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Treatment of Depression in Elderly Patients
Recent Advances
Krishna DasGupta, MD
Arch Fam Med. 1998;7:274-280.
ABSTRACT
Although sometimes difficult to diagnose because of concurrent stressors, medical illness, or dementia, depression in elderly patients responds readily to appropriate therapy. When untreated, this disorder may result in increased morbidity and mortality or suicide. Effective therapeutic options for late-life depression, as in younger patients, include psychotherapy and pharmacotherapy. Short-term, highly focused forms of psychotherapy are helpful for elderly patients who are reluctant or unable to tolerate antidepressant medication. Because of their favorable adverse effect profiles and safety in cases of overdose, the selective serotonin reuptake inhibitors have, in most cases, replaced tricyclic antidepressants as first-line therapy when antidepressants are indicated. Psychostimulants may be helpful for medically ill elderly patients with depressive symptoms. Finally, electroconvulsive therapy offers a safe and effective alternative for patients refractory to or unable to tolerate antidepressant medication.
INTRODUCTION
Most elderly persons with depression seek help from primary care providers rather than mental health professionals. For this reason, it is crucial that clinicians become accustomed to screening for and treating this disorder.1-3 This article will briefly discuss the epidemiology and diagnosis of depression in elderly patients and will review treatment alternatives for this patient population.
CHARACTERISTICS OF DEPRESSION IN ELDERLY PATIENTS
Epidemiology
The prevalence of depression varies depending on the criteria used for diagnosis and the population studied. A large epidemiological study of community-dwelling elderly persons showed that mild to moderate depressive symptoms are more common (24%) than major depression (<1%).4 Major depression is present in 5% to 13% of hospitalized patients and in 12% to 16% of nursing home residents.5
Diagnosis
The criteria outlined in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition6 should be used as a guideline for the diagnosis of major depression. According to these criteria, patients must experience 5 of the following symptoms for at least 2 weeks: depressed mood, diminished interest or pleasure in daily activities, significant changes in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of guilt or worthlessness, impaired concentration, or suicidal ideation.6 Because some medical conditions may mimic or precipitate depressive symptoms, a thorough medical history, physical examination, and review of systems should be performed prior to the initiation of antidepressant therapy. Laboratory evaluations should be performed when appropriate.
Consequences of Untreated Depression
Depressive symptoms are associated with increased risk of disability, increased mortality, and impaired psychosocial functioning.7-10 Furthermore, failure to detect major depression may lead to overutilization of physical and laboratory examinations, unnecessary consultations with medical specialists, frequent office visits, and costly medication or other treatments.11-12 Disability from milder depressive syndromes appears comparable to that associated with major depression.10, 13-14 Finally, approximately 15% of untreated depressed patients eventually commit suicide, and up to 70% of suicide victims suffer from depression. Because the suicide rate for 80- to 84-year-old patients is 26.5 of 100000, compared with a rate of 12.4 of 100000 for the general population, with elderly white men at highest risk,15 clinicians should inquire about suicidal thinking and/or plans whenever depression is suspected.
TREATMENT
As in younger patients, the goals of treating depression in elderly patients include alleviating depressive symptoms, reducing risk of recurrence and relapse, decreasing morbidity and mortality, and improving quality of life. Treatment options include psychotherapy, pharmacotherapy and, in some cases, electroconvulsive therapy (ECT).
Because data providing clinical recommendations for depressed elderly patients are limited, treatment recommendations are usually based on data from younger patient populations or from small studies of elderly patients. In addition, the medically ill and the "oldest old" (>85 years) are generally not included in clinical trials; data regarding such patients are even more limited. Finally, little information is available regarding antidepressant efficacy in dysthymic disorder, minor depression, or mixed anxiety and depression, syndromes that are the most common mood disorders in elderly patients. Early data indicate that antidepressants may be effective in dysthymia, although elderly patients have not been specifically studied.16-17 Prospective, controlled studies of specific therapeutic modalities for dysthymic disorder, minor depression, mixed anxiety and depression, and bereavement-related depressions are needed so that therapeutic guidelines can be established.
Psychotherapy
For many years it was thought that elderly patients could not benefit from psychotherapy because they were "no longer educable and, on the other hand, the mass of material to be dealt with would prolong the duration of the treatment indefinitely."18 However, recent work has shown that the same highly focused types of psychotherapy that are effective in younger persons are also effective in elderly patients. A landmark study demonstrated that 16 to 20 sessions of behavioral, cognitive, and brief dynamic psychotherapy were all significantly more effective than a delayed-treatment control condition.19 Interpersonal psychotherapy is a highly precise type of psychotherapy specifically developed for the treatment of depression. In a recent investigation examining the efficacy of concurrent interpersonal psychotherapy and pharmacotherapy, 79% of moderately to severely depressed elderly patients receiving an adequate trial of the tricyclic antidepressant (TCA) nortriptyline in combination with interpersonal psychotherapy achieved full remission.20 Although these results are encouraging, prospective, controlled trials will be necessary to determine whether combination therapy is superior to either antidepressant treatment or psychotherapy alone. In addition, no data are available regarding efficacy of psychotherapy alone or in combination with medication for the treatment of dysthymic disorder, minor depression, or mixed anxiety and depression. Prospective, controlled trials are needed so that guidelines regarding the role of psychotherapy in the treatment of these disorders in elderly patients can be established.
It may be worthwhile to consider psychotherapy in cases of mild to moderate major depression or for patients unable or unwilling to take antidepressants. In addition, psychotherapy may be helpful in combination with antidepressant medication when specific stressors or maladaptive personality factors are present. However, because of the relatively high cost and social stigma associated with psychotherapy, many elderly patients may be unwilling to accept this treatment modality.
Pharmacotherapy
For several reasons, the pharmacologic treatment of depression in elderly patients is particularly challenging. Reduced lean body mass and increased body fat result in higher concentrations of drugs that distribute in body fluids, such as lithium, and increase distribution and prolong the elimination half-life of fat-soluble drugs, such as antidepressants.21 Second, hepatic and renal drug and metabolite clearance may decrease with age, resulting in slower drug clearance. Third, the presence of medical illness may result in pharmacodynamic changes. For example, the presence of dementia or other brain diseases may increase sensitivity to the central nervous system effects of psychotropic medications. Finally, because elderly patients are often taking multiple medications, drug-drug interactions are a source of concern. For these reasons, elderly patients should initially receive lower antidepressant doses than those recommended for younger patients.22-24 The dose can then be slowly titrated upward based on clinical response and emergence of adverse effects. Older patients may take longer to respond to antidepressants, and should receive a 6- to 12-week antidepressant trial, if possible, before assessing for efficacy.5 Estimates of drug noncompliance in elderly patients range from 40% to 75%.25 Simplification of multidrug treatment regimens and dosing schedules and the use of daily-dosing pillboxes may facilitate compliance. Lack of medical literacy may also contribute to noncompliance.
Patients and significant others should receive verbal and written information outlining dosing schedules and potential adverse effects. Because many elderly patients receive fixed incomes, physicians must consider drug costs as well as the cost of associated risks, such as falls, and follow-up monitoring, such as office visits and laboratory tests, when selecting an antidepressant.
Tricyclic Antidepressants
For several decades, TCAs were considered the cornerstone of antidepressant therapy. Although the TCAs are effective antidepressants, their adverse effect profile limits their use (Table 1). For example, muscarinic receptor blockade results in several particularly troublesome adverse effects for elderly patients such as dry mouth, sweating, tachycardia, urinary retention, blurred vision, and confusion. Postural hypotension is another TCA effect that may have grave consequences. Sudden drops in blood pressure increase the potential for hip fracture, stroke, or myocardial infarction.5 A study of 1021 patients with hip fracture demonstrated a clear relationship between TCA therapy and risk for hip fracture.27 In addition, TCAs prolong cardiac conduction, which precludes their use in those with preexisting bundle branch block. Some investigators caution against the use of TCAs in patients with ischemic heart disease or recent myocardial infarction because of their Type I antiarrhythmic effects.28 Subtle cognitive changes also can be observed in elderly patients taking TCAs. Finally, TCAs have a low therapeutic index and are potentially fatal in overdose.
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Table 1. Common Adverse Effects of Tricyclic Antidepressants*
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Because most elderly patients are taking multiple medications, awareness of potential drug interactions is crucial. The combination of TCAs and cytochrome P450 enzyme inhibitors such as cimetidine, fluoxetine, paroxetine, and sertraline may result in elevated plasma TCA levels and increased adverse effects (Table 2).26 Cytochrome P450 enzyme inducers, such as carbamazepine and barbiturates, may lower plasma TCA levels, resulting in a loss of antidepressant effect. Because TCAs can block the therapeutic effects of centrally active antihypertensive drugs, elevated blood pressure may occur if TCAs are coadministered with clonidine or guanethidine.30 In contrast, an enhanced antihypertensive effect may occur when TCAs are coadministered with diuretics or vasodilators.30
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Table 2. Drugs That Are Metabolized by and/or Inhibit Cytochrome P450 Enzymes*
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All TCAs are equally effective, but their adverse effect profiles differ. The secondary amines, nortriptyline and desipramine, cause fewer anticholinergic effects than other TCAs. In addition, nortriptyline causes less postural hypotension than other TCAs, even in patients with reduced left ventricular function (Table 1). 31-32 Although age seems to be associated with reduced clearance of imipramine and amitriptyline, clearance of desipramine and nortriptyline does not seem to decrease with age.33 For these reasons, the secondary amines are preferred over the tertiary amines (imipramine and amitriptyline) for use in elderly patients. Recommended starting doses are 10 mg of desipramine or 10 mg of nortriptyline given at bedtime, with increases of 10 to 25 mg every 3 to 7 days until a total dose of 50 to 75 mg/d is reached (Table 3).
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Table 3. Pharmacologic Agents Available to Treat Depression
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Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine, paroxetine, and sertraline have become first-line agents for the treatment of depression in elderly patients because of their favorable adverse effect profiles, once-daily dosing schedule, and safety in cases of overdose. They have been demonstrated to be efficacious for the treatment of mild depression, and clinical evidence is accumulating that supports their use in severe depression.34-38 In the several hundred elderly patients included in SSRI clinical trials, all agents have shown comparable efficacy to the tricyclics and to each other.39 In addition, the SSRIs cause fewer adverse effects than amitriptyline, imipramine, and doxepin.40-46
In contrast to the TCAs, the SSRIs are highly selective for serotonin receptors and have little effect on other neurotransmitter systems, resulting in fewer adverse effects.26 Most adverse effects associated with SSRIs are mild and include gastrointestinal symptoms (eg, nausea, anorexia, diarrhea, flatulence, and constipation), headache, agitation, insomnia, somnolence, and sexual dysfunction (Table 4). Diarrhea seems to be more common with sertraline and constipation with paroxetine.47-48 Although some suggest activation is more common with fluoxetine and sedation more common with paroxetine, no consistently significant differences in these adverse effects have been found in the few head-to-head comparisons of SSRIs performed in elderly subjects. Weight loss is sometimes associated with SSRIs, which is a desirable effect for many but could be a problem for frail, medically ill patients.49 The SSRIs have a favorable cardiovascular profile and do not cause postural hypotension or slow cardiac conduction. However, fluoxetine has been reported to cause bradycardia and syncopal episodes,50 which may be a problem in those with preexisting sinus node disease. In addition, the SSRIs do not seem to significantly affect cognitive function, although those with preexisting memory deficits may be at higher risk for worsening of such symptoms.
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Table 4. Incidence of Primary Adverse Effects of SSRIs*
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The SSRIs are lipophilic compounds that are eliminated by extensive hepatic biotransformation involving the cytochrome P450 enzyme system.51 In addition, all SSRIs inhibit one or more cytochrome P450 enzymes, resulting in elevated levels of other commonly used medications (Table 2). Fluoxetine, sertraline, and paroxetine inhibit cytochrome P4502D6, the enzyme responsible for metabolizing many different classes of drugs including antidepressants, antipsychotics,  -blockers, Type IC antiarrhythmics (eg, encainide, flecainide, propafenone), dextromethorphan, and some chemotherapeutic agents.29 The potential for drug interactions between cytochrome P4502D6 and sertraline may be lower at the reduced doses typically used in elderly patients (50 mg), but enzyme inhibition is clinically significant at the higher doses of sertraline (100 to 200 mg) that are sometimes required in younger patients to achieve a full antidepressant effect. Inhibition of cytochrome P4502C isoenzymes may be the mechanism for elevated phenytoin and diazepam levels when fluoxetine is concomitantly administered with these drugs.52
Although the SSRIs offer the advantage that the starting dose is often the therapeutic dose in younger patients, the aphorism "start low and go slow" is best followed when treating elderly depressed patients. Recommended starting doses are 5 to 10 mg of fluoxetine, 5 to 10 mg of paroxetine, or 12.5 to 25 mg of sertraline once daily (Table 3). The dose should be increased every 1 to 2 weeks until clinical response is achieved. In general, effective therapeutic doses for elderly patients are 5 to 20 mg/d for fluoxetine, 5 to 40 mg/d for paroxetine, and 12.5 to 200 mg/d for sertraline.
Monoamine Oxidase Inhibitors (MAOIs)
Although MAOIs are effective agents for major depression, the depressive phase of bipolar disorder, and "atypical" depression (ie, depression with hypersomnia and hyperphagia), they are currently not first-line drugs for these conditions53 and are infrequently used in elderly patients. To reduce the risk of hypertensive crisis caused by food or drug interactions, patients must avoid tyramine-containing foods (eg, cheese, red wine) as well as sympathomimetic medications.54 Furthermore, MAOIs are associated with orthostatic hypotension. Monoamine oxidase inhibitors, however, have virtually no anticholinergic effects when compared with TCAs and are less sedating.55 In general, MAOIs are used for patients who have not responded to several antidepressants. Recommended starting doses are 15 mg of phenelzine or 10 mg of tranylcypromine once daily with slow titration to 2 or 3 times daily during a 2- to 4-week period (Table 3).
SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS
Venlafaxine, a phenylethylamine, and its active metabolite, O-desmethylvenlafaxine, inhibit serotonin and norepinephrine reuptake. Venlafaxine has been shown to be safe and well tolerated in a total of 229 elderly patients treated in premarketing trials, 66 of whom continued therapy for at least 1 year.56 The half-lives of venlafaxine and its active metabolite are approximately 5 and 11 hours, respectively, necessitating twice-daily dosing. The most common adverse effects associated with venlafaxine include nausea, drowsiness, dry mouth, dizziness, constipation, nervousness, sweating, asthenia, sexual dysfunction, and anorexia.57 At doses above 225 mg per day, venlafaxine has been associated with diastolic hypertension; therefore, blood pressure monitoring is recommended. Whether those with preexisting hypertension are at increased risk for this adverse effect is not known because such patients were excluded from clinical trials. Because venlafaxine has little effect on cytochrome P450 enzymes, there are few drug interactions between venlafaxine and other drugs.
Recommended starting doses are 12.5 mg (half of a 25-mg tablet) 2 times daily, with increases after 5 to 7 days to 37.5 mg twice daily. Therapeutic doses range from 37.5 to 375 mg/d (Table 3). When using the extended-release formulation of venlafaxine, starting doses should be 37.5 mg once daily. After 1 week, the dosage can be raised to 75 mg once daily. Total daily dosage of the extended-release formulation of venlafaxine should not exceed 225 mg/d.
ATYPICAL ANTIDEPRESSANTS
Trazodone
Trazodone is a triazolopyridine derivative that blocks  -adrenergic receptors and is a relatively selective inhibitor of serotonin reuptake. It is relatively safe in cases of overdose but can cause several troublesome adverse effects. The most common adverse effect associated with trazodone therapy is sedation.26 However, this may be useful for the treatment of antidepressant-associated insomnia. A 25- to 100-mg dose of trazodone at bedtime may effectively improve sleep.58 Other adverse effects associated with trazodone use include blurred vision, light-headedness, headache, nausea, dry mouth, and priapism.59 Due to the wide effective dose range, the optimal dose of trazodone may be difficult to determine.
Bupropion
Bupropion, an aminoketone compound with 3 pharmacologically active metabolites, is an effective and well-tolerated antidepressant in elderly patients. Although its mechanism of action remains unclear, bupropion may exert its antidepressant activity via noradrenergic systems.60 Principal adverse effects of bupropion include insomnia, agitation, and headache. Like the SSRIs, bupropion can cause weight loss, which may be a problem for frail, debilitated, elderly persons. Unlike the TCAs, however, bupropion has few anticholinergic effects and is not associated with electrocardiographic changes. In addition, bupropion does not seem to impair sexual function. Bupropion can cause seizures at doses greater than 450 mg daily61 and its use should be avoided in patients with other risk factors for seizures (eg, history of seizures, focal central nervous system disease, or an abnormal electroencephalogram result).
Recommended starting doses in elderly patients are 37.5 to 75 mg/d, with increases every 7 days to 75 mg 2 to 3 times daily (Table 3). To reduce seizure risk, no more than 150 mg should be taken at one time, and the total daily dose should not exceed 450 mg. When using the sustained-release formulation of bupropion, starting doses should be 100 mg once or twice daily. After 1 to 2 weeks, bupropion can be increased to 150 mg 1 to 2 times daily. The total daily dose of the sustained-release formulation of bupropion should not exceed 400 mg/d and doses should be taken at least 8 hours apart. Bupropion is generally used as a second- or third-line drug for depression refractory to SSRIs, when antidepressant-induced sexual dysfunction is a problem, for patients with cardiovascular disease, or in combination with SSRIs for treatment-resistant depression.
Nefazodone
Nefazodone, a structural analog of trazodone, inhibits serotonin reuptake and blocks 5-HT2 receptors.62 The parent compound and its primary metabolite, hydroxynefazodone, each have a half-life of 4 hours. Therefore, twice-daily dosing is recommended.63 Nefazodone was well tolerated in several hundred elderly patients included in clinical trials, and has a relatively favorable adverse effect profile. Adverse events most commonly seen with nefazodone include somnolence, asthenia, dizziness, dry mouth, nausea, and constipation. In addition, nefazodone seems to be relatively safe in cases of overdose.64 Because it inhibits cytochrome P4503A4, coadministration of nefazodone with triazolam and alprazolam has resulted in elevated plasma concentrations of the 2 benzodiazepines. Concomitant nefazodone administration with astemizole or cisapride is contraindicated, owing to potential risk of QT prolongation and other adverse cardiovascular events.65
The recommended starting dose is 50 mg 1 or 2 times daily with gradual titration upward to a total daily dose of 300 to 600 mg/d (Table 3). Some studies have reported efficacy with as little as 100 mg/d. Nefazodone is generally used as a second- or third-line agent for patients who do not respond to or tolerate SSRIs. Nefazodone therapy may be particularly useful for patients experiencing jitteriness or sexual adverse effects while receiving SSRIs.
Mirtazapine
Mirtazapine is a new antidepressant that antagonizes both 5-HT2 and 5-HT3 receptors as well as central presynaptic 2-adrenoreceptors. This antagonism results in increased central serotonin and noradrenergic transmission.66 Mirtazapine has been demonstrated to be as effective as amitriptyline for the treatment of moderate to severe depression and is generally well tolerated.67 Sedation, dry mouth, constipation, appetite stimulation, and weight gain are the most common adverse reactions seen with this agent.67-68 The recommended starting dose is 7.5 mg at bedtime, with gradual increases to 15 to 45 mg/d (Table 3).
PSYCHOSTIMULANTS
The efficacy of psychostimulants for the treatment of major depression remains controversial despite more than 50 years of use in the clinical setting. Although clinical studies assessing the efficacy of these agents have generally been poorly designed and have reported conflicting results, psychostimulants may be useful for treating medically ill patients with depressive symptoms such as apathy, fatigue, or psychomotor retardation.69 In the only double-blind, placebo-controlled study of psychostimulant treatment (ie, methylphenidate) in medically ill elderly patients with major depression,70 patients treated with methylphenidate significantly improved within 4 days after treatment initiation.
Principal adverse effects of psychostimulants include restlessness, hypertension, and tachycardia, but at lower doses adverse effects are usually not a problem. Recommended starting doses are methylphenidate 5 mg at 8 AM and noon with increases of 5 mg every 2 to 7 days. Onset of action is rapid, usually within 2 to 3 days, and in most cases, effective doses range from 10 to 40 mg/d.
ELECTROCONVULSIVE THERAPY
Electroconvulsive therapy is usually reserved for patients who do not respond to several antidepressant trials, are unable to tolerate antidepressant adverse effects, or suffer from psychotic depression not responsive to the combination of antidepressant and antipsychotic medications.71-73 Although it may be more effective than antidepressants, ECT is a more expensive and complicated treatment requiring hospitalization during the initiation of therapy. The primary adverse effect of ECT is transient memory impairment, which may limit its use in elderly patients with preexisting cognitive deficits.74 In addition, ECT produces transient systemic hypertension and abrupt changes in heart rate.75-76 However, labetalol and nifedipine can be used to attenuate the cardiac effects of ECT.77 If patients with preexisting cardiovascular disease are carefully evaluated and managed before and during ECT, they have little or no greater risk of clinically significant adverse cardiac events during ECT than those without cardiac risk factors.75-76
MAINTENANCE THERAPY
Although elderly patients respond well to treatment of the acute phase of depression, long-term prognosis is not as good. Only 25% to 35% of patients remain well after 1 to 3 years of follow-up.78 Although the protective effect of maintenance antidepressant therapy is well-established in young adults, conflicting data exist as to whether elderly patients benefit from maintenance treatment beyond the continuation phase (4-6 months). Current recommendations are for at least 6 to 12 months of antidepressant treatment at the dose that was effective during the acute phase following return to baseline mood. A longer duration of treatment is indicated for a second episode, especially if the first episode was less than 2 to 3 years earlier. After a third episode, indefinite maintenance treatment should be strongly considered.
CONCLUSION
Depression in elderly patients is often unrecognized or minimized by patients, family members, and clinicians. Because elderly patients may present with somatic rather than psychological symptoms, the diagnosis of depression is sometimes more complicated. Consequences of untreated depression include increased disability, morbidity, and mortality. Pharmacologic therapy remains the mainstay of treatment for major depression in elderly patients. The advent of 7 new antidepressant medications has provided clinicians and patients with more tolerable alternatives to TCAs and MAOIs. Availability of these new medications will result in greater recognition and treatment of depressive disorders in this patient population.
AUTHOR INFORMATION
Accepted for publication July 16, 1997.
Reprints: Krishna DasGupta, MD, Indiana University School of Medicine, Parkview Behavioral Health–Citadel, 2001 Reed Rd, Fort Wayne, IN 46815.
From the Indiana University School of Medicine, Parkview Behavioral Health–Citadel, Fort Wayne.
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