Clinical Contributions

Clinical Vignettes
Evidence-Based Clinical Vignettes from the Care Management Institute: Major Depression
By David Price, MD, FAAFP

Introduction

Depressive syndromes are commonly seen in the primary care setting. Major depression affects 4.8% to 8.6% of the general US population in any given year; other types of depression affect an additional 3% to 8.4% of patients.¹ Total costs of depression, including direct medical costs and indirect costs due to days lost from work, exceed $43 billion annually.^1,2

In the primary care setting, treatment of depression usually includes evaluation by a physician, brief patient education, and either antidepressant therapy, referral to a behavioral health specialist, or both a prescription and a referral. Although most depressed patients can be successfully treated by primary care clinicians, depression remains unrecognized or undertreated in many patients.

In 2001, the Kaiser Permanente Care Management Institute (CMI) revised its guideline for evidence-based care of depressed adult outpatients in the primary care setting.³ This article and case example highlight key steps and recommendations from this guideline.

Case Example

A 28-year-old married, employed female computer programmer with two young children (one aged four years, the other aged nine months) is seen for a four-week history of fatigue, insomnia, headache, abdominal discomfort, and difficulty concentrating at work. She denies signs and symptoms of an acute infectious process and did not have headache or abdominal pain before the previous month. She is breastfeeding. She has obtained intermittent relief from headache by using acetaminophen, and she takes a multivitamin regularly. Normal menses has resumed. She is appropriately and professionally dressed, and her children accompany her in the examination room. She appears tired but in no acute distress. Results of physical examination, including neurologic screening, are normal.

How should you proceed toward making a diagnosis? What treatment options are available? How should you follow this patient over time?

Definition of Major Depressive Disorder

Major depressive disorder (MDD) is characterized by at least two weeks of either depressed mood or loss of interest in previously pleasurable activities⁴ along with four or more additional symptoms, including:

• guilt
• sleep disturbance
• psychomotor retardation or agitation
• appetite disturbance
• difficulty concentrating
• decreased energy
• suicidal ideation, intention, or plan⁴

The mnemonic device DIGSPACES is a helpful way to remember these key symptoms of MDD. Diagnosis and treatment of other types of depression (eg, adjustment disorder with depressed mood; dysthymia; minor depressive disorders; depression with psychotic features; and bipolar disorder) are beyond the scope of this article.

Who Should be Screened for Depression?

Patients with cancer,⁵ chronic pain,⁶ heart failure,⁷ diabetes,⁸ recent stroke,⁹ or a recent acute cardiac event¹⁰ have higher rates of depression than the general population. Elderly patients with multiple medical comorbidity may also be at increased risk for depression.¹¹ Patients with a prior history of MDD are at risk for recurrence.^2,12 Other patients--those with multiple somatic complaints without known cause, women in the antenatal and postpartum periods, victims of domestic abuse, and HIV-positive patients--may also be candidates for screening.

Some evidence indicates that one-time screening of adults 40 years of age or older may be cost-effective from a societal perspective.^1,13 However, screening of asymptomatic adults at low risk may result in many false-positive tests. Thus, clinicians should weigh the potential societal benefits of screening asymptomatic low-risk adults against other clinical and operational priorities (including depression screening of higher-risk patients).

Diagnosis of MDD

Several screening tools are available to assist clinicians in screening for depression (Table 1).^14-23 Many of these tools can be completed by the patient and easily scored by the clinician or by an assistant. These tools have similar false-positive and false-negative rates.^20,22,24-32 A "yes" answer to one of the following two questions is as sensitive a screen for MDD as most of these screening tools.¹⁴

• "During the past month, have you often been bothered by feeling down, depressed, or hopeless?"
• "During the past month, have you often been bothered by little interest or pleasure in doing things?"

All positive screening results should be confirmed with careful attention to possible substance abuse, medical, and other psychological causes or comorbidity (Table 2). The patient in the above example denied using alcohol or drugs and denied current or past physical, sexual, or emotional abuse; in addition, the complete blood cell count (CBC) and thyroid-stimulating hormone (TSH) level were normal. (TSH is measured to rule out hypothyroidism, a common postpartum condition that can cause depression.)

Assessing Severity of Depressive Symptoms
Symptom severity is an important guide to selecting proper treatment for MDD. Many depression-screening instruments provide a range of scores corresponding to mild, moderate, and severe depression. Patients with five or six symptoms of MDD who have slightly impaired daily functioning are mildly depressed. Patients with six or seven MDD symptoms and moderately impaired daily functioning are moderately depressed. Patients with eight or nine MDD symptoms with profoundly impaired functioning in daily activities or suicidal intention or plans are severely depressed.

Assessing Suicidal Ideation
All depressed patients, regardless of illness severity, should be screened for suicidal ideation. Many patients with depression have thoughts of suicide; asking "Have you thought about taking your life?" does not make patients more prone to attempt suicide. Patients with current suicidal ideation should be asked about their intentions ("Do you think you will commit suicide?") and if they have a plan ("Have you thought about how you would kill yourself?" "Do you plan to kill yourself? If so, when?"). Clinicians should elicit a promise from actively suicidal patients not to harm themselves and should assess adequacy and availability of patient support systems (family, friends, and clergy). A behavioral health specialist should be contacted immediately in these cases. Risk factors for suicide include: recent loss; medical hospitalization within the past year; history of psychiatric hospitalization or suicide attempts; living alone; severe vegetative symptoms; severe hopelessness; comorbid substance abuse; and other comorbid psychiatric conditions. Patients with these risk factors should be closely monitored.^33-36 Although men are statistically more likely than women to successfully commit suicide, women attempt suicide more often.³⁷

Treatment of MDD

Medication vs Psychotherapy
For most mildly or moderately depressed adult primary care outpatients, medication and psychotherapy are equally effective,^38-41 although psychotherapy might be slower to take effect.^40,41 A shared decision-making approach describing the pros and cons of each option should be used with these patients to help them select initial treatment options consistent with their values and concerns. One study⁴¹ found that patients who select psychotherapy achieve better outcomes than patients who are "assigned" to it. Another study⁴² found that patients of different cultural backgrounds often prefer psychotherapy to medication. A shared decision-making approach in patients with other conditions has been shown to improve patient knowledge and to decrease patient uncertainty about type of treatment.^43-45 This approach can also help instill a sense of control in depressed patients, who often feel "lost" as a result of their depression.

Severely depressed patients may respond better to medication than psychotherapy⁴⁶ and may respond better to the combination of medication and psychotherapy.^46,47 Consultation with a psychiatrist or other behavioral health specialist is recommended for severely depressed patients seen in the primary care setting.

Types of Antidepressant Medication
All antidepressant classes appear to be equally effective in depressed patients regardless of their age⁴⁸ and regardless of whether they are affected by any of the following conditions: diabetes;^49,50 cancer;^51,52 recurrent, chronic, or refractory depression;^53-59 or mixed anxiety and depression.^59-65 The CMI Depression Guideline group did not find high-quality studies comparing the effectiveness of different antidepressants in patients of different ethnic groups.

In the first six to 12 weeks of therapy, selective serotonin reuptake inhibitors (SSRIs) are somewhat better tolerated than tricyclic agents (TCAs) (number needed to treat, 20-33).^66,67 Risk of death by overdose is greater with TCAs than with SSRIs, although rate of suicide from all causes does not differ on the basis of type of antidepressant.^59,68,69 However, given the lethality of TCAs when overdosed, the CMI guideline workgroup strongly recommends that TCAs be avoided by patients who are suicidal. Antidepressant agents have different side effect profiles that clinicians should consider when prescribing for patients with other comorbidities; patients may express a preference for a type of medication on the basis of discussing class-specific side effects with the clinician.

Patients successfully treated for depression with a particular antidepressant in the past should be offered that agent again. Partly on the basis of favorable pricing obtained from the manufacturer, fluoxetine is now Kaiser Permanente's preferred SSRI.

Hypericum (St John's wort) has been shown to be as effective as low-dose TCAs or SSRIs in treatment of mildly depressed adults and is better tolerated than TCAs.^59,70-75 However, the CMI depression guideline workgroup has several concerns regarding the trials studying St John's wort, including difficulty in blinding as well as lack of standardized preparations across trials. The US Food and Drug Administration (FDA) does not regulate St John's wort, and the amount of active ingredient may vary widely between and within brands. For these reasons, the CMI guideline workgroup recommends caution in prescribing St John's wort for treatment of depression. Clinicians should consider discussing these concerns with patients who wish to use St John's wort. This substance should not be used in combination with other antidepressant agents.

Treatment Phases and Follow-up

Acute Phase
The acute phase of treatment for MDD is defined as the period extending from the start of treatment that achieves symptom remission for a period of three months. No scientific evidence suggests an optimal frequency of follow-up during the acute phase, but Health Plan Employer Data Information Set (HEDIS) criteria require three follow-up contacts (including one face-to-face contact with a prescribing provider) in the first 12 weeks of treatment.⁷⁶ The risk of patients discontinuing treatment is highest in the first months of treatment;⁶⁷ therefore, follow-up is needed to assess patient adherence to therapy, symptom remission, and, if medication is chosen, presence of worrisome or unacceptable side effects.

Several options are available for patients who do not achieve symptom remission within 6 to 12 weeks. The diagnosis should be reevaluated, and possible presence of other untreated comorbid conditions should be considered. Adherence to treatment regimen should be assessed and reinforced. Dosage of medication may be increased or the medication can be changed. Psychotherapy and medication can be combined, or a second, low-dose antidepressant from a different class can be added. At this point, referral to a behavioral health specialist is also an available option for patients who do not respond to prescribed medication.

Continuation Phase
After the acute phase has ended, patients should continue treatment for an additional 4 to 12 months. Terminating treatment sooner is associated with early recurrence of symptoms.⁷⁷ No available data exist to suggest an optimal frequency of patient follow-up during the continuation phase. The CMI guideline panel consensus opinion recommends at least one follow-up during the fifth or sixth month of treatment to assure continued remission of symptoms and patient adherence to treatment as well as to determine necessity of adjusting treatment. More frequent follow-up can be scheduled on the basis of clinical judgment and patient preference.

Discontinuation
After successfully completing treatment in the acute and continuation phases, patients for whom the treated episode was the first should be offered a trial of medication discontinuation.¹² Fluoxetine regimens of less than 20 mg daily can be stopped; higher fluoxetine doses and other medications should be tapered over a two- to four-week period.^78,79 Because a single episode of MDD is associated with a 50% lifetime risk of recurrence,² patients with MDD should be educated about this risk and instructed to call their clinician at the first signs or symptoms of recurrent MDD. Data suggest that risk of recurrence is highest during the first year after medication is discontinued.¹² The CMI guideline panel suggests that patients be reassessed three months after discontinuing medication and again at 12 months.

Maintenance
Patients who have had three or more episodes of MDD have a 90% lifetime risk of recurrence after medication discontinuation.² Studies^12,80 suggest that continuing medication for at least five years is beneficial for these patients because it decreases risk of relapse. No available data exist to suggest an optimal frequency of patient follow-up during maintenance treatment. The CMI guideline recommends at least one annual contact with the patient to detect symptom relapse and to determine need for treatment adjustment.

No evidence is available to indicate the best therapeutic approach (maintenance vs discontinuation) for patients who have had two episodes of MDD. Expert opinion⁸¹ suggests that if these patients have a history of suicide attempt, substance abuse, or psychiatric comorbidity, they should continue maintenance therapy. For patients experiencing their second episode of MDD without these types of comorbidity, a shared decision-making approach should be used for selecting maintenance or discontinuation of treatment. For these patients, the lifetime risk of MDD recurrence is approximately 70%;² therefore, these patients should receive both follow-up and patient education on symptom relapse.

Patient Education

Despite a trend toward increasing acceptance, many patients still feel stigmatized by the diagnosis of MDD. Therefore, clinicians should explain to these patients that MDD is a real illness and is not "all in their head." Comparison with diabetes may be helpful (Table 3). Patients choosing medication should be informed about side effects and given instructions designed to enhance compliance with prescribed medication regimens (Table 4).⁸² Patients should also be educated about the signs and symptoms of relapsing or worsening depression.

Specialty Referral

The CMI Depression Guideline workgroup recommends referral or consultation with a behavioral health specialist for the situations listed in Table 5.³

Case ExampleDiagnostic and Treatment Approach

In addition to sleep disturbance, decreased energy, and difficulty concentrating, the patient in the above example admitted being sad and tearful as well as feeling guilty and worrying about her parenting skills, and she had lost interest in socializing. She also admitted to worrying about work performance and being somewhat irritable with her husband. She was not suicidal and had no prior history of depression or other psychiatric illness, but she thought her mother may have been depressed. Other medical comorbidity was excluded, and she was diagnosed with MDD, first episode, with secondary anxiety (not meeting criteria for generalized anxiety disorder). After participating in a shared decision-making approach, she selected pharmacotherapy with a SSRI and started fluoxetine, 10 mg daily, the next morning. At two-week follow-up, her depressed mood and energy were "50% better," but she was still having trouble concentrating and sleeping and was still irritable. The dose of fluoxetine was increased to 20 mg in the morning, and 50 mg of trazodone was added at bedtime. At six-week follow-up, she was sleeping better, and her depressed mood and guilt about parenting were "almost gone." Her energy was "returning to normal," but she still worried about her work performance and reported having continued irritability with her husband. She elected not to change her medication regimen or to add psychotherapy and, at 12-week follow-up, reported total symptom resolution.

She remained on medication, without further symptoms, for one year (three months of acute-phase treatment plus nine months of continuation-phase treatment). She was then offeredand electeda trial of medication discontinuation. Follow-up calls at three weeks and at three months revealed continued absence of symptoms. During a health maintenance visit one year after medication discontinuation, she reported slight decrease in appetite as well as increase in worry and irritability, which she attributed to job stress. Repeat screening was not diagnostic for recurrent MDD or anxiety. The patient was reeducated on the symptoms of MDD and elected to monitor symptoms without resuming medication. At follow-up three months, six months, and 12 months later, the symptoms had resolved, and the patient remained in remission.

Conclusion

CMI recently completed an extensive, evidence-based revision of the adult depression guideline,³ which also discusses different cultural backgrounds, the elderly, and (briefly) depression among adolescents. The guideline group views the depression guideline as a work in progress: Future revisions will update current evidence and explore evidence in areas not covered in the current guideline. The full document will be available on the Permanente Knowledge Connection Web site: http://pkc.kp.org/national/cmi/programs/depression/DP_Guidelines.html.

Acknowledgments

Thank you to Trina Histon, PhD, at CMI, for her help in compiling the reference list and for her expert facilitation of the Depression Guideline process in her role as project manager.

Thank you to Erin Stone, MD, for his methodologic expertise during the Depression Guideline Process.

Thank you to the members of the guideline work group for their hard work during the guideline development process. A complete list of guideline work group members can be found in the Depression Guideline, available online at http://pkc.kp.org.

References

1. Valenstein M, Vijan S, Zeber JE, et al. The cost-utility of screening for depression in primary care. Ann Intern Med 2001 Mar 6;134(5):345-60.
2. Trivedi MH, Kleiber BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry 2001;62 Suppl 6:22-9.
3. Kaiser Permanente Medical Care Program. Care Management Institute. Clinical practice guidelines for the management of depression in primary care. [Oakland (CA): Kaiser Permanente Medical Care Program, Care Management Institute; 2002. In press]. Will be available on the World Wide Web: http://pkc.kp.org/national/cmi/programs/depression/DP_Guidelines.html.
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed, text revision. Washington (DC): American Psychiatric Association; 2000. p 349-56.
5. Minagawa H, Uchitomi Y, Yamawaki S, et al. Psychiatric morbidity of terminally ill cancer patients. A prospective study. Cancer 1996 Sep 1;78(5):1131-7.
6. Fishbain DA, Goldberg M, Meagher BR, et al. Male and female chronic pain patients categorized by DSM-III psychiatric diagnostic criteria. Pain 1986 Aug;26(2):181-97.
7. Havranek EP, Ware MG, Lowes BD. Prevalence of depression in congestive heart failure. Am J Cardiol 1999 Aug 1;84(3):348-50.
8. Anderson RJ, Freedland KE, Clouse RE, et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001 Jun;24(6):1069-78.
9. Kotila M, Numminen H, Waltimo O, et al. Depression after stroke: results
   of the FINNSTROKE Study. Stroke 1998 Feb;29(2):368-72.
10. Lehto S, Koukkunen H, Hintikka J, et al. Depression after coronary heart disease events. Scand Cardiovasc J 2000 Dec;34(6):580-3.
11. Lyness JM, King DA, Cox C, et al. The importance of subsyndromal depression in older primary care patients: prevalence and associated functional disability. J Am Geriatr Soc 1999 Jun;47(6):647-52.
12. Viguera AC, Baldessarini RJ, Friedberg J. Discontinuing antidepressant treatment in major depression. Harv Rev Psychiatry 1998 Mar-Apr;5(6):293-306.
13. Schoenbaum M, Unutzer J, Sherbourne C, et al. Cost-effectiveness of practice-initiated quality improvement for depression: results of a randomized controlled trial. JAMA 2001 Sep 19;286(11):1325-30.
14. Whooley MA, Avins AL, Miranda J, et al. Case-finding instrument for depression. Two questions are as good as many. J Gen Intern Med 1997 Jul;12(7):439-45.
15. Beck Depression Inventory [Web site]. Available on the World Wide Web (accessed November 13, 2001): www.criminology.unimelb.edu.au/victims/resources/assessment/affect/bdi.html.
16. Irwin M, Artin KH, Oxman MN. Screening for depression in the older adult: criterion validity of the ten-item Center for Epidemiological Studies Depression Scale (CES-D). Arch Intern Med 1999 Aug 9-23;159(15):1701-4.
17. NetOutcomes [Web site of the University of Arkansas for Medical Sciences Center for Outcomes Research and Effectiveness]. Depression Outcomes Module. Available on the World Wide Web (accessed November 13, 2001): www.netoutcomes.net/body.asp?module=DOM&menu=content s.
18. University of Oxford. Department of Clinical Geratology. The Geriatric Depression Scale [Web site]. Available on the World Wide Web (accessed November 13, 2001): www.jr2.ox.ac.uk/geratol/GDSdoc.htm.
19. Lambert MJ, Burlingame GM, Umphress V, et al. The reliability and validity of the Outcome Questionnaire. Clin Psychol Psychother 1996 Dec;3(4):249-58.
20. Spitzer RL, Williams JB, Kroenke K, et al. Utility of a new procedure for
    diagnosing mental disorders in primary care. The PRIME-MD 1000 study. JAMA 1994 Dec 14;272(22):1749-56.
21. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001 Sep;16(9):606-13.
22. Shedler J, Beck A, Bensen S. Practical mental health assessment in primary care. Validity and utility of the Quick PsychoDiagnostics Panel. J Fam Pract 2000 Jul;49(7):614-21.
23. Zung WW. A self-rating depression scale. Arch Gen Psychiatry 1965 Jan;12(1):63-70.
24. Mulrow CD, Williams JW Jr, Gerety MB, et al. Case-finding instruments for depression in primary care settings. Ann Intern Med 1995 Jun;122(12):913-21.
25. Schein RL, Koenig HG. The Center for Epidemiological StudiesDepression (CES-D) Scale: assessment of depression in the medically ill elderly. Int J Geriatr Psychiatry 1997 Apr;12(4):436-46.
26. Agrell B, Dehlin O. Comparison of six depression rating scales in geriatric stroke patients. Stroke 1989 Sep;20(9):1190-4.
27. Cho MJ, Kim KH. Use of the Center for Epidemiologic Studies Depression (CES-D) Scale in Korea. J Nerv Ment Dis 1998 May;186(5):304-10.
28. Beekman AT, Deeg DJ, Van Limbeek J, et al. Criterion validity of the Center for Epidemiologic Studies Depression Scale (CES-D): results from a community-based sample of older adult subjects in the Netherlands. Psychol Med 1997 Jan;27(1):231-5.
29. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA 1999 Nov 10;282(18):1737-44.
30. Steer RA, Cavalieri TA, Leonard DM, et al. Use of the Beck Depression
    Inventory for Primary Care to screen for major depressive disorders. Gen Hosp Psychiatry 1999 Mar-Apr;21(2):106-11.
31. Lasa L, Ayuso-Mateos JL, Vazquez-Barquero JL, et al. The use of the Beck Depression Inventory to screen for depression in the general population: a preliminary analysis. J Affect Disord 2000 Jan-Mar;57(1-3):261-5.
32. Kramer TL, Smith GR. Tools to improve the detection and treatment of depression in primary care. In: Maruish ME, editor. Handbook of psychological assessment in primary care settings. Mahwah (NJ): Lawrence Erlbaum Associates; 2000. p.463-90.
33. Hirschfeld RM, Russell JM. Assessment and treatment of suicidal patients. N Engl J Med 1997 Sep 25;337(13):910-5.
34. Isacsson G, Bergman U, Rich CL. Antidepressants, depression and suicide: an analysis of the San Diego study. J Affect Disord 1994 Dec;32(4);277-86.
35. Cooper-Patrick L, Crum RM, Ford DE. Identifying suicidal ideation in general medical patients. JAMA 1994 Dec 14;272(22):1757-62.
36. Lin EH, Von Korff M, Wagner EH. Identifying suicide potential in primary care. J Gen Intern Med 1989 Jan-Feb;4(1):1-6.
37. United States. National Institute of Mental Health. Suicide facts. Available on the World Wide Web (accessed December 5, 2001): www.nimh.nih.gov/research/suifact.htm.
38. Mynors-Wallis LM, Gath DH, Day A, et al. Randomized controlled trial of problem solving treatment, antidepressant medication, and combined treatment for major depression in primary care. BMJ 2000 Jan 1;320(7226):26-30.
39. Williams JW Jr, Barrett J, Oxman T, et al. Treatment of dysthymia and minor depression in primary care: A randomized controlled trial in older adults. JAMA 2000 Sep 27;284(12):1519-26.
40. Schulberg HC, Block MR, Madonia MJ, et al. Treating major depression in primary care practice. Eight-month clinical outcomes. Arch Gen Psychiatry 1996 Oct;53(10):913-9.
41. Chilvers C, Dewey M, Fielding K, et al. Antidepressant drugs and generic counselling for treatment of major depression in primary care: randomized trial with patient preference arms. BMJ 2001 Mar 31;322(7289):772-5.
42. Dwight-Johnson M, Sherbourne CD, Liao D, et al. Treatment preferences among depressed primary care patients. J Gen Intern Med 2000 Aug;15(8):527-34.
43. Morgan MW, Deber RB, Llewellyn-Thomas HA, et al. Randomized, controlled trial of an interactive videodisc decision aid for patients with ischemic heart disease. J Gen Intern Med 2000 Oct;15(10):685-93.
44. Murray E, Davis H, Tai SS, et al. Randomized controlled trial of an interactive multimedia decision aid on benign prostatic hypertrophy in primary care. BMJ 2001 Sep 1;323(7311):493-6.
45. Murray E, Davis H, Tai SS, et al. Randomized controlled trial of an interactive multimedia decision aid on hormone replacement therapy in primary care. BMJ 2001 Sep 1;323(7311):490-3.
46. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression [published erratum appears in N Engl J Med 2001 Jul 19;345(3):232]. N Engl J Med 2000 May 18;342(20):1462-70.
47. Thase ME, Greenhouse JB, Frank E, et al. Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry 1997 Nov;54(11):1009-15.
48. Wilson K, Mottram P, Sivanranthan A, et al. Antidepressant versus placebo for depressed elderly (Cochrane Review). Cochrane Database Syst Rev 2001;2:CD000561.
49. Lustman PJ, Freedland KE, Griffith LS, et al. Fluoxetine for depression in diabetes: a randomized double-blind placebo-controlled trial. Diabetes Care 2000 May;23(5):618-23.
50. Lustman PJ, Griffith LS, Clouse RE, et al. Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial. Psychosom Med 1997 May-Jun;59(3):241-50.
51. Holland JC, Romano SJ, Heiligenstein JH, et al. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology 1998 Jul-Aug;7(4):291-300.
52. Razavi D, Allilaire JF, Smith M, et al. The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand 1996 Sep;94(3):205-10.
53. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomized comparison [published erratum appears in Br J Psychiatry 1999 Oct;175:394]. Br J Psychiatry 1999 Jul;175:12-6.
54. Landen M, Bjorling G, Agren H, et al. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry 1998 Dec;59(12):664-8.
55. Smeraldi E. Amisulpride versus fluoxetine in patients with dysthymia or major depression in partial remission: a double-blind, comparative study. J Affect Disord 1998 Feb;48(1):47-56.
56. Keller MB, Harrison W, Fawcett JA, et al. Treatment of chronic depression with sertraline or imipramine: preliminary blinded response rates and high rates of undertreatment in the community. Psychopharmacol Bull 1995;31(2):205-12.
57. Keller MB, Kocsis JH, Thase ME, et al. Maintenance phase efficacy of sertraline for chronic depression: a randomized controlled trial. JAMA 1998 Nov 18;280(19):1665-72.
58. Stewart JW, McGrath PJ, Quitkin FM, et al. Chronic depression: response to placebo, imipramine, and phenelzine. J Clin Psychopharmacol 1993 Dec;13(6):391-6.
59. San Antonio Evidence-based Practice Center, The Veterans Evidence-based Research, Dissemination, and Implementation Center. Treatment of depression: newer pharmacotherapies. Rockville (MD): Agency for Health Care Policy and Research; 1999. Evidence Report/Technical Assessment No. 7; AHCPR Publication No. 99-E014. Available on the World Wide Web (accessed December 5, 2001): http://hstat.nlm.nih.gov/ftrs/pick?collect=epc&dbName=dep&cd=1&t=1007592968
60. Silverstone PH, Ravindran A. Once-daily venlafaxine extended release (XR) compared with fluoxetine in outpatients with depression and anxiety. Venlafaxine XR 360 Study Group. J Clin Psychiatry 1999 Jan;60(1):22-8.
61. Fava M, Rosenbaum JF, Hoog SL, et al. Fluoxetine versus sertraline and paroxetine in major depression: tolerability and efficacy in anxious depression. J Affect Disord 2000 Aug;59(2):119-26.
62. Marchesi C, Ceccherininelli A, Rossi A, et al. Is anxious-agitated major depression responsive to fluoxetine? A double-blind comparison with amitriptyline. Pharmacopsychiatry 1998 Nov;31(6):216-21.
63. Feighner JP, Entsuah AR, McPherson MK. Efficacy of once-daily venlafaxine extended release (XR) for symptoms of anxiety in depressed patients. J Affect Disord 1998 Jan;47(1-3):55-62.
64. Khan A, Upton GV, Rudolph RL, et al. The use of venlafaxine in the treatment of major depression and major depression associated with anxiety: a dose-response study. Venlafaxine Investigator Study Group. J Clin Psychopharmacol 1998 Feb;18(1):19-25.
65. Versiani M, Ontiveros A, Mazzotti G, et al. Fluoxetine versus amitriptyline in the treatment of major depression with associated anxiety (anxious depression): a double-blind comparison. Int Clin Psychopharmacol 1999 Nov;14(6):321-7.
66. Geddes JR, Freemantle N, Mason J, et al. SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst Rev 2000;(2):CD001851.
67. Barbui C, Hotopf M, Freemantle N, et al. Selective serotonin reuptake inhibitors versus tricyclic and hetrocyclic antidepressants: comparison of drug adherence. Cochrane Database Syst Rev 2000;(4):CD002791.
68. Henry JA, Alexander CA, Sener EK. Relative mortality from overdose of antidepressants [published erratum appears in BMJ 1995 Apr 8;310(6984):911]. BMJ 1995 Jan 28;310(6974):221-4.
69. Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995 Jan 28;310(6974):215-8.
70. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John's wort in major depression: a randomized controlled trial. JAMA 2001 Apr 18;285(15):1978-86.
71. Harrer G, Schmidt U, Kuhn U, et al. Comparison of equivalence between the St John's wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung 1999 Apr;49(4):289-96.
72. Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomized multicentre study of treatment for eight weeks. BMJ 1999 Dec 11;319(7224):1534-8.
73. Brenner R, Azbel V, Madhusoodanan S, et al. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther 2000 Apr;22(4):411-9.
74. Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000 Mar;15(2):61-8.
75. Woelk H. Comparison of St John's wort and imipramine for treating depression: randomised controlled trial. BMJ 2000 Sep 2;321(7260):536-9.
76. National Committee for Quality Assurance. HEDIS 2002. Volume 2. Technical specifications. Washington (DC): National Committee for Quality Assurance; 2001. p 103.
77. Geddes J, Butler B. Depressive disorders. Clinical evidence 2001 Jun;(5):652-67.
78. Zajecka J, Fawcett J, Amsterdam J, et al. Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study. J Clin Psychopharmacol 1998 Jun;18(3):193-7.
79. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998 Jul 15;44(2):77-87.
80. Kupfer DJ, Frank E, Perel JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1992 Oct;49(10):769-73.
81. Depression Guideline Panel. Depression in Primary Care. Vol 2. Treatment of major depression. Clinical Practice Guideline No. 5. Rockville (MD): US Department of Health and Human Services, Public Health Service, and Agency for Health Care Policy and Research; 1993.
82. 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 Jan;33(1):67-74.

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