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Linda H. Harpole, MD, MPH, and John W. Williams Jr, MD, MHSc

Primary Psychiatry. 2004;11(5):31-36

 

 

Dr. Harpole is assistant consulting professor of medicine in the Division of General Internal Medicine in the Department of Medicine at Duke University Medical Center in Durham, North Carolina, and director of Full Development Clinical Pharmacology and Discovery Medicine-Metabolic at GlaxoSmithKline in Research Triangle Park, North Carolina.

Dr. Williams is associate professor of medicine in the Division of General Internal Medicine in the Department of Medicine at Duke University Medical Center, and staff physician and research scientist at the Durham Veterans’ Administration Medical Center in North Carolina.

Disclosure: Dr. Harpole has served as a consultant to Wyeth, has received grant and/or research support from AstraZeneca and Eli Lilly, and is currently employed by GlaxoSmithKline. Dr. Williams has served as a consultant to GlaxoSmithKline and Pfizer; has received grant and/or research support from Eli Lilly and Pfizer; and has received honorarium and/or expenses from Pfizer and Wyeth.

Please direct all correspondence to: Linda H. Harpole, MD, MPH, GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC 27709-3398; Tel: 919-483-7434; Fax: 919-315-0984; E-mail: linda.h.harpole@gsk.com.


 

Focus Points

Making the diagnosis of depression in late life is challenging in that the cardinal symptom of depression, depressed mood, may be less prominent than symptoms such as loss of interest and enjoyment in life, anergia, sleeplessness, and loss of appetite.

Depression is more common in patients with moderate-to-severe physical illness; concomitant depression can detrimentally affect patient outcomes.

Medication treatment includes selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, or other newer agents, though treatment should generally avoid tricyclic antidepressants.

After initiating treatment, patients should be monitored routinely for response; those who fail to respond by 4–6 weeks or fail to achieve remission by 8–10 weeks should have their treatment altered through medication change, augmentation, or the addition of psychotherapy.

Promising new models enhancing the care and outcomes of depressed older adults have included collaborative stepped-care management, in which mental health specialists and primary care physicians provide coordinated treatment in the primary care setting.

 

Abstract

Approximately 5% to 10% of older patients who visit a primary care provider suffer from clinically significant depression. Making the diagnosis in the older population can be challenging, as the cardinal symptom of depression, depressed mood, is less prominent than symptoms such as loss of interest and enjoyment in life, anergia, sleeplessness, and loss of appetite. Significant barriers to successful treatment exist in this population, including patient resistance to accepting the diagnosis and its perceived stigma, the inappropriate attribution of depressive symptoms to natural aging, and the primary care physician’s lack of time and resources to provide adequate treatment. Primary care physicians should make special efforts to screen for depression in their older patients, and once identified, provide education and close follow-up, with the goal of achieving remission from depressive symptoms. Collaborative care models, incorporating patient education, case management, and liaison mental health care, which were developed to overcome some of the barriers to successful treatment of depression in older adults, have proven to be successful. Elements of these models can be incorporated into current practice with the goal of improving the quality of depression care in older adults.

 

Introduction

Depressive symptoms occur in approximately 15% of community residents >65 years of age.1 Of patients who visit a primary care provider, 5% to 10% of older adults suffer from clinically significant depression.2-6 For many older adults, its course is chronic or recurrent and is associated with significant functional impairment, decreased health-related quality of life, and suffering.7 Depressed older adults are also high utilizers of healthcare services8-11 and are likely to adhere poorly to medical treatment.12 The suicide rate of people ≥65 years of age is the highest of any age group (19 deaths per 100,000 persons),13 with elderly white men being at highest risk14; even so, many primary care physicians (PCPs) are unwilling to treat suicidal ideation in the older patient.15 Overall, mental illness is the leading cause of disability in the United States, Canada, and Western Europe,16 and major depressive disorder (MDD) is projected to be the second leading cause of disability by 2020.17

Compared with younger patients, older adults are less likely to present to their physician with complaints of depression; therefore, the challenge of making the diagnosis and providing adequate treatment falls upon the PCP. The presentation of depression in older adults is often complicated by concomitant medical illnesses or vague somatic complaints.18 Furthermore, the concomitant presence of dementia may also hinder the diagnosis (see “Cognition and Late-Life Depression”19 in this issue). Moreover, barriers, such as a patient’s resistance to accepting a diagnosis of a mental health disorder, make it more difficult for the primary care physician to engage the patient in treatment. Therefore, a concerted effort needs to be made to identify MDD when it exists, to educate the patient about the disease, and to engage him or her in treatment. Frequent follow-ups and assessments must be scheduled to evaluate response. This article provides an overview of the assessment and management of depression in older adults seen in the primary care setting.

 

Assessment

Mood disorders for depression can be characterized as MDD, dysthymia, and depression not otherwise specified. These diagnoses are based upon criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.20

An updated systematic review for the US Preventive Services Task Force21 concluded that, compared with usual care, screening for depression can improve outcomes, especially when the screening is coupled with system changes that ensure adequate treatment and follow-up. In practice, this could be done by utilizing a screening questionnaire of all patients in one’s practice, or through targeted evaluation of patients at higher risk for MDD, namely those with multiple unexplained physical symptoms; chronic medical illnesses, such as cardiovascular disease, cerebrovascular disease, dementia, or diabetes; chronic pain syndromes; or recent life changes or stressors.22 If any of these factors are present, the likelihood of a depressive disorder increases by approximately 1.5 to 3.5.23

 

Tools for Screening and Monitoring

There are 11 good quality questionnaires that have been used to screen for MDD in the primary care setting.24 These include the Beck Depression Inventory, the Center for Epidemiologic Studies Depression screen, the Geriatric Depression Scale (GDS), the Zung Self-Assessment Depression Scale, the Duke Anxiety and Depression Scale, the Hopkins Symptom Check List, Primary Care Evaluation of Mental Disorders (PRIME-MD), and the nine-item PRIME-MD Patient Health Questionnaire (PHQ-9).25 All of these questionnaires are relatively brief and straightforward. Of the above-listed instruments, the GDS was developed primarily for use in populations
≥60 years of age.

Although there are many validated questionnaires, the PHQ-9 is recommended in this population for several reasons: it is shorter than the GDS (9 versus 15 items); the PHQ-9 contains all depression criteria symptoms, unlike the GDS; and the PHQ-9 has been used in a large primary care treatment trial.26 These characteristics of the PHQ-9 provide a common platform for communication between primary care and psychiatry.

As opposed to initially using a full questionnaire, a simple method for screening in the primary care setting could include asking the first two questions of the PHQ-9 (Table)25; if the patient has a score of >3 (score of 0 for “not at all” to 3 for “nearly every day”),27 then the physician should perform a formal clinical assessment for depression.

Another benefit to this screening instrument is that it can be utilized to follow response to treatment over time. Just as one would follow blood pressure readings at subsequent visits, a score, such as one obtained from the PHQ-9, can be followed over time to determine if the patient is responding to the prescribed treatment; the score provides an objective measurement upon which decisions to change dose or therapy can be made.

 

Suicide Assessment

When a depressed patient is identified, the assessment should include an evaluation of suicidality. The US mortality statistics indicate that approximately 19% of suicides were committed by individuals >65 years of age.28 In the month prior to their suicide, 75% of elderly persons had visited a physician.29,30 Given the high likelihood of a visit prior to suicide, the primary care provider is in the unique position of having the opportunity to assess for suicide, and if identified, can serve as a key resource in suicide prevention. Unfortunately, many physicians perceive suicidality or depression as “normal” in older patients, compared with the same symptoms in younger patients,15 and therefore miss the opportunity to intervene.

All depressed patients should be asked if they have thoughts of death or suicide, or if they feel that life is not worth living. If they answer yes to either of these questions, further probing is required to determine if there is a specific plan for carrying out a suicide. Attention should be paid to variables associated with an increased risk of suicide, namely prior suicide attempts, family history of suicide, substance abuse, advanced age, male gender, Caucasian race, medical illness, psychosis, living alone, or feelings of hopelessness. If the patient does have general plans for suicide but does not have an active plan, the patient should receive aggressive depression treatment, with suicide risk assessment at each visit. For patients with active ideation and risk factors, the physician should consider psychiatric referral early. If current lethal means for suicide are available, immediate psychiatric consultation is required.31 Although many physicians utilize a contract for safety when managing suicidal patients, this effort has not been demonstrated to be effective in preventing suicidal acts, and they are not protective in malpractice suits.32

 

Special Considerations and Populations

A review of current medications is warranted when evaluating the older depressed patient. Medications, such as glucocorticoids, anabolic steroids, and high dose reserpine, or withdrawal from cocaine or amphetamines, may cause depression.33,34 Although case-reports have associated b-blockers with the occurrence of MDD, carefully designed studies evaluating this issue have not found a significantly increased risk of MDD in patients on β-blockers.35 The potential for drug-drug interactions should be considered before initiating treatment with an antidepressant.

Beyond causality, depression in late life often coexists with multiple chronic diseases and disabilities. For example, depression is often seen in patients with cardiovascular disease, cerebrovascular disease, diabetes, arthritis, dementia, and chronic pain syndromes, and the rate of depression doubles in patients with moderate or severe physical illnesses compared to those with no or mild physical illnesses.36 Moreover, the presence of depression with comorbid medical illness can detrimentally affect patient outcome. Patients with depression and ischemic heart disease, for example, are significantly more likely to develop symptomatic and fatal ischemic heart disease.37-40 In addition, patients with type-1 diabetes and depression have been shown to have worse glycemic control than those without depression.41 Patients with comorbid pain and depression have worse outcomes than those without a depressive disorder.42 Patients hospitalized for major medical illness with concomitant depression do not respond to depression therapy at rates seen in patients without comorbid disease,43 and hospitalized elderly patients with depression have been shown to have higher long-term mortality that is not explained by levels of comorbid illness and functional impairment.44

In the outpatient setting, depressed patients with comorbid disease have been shown to receive similar rates of treatment but experience worse depression outcomes than those without comorbid disease.45 Therefore, given that depression is more prevalent in patients with comorbid disease, can be less responsive to therapy, and can confer increased risk for morbidity and mortality, special care needs to be taken when evaluating and treating these patients. It remains to be seen if effective treatment of depression will indirectly benefit the outcomes of medical illnesses, such as cardiovascular disease.

 

Bereavement

Among older adults, loss of a spouse or loved one, loss of functionality, or retirement are common and can lead to significant bereavement. The majority of bereaved individuals cope with their losses without developing MDD; however the risk of developing depression is high. For example, ≥16% of widows and widowers develop clinically significant depression within 1 year after the death of a spouse.46 In these patients, physicians should note the intensity of grief and monitor for depressive symptoms. A prolonged period of grief, symptoms of MDD that are present for >3 months, or severe depressive symptoms even within the first month of loss are situations where depression treatment is indicated. Although studies have suggested that the intensity of grief does not necessarily improve with medication treatment, the depressive symptoms do get better.47

 

Management

Treatment Adherence

Treatment trials have shown that older adults respond to antidepressants at rates similar to younger adults.48 However, given the significant barriers inherent to treating MDD in older adults, particular attention needs to be paid to patient education at the onset of diagnosis. Studies have demonstrated that patients who receive specific instructions about continuation of their medication are more likely to comply with treatment in the first month.49,50 Specifically, patients should be told to take their medication daily, that antidepressants need to be taken for 2–4 weeks to see an effect, that the medication should be continued even if one is feeling better, and that medications should not be stopped without checking with the physician. Furthermore, it is important for the physician to explain the nonaddictive properties of antidepressant medications. Helpful educational handouts can be found in the MacArthur Foundation-sponsored Depression Management Tool Kit.51

 

Patient Preference

When initiating therapy for depression, it is important to elicit and respond to patient treatment preferences. Previous studies have suggested that patients who are not offered treatments they prefer may be less likely to engage in mental health treatment.52-54 Many older adults are concerned about the stigma attached to mental illness and are resistant to seeking mental health care unless it is delivered in a primary care setting, where psychotherapy is not routinely available. For those willing to accept a referral to specialty mental health, the process can be slow and cumbersome, thereby decreasing the likelihood that patients will follow through with treatment. Therefore, primary care physicians should follow-up with patients who choose referral for psychotherapy or for psychiatric assessment to confirm that the referral has been successful.

 

Medication

When selecting antidepressants for older adults, particular attention needs to be paid to side effects, tolerability, and drug-drug interactions. Tricyclic antidepressants (TCAs) with anticholinergic potency should generally be avoided as first-line treatments, especially in patients with cognitive impairment55 and in those with cardiac conduction problems or congestive heart failure. Selective serotonin reuptake inhibitors (SSRIs) are commonly utilized first-line treatments for older adults with depression, as they have been proven safe and effective in this population.56-59 Specifically, sertraline has been shown to be both safe and effective in patients with recent myocardial infarction or unstable angina.60 Initial dosing of SSRIs in the elderly should be lower than that used in a younger person, due in part to metabolic changes with aging and because of the potential for interactions with concomitantly prescribed drugs. For example, their inhibition of hepatic liver isoenzymes is of concern when considering potential drug-drug interactions. In general, SSRIs may increase levels of the b-blockers metoprolol and propranolol, and many antidepressants may affect serum levels of digoxin, warfarin, and theophyline. However, citalopram and escitalopram have less cytochrome P450 (CYP) isoenzyme inhibition than many of the other SSRIs.61 Moreover, age-related illnesses, such as congestive heart failure, can compromise hepatic blood flow through a reduction of hepatic metabolism, thereby resulting in higher peak and steady-state plasma drug levels compared with those of younger patients.55 SSRIs are also associated with hyponatremia in older adults, which is often under-recognized.62

Other treatment options include serotonin noradrenaline reuptake inhibors (SNRIs) such as venlafaxine. Venlafaxine minimally inhibits hepatic isoenzymes,63 though it has been shown to elevate diastolic blood pressure in 3% of those on the extended-release formulation.61,64 Mirtazapine, a noradrenergic and specific serotonergic antidepressant, is another option which has been shown to be useful in the geriatric population. It has a dual-action mechanism and has low CYP isoenzyme inhibition.65 Bupropion is also useful in patients who require an activating agent; however, it should not be used in patients with a history of seizures.

 

Psychotherapy

Psychotherapy is an important modality for treating patients with depression. Cognitive-behavioral therapy and interpersonal therapy (8–20 visits) have been shown to be as effective as antidepressant medications, although improvement is initially slower than that seen with medications.66 Another therapy option that has been shown to be effective in the primary care setting is problem-solving treatment (PST-PC), a 6–8-session brief, structured psychotherapy for depression, in which patients work with the therapist toward developing solutions to a central, focused problem (see “Psychosocial Treatments for Depression in the Elderly”67 in this issue).68 PST-PC has been demonstrated to be effective in depressed elderly.26

Psychotherapy can be utilized as primary therapy in those with mild-to-moderate depression or as an adjunct to medication therapy when only a partial response is realized. In patients with severe depression, psychotherapeutic modalities should be used only in conjunction with antidepressants.66

 

Other Treatment Issues

When assessing patients who are only partially responding to treatment, it is important to determine first if the patient is taking his or her prescribed medications. Barriers to adherence, including the cost of medication and frequency of dosing, should be considered when making medication adjustments. Further discussion on medication augmentation strategies for treatment-refractory depression can be found in “Pharmacotherapy of Depression in the Elderly: Achieving and Maintaining Optimal Outcomes”69 in this issue.

In addition to medication and psychotherapy, electroconvulsive therapy (ECT) may be appropriate for select patients. For example, ECT should be considered in patients with psychotic depression, catatonia, malnutrition or failure to hydrate due to depression, active suicidal ideation, or severe treatment-refractory depression. For patients identified in primary care as having significant comorbid psychiatric illness, such as bipolar disease, psychoses, or disabling personality disorders specialty consultation early in the treatment process should be considered. Patients with significant substance abuse complicating their depression should also be referred, as should those who are at high risk for suicide.

Assessing response to treatment at regularly scheduled intervals is paramount to maximizing the likelihood of success. Assessing response to treatment (either medication or counseling) can be done utilizing the PHQ-9, or through a clinical assessment at each visit. Patients should be assessed every 2 weeks to monitor compliance, symptom improvement, and medication side effects. The optimal goal is for the patient to experience a partial response by 4–6 weeks (50% reduction in symptoms) and full remission (PHQ-9 score <5) by 10–12 weeks. Medication dosage should continue to be increased to meet this goal; medication should be changed if it is ineffective, if the above end points are not reached, or if the medication is not tolerable to the patient. If a response to therapy is not obtained, the diagnosis should be reconsidered and specialty referral considered. If a partial response is obtained, consider combination therapy with another antidepressant. Once remission is obtained, continuing antidepressants for a minimum of 4–9 months decreases relapse rates by >70%.66 Patients who have had two or more prior episodes of MDD or who have persistent dysthymia should be considered for long-term maintenance therapy.

 

Collaborative Care Models

Multiple barriers to successfully treating depression in older adults in the primary care setting exist. For one, older patients attach significant stigma to a mental health diagnosis and are often unwilling to seek treatment in either the primary care or specialty arena. They do not bring their depressive symptoms to the attention of their physician, and often attribute them to a natural part of aging. Physicians may do the same, attributing somatic complaints to medical illness. Even if the primary care providers do suspect MDD, they are often so busy caring for patients with multiple medical problems that they may not have the time and resources to treat depression and may be unable to provide the close follow-up necessary to ensure compliance and adequate treatment trials. Lower reimbursement rates for mental health illnesses can also contribute to inadequate treatment.70

Attempts to overcome these barriers have led to the development and evaluation of many organizational and educational strategies to improve the management of depression.71 Strategies that have been successful have involved complex interventions that incorporate physician and patient education, nurse case management, and better collaboration between primary and specialty care. A multifaceted intervention, “Improving Mood-Promoting Access to Collaborative Treatment,”26 was the first study in an older depressed population to demonstrate that a collaborative, stepped-care management intervention for depression was both feasible and significantly more effective than usual care in treating older adults with depression. Additionally, it was delivered in the primary care setting, removing the stigma associated with receiving mental health care in the mental healthcare setting.

 

Conclusion

Making the diagnosis of depression in older adults and providing adequate treatment can be challenging. Primary care providers can improve their detection of depression by screening every patient for the presence of depressed mood, loss of interest, or loss of pleasure in doing things. Patients who endorse any of these items should have a more formal assessment. If depression is diagnosed, an assessment for suicidality must be performed, due to its high prevalence in depressed older adults. Special attention should be paid to older patients with multiple existing medical illnesses. Patients with comorbid disease are more likely to suffer from depression, are at increased risk for suicide and are more likely to suffer worse outcomes.

Medication treatment of depression in the elderly can be challenging. Generally, physicians should avoid TCAs, due to their cardiac side effects. SSRIs are often the drug of choice, although SNRIs, bupropion, or mirtazapine are other viable options. Response to therapy should be assessed routinely, with a goal of remission of symptoms by 12 weeks. If remission is not achieved in this time frame, treatment should include a medication change, augmentation, or addition of psychotherapy. Referral to specialty mental health services may be required if patients fail to respond; however, models of care that incorporate these services into the primary care setting may prove to have the greatest success in treating older adults with depression.

In summary, depression in the elderly can be effectively managed in the primary care setting. Clinicians now have the tools to assess depressed patients and to follow them longitudinally. Antidepressants are efficacious in older adults and can be prescribed safely in most patients with comorbid medical conditions.  PP

 

References


1. NIH Consensus Conference. Diagnosis and treatment of depression in late life. JAMA
. 1992;268(8):1018-1024.

2. Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life. Consensus statement update. JAMA. 1997;278(14):1186-1190.

3. Barry KL, Fleming MF, Manwell LB, Copeland LA, Appel S. Prevalence of and factors associated with current and lifetime depression in older adult primary care patients. Fam Med. 1998;30(5):366-371.

4. Gurland BJ, Cross PS, Katz S. Epidemiologic perspectives on opportunities for treatment of depression. Am J Geriatr Psychiatry. 1996:4(suppl 1):S7-S13.

5. Lyness JM, Caine ED, King DA, Cox C, Yoediono Z. Psychiatric disorders in older primary care patients. J Gen Intern Med. 1999;14(4):249-254.

6. Schulberg HC, Block MR, Madonia MJ, et al. Treating major depression in primary care practice. Eight-month clinical outcomes. Arch Gen Psychiatry. 1996;53(10):913-919.

7. Unutzer J, Patrick DL, Diehr P, Simon G, Grembowski D, Katon W. Quality adjusted life years in older adults with depressive symptoms and chronic medical disorders. Int Psychogeriatr. 2000;12(1):15-33.

8. Callahan CM, Hui SL, Nienaber NA, Musick BS, Tierney WM. Longitudinal study of depression and health services use among elderly primary care patients. J Am Geriatr Soc. 1994;42(8):833-888.

9. Luber MP, Hollenberg JP, Williams-Russo P, et al. Diagnosis, treatment, comorbidity, and resource utilization of depressed patients in a general medical practice. Int J Psychiatry Med. 2000;30(1):1-13.

10. Luber MP, Meyers BS, Williams-Russo PG, et al. Depression and service utilization in elderly primary care patients. Am J Geriatr Psychiatry. 2001;9(2):169-176.

11. Unutzer J, Patrick DL, Simon G, et al. Depressive symptoms and the cost of health services in HMO patients aged 65 years and older. A 4-year prospective study. JAMA. 1997;277(20):1618-1623.

12. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med. 2000;160(21):3278-3285.

13. National Center for Health Statistics. Vital Statistics of the United States, 1988: Mortality, Part A. Vol II. Washington, DC: US Public Health Service; 1991.

14. Conwell Y, Duberstein PR, Cox C, Herrmann JH, Forbes NT, Caine ED. Relationships of age and axis I diagnoses in victims of completed suicide: a psychological autopsy study. Am J Psychiatry. 1996;153(8):1001-1008.

15. Uncapher H, Arean PA. Physicians are less willing to treat suicidal ideation in older patients. J Am Geriatr Soc. 2000;48(2):188-192.

16. World Health Organization. The World Health Report, 2001—Mental Health: New Understanding, New Hope. Geneva, Switzerland: World Health Organization; 2001.

17. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498-1504.

18. Charney DS, Reynolds CF 3rd, Lewis L, et al, for the Depression and Bipolar Support Alliance. Depression and Bipolar Support Alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. Arch Gen Psychiatry. 2003;60(7):664-672.

19. Murphy CF, Alexopoulos GS. Cognition and late-life depression.?Primary Psychiatry. 2004;11(5):54-58.

20. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

21. Pignone MP, Gaynes BN, Rushton JL, et al. Screening for depression in adults: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002;136(10):765-776.

22. Kroenke K, Spitzer RL, Williams JB, et al. Physical symptoms in primary care. Predictors of psychiatric disorders and functional impairment. Arch Fam Med. 1994;3(9):774-779.

23. Kroenke K, Jackson JL, Chamberlin J. Depressive and anxiety disorders in patients presenting with physical complaints: clinical predictors and outcome. Am J Med. 1997;103(5):339-347.

24. Williams JW Jr, Noel PH, Cordes JA, Ramirez G, Pignone M. Is this patient clinically depressed? JAMA. 2002;287(9):1160-1170.

25. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613.

26. Unutzer J, Katon W, Callahan CM, et al, for the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) Investigators. Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA. 2002;288(22):2836-2845.

27. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003;41(11):1284-1292.

28. Hoyert DL, Arias E, Smith BL, Murphy SL, Kochanek KD. Deaths: final data for 1999. Natl Vital Stat Rep. 2001;49(8):1-113.

29. Conwell Y, Lyness JM, Duberstein P, et al. Completed suicide among older patients in primary care practices: a controlled study. J Am Geriatr Soc. 2000;48(1):23-29.

30. Public Health Service. National Strategy for Suicide Prevention. Goals and Objectives for Action. Rockville, MD: US Department of Health and Human Services; 2001.

31. Veterans Evidence-based Research Dissemination Implementation Center (VERDICT) Web site. Four steps to suicide risk assessment and management. Available at: http://www.verdict.uthscsa.edu/decal/htmlfiles/diagnosis/mod2_2_suicide_risk.htm. Accessed April 12, 2004.

32. Practice guideline for the assessment and treatment of patients with suicidal behaviors. Am J Psychiatry. 2003;160(suppl 11):1-60.

33. Goodwin FK, Bunney WE Jr. Depressions following reserpine: a reevaluation. Semin Psychiatry. 1971;3(4):435-448.

34. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature. J Affect Disord. 1983;5(4):319-332.

35. Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288(3):351-357.

36. Berardi D, Menchetti M, De Ronchi D, Rucci P, Leggieri G, Ferrari G. Late-life depression in primary care: a nationwide Italian epidemiological survey. J Am Geriatr Soc. 2002;50(1):77-83.

37. Roose SP, Glassman AH, Seidman SN. Relationship between depression and other medical illnesses. JAMA. 2001;286(14):1687-1690.

38. Ferketich AK, Schwartzbaum JA, Frid DJ, Moeschberger ML. 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):1261-1268.

39. Lesperance F, Frasure-Smith N, Juneau M, Theroux P. Depression and 1-year prognosis in unstable angina. Arch Intern Med. 2000;160(9):1354-1360.

40. Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58(3):221-227.

41. Van Tilburg MA, McCaskill CC, Lane JD, et al. Depressed mood is a factor in glycemic control in type 1 diabetes. Psychosom Med. 2001;63(4):551-555.

42. Geerlings SW, Twisk JW, Beekman AT, Deeg DJ, van Tilburg W. Longitudinal relationship between pain and depression in older adults: sex, age and physical disability. Soc Psychiatry Psychiatr Epidemiol. 2002;37(1):23-30.

43. Popkin MK, Callies AL, Mackenzie TB. The outcome of antidepressant use in the medically ill. Arch Gen Psychiatry. 1985;42(12):1160-1163.

44. Covinsky KE, Kahana E, Chin MH, Palmer RM, Fortinsky RH, Landefeld CS. Depressive symptoms and 3-year mortality in older hospitalized medical patients. Ann Intern Med. 1999;130(7):563-569.

45. Koike AK, Unutzer J, Wells KB. Improving the care for depression in patients with comorbid medical illness. Am J Psychiatry. 2002;159(10):1738-1745. Erratum in: Am J Psychiatry. 2003;160(1):204.

46. Reynolds CF 3rd, Dew MA, Frank E, et al. Effects of age at onset of first lifetime episode of recurrent major depression on treatment response and illness course in elderly patients. Am J Psychiatry. 1998;155(6):795-799.

47. Pasternak RE, Reynolds CF 3rd, Schlernitzauer M, et al. Acute open-trial nortriptyline therapy of bereavement-related depression in late life. J Clin Psychiatry. 1991;52(7):307-310.

48. Williams JW Jr, Mulrow CD, Chiquette E, Noel PH, Aguilar C, Cornell J. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med. 2000;132(9):743-756.

49. Lin EH, Von Korff M, Katon W, et al. The role of the primary care physician in patients’ adherence to antidepressant therapy. Med Care. 1995;33(1):67-74.

50. Haynes RB, McKibbon KA, Kanani R. Systematic review of randomised trials of interventions to assist patients to follow prescriptions for medications. Lancet. 1996;348(9024):383-386. Erratum in: Lancet. 1997;349(9059):1180.

51. Macarthur Initiative on Depression in Primary Care at Dartmouth and Duke Web site. Depression management tool kit. Available at: http://www.depression-primarycare.org/clinicians/toolkits/. Accessed April 12, 2004.

52. Eisenthal S, Emery R, Lazare A, Udin H. “Adherence” and the negotiated approach to patienthood. Arch Gen Psychiatry. 1979;36(4):393-398.

53. Fairhurst K, Dowrick C. Problems with recruitment in a randomized controlled trial of counselling in general practice: causes and implications. J Health Serv Res Policy. 1996;1(2):77-80.

54. Dwight-Johnson M, Sherbourne CD, Liao D, Wells KB. Treatment preferences among depressed primary care patients. J Gen Intern Med. 2000;15(8):527-534.

55. Zubenko GS, Sunderland T. Geriatric neuropsychopharmacology: why does age matter? In: Coffey CE, Summings JL, eds. The American Psychiatric Press Textbook of Geriatric Neuropsychiatry. 2nd ed. Washington, DC: American Psychiatric Press; 2000:749-778.

56. Newhouse PA, Krishnan KR, Doraiswamy PM, Richter EM, Batzar ED, Clary CM. A double-blind comparison of sertraline and fluoxetine in depressed elderly outpatients. J Clin Psychiatry. 2000;61(8):559-568.

57. Tollefson GD, Holman SL. Analysis of the Hamilton Depression Rating Scale factors from a double-blind, placebo-controlled trial of fluoxetine in geriatric major depression. Int Clin Psychopharmacol. 1993;8(4):253-259.

58. Dunner DL, Cohn JB, Walshe T 3rd, et al. Two combined, multicenter double-blind studies of paroxetine and doxepin in geriatric patients with major depression. J Clin Psychiatry. 1992;53(suppl):57-60.

59. Walters G, Reynolds CF 3rd, Mulsant BH, Pollock BG. Continuation and maintenance pharmacotherapy in geriatric depression: an open-trial comparison of paroxetine and nortriptyline in patients older than 70 years. J Clin Psychiatry. 1999;60(suppl 20):21-25.

60. Glassman AH, O’Connor CM, Califf RM, et al, for the Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288(6):701-709. Erratum in: JAMA. 2002;288(14):1720.

61. The Physicians’ Desk Reference. 56th ed. Montvale, NJ: Thomson PDR; 2003.

62. Fabian TJ, Amico JA, Kroboth PD, et al. Paroxetine-induced hyponatremia in older adults: a 12-week prospective study. Arch Intern Med. 2004;164(3):327-332.

63. Ereshefsky L. Drug-drug interactions involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol. 1996;16(3 suppl 2):37S-50S. Discussion in: J Clin Psychopharmacol. 1996;16(3 suppl 2):50S-53S.

64. Zimmer B, Kant R, Zeiler D, Brilmyer M. Antidepressant efficacy and cardiovascular safety of venlafaxine in young vs old patients with comorbid medical disorders. Int J Psychiatry Med. 1997;27(4):353-364.

65. Raji MA, Brady SR. Mirtazapine for treatment of depression and comorbidities in Alzheimer disease. Ann Pharmacother. 2001;35(9):1024-1027.

66. Depression Guideline Panel. Clinical Practice Guideline. Depression in Primary Care: Treatment of Major Depression. Vol 2. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1993:AHCPR Publication No. 93-0551.

67. Areán PA. Psychosocial treatments for depression in the elderly. Primary Psychiatry. 2004;11(5):48-52.

68. Mynors-Wallis LM, Gath DH, Day A, Baker F. Randomised controlled trial of problem solving treatment, antidepressant medication, and combined treatment for major depression in primary care. BMJ. 2000;320(7226):26-30.

69. Karp JF, Reynolds CF 3rd. Pharmacotherapy of depression in the elderly: achieving and maintaining optimal outcomes. Primary Psychiatry. 2004;11(5):37-46.

70. Unutzer J, Katon W, Sullivan M, Miranda J. Treating depressed older adults in primary care: narrowing the gap between efficacy and effectiveness. Milbank Q. 1999;77(2):174,225-256.

71. Gilbody S, Whitty P, Grimshaw J, Thomas R. Educational and organizational interventions to improve the management of depression in primary care: a systematic review. JAMA. 2003;289(23):3145-3151.