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Jürgen Unützer, M.D., M.P.H. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's A 71-year-old man, whose wife died 6 months previously, presents with foot painfrom diabetic neuropathy, poor sleep, lack of energy, and increasing frustrationabout his inability to "keep his diabetes under control." On examination, he alsonotes lack of interest in usual activities, decreased appetite, a weight loss of 4.5kg (10 lb) over the past 3 months, and intermittent thoughts that he would bebetter off dead. How should his case be managed? The Clinical Problem
As many as 10% of adults 65 years of age or older who are seen in primary caresettings have clinically significant depression.1 Depression is particularly commonin women, in patients with chronic medical disorders2 or persistent insomnia, andin patients who have experienced stressful life events (e.g., the loss of a spouse),functional decline, or social isolation.3 Criteria for the diagnosis of an episode ofmajor depression are summarized in Table 1.
Late-life depression is often undetected or undertreated in primary care,4especially in men and members of racial and ethnic minority groups.5 Reasonsfor undertreatment include stigma associated with depression6 and the belief thatdepression is a normal part of aging.7 Patients and providers may correctlyassociate depression with the loss of a loved one; however, if symptoms of majordepression persist for more than 2 months after a loss, treatment for depressionshould be strongly considered. Coexisting problems, such as chronic medicaldisorders, pain, cognitive impairment (which can be associated with depression ordementia), and alcohol or substance misuse, may also complicate the diagnosisand treatment of depression.
Late-life depression that is untreated can last for years and is associated with apoor quality of life, difficulty with social and physical functioning, poor adherenceto treatment, worsening of chronic medical problems,2 and increased morbidityand mortality from suicide and other causes. Older men have the highest rates ofcompleted suicide (with the use of firearms in most cases).8 Recognizing andtreating depression9,10 and reducing access to firearms may be the mostimportant things primary care providers can do to reduce the risk of suicide.
Strategies and Evidence
The Patient Health Questionnaire 2 (PHQ-2), a two-item screening instrumentthat asks about depressed mood and anhedonia (loss of interest and pleasure) inthe previous 2 weeks, is easily administered by an office staff member or aphysician during a primary care visit. This questionnaire is useful in identifyingpatients at high risk for depression, and it has a sensitivity of 100%, a specificityof 77%, and a positive predictive value of 14%.11 (The full questionnaire isavailable at Positive results shouldprompt a clinical evaluation for major depression.
Evaluation of the patient should include a review of the nine symptoms of majordepression (Table 1), including thoughts of suicide. This evaluation can befacilitated with the use of a brief, nine-item self-rating scale cal ed the PatientHealth Questionnaire 9 (PHQ-9).12 (The full questionnaire is available atClinicians should assess the duration of the patient's current depressive episode,associated functional impairment, and history of and treatment for depression.
Providers should ask whether the patient has a history of bipolar disorder, ormanic depression, which may be misdiagnosed as unipolar depression.
Screening can be facilitated by the use of a brief questionnaire called the MoodDisorder Questionnaire, which asks about symptoms and behaviors suggestive ofmania. Screening questions for symptoms of mania include questions aboutperiods of excess energy or talkativeness, racing thoughts, being much moreactive than usual, needing much less sleep than usual, doing things that othersthought were excessive or risky, or spending too much money.13 Clinicians should also obtain a medical history and perform a physicalexamination and laboratory tests as clinically indicated to assess medicalconditions or medications that may be contributing to depression. Measurementof hypothyroidism (e.g., fatigue, weight gain, or cold intolerance), but the value ofroutine thyrotropin screening in patients with depression is not well established.14Additional screening is recommended for patients with cognitive impairment oralcohol or substance misuse (including misuse of prescription drugs) becausethese conditions can complicate the management of depression.
Effective treatment of late-life depression has been associated with improvedemotional, social, and physical functioning and quality of life. It has also beenassociated with better self-care for chronic medical conditions and reducedmortality.9,10,15,16 In primary care, antidepressant medications are the most commonly usedtreatments for major depression, but there are several other evidence-basedtreatments, including structured psychotherapies.17 A recent meta-analysis ofrandomized, controlled trials indicated that antidepressant medications andstructured psychotherapies have roughly equivalent efficacies in older adults.18 Acombination of pharmacotherapy and psychotherapy is recommended for severeor chronic forms of depression.19,20 Other evidence-based treatments includeelectroconvulsive therapy (ECT) and physical-exercise programs. Specifictherapies are discussed below.
Treatment plans for late-life depression should take into account the patient'spreferences, treatment history (focusing on treatments that have been helpful inthe past), and coexisting medical and psychiatric conditions. Treatmentavailability should also be considered. Before initiating treatment, cliniciansshould address common patient concerns about side effects. They shouldreassure patients that dependence is not a realistic concern with antidepressantmedications and that medications will not inhibit normal emotional reactions suchas bereavement.21 Careful listening, education, and reassurance can helpaddress such concerns.
Several forms of psychotherapy have been shown in randomized, controlled trialsto be effective for late-life depression, including cognitive behavioral therapy(which helps patients correct negative thoughts associated with depression),interpersonal psychotherapy depression), and problem-solving therapy (which helps patients learn strategiesfor solving everyday problems associated with depression).22 Such structuredpsychotherapies, which can be delivered by trained therapists in 6 to 12 sessionsin mental health or primary care settings, should be strongly considered ifantidepressant treatment is not preferred or not effective in a patient. The efficacyof psychotherapy having substantial improvement in depression (at least a 50%reduction in symptoms of depression) as compared with 25 to 35% ofcontrols.18,22 Exercise Programs Several randomized, controlled trials suggest that short-term (e.g., 12-week),supervised, group-based physical-exercise programs involving walking or otherforms of aerobic exercise can reduce depression in older adults; 45 to 65% ofprogram participants have a substantial reduction in symptoms of depression ascompared with 25 to 30% of controls.17,23 A physical-exercise program could be afirst-line strategy for patients with mild-to-moderate depression who prefer thisapproach, but it may be difficult for patients with depression to engage in such a program, and additional treatment with antidepressants or psychotherapy may beneeded.
Pharmacologic Management More than 20 antidepressants have been approved by the Food and DrugAdministration (FDA) for the treatment of depression in older adults. Selectiveserotonin-reuptake inhibitors (SSRIs) are most often used as first-line treatments(Table 2). The most common side effect is gastrointestinal irritation (dyspepsia ornausea), which usual y resolves within 7 to 10 days. Serotonin–norepinephrinereuptake inhibitors (SNRIs) may be particularly useful for patients with coexistingpain, particularly if it is neuropathic. Side effects include nausea, agitation,insomnia, and hypertension, especially at high doses. Although head-to-headcomparisons are scarce, some research suggests that SNRIs may be less welltolerated by frail older adults than SSRIs.26 Mirtazapine, an antidepressant withserotonergic and noradrenergic properties, is associated with sedation, increasedappetite, and weight gain; thus, it may be particularly useful for patients withinsomnia or weight loss. Bupropion may cause jitteriness and insomnia, and itmay be particularly useful in patients with lethargy, daytime sedation, or fatigue.
Neither mirtazapine nor bupropion has sexual side effects. Trazodone is notrecommended as a primary antidepressant because of sedation and orthostatichypotension at therapeutic doses, but in low doses (e.g., 25 to 50 mg) it is usefulfor insomnia associated with depression.27 Priapism is a rare but potentiallyserious side effect.28 Tricyclic antidepressants are effective but are no longer considered to be first-linetreatments because of their side effects (Table 2) and because of cardiotoxiceffects in patients who take an overdose. They should be considered in patientswho have previously had a good response to tricyclic antidepressants or whohave depression that does not improve with other antidepressants. Tricyclicantidepressants are contraindicated in patients with a recent history (e.g., within 2weeks) cardiac conduction hypotension, narrow-angle glaucoma, urinary retention, prostatic hypertrophy, orcognitive impairment. Monoamine oxidase inhibitors have a narrow therapeuticindex and require special dietary and medication restrictions. Their use, which isgenerally limited to patients in whom other antidepressants have failed or inpatients who have had a previous response to this class of drugs, should involveconsultation with a physician who is experienced in prescribing them.
antidepressants in older adults, but data from randomized, placebo-controlledtrials of various agents in older adults suggest similar efficacies.29 However, ascompared with SSRIs, tricyclic antidepressants may be associated with higherdropout rates due to side effects.30 In addition to side-effect profiles, otherconsiderations in the selection of antidepressants include the patient's response to previous treatment, the potential for drug interactions, the frequency of dosing,the safety of the drug in overdose, and cost. The consideration of responses totreatment in close relatives with depression may also be helpful predicting apatient's responsiveness, although this correlation has not been wel studied. Onecommonly used approach involves initial treatment with an SSRI, with a switch toa different class according to the patient's symptoms and the side-effect profile ofthe drug if the SSRI is not effective or is poorly tolerated.31 Up to 12 weeks of treatment with antidepressant medications may be needed toelicit a full response. However, a recent study suggests that a full response isexpected in two thirds of patients who have partial improvement after 4 weeks oftreatment, as compared with about one third of patients without a response at 4weeks.32 Even under the best of circumstances, only 40 to 65% of patients havean adequate response to any given antidepressant, and trials of alternativeantidepressants psychotherapy, are required in a substantial number of patients.33,34,35 Antidepressant monotherapy is preferred in order to minimize side effects anddrug interactions, reduce out-of-pocket costs, and enhance the likelihood oftreatment adherence. To minimize side effects, starting doses for older adultsmay be lower than those for younger adults, but older adults often require fulladult doses for an adequate response (Table 2).
Recent FDA analyses suggest that antidepressant use may increase the risk ofsuicidal thoughts in youths and adults younger than 25 years of age. However,these drugs have a neutral or protective effect against suicidal ideation orbehavior in older adults.36 Antidepressant treatment should be continued at full doses for at least 6 to 12months after patients are in remission because recurrence rates after earlierdiscontinuation are as high as 70%. In controlled trials involving older adults withdepression who had a response to antidepressant treatment, patients who wererandomly assigned to receive such continuation treatment had a 60% reduction inthe risk of recurrence as compared with patients who received placebo afterdiscontinuation of antidepressant therapy.37,38 Several randomized, controlled trials have established the efficacy of ECT forsevere late-life depression, with efficacy rates ranging from 60 to 80%.39,40,41,42ECT is particularly indicated for patients with depression that is resistant to othertreatments and for patients at risk for serious harm because of psychoticdepression, suicidal ideation, or severe malnutrition. ECT is usual y administeredas a series of 6 to 12 treatments in an inpatient psychiatric setting over a periodof 2 to 4 weeks. Common side effects include headache that usually responds toanalgesics and temporary confusion or memory impairment. Less common side effects include memory loss for events during the period surrounding treatmentand falls immediately after treatment sessions. The mortality associated with ECTis less than 1 death in 10,000 patients. A successful course of ECT should befollowed by maintenance pharmacologic treatment because of high rates ofrelapse. In a randomized trial involving patients with depression that hadimproved after ECT, 6-month relapse rates were 84% among patients receivingplacebo, 60% among patients receiving nortriptyline, and 39% among patientsreceiving lithium plus nortriptyline.43 During the initial 8 to 10 weeks of pharmacologic or nonpharmacologictreatments for depression, patients should be followed closely (e.g., weekly orevery other week, either in person or by telephone) for side effects, druginteractions, and worsening of depression (e.g., psychotic or manic symptoms orsuicidal ideation) and in order to adjust treatment as needed. Such close follow-up during this initial treatment phase may reduce the rates of prematurediscontinuation of antidepressant medication; such discontinuation has beenreported in up to 50% of patients within 4 weeks after initiating treatment. Theuse of rating scales such as the PHQ-944 can facilitate monitoring, with the goal oftreatment being a complete remission of depression (e.g., a PHQ-9 score of <5on a scale of 0 to 27, with higher scores indicating more depression).
Consultation with a mental health specialist is recommended for patients whoprefer nonpharmacologic treatments such as psychotherapy or who havepersistent depression after one or more trials of antidepressants. Other reasonsfor referral include psychosis, a history of mania or the emergence of manicsymptoms during treatment for depression, and concern about suicide.
Several randomized trials have shown that, as compared with usual care,systematic programs of care management for depression can significantlyincrease treatment.9,10,15,45 In these programs, a care manager (usually a nurse or socialworker) supports the treating physician by providing the patient with informationabout depression, proactively tracking depression with the use of a scale such asthe PHQ-9, monitoring treatment adherence and side effects, providing briefevidence-based psychotherapy, and facilitating consultation with a psychiatrist.
Areas of Uncertainty
antidepressant medications in patients with depression that does not meet the fulldiagnostic criteria for major depression.46,47 Watchful waiting may be appropriatefor such patients as long as the depression is careful y tracked and treatment isinitiated if symptoms worsen.
The optimal care of patients with depression that is resistant to one or moreantidepressants remains uncertain. Studies involving younger adults33,34 suggestthat several trials of antidepressant medications, alone or in combination withother medications or psychotherapy, are indicated. A recent trial involving olderadults with depression showed that 50% of patients with an incomplete responseto the SSRI paroxetine had a full response when a second antidepressant wasadded.35 ECT has been shown to be efficacious in patients in whom othertreatments have failed, but its use is frequently not considered in primary care.
More research comparing ECT with other active treatments is needed. Otherstrategies that may improve depression include aggressively treating coexistingconditions such as pain48 and addressing psychosocial stressors that contributeto depression. However, such strategies have not been carefully studied.
More research is needed to guide the treatment of older patients with depressionand associated cognitive impairment or dementia. In the absence of definitiveevidence, many clinicians prefer a stepwise treatment approach that starts with atrial of an antidepressant before considering the addition of an antidementiaagent such as a cholinesterase inhibitor or memantine.49 More research is alsoneeded regarding improved access to treatment for older adults who are at highrisk for undertreatment; these patients include elderly men and members ofminority groups.
Although they were not specifically developed for older adults, the Agency forHealth Care Policy and Research guidelines for the treatment of depression inprimary care, which were first published in 199350 and were updated in 1998,51are largely applicable to the treatment of late-life depression. A recent Britishpractice guideline52 and several consensus statements53,54,55 focus on thetreatment of depression in older adults. The recommendations in this article aregenerally concordant with those guidelines.
Conclusions and Recommendations
The patient described in the vignette has symptoms that are typical of majordepression, although other causes of his depressive symptoms (e.g., coloncancer as a potential cause of weight loss) should also be investigated.
Untreated, he would be at substantial risk for poor functioning, poor self-care,worsening of his chronic medical problems,2 and suicide.
Initial treatment may involve either a trial of an antidepressant or psychotherapy(e.g., interpersonal therapy); the choice should be guided by the patient'spreferences, his treatment history, and the costs and availability of treatments. Ifmedication is used, I would generally start with a low dose of an SSRI andincrease the dose gradually over the next 2 to 4 weeks to a therapeutic dose, astolerated (Table 2). The patient should be closely monitored for adherence to and the effectiveness and adverse effects of treatment, and the medication should beadjusted if the depression does not show improvement after 2 to 4 weeks oftreatment.
Patients with depression that persists after one or more trials of medication, eachlasting 8 to 12 weeks, and those who are at high risk for suicide, who have hadprevious mania or manic symptoms while receiving antidepressant medications,or who have psychotic symptoms should be referred for psychiatric consultation.
For patients with depression that has improved, maintenance treatment for atleast 6 to 12 months should be considered in order to reduce the risk of relapse.
Educational information about late-life depression is available from the NationalInstitute Association for Geriatric Psychiatry , and the IMPACTProgram for Late-Life Depression ).
Dr. Unützer reports receiving fees for a continuing medical education symposiumsponsored by an unrestricted grant from Eli Lilly. No other potential conflict ofinterest relevant to this article was reported.
From the Department of Psychiatry and Behavioral Sciences, University ofWashington, Seattle.
Address reprint requests to Dr. Unützer at Box 356560, Seattle, WA 98195, or [email protected].
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