinical pharmacology. In: Burke MM, Laramie JA, eds. Primary Care of the Older Adult: A Multidisciplinary Approach. St Louis: Mosby; 2000: 92.
8. Papaioannou A, Clark JA, Campbell G, et al. Assessment of adherence to renal dosing guidelines in long-term care facilities. J Am Geriatr Soc. 2000;48: 1470-1473.
9. Schwartz JB. Clinical pharmacology. In: Hazzard WR, Blass JP, Ettinger WH, et al, eds. Principles of Geriatric Medicine and Gerontology. 4th ed. New York: McGraw-Hill; 1999:309-319.
10.Cefalu CA, Agcaoli D. Preventing antibiotic misuse in older patients. Hospital Med. 1998:39-43.
11. Hutchison LC. The pharmacology of aging. In: Dharmarajan TS, Norman RA, eds. Clinical Geriatrics. Boca Raton, Fla: Parthenon Publishing; 2003:86.
12.Geriatric Pharmaceutical Care Guidelines. The Omnicare Formulary. Covington, Ky: Omnicare Inc; 2005:523, 561.
13. Delirium. In: Cobb E, Duthie EH Jr, Murphy JB, eds. Geriatrics Review Syllabus: A Core Curriculum in Geriatric Medicine. 5th ed. New York: Blackwell Publishing; 2002:136.
14. Lu C, Tune LE. Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease. Am J Geriatr Psychiatry. 2003;11: 458-461.
15. Hall KE, Wiley JW. Age-associated change in gastrointestinal function. In: Hazzard WR et al, eds. Principles of Geriatric Medicine and Gerontology. 4th ed. New York: McGraw-Hill; 1999:835-842.
16. Singh MAF, Rosenberg IH. Nutrition and aging. In: Hazzard WR, Blass JP, Ettinger WH, et al, eds. Principles of Geriatric Medicine and Gerontology. 4th ed. New York: McGraw-Hill; 1999:88.
17. Thompson MP, Morris LK. Unexplained weight loss in the ambulatory elderly. JAm Geriatr Soc. 1991;39:497-500.
18.Geriatric Pharmaceutical Care Guidelines. The Omnicare Formulary. Covington, Ky: Omnicare Inc; 2005:232.
19. Cook DJ, Fuller HD, Guyat GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med. 1994;330:377-381.
20. Cahill L, Prins B, Weber M, et al. Beta-adrenergic activation and memory for emotional events. Nature. 1994;371:702-704.
21. Newbern VB. Cautionary tales on using beta blockers. Geriatr Nurs. 1991;12;119-122.
22. Australia/New Zealand Heart Failure Research Collaborative Group; 1997.
23. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Intern Med. 2003;163: 2716-2724.
24. Geriatric Pharmaceutical Care Guidelines. The Omnicare Formulary. Covington, Ky: Omnicare Inc; 2005:291-293.
25. Guthrie R. Terazosin in the treatment of hypertension and symptomatic benign prostatic hyperplasia: a primary care trial. J Fam Pract. 1994;39: 129-133.
26. Schwartz GL, Sheps SG. A review of the sixth report of the Joint Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Curr Opin Cardiology. 1999;12:161-168.
27. Heidrich FE, Stergachis A, Gross KM. Diuretic drug use and the risk of hip fracture. Ann Intern Med. 1991;115:1-6.
28. Monane M, Gurwitz JH, Bohn RL, et al. The impact of thiazide diuretics on the initiation of lipid-reducing agents in older people: a population-based analysis. J Am Geriatr Soc. 1997;45:71-75.
29. Cefalu CA. Clinical pharmacology. In: Burke MM, Laramie JA, eds. Primary Care of the Older Adult: A Multidisciplinary Approach. St Louis: Mosby; 2000:136.
30. Grisso JA, Kelsey JL, Strom BL, et al. Risk factors for falls as a cause of hip fracture in women. N Engl J Med. 1991;324:1326-1331.
31. Jeste DV, Lacro JP, Bailey A, et al. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc. 1999;47:716-719.
32. Lee PE, Sykora K, Gill SS, et al. Antipsychotic medications and drug-induced movement disorders other than parkinsonism: a population-based cohort study in older adults. J Am Geriatr Soc. 2005;53: 1374-1379.
33. Fishkind D, Paris BE, Aronow WS. Use of digoxin, diuretics, beta blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers in older patients in an academic hospital-based geriat-rics practice. J Am Geriatr Soc. 1997;45: 809-812.
34. Carson JL, Strom BL. Use of nonsteroidal anti--inflammatory drugs. In: Hazzard WR, Blass JP, Ettinger WH, et al, eds. Principles of Geriatric Medicine and Gerontology. 4th ed. New York: McGraw-Hill; 1999:1113-1119.
35. Delanty N, Vaughan C. Risk of Alzheimer's disease and duration of NSAID use. Neurology. 1997;48: 626-632.
36. Tabet N, Feldmand H. Ibuprofen for Alzheimer's disease. Cochrane Database Syst Rev. 2003;(2): CD004031.
37. Bombardier C. An evidence-based evaluation of the gastrointestinal safety of coxibs. Am J Cardiol. 2002;89(6A):3D-9D.
38. Konstam MA, Weir MR. Current perspective on the cardiovascular effects of coxibs. Cleve Clin J Med. 2002;69(suppl 1):S147-S152.
39.Geriatric Pharmaceutical Care Guidelines. The Omnicare Formulary. Covington, Ky: Omnicare Inc; 2005:71-72, 117-118.
40. Frierson RL, Wey JJ, Tabler JB. Psychostimulants for depression in the mentally ill. Am Fam Physician. 1991;43:163-170.