SYMPOSIUM ON GERIATRIC PSYCHIATRY

Depression in the elderly

Tailoring medical therapy to their special needs

Ashok Raj, MD

VOL 115 / NO 6 / JUNE 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To be aware of the risk factors for late-onset depression
• To understand that depression has different clinical presentations in elderly patients than in younger patients
• To become familiar with the benefits and disadvantages of selective serotonin reuptake inhibitors

The author discloses no financial interests in this article and no unlabeled uses of any product mentioned.

Preview: Depression is often overlooked as a clinical diagnosis in older patients because it is assumed to be a normal response to aging, physical losses, or other life events. However, medical intervention for depression is appropriate in this population, especially those patients with severe chronic disease. In this article, Dr Raj discusses the prevalence of depression in the elderly, the role of cognitive impairment, the risk factors for first onset in old age, typical presentations in this age-group, and the response to treatment.
Raj A. Depression in the elderly: tailoring medical therapy to their special needs. Postgrad Med 2004;115(6):26-42

It has been said that old age is a season of losses. According to this line of thinking, a high prevalence of depression might be expected in the elderly. In addition, depression in an older person may be presumed to be a reaction to a physical or environmental event and not something that merits medical intervention. However, the reality is that the majority of elderly persons lead productive, depression-free lives, and the presence of depression in an older person warrants medical management.

Prevalence

Community studies have shown that 25% of elderly persons report having depressive symptoms, but only 1% to 9% meet the criteria for major depression (1) (figure 1). However, prevalence varies according to the population being sampled. For example, higher prevalence rates are reported in the hospitalized elderly (36% to 46%) and those in long-term care facilities (10% to 22%) (2).

In evaluation of a first episode of depression in older patients, numerous medical disorders and other factors associated with age and depression should be considered (table 1). Onset of depression may precede a medical disorder (eg, Alzheimer's disease, Parkinson's disease), may be comorbid with a medical disorder (eg, myocardial infarction [MI]), or may follow a medical condition, as often happens after a stroke. Depression is common in patients with cancer, and 80% of all cancers occur in persons older than 60 years. The danger arises in accepting such depression as a natural and expected reaction to catastrophic news. Depressed mood in patients with a serious medical illness needs to be distinguished from the syndrome of major depression. Although depressed and anxious mood is almost always present in response to catastrophic news, the syndrome of depression is not.

Table 1. Risk factors for late-onset depression

Female sex (female-male ratio, 2.5:1) Medical illness Hypothyroidism (50%) Myocardial infarction (45%) Macular degeneration (33%) Diabetes (8% to 28%) Cancer (24%) Coronary artery disease (20%) Medications Beta-blockers Interferon alfa Many anticancer drugs Central nervous system disease Parkinson's disease (25% to 70%) Alzheimer's disease (15% to 57%) Multiple sclerosis (27% to 54%) Stroke (26% to 54%) Huntington's disease (9% to 44%) Microvascular ischemic disease of the brain (20%) Mini-Mental State Examination score <24

Various cancers seem to carry different risks of depression. For example, pancreatic cancer has the highest risk (50%), whereas acute leukemia has the lowest risk (1.5%). Other cancers with a substantial prevalence of depression include cancer of the oropharynx (22% to 40%), colon cancer (26%), breast cancer (13% to 26%), gynecologic cancers (23%), lymphoma (17%), and gastric cancer (11%) (3).

MI is another acute medical event associated with depression. In the first 10 days after infarction, the prevalences of minor and major depression are 27% and 18%, respectively. By the third month post infarction, the overall prevalence has dropped to 33%, but three quarters of hospitalized patients with major depression continue to exhibit significant depression (4).

Over the years the medical literature has supported a relationship between stroke and depression. The risk of depression increases (1) if the left cerebral cortex is affected and (2) the closer the stroke damage is to the frontal pole. The risk is highest within the first 2 years after a stroke, when major depression develops in about 1 in 5 patients and minor depression in another 1 in 5 patients. Without treatment, most poststroke depressions are likely to resolve within a year after onset. However, in a minority of cases, depression becomes chronic and can last 3 years or longer (5,6). Subcortical infarcts in the thalamus and caudate also predispose patients to depression.

In recent years a concept called vascular depression has emerged (7). It is hypothesized that cerebrovascular disease disrupts mood-regulating circuits in the brain, which results in depression. Patients with vascular depression have extensive microvascular ischemic disease readily identifiable on magnetic resonance imaging of the brain. Such lesions represent areas of gliosis that are a secondary effect of chronic ischemia. Patients with systolic hypertension or diabetes, or both, are at high risk for this kind of vascular change in the brain. Some studies have found that vascular depressions are characterized by excessive psychomotor retardation, poor insight, increased disability, and absence of a family history of depression (8).

Diagnostic factors

The "gold standard" for diagnosis of depression continues to be the mental status examination. Physicians who are familiar with the diagnostic criteria for depression in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition revised (9) (table 2) should be able to identify most cases. When a medical disorder or event is identified as causative, a diagnosis of mood disorder due to medical condition or event is made.

Table 2. Signs and symptoms of depression

For diagnosis of major depression, five or more of nine symptoms must be present for at least 2 weeks and must include symptom 1 or 2. For minor depression, two to four of nine symptoms must be present for at least 2 weeks. 1. Depressed mood 2. Loss of interest 3. Weight change 4. Sleep disturbance 5. Agitation or retardation 6. Fatigue 7. Guilt 8. Inability to make decisions 9. Suicidal ideation or attempt

Several aspects of mental status in the elderly can be troublesome, such as somatization and severe lack of motivation and ambition (apathy). The term somatization is used when the patient focuses on physical symptoms. For example, it is not unusual for depressed elderly patients to be focused on bowel problems as their presenting complaint. Or they may agree that they are depressed but blame it on back pain or other chronic pain. The consequences of somatization are multiple workups and a delay in initiation of antidepressant treatment. When lassitude and lack of drive and volition dominate the clinical picture, the patient may appear demented rather than depressed. This is called pseudodementia or the dementia syndrome of depression. However, the combination of depression and dementia is much more common than true pseudodementia. Clues to establishing the diagnosis can be found in the patient's history and physical examination (table 3).

Another area of potential confusion is the attribution of symptoms in patients with depression in addition to a medical illness. For example, fatigue may be the result of depression or anemia, or both. Similarly, loss of appetite may be due to depression or cancer, or both. In an effort to mitigate diagnostic problems, several scales have been developed, such as the Geriatric Depression Scale (GDS) and the Cornell Scale for Depression in Dementia. The GDS tends to focus on the psychologic symptoms of depression and excludes somatic symptoms. The Cornell Scale excludes symptoms that may be attributed to both depression and dementia.

It has been observed that melancholic and psychotic depressions may be more prevalent in the elderly than in younger persons. Psychosis is important to identify because affected patients are at risk for self-injurious behaviors, and they respond better to combination treatment with antidepressant and antipsychotic agents than to antidepressant treatment alone.

Consequences of depression

The most serious consequence of depression is suicide. Other consequences include impairment in function, excessive use of medical resources, and increased mortality from causes other than suicide. Suicide is the eighth leading cause of death in the United States. In 2000, persons aged 65 years and older composed 13% of the US population but accounted for 18% of all suicides (10). Suicide risk factors in the elderly include male sex, white race, medical comorbidity, substance abuse, and lack of support systems. The rate in older white men is 59 per 100,000, which is more than five times higher than the national rate of 10.6 per 100,000. Compared with women, elderly men are more likely to use extremely lethal methods, such as gunshot, hanging, and inhalation of carbon monoxide.

At every visit with a depressed elderly patient, the physician should not hesitate to directly ask about passive or active suicidal ideation. If possible, a family member also should be queried, because the patient is much more likely to share such ideation with family members than with his or her physician. Other useful information about dealing with suicide is available at a Web site sponsored by the Surgeon General (http://www.mentalhealth.org).

Several studies have shown that independent of other variables (eg, smoking), depression increases the risk for coronary heart disease and related events (11). After an MI, the development of major depression results in a fivefold increase in risk of death over the next 6 months (12). It has been suggested that in the course of an acute MI, depression is as strong a predictor of increased risk for mortality as older age, left ventricular ejection fraction of less than 35%, and previous history of acute MI (13,14).

Depression also has a negative effect on other conditions. It affects rehabilitation after hip surgery as well as worsens dysfunction in patients with arthritis. Within 10 years after a stroke, the risk of death is 3.5 times higher in depressed patients than in those without depression (15).

Pharmacologic options

Currently, selective serotonin reuptake inhibitors (SSRIs) are the first choice for treatment of depression in elderly patients. Compared with tricyclic antidepressants (TCAs), they are much safer in overdose and, for the most part, their side effects are better tolerated. In double-blind studies, the SSRIs sertraline hydrochloride (Zoloft), fluoxetine hydrochloride (Prozac), paroxetine hydrochloride (Paxil), and venlafaxine hydrochloride (Effexor) and the TCAs nortriptyline hydrochloride (Aventyl, Pamelor) and clomipramine hydrochloride (Anafranil) have been shown to be effective in geriatric depression. Given that most antidepressants are effective in the elderly, choice of drug is based on an agent's side effect profile and its potential to interact with other medications.

Side effects
Anticholinergic side effects are particularly troublesome to elderly patients. Cholinergic blockade results in symptoms that range from being inconvenient to potentially dangerous. Dry mouth promotes dental decay and denture problems and may cause the patient to choke on food. Pupillary dilatation causes blurred vision and increases the risk of falls and angle-closure glaucoma. Constipation, an increasing problem with age, may lead to laxative abuse, which is worsened by anticholinergic drugs and occasionally results in ileus or obstruction. Men who have an enlarged prostate are at risk for urinary retention. In addition, anticholinergic effects on cognition can be significant and additive from multiple drugs and may result in delirium. Sedation and increased appetite due to histamine blockade and hypotension from adrenergic blockade are also cause for concern.

In elderly patients, it is usually prudent to avoid antidepressants with significant blockade of cholinergic receptors. As a group, TCAs have significant blockade of all cholinergic receptors, but the effects of SSRIs vary. For example, fluoxetine and sertraline (unlike paroxetine) have almost no impact on these receptors. In vitro, paroxetine has more anticholinergic activity than the TCAs desipramine hydrochloride (Norpramin) and nortriptyline. This does not mean that paroxetine is contraindicated in elderly patients. However, before prescribing paroxetine, physicians should carefully review the patient's record for concomitant medications that are also anticholinergic, because the potential for anticholinergic toxicity increases with the number of such medications ingested.

Venlafaxine is predominantly a serotonin reuptake inhibitor at doses less than 150 mg per day. At higher doses, it also inhibits norepinephrine uptake and increases blood pressure in 3% to 5% of patients. In addition, higher doses produce anticholinergic side effects.

Sometimes physicians exploit a drug's side effects to meet a clinical need. For example, the SSRI trazodone hydrochloride (Desyrel) is sedating, and for the most part these days, it is prescribed for the induction of sleep. However, it also causes hypotension, and this side effect limits the doses that can be used. Another agent, mirtazapine (Remeron), is a unique antidepressant that works by enhancing the release of norepinephrine from the proximal neuron. Because it is a histamine blocker, it sedates and increases appetite and therefore is potentially useful in patients with insomnia and anorexia.

Drug interactions
Drug interactions are another major consideration in the selection of an appropriate antidepressant. Most drugs are metabolized in the liver by the cytochrome P-450 system. Inhibition of one of these enzymes results in higher blood levels of any drug that is metabolized by that enzyme, and induction of that enzyme results in lower levels of such drugs. Two of these enzymes, CYP2D6 and CYP3A3/4, have particular relevance to the treatment of depression.

CYP2D6 mediates the metabolism of antiarrhythmic agents, antipsychotics (eg, risperidone [Risperdal]), beta-blockers, TCAs, dextromethorphan hydrobromide, and codeine. The enzyme is inhibited by fluoxetine, paroxetine, fluphenazine (Prolixin Decanoate), erythromycin, cimetidine (Tagamet), and quinidine.

Both fluoxetine and paroxetine are powerful inhibitors of CYP2D6 (table 4). If either of these agents is given to a patient who is receiving TCA therapy, the blood level of the TCA and the risk of toxicity are increased. Such a drug interaction is likely to occur in the following clinical situation: A patient with depression is prescribed fluoxetine, for example, by his primary care physician or psychiatrist. The patient then sees a neurologist for neuropathic pain and is prescribed amitriptyline hydrochloride (Elavil) in a low dose of 25 to 50 mg. However, due to CYP2D6 inhibition, the amitriptyline dose is now equivalent to 75 to 150 mg, and the potential for anticholinergic toxicity is increased.

The enzyme CYP3A3/4 metabolizes calcium channel blockers, carbamazepine, pimozide (Orap), and alprazolam (Xanax). It is inhibited by erythromycin, ketoconazole (Nizoral), fluoxetine, and nefazodone hydrochloride (Serzone). A drug interaction can occur in patients taking alprazolam (a triazolobenzodiazepine) who are then prescribed fluoxetine or nefazodone. The addition of one of these agents will inhibit CYP3A3/4 and result in higher levels of alprazolam, causing sedation or ataxia in patients who previously experienced no side effects.

Other potential interactions among antidepressants occur with monoamine oxidase (MAO) inhibitors. At present, this class of agents is infrequently used for treating depression. However, selegiline hydrochloride (Carbex, Eldepryl) is a selective MAO type B inhibitor that is given in doses of 10 mg or less to treat Parkinson's disease and Alzheimer's disease, two diseases that are commonly accompanied by depressive disorders. Use of a TCA or an SSRI with selegiline increases the risk of serotonin syndrome, which is characterized by a change in mental state, tremor, sweating, myoclonus, hyperreflexia, ataxia, and fever. The risk is greater in patients who are being treated with a nonselective MAO inhibitor, such as tranylcypromine sulfate (Parnate) or phenelzine sulfate (Nardil).

Controlled studies have shown the efficacy of TCAs and bupropion hydrochloride (Wellbutrin) in the treatment of depression in patients with Parkinson's disease, but no controlled studies of SSRIs are available. Nevertheless, a survey (16) reported that the majority of neurologists choose an SSRI as first-line treatment of depression in Parkinson's disease. A number of case reports have noted that SSRIs worsen the motor symptoms of Parkinson's disease. In most of these reports, the SSRI used was fluoxetine. However, several open-label trials involving either sertraline or fluoxetine in Parkinson's disease did not identify a problem with worsening motor symptoms (17).

Efficacy and safety of SSRIs
Despite their side effects and potential for drug interactions, SSRIs truly represent a major advance in the treatment of geriatric depression because of their efficacy and overall safety. One of the best examples of the efficacy and safety of SSRIs is the Sertraline Antidepressant Heart Attack Randomized Trial (18). In this study, patients meeting criteria for major depression after an MI were randomly assigned to receive sertraline or placebo. The goals of the study were to evaluate primarily the safety and secondarily the efficacy of sertraline in this population. Patients included in the study did not have congestive failure, Killip class III or IV status, unstable angina, or uncontrolled hypertension. Patients with mild depression responded equally to drug therapy or placebo. Those with moderate or severe depression did better with drug therapy. Sertraline had no negative impact on cardiac measures (eg, left ventricular ejection fraction, ventricular premature complexes, corrected QT interval). Over the 6 months of the trial, more deaths occurred in the placebo group than in the treatment group. A number of placebo-controlled studies of post-stroke depression have shown efficacy for citalopram hydrobromide (Celexa) at doses of 10 mg (19) and for nortriptyline (100 mg) but not for fluoxetine (20 mg) (20).

Maximizing treatment outcomes

Successful pharmacotherapy begins with choosing a medication that is compatible with the patient's other medications and has side effects that are minimally disruptive to the patient. Beyond this, patients need to be informed that the medication can take anywhere from 6 to 12 weeks to work. Physicians need to know the dosing range of the antidepressant prescribed and systematically adjust the dose to achieve therapeutic levels (table 5). In my experience, the most common reasons for a poor response to antidepressant treatment are inadequate length of treatment and subtherapeutic dosing.

The prognosis of geriatric depression has remained remarkably constant over the years. Roughly one third of depressed elderly patients get better and remain well, one third follow a relapsing course, and one third do not get better (21). A number of factors affect response to treatment, such as duration of illness of more than 1 year before the start of treatment and the presence of cognitive impairment or cortical atrophy. Although studies in the elderly are lacking, experience with younger patients with depression has shown that the dose that produces remission is also the appropriate maintenance dose. After remission is achieved, treatment should continue for at least 1 year. Patients who have had three or more depressive episodes, have severe depression, or experienced onset after age 50 years may need lifelong treatment.

In a randomized, controlled study of recurrent depression in the elderly (22), the relapse rates over 3 years were 20% for patients who received nortriptyline plus monthly interpersonal therapy, 43% for those in the nortriptyline plus medication clinic group, 64% for the interpersonal psychotherapy only group, and 90% for the placebo plus medication clinic group. These results suggest that interpersonal psychotherapy has additive effects to pharmacotherapy but is not effective in preventing relapse when used by itself.

Despite effective treatment, relapse is more likely in patients who initially take longer to respond and who have high anxiety scores (23), in those with high depression scores at the beginning of the maintenance phase (24), and in those experiencing a medical or interpersonal event. Having a confidant or a strong social support system helps prevent relapse.

It has been shown that a system of collaborative care (25) is very effective in improving outcomes in primary care. In this system, patients should have access to nonpharmacologic interventions, such as cognitive behavior therapy and interpersonal therapy, and the services of a case manager and a psychiatrist. Cases that are resistant to treatment may require augmentation or combination medication strategies or electroconvulsive therapy.

Conclusion

Depression in the elderly is multifactorial, and treatment is complex in that it involves consideration of the role of comorbid disease, cognitive changes, concomitant medications, and the status of the patient's support systems. Optimum results are achieved with a management approach that incorporates a system of collaborative care.

References

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11. Ferketich AK, Schwartzbaum JA, Frid DJ, et al. Depression as an antecedent to heart disease among women and men in the NHANES I study. National Health and Nutrition Examination Survey. Arch Intern Med 2000;160(9):1261-8
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14. Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol 2001;88(4):337-41
15. Morris PL, Robinson RG, Andrzejewski P, et al. Association of depression with 10-year poststroke mortality. Am J Psychiatry 1993;150(1):124-9
16. Richard IH, Kurlan RA. A survey of antidepressant drug use in Parkinson's disease. Parkinson Study Group. Neurology 1997;49(4):1168-70
17. Zesiewicz TA, Gold M, Chari G, et al. Current issues in depression in Parkinson's disease. Am J Geriatr Psychiatry 1999;7(2):110-8
18. Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group. JAMA 2002;288(6):701-9 [Erratum, JAMA 2002;288(14):1720]
19. Andersen G, Vestergaard K, Lauritzen L. Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 1994;25(6):1099-104
20. Robinson RG, Schultz SK, Castillo C, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry 2000;157(3):351-9
21. Cole MG, Bellavance F. The prognosis of depression in old age. Am J Geriatr Psychiatry 1997;5(1):4-14
22. Reynolds CF 3rd, Frank E, Perel JM, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA 1999;81(1):39-45
23. Flint AJ, Rifat SL. Maintenance treatment for recurrent depression in late life: a four-year outcome study. Am J Geriatr Psychiatry 2000;8(2):112-6
24. Bump GM, Mulsant BH, Pollock BG, et al. Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly. Depress Anxiety 2001;13(1):38-44
25. Unutzer J, Katon W, Callahan CM, et al. Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA 2002;288(22):2836-45

Dr Raj is professor and director, division of geriatric psychiatry, University of South Florida College of Medicine, Tampa. Correspondence: Ashok Raj, MD, USF Psychiatry Center, 3515 E Fletcher Ave, Tampa, FL 33613. E-mail: araj@hsc.usf.edu.

Symposium Index

• DEPRESSION IN THE ELDERLY:Tailoring medical therapy to their special needs. By Ashok Raj, MD
• BEHAVIORAL PROBLEMS IN DEMENTIA: Strategies for pharmacologic and nonpharmacologic management. By Amanda G. Smith, MD
• Clinical Commentary. WHY DON'T PHYSICIANS CONSIDER DEPRESSION IN THE ELDERLY? By Jonathan T. Stewart, MD

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