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Depression
Screening Diagnosis Treatment Practice Improvement CME Questions
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Section Editor Barbara Turner, MD, MSED Sankey Williams, MD Darren Taichman, MD, PhD Physician Writer Tonya L. Fancher, MD Richard L. Kravitz, MD

The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians Information and Education Resource) and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACPs Medical Education and Publishing Division and with the assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://pier.acponline.org, http://www.acponline.org/products_services/ mksap/15/?pr31, and other resources referenced in each issue of In the Clinic. CME Objective: To review current evidence for the screening, diagnosis, and treatment of depression The information contained herein should never be used as a substitute for clinical judgment. 2010 American College of Physicians

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Screening

epression affects 5% to 10% of primary care patients (1) on average; however, this varies widely among clinical populations (2, 3). Only about half of depressed patients receive treatment (4). Untreated depression may prevent effective treatment of common co-occurring illnesses, such as diabetes (5). Depression causes disability similar to that of other chronic medical conditions (6, 7). Effective treatment reduces symptoms and improves quality of life (8). Asking about depression is sometimes viewed as opening Pandoras box, but primary care clinicians can efficiently identify and manage most cases.

1. Pignone MP, Gaynes BN, Rushton JL, et al. Screening for depression in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:765-76. [PMID:12020146] 2. Lustman PJ, Anderson RJ, Freedland KE, et al. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care. 2000;23:934-42. [PMID: 10895843] 3. Miranda J, Chung JY, Green BL, et al. Treating depression in predominantly lowincome young minority women: a randomized controlled trial. JAMA. 2003;290:57-65. [PMID: 12837712] 4. Gonzlez HM, Vega WA, Williams DR, et al. Depression care in the United States: too little for too few. Arch Gen Psychiatry. 2010;67:37-46. [PMID:20048221] 5. Katon WJ, Schoenbaum M, Fan MY, et al. Cost-effectiveness of improving primary care treatment of late-life depression. Arch Gen Psychiatry. 2005;62:1313-20. [PMID:16330719] 6. Hays RD, Wells KB, Sherbourne CD, et al. Functioning and well-being outcomes of patients with depression compared with chronic general medical illnesses. Arch Gen Psychiatry. 1995;52:11-9. [PMID:7811158] 7. Remick RA. Diagnosis and management of depression in primary care: a clinical update and review. CMAJ. 2002;167:1253-60. [PMID:12451082]

Which patients are at especially high risk for depression? Risk factors for depression include older age (9) and associated neurologic conditions, female sex, alcohol dependence, comorbid medical and psychiatric conditions (10, 11), personal or family history of depression, recent childbirth (12), and stressful life events (13) (Box). Although specific biological factors predisposing to depression may emerge, no clinically useful biological markers of depression have been identified.
A meta-analysis of the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events yielded no association with risk for depression (14).

Clinicians should consider screening patients with identified risk factors or who present with unexplained somatic symptoms, comorbid psychological conditions (for example, panic disorder), substance abuse, chronic pain, or nonreponse to effective treatments for medical conditions (16).
A meta-analysis of screening studies suggested that screening is associated with a 9% absolute reduction in the proportion of patients with persistent depression at 6 months. Assuming a prevalence of 10%, 110 primary care patients would need to be screened for depression to produce 1 additional remission (1).

Should clinicians screen for depression? Depression screening instruments do not diagnose depression but can accurately identify patients at risk. A 2009 U.S. Preventive Services Task Force guideline recommends screening adults for depression when staff-assisted depression care supports are in place to assure accurate diagnosis, effective treatment, and follow-up (15). Such supports include outreach personnel and depression educators. Follow-up by the clinician after diagnosis and beginning of treatment is critical.
Risk Factors for Depression
Age Alcohol dependence Comorbid conditions Female sex Personal or family history of depression Recent childbirth Recent stressful events

However, the absolute reduction, and therefore the utility of screening for depression, is highly dependent on the prevalence of the illness in the population being assessed. The optimum interval for rescreening is unknown. What methods should clinicians use to screen for depression? A positive response to a 2-item instrument (Box) had a sensitivity of 96% and a specificity of 57%, similar to longer instruments (17).
A meta-analysis of 9 case-finding instruments in 18 studies and a head-to-head study of screening instruments showed that the 2-question instrument performed as well as many of the longer ones (18).

Screening Questions for Depression

Over the past 2 weeks have you felt down, depressed, hopeless? Over the past 2 weeks have you felt little interest or pleasure in doing things?

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Patients with a positive response to 1 or both questions should have a more complete assessment to determine whether they meet the criteria for depression disorders according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (19). Other screening tools, such as the Beck Depression Inventory Scales II, the Center for Epidemiologic Studies Depression Scale-Revised, and the Zung Self-Rating Depression Scale are also used. The Edinburgh Postnatal Depression Scale was developed to assess postpartum depression (18, 20, 21). In elderly persons, the Geriatric Depression Rating Scale (22)

can be used, but clinicians should also assess with the Mini-Mental State Examination, because cognitive impairment requires a specific instrument (such as the interviewer -administered Cornell Scale for Depression in Dementia [23]). The Hopkins Symptom Checklist25 has been validated in refugee populations and is available in many languages. These instruments are designed to assess the severity of depressed mood, not the diagnostic criteria for Major Depressive Disorder as defined in DSM-IV Text Revision. The Patient Health Questionnaire (PHQ-9) is both a diagnostic and severity rating instrument (24).

Screening... Clinicians should screen for depression as the first step in a systematic evaluation of mood disorders in all adults. Adults who are older, are postpartum, have personal or family history of depression, or have comorbid medical illness are at increased risk. Little evidence recommends one screening method over another, so physicians can choose the method that best suits their patient population and practice setting. The 2-question instrument is more efficient and performs as well as longer instruments.

CLINICAL BOTTOM LINE

Diagnosis
What are the diagnostic criteria for depression? Depression is diagnosed when 5 or more DSM-IV symptoms occur in the same 2 weeks with a change from previous functioning (Table 1) (19). One symptom must be either depressed mood or anhedonia. The core symptoms of DSM-IV major depression describe a specific depression syndrome and do not necessarily represent a severity index. Only a clinical interview or use of 1 of the previously described instruments can assess severity. How can clinicians determine the severity of depression? Assessment of depressive symptom severity helps guide treatment. Mild depression may not require medication (25). Mild-to-moderate depression responds equally well to medication or psychotherapy (26). Patients with severe major depressive disorder benefit more from medication alone or combined with psychotherapy than from psychotherapy alone. The PHQ-9 is easily scored to quantify the severity of depression (Table 2) (24). Like suicidality, severe functional impairment, such as inability to bathe or eat, may suggest the need for psychiatric consultation or hospitalization (27). How can clinicians and patients distinguish between normal reactions to life events and depression? Subsyndromal depression is characterized by 2 to 4 DSM-IV

8. Heiligenstein JH, Ware JE Jr, Beusterien KM, et al. Acute effects of fluoxetine versus placebo on functional health and well-being in late-life depression. Int Psychogeriatr. 1995;7 Suppl:125-37. [PMID:8580388] 9. McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinsons disease. Biol Psychiatry. 2003;54:363-75. [PMID:12893111] 10. Kendler KS, Gardner CO, Prescott CA. Clinical characteristics of major depression that predict risk of depression in relatives. Arch Gen Psychiatry. 1999;56:3227. [PMID:10197826] 11. Runeson B, Asberg M. Family history of suicide among suicide victims. Am J Psychiatry. 2003;160:1525-6. [PMID:12900320] 12. Beck CT. Predictors of postpartum depression: an update. Nurs Res. 2001;50:275-85. [PMID:11570712] 13. Person C, Tracy M, Galea S. Risk factors for depression after a disaster. J Nerv Ment Dis. 2006;194:659-66. [PMID:16971817] 14. Risch N, Herrell R, Lehner T, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a metaanalysis. JAMA. 2009;301:2462-71. [PMID:19531786] 15. OConnor EA, Whitlock EP, Beil TL, et al. Screening for depression in adult patients in primary care settings: a systematic evidence review. Ann Intern Med. 2009;151:793803. [PMID:19949145] 16. Terre L, Poston WS, Foreyt J, et al. Do somatic complaints predict subsequent symptoms of depression? Psychother Psychosom. 2003;72:261-7. [PMID:12920330] 17. Whooley MA, Avins AL, Miranda J, et al. Case-finding instruments for depression. Two questions are as good as many. J Gen Intern Med. 1997;12: 439-45. [PMID: 9229283]

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Table 1. Criteria for Major Depressive Episode, Based on the Diagnostic and Statistical Manual of Mental Disorders*
Five or more of the following symptoms (one of which is depressed mood or loss of interest or pleasure) have occurred together for a 2-wk period and represent a change from previous functioning: Depressed mood most of the day, nearly every day as self-reported or observed by others Diminished interest or pleasure in all or almost all activities most of the day, nearly every day Significant weight loss when not dieting, or weight gain; or decrease or increase in appetite nearly every day Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day Fatigue or loss of energy nearly every day Feelings of worthlessness or excessive or inappropriate guilt nearly every day Diminished ability to think or concentrate nearly every day Recurrent thoughts of death, recurrent suicidal ideation without a specific plan. The symptoms do not meet criteria for a mixed episode. The symptoms cause clinically significant distress or impairment in social, occupational, or other areas of functioning. The symptoms are not due to the direct physiologic effects of a substance (drug or medication) or a general medical condition (hypothyroidism). The symptoms are not better accounted for by bereavement, or the symptoms persist for more than 2 mo or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
* From American Psychiatric Association. Guidelines for the Treatment of Patients with Major Depressive Disorder. Washington, DC: American Psychiatric Publishing; 1994.

18. Mulrow CD, Williams JW Jr, Gerety MB, et al. Case-finding instruments for depression in primary care settings. Ann Intern Med. 1995;122:913-21. [PMID:7755226] 19. Diagnosis and Statisitical Manual of Mental Disorders 4th Edition. Washington, DC: American Pyschiatric Association; 1994. 20. Beck AT, Steer RA, Brown GK. BDI-II, Beck Depression Inventory: Manual. 2nd ed. Boston: Harcourt-Brace; 1996. 21. Georgiopoulos AM, Bryan TL, Yawn BP, et al. Population-based screening for postpartum depression. Obstet Gynecol. 1999;93:653-7. [PMID:10912961] 22. Yesavage JA. Geriatric Depression Scale. Psychopharmacol Bull. 1988;24:709-11. [PMID: 3249773] 23. Alexopoulos GS, Abrams RC, Young RC, et al. Cornell Scale for Depression in Dementia. Biol Psychiatry. 1988;23:271-84. [PMID:3337862] 24. Lwe B, Untzer J, Callahan CM, et al. Monitoring depression treatment outcomes with the patient health questionnaire-9. Med Care. 2004;42:1194-201. [PMID:15550799] 25. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patientlevel meta-analysis. JAMA. 2010;303:4753. [PMID:20051569] 26. Thase ME, Greenhouse JB, Frank E, et al. Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry. 1997;54:1009-15. [PMID:9366657] 27. Depression in primary care: detection, diagnosis, and treatment. Agency for Healthcare Policy and Research. Clin Pract Guidel Quick Ref Guide Clin. 1993;5:1-20.

Table 2. Patient Health Questionnaire-9*

Over the last 2 wk, how often have you been bothered by any of the following problems? (0 = not at all; 1 = several days; 2 = more than one half the days; 3 = nearly every day) 1. Little interest or pleasure in doing things 2. Feeling down, depressed, or hopeless 3. Trouble falling or staying asleep or sleeping too much 4. Feeling tired or having little energy 5. Poor appetite or overeating 6. Feeling bad about yourself or that you are a failure or have let yourself or your family down 7. Trouble concentrating on things, such as reading the newspaper or watching television 8. Moving or speaking so slowly that other people have noticed or the opposite (i.e., being so fidgety or restless that you have been moving around a lot more than usual) 9. Thoughts that you would be better off dead or hurting yourself in some way 10. If you have checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?
* The 9 items reflect the 9 DSM-IV criteria. Item 10 assesses functional impairment. Like symptom severity, severe functional impairment may suggest the need for hospitalization and psychiatric consultation. 1999 Pfizer Inc. All rights reserved. Reproduced with permission.` Items 1 through 9 are summed to yield a scale score ranging from 0 to 27. On this scale, 0 to 4 is considered nondepressed, 5 to 9 is considered minor depression, 10 to 14 is considered mild depression, 15 to 19 is considered moderately severe depression, and 20 to 27 is considered severe depression.

depressive symptoms, including depressed mood or anhedonia, for more than 2 weeks (Table 1). Situational adjustment reaction with depressed mood (adjustment disorder) is subsyndromal depression with a clear precipitant. Adjustment disorder must abate within 6 months of the resolution of the stressor, and careful observation and supportive

counseling are indicated. If the patient meets criteria for major depression, having a stressor does not alter the diagnosis; however, the clinician may chose careful watchful waiting if the major depressive syndrome occurred only after a defined event. Differentiating normal grieving and pathologic grief from depression can

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be difficult. Major depression may be transiently present in normal grief; however, sadness without the complete syndrome is more common. In some cultures, transient and limited hallucinations (hearing or seeing the deceased person) or passive suicidal thoughts (feeling that one would be better off dead or should have died with the deceased person) may be part of normal grief. The boundaries of normal grief are shaped by sociocultural factors. Symptoms of clinical depression beyond normal grief include inappropriate guilt, persistent thoughts of death, morbid preoccupation with worthlessness, marked psychomotor retardation, prolonged functional impairment, and hallucinations or delusions. Symptoms persisting beyond 2 months should raise concern about major depression. How should clinicians assess a depressed patients risk for selfharm, including suicide? Each year, more than 30 000 U.S. citizens die by suicide. Mental health conditions and addictive disorders, such as alcohol use disorders, are the most powerful risk factors for suicide in all age groups, present in more than 90% of all suicides (28). In a patient with major depression, previous suicide attempts are the best predictor of completed suicide (29). Most patients who die by suicide have seen a physician in the preceding months. Clinicians should assess for suicidal intent at each visit for depression. Asking about and reducing access to lethal means (especially firearms) can reduce this risk (30). Close telephone follow-up by an experienced psychiatrist can reduce the risk for suicide after a previous attempt (31). Accurate assessment of suicidal risk and the need for hospitalization is critical. A psychiatrist should be consulted for any uncertainty regarding suicidal risk. Previously, physicians used the No Harm Contract (32), which is a verbal or written agreement in which suicidal patients agree not to harm or

kill themselves for a particular timeframe and to seek immediate care if suicide is seriously considered or planned.
A recent meta-analysis showed that there is no evidence for the utility of these safety contracts and that they afford the physician little, if any, medicolegal protection (33).

In the absence of exacerbating factors, when the patient has adequate social support and is able to give reasons for living, proceed with outpatient treatment and close follow-up. For poor social support, no clear indication of alliance for safety, or alcohol or drug disorders, choose emergency referral for hospitalization and psychiatric assessment. When should clinicians consult a mental health professional for help diagnosing depression or a related mood disorder? Although many mood disorders can be successfully managed by the primary care clinician, psychiatric consultation should be considered for diagnostic uncertainty, psychiatric comorbid conditions, significant suicidal ideation, or inadequate response to treatment. Psychiatric evaluation is warranted if the clinician finds psychotic symptoms (delusions, hallucinations, disorganized speech, or episodes of catatonia) or substance abuse. Patients with psychotic symptoms or comorbid substance abuse are at greater risk for suicide and warrant psychiatric evaluation (34). Also, screen patients for history of manic episodes (days to weeks marked by unusually high energy, euphoria, hyperactivity, or impaired judgment). The Mood Disorders Questionnaire (MDQ) is a useful tool to identify a history of bipolar illness (35). Patients with a depressed mood and an undiagnosed bipolar affective disorder may convert to frank mania if prescribed an antidepressant without a concurrent mood-stabilizing medication. Consult a psychiatrist for manic or

28. Moscicki EK. Identification of suicide risk factors using epidemiologic studies. Psychiatr Clin North Am. 1997;20:499517. [PMID:9323310] 29. Brody DS, Thompson TL 2nd, Larson DB, et al. Recognizing and managing depression in primary care. Gen Hosp Psychiatry. 1995;17:93-107. [PMID:7789790] 30. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA. 2005;294:2064-74. [PMID:16249421] 31. Vaiva G, Vaiva G, Ducrocq F, et al. Effect of telephone contact on further suicide attempts in patients discharged from an emergency department: randomised controlled study. BMJ. 2006;332:1241-5. [PMID:16735333] 32. Stanford EJ, Goetz RR, Bloom JD. The No Harm Contract in the emergency assessment of suicidal risk. J Clin Psychiatry. 1994;55:344-8. [PMID:8071303] 33. Garvey KA, Penn JV, Campbell AL, et al. Contracting for safety with patients: clinical practice and forensic implications. J Am Acad Psychiatry Law. 2009;37:36370. [PMID: 19767501] 34. Karch DL, Barker L, Strine TW. Race/ethnicity, substance abuse, and mental illness among suicide victims in 13 US states: 2004 data from the National Violent Death Reporting System. Inj Prev. 2006;12 Suppl 2:ii22ii27. [PMID: 17170166] 35. Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the community. J Clin Psychiatry. 2003;64:53-9. [PMID: 12590624]

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hypomanic symptoms after starting an antidepressant. Mania may also present as a mixed state of depression with significant psychomotor agitation or racing thoughts. Thus, agitation after starting antidepressant treatment is a source of concern. Delays in starting mood-stabilizing drug therapy for bipolar disorder, even when mild, increases the risk

for suicidal behavior, poor social adjustment, and more hospitalization (36). Adherence to antidepressants should be assessed, because it affects response. The physician might obtain data, as needed, for related conditions (for example, thyroid disorders, HIV testing, urine toxicology), but extensive testing without a clear indication is not recommended.

Diagnosis... The DSM-IV criteria are the standard for diagnosing major depression. The risk for suicide and comorbid mental and physical illness should be assessed in each patient. If clinicians are uncertain about the diagnosis, risk for suicide, or need for hospitalization, psychiatric consultation should be considered.

CLINICAL BOTTOM LINE

Treatment
How should clinicians decide whether to recommend psychotherapy, drug therapy, or both? A recent meta-analysis questions the benefits of antidepressant medication compared with placebo in patients with mild or moderate symptoms (25).
Fournier and colleagues examined individual patient-level data from 6 randomized, controlled trials and found that the magnitude of benefit from antidepressants increased with the severity of depression symptoms and may be minimal (or nonexistent) in patients with mild or moderate symptoms (25).

36. Goldberg JF, Ernst CL. Features associated with the delayed initiation of mood stabilizers at illness onset in bipolar disorder. J Clin Psychiatry. 2002;63:985-91. [PMID:12444811] 37. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy: a controlled trial. Arch Gen Psychiatry. 1999;56:829-35. [PMID: 12884889] 38. Fava GA, Rafanelli C, Grandi S, et al. Sixyear outcome for cognitive behavioral treatment of residual symptoms in major depression. Am J Psychiatry. 1998;155:1443-5. [PMID:9766780] 39. Kessler D, Lewis G, Kaur S, et al. Therapist-delivered Internet psychotherapy for depression in primary care: a randomised controlled trial. Lancet. 2009;374:628-34. [PMID:19700005] 40. Warmerdam L, van Straten A, Twisk J, et al. Internet-based treatment for adults with depressive symptoms: randomized controlled trial. J Med Internet Res. 2008;10:e44. [PMID:19033149]

Patients with mild-to-moderate major depression may benefit equally from psychotherapy or medication (26). Combined therapy shows no short-term benefit, although psychotherapy may protect better against relapse (37). Patient preference remains the primary factor in choosing initial therapy. Therapist availability and insurance policies can also be barriers to care. Severely depressed patients benefit more from antidepressant medication, alone or in combination with psychotherapy, than from psychotherapy alone (26).

What types of behavioral interventions and psychotherapy are most likely to be effective for depression? Three types of psychotherapeutic options have proven to be effective: cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and problem-solving therapy (PST). The aim of CBT is to modify thoughts and behaviors to yield positive emotions. It is also used to treat residual symptoms after drug therapy and may help prevent relapse in patients with a history of recurrent depression (38). IPT targets conflicts and role transitions contributing to the depressive episode. It is only useful when the patient has the capacity for psychological insight and is committed to longer-term therapy. In PST, patients learn to cope better with specific everyday problems. Sophisticated behavioral interventions and psychotherapy require specialized training, but primary care clinicians can often employ basic tenets of these therapies, such as asking a patient to keep a journal about situations in which they feel more depressed to review at monitoring visits. Therapists often combine all 3 techniques. Webbased CBT and PST lessons are effective and may provide another

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Table 3. Drug Treatment for Depression

Agent, Daily Dose* Benefits Side Effects and Notes

Second-generation antidepressants

As a class: Effective, well tolerated

Bupropion, 300450 mg (75225 mg)

Less weight gain than other second-generation agents, fewer sexual side effects. Approved for smoking cessation Few drug interactions

Citalopram, 2060 mg (1040 mg) Duloxetine, 3060 mg

May be effective in comorbid pain and depression Escitalopram, 520 mg (510 mg) Few drug interactions Fluoxetine, 2060 mg (540 mg) Longest clinical experience. Long half-life mitigates effects of missed doses. Withdrawal symptoms rare Mirtazapine, 1545 mg Faster onset of action than (7.530 mg) citalopram, fluoxetine, paroxetine or sertraline Paroxetine, 2050 mg (540 mg) Long clinical experience

As a class: Nausea, diarrhea, decreased appetite, nervousness, insomnia, somnolence, sweating, impaired sexual function; hyponatremia in the elderly. Contraindicated with MAOIs. Potential for drug interactions with drugs metabolized in liver. Delicate risk/benefit calculus in pregnancy. Lowers seizure threshold. Relatively contraindicated in patients with history of seizures, family history of seizures, or head trauma. Missed doses should not be taken with next dose. Use with caution with other drugs that may lower seizure threshold and in patients with impaired hepatic function or anorexia/bulimia. See class effects. Relatively selective 5-HT reuptake inhibitor, but clinical implications unclear. Agitation, urinary retention. Withdrawal symptoms may occur. See class effects. Similar to citalopram. See class effects. Among the first newer antidepressants on the market.

Sertraline, 50200 mg (25150 mg) Trazodone, 50400 mg

Long clinical experience Less effective in doses <300 mg

Increased appetite, somnolence. Both may be an advantage in hospitalized patients. Use caution with renal impairment. Avoid concomitant benzodiazepines and alcohol. More weight gain and sexual adverse events. Withdrawal syndrome not uncommon. Long-acting formulations may be less prone to withdrawal syndrome. Higher incidence of diarrhea. Generally well-tolerated. Somnolence, rare priapism in young men. Used in low doses (50100 mg) sleeping aid in patients taking more stimulating antidepressants. Higher incidence of nausea, vomiting, dry mouth, sexual side effects, hypertension. Occasional hypertensive urgencies. As a class: Dry mouth, dizziness, nausea, sedation, anticholinergic effects, orthostatic hypotension. Contraindicated with MAOIs. Do not use with prolonged QT interval. Use with caution in patients with cardiovascular disease or predisposition to urinary retention or narrow angle glaucoma. Follow ECGs and orthostatic blood pressure changes. Highly sedating and anticholinergic. See class effects. See class effects. Rarely used in United States. See class effects. Especially prone to serious interactions with MAOIs, which should be strictly avoided. See class effects. Dry mouth, sedation. May be slightly less potent than imipramine.

Venlafaxine, 75350 mg (50225 mg) First-generation antidepressants

Similar efficacy to other second-generation antidepressants As a class: Effective

Amitriptyline, 25300 mg Amoxapine, 50300 mg Clomipramine, 25250 mg Desipramine, 25300 mg Doxepin, 25300 mg

Imipramine, 25300 mg Protriptyline, 1560 mg Trimipramine, 50300 mg

May aid with sleep. Low doses effective for neuropathic pain May be effective in psychotic depression Possibly useful in comorbid anxiety, panic disorders See class effects Potent antihistaminic properties may have advantages in allergic syndromes See class effects See class effects See class effects

See class effects. See class effects. See class effects.

5-HT = 5-hydroxytryptophan (serotonin); ECG = electrocardiogram; MAOI = monoamine oxidase inhibitor. * Dose range for geriatric patients is in parentheses. Wright SK, Schroeter S. Hyponatremia as a complication of selective serotonin reuptake inhibitors. J Am Acad Nurse Pract. 2008;20:47-51. [PMID: 18184165] Kroenke K, Krebs EE, Bair MJ. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry. 2009;31:206-19. [PMID: 19410099]
Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:725-33. [PMID: 19017591]

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approach for patients to access psychotherapeutic interventions (39, 40).

41. Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using secondgeneration antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:725-33. [PMID:19017591] 42. Cipriani A, La Ferla T, Furukawa TA, et al. Sertraline versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2010:CD006117. [PMID: 20091586] 43. Williams JW Jr, Mulrow CD, Chiquette E, et al. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med. 2000;132:743-56. [PMID:10787370] 44. STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:124352. [PMID:16554526] 45. 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;33:67-74. [PMID:7823648] 46. Wells KB, Sherbourne C, Schoenbaum M, et al. Impact of disseminating quality improvement programs for depression in managed primary care: a randomized controlled trial. JAMA. 2000;283:212-20. [PMID:10634337] 47. Dubicka B, Hadley S, Roberts C. Suicidal behaviour in youths with depression treated with newgeneration antidepressants: metaanalysis. Br J Psychiatry. 2006;189:393-8. [PMID:17077427] 48. Stone M, Laughren T, Jones ML, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ. 2009;339:b2880. [PMID:19671933]

How should clinicians select from the many antidepressant drug therapies? Clinicians face a wide array of antidepressant drug options (Table 3). The most commonly prescribed drugs are the second-generation antidepressants: selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], and bupropion. First-generation antidepressants (tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors [MAOIs]) may offer similar effectiveness, but with more toxicity (41). Generally, TCAs are avoided because of considerable dry mouth, constipation, and dizziness. TCAs are relatively contraindicated in patients with coronary artery disease, congestive heart failure, and arrhythmias. They are also potentially fatal in overdose. MAOIs are also used infrequently, even by psychiatric specialists, because of the many dietary restrictions and the potential for hypertensive crisis (except for the newer selegeline patch). Primary care clinicians should consult with a psychiatrist before considering MAOI therapy. Drug selection is based on tolerability, safety, evidence of effectiveness in the patient or a first-degree relative, and cost.

A recent review of 59 mostly low-quality studies found a trend in favor of sertraline over other antidepressants in terms of efficacy and acceptability (42).

Regardless of the drug, most patients treated with antidepressants experience improvement by 6 weeks (43). However, relatively few achieve baseline levels of mood and functioning at this point (44), and many require dose adjustment, switching to another drug, augmentation with a second agent, or the addition of psychotherapy. How should clinicians monitor response to drug therapy? Treatment for depression requires at least 6 to 9 months with close follow-up (Table 4). The first 2 weeks of drug therapy are often the most challenging. The pessimism and hopelessness intrinsic to depression and the relatively rapid onset of side effects can lead to nonadherence: 28% of depressed primary care patients stop taking their medication in the first month, and 44% stop within 3 months (45). Clinicians should follow up patients within 1 to 2 weeks of starting therapy to ask about acceptance of medication, reinforce educational messages, reassess suicidality, and address adverse events. Telephone follow-up by a trained nurse is also effective (46). Addressing specific adverse effects is critical to

Table 4. Follow-up for Depression*

Depression Severity Suggested Follow-up

Minor Mild (PHQ-9 score of 1014) Moderate (PHQ-9 score of 1519) Severe (PHQ-9 score of 20) If no active treatment, receiving on-going stable antidepressants or counseling
PHQ-9 = Patient Health Questionnaire.

Watchful waiting, re-evaluate in 48 wk Contact by phone or in-person monthly (whether or not antidepressants are prescribed) Contact by phone or in-person every 24 wk Contact by phone or in-person every 24 wk until PHQ-9 score improved by at least 5 points Contact by phone or in-person every 23 mo after remission

* Adapted from The MacArthur Initiative in Depression and Primary Care (www.depression-primarycare.org).

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maintaining adherence until patients respond. In addition, antidepressants may be associated with an increased risk for suicide in children, adolescents, and young adults.
A meta-analysis of 2741 patients age 6 to 18 years showed an increased relative risk for self-harm or suicide-related events in patients treated with newer-generation antidepressants compared with those given placebo (4.8% vs. 3.0%; P = 0.01; number-needed-to-treat for harm, 55). Because actual suicide is rare in such studies, the increase in risk for suicide, rather than for suicidal behaviors, can only be inferred (47).

The U.S. Food and Drug Administration (FDA) has issued a Public Health Advisory recommending close monitoring of all patients treated with antidepressants, particularly in the first 1 to 2 months of treatment. A warning statement regarding a possible increased risk for suicide has been added to FDA Patient Information Sheets for citalopram, duloxetine, venlafaxine, escitalopram, fluvoxamine, paroxetine, fluoxetine, mirtazapine, bupropion, and sertraline. Clinicians should ask about agitation, irritability, or unusual changes in behavior. Compared with placebo, adults younger than 25 years have an increased risk for suicidal behavior (odds ratio, 2.3) (48). The FDA recommends weekly follow-up in these patients for the first month, biweekly for the next month, and monthly thereafter. Most evidence suggests that, when properly administered, antidepressants avert many more suicides than they cause (49). If response to medication is inadequate after 6 to 8 weeks of therapy, treatment should be modified. Recurrence of depression after a first episode is common. Clinicians should educate patients and their families to self-assess for symptoms and risk for recurrent episodes. Surveillance for recurrence or relapse should continue indefinitely.

How long should clinicians treat depressed patients with drugs, and when should they consider longterm maintenance on drug therapy? The goal of treatment is complete remission of symptoms and return to normal functioning. For the first episode, antidepressant treatment may take 1 to several months until remission is achieved and should be continued for another 4 to 9 months. Although not strictly evidence-based, some clinicians advocate treatment for at least 1 year to maintain remission for a full annual cycle of holidays and anniversaries. For multiple episodes of depression, an even longer duration of therapy may be beneficial (41). For older patients (>70 years) with major depression who respond to an SSRI, consider treating for 2 years to prevent recurrence (50). When should clinicians consider switching drugs because of a suboptimum response to initial drug therapy? Most patients starting antidepressant therapy do not achieve complete remission, so increasing the dose of the current medication or changing drugs is often necessary.
STAR*D (Sequenced Treatment Alternatives to Relieve Depression) randomly assigned patients to 1 of several treatment sequences, all starting with 12 weeks of citalopram. The study showed that 30% of patients achieved complete remission after 12 weeks of citalopram. Of those who did not improve with citalopram, about 25% responded to an alternative agent (sertraline, venlafaxine, or bupropion) and another one-third responded to augmentation with bupropion (44)

For a partial response, the dose of the initial agent should be maximized as tolerated before switching to another medication or adding a second drug. When a partial response continues, the clinician can refer for psychotherapy, change antidepressants, or augment treatment with bupropion, mirtazapine, or a nontraditional agent.

49. Grunebaum MF, Ellis SP, Li S, et al. Antidepressants and suicide risk in the United States, 1985-1999. J Clin Psychiatry. 2004;65:1456-62. [PMID:15554756] 50. Reynolds CF 3rd, Dew MA, Pollock BG, et al. Maintenance treatment of major depression in old age. N Engl J Med. 2006;354:1130-8. [PMID:16540613] 51. Spier SA. Use of bupropion with SRIs and venlafaxine. Depress Anxiety. 1998;7:73-5. [PMID:9614595] 52. Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry. 1999;60:45-9. [PMID:10074878]. 53. Shelton RC, Papakostas GI. Augmentation of antidepressants with atypical antipsychotics for treatment-resistant major depressive disorder. Acta Psychiatr Scand. 2008;117:2539. [PMID:18190674] 54. Candy M, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev. 2008:CD006722. [PMID:18425966] 55. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7:34-59. [PMID:19281939] 56. Obrocea G. Thyroid hormone augmentation in treatment resistant depression. Clin Pyschopharmacol Neurosci. 2008;6:3-10 57. Cooper-Kazaz R, Lerer B. Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors. Int J Neuropsychopharmacol. 2008;11:685-99. [PMID:18047754]

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58. Carney RM, Freedland KE, Rubin EH, et al. Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial. JAMA. 2009;302:1651-7. [PMID:19843899] 59. Golden RN, Gaynes BN, Ekstrom RD, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry. 2005;162:656-62. [PMID:15800134] 60. Mead GE, Morley W, Campbell P, et al. Exercise for depression. Cochrane Database Syst Rev. 2009:CD004366. [PMID:19588354] 61. Morgan AJ, Jorm AF. Self-help interventions for depressive disorders and depressive symptoms: a systematic review. Ann Gen Psychiatry. 2008;7:13. [PMID:18710579] 62. Nurnberg HG, Hensley PL. Selective phosphodiesterase type-5 inhibitor treatment of serotonergic reuptake inhibitor antidepressant-associated sexual dysfunction: a review of diagnosis, treatment, and relevance. CNS Spectr. 2003;8:194-202. [PMID:12595814] 63. Wright SK, Schroeter S. Hyponatremia as a complication of selective serotonin reuptake inhibitors. J Am Acad Nurse Pract. 2008;20:47-51. [PMID:18184165] 64. Osteoporotic Fractures in Men Study Group. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007;167:1246-51. [PMID: 17592097] 65. Smoller JW, Allison M, Cochrane BB, et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Womens Health Initiative study. Arch Intern Med. 2009;169:212839. [PMID:20008698]

Compared with withdrawing one drug and starting another, combination therapy offers faster effects, potential for synergistic or complementary effects, and avoidance of withdrawal symptoms when stopping the first agent. But with a more complex regimen, drug interactions and adverse effects can increase. Adding bupropion to an SSRI or venlafaxine therapy may enhance response or treat side effects in many patients (51). Similar response rates occur when adding mirtazapine to SSRI treatment (52). Combinations of MAOIs and either SSRIs or TCAs are not recommended, because of increased risk for the serotonin syndrome (with confusion, nausea, autonomic instability, and hyperreflexia). Adding atypical antipsychotics, psychostimulants, and thyroid hormone remains controversial. Antipsychotics added to SSRIs for treatment-resistant depression show some benefit but also carry significant risks, so their use should be limited to psychiatrists (53).
A Cochrane review of psychostimulants (dexamphetamine, methylphenidate, methylamphetamine, demoline, modafinil) for moderate-to-severe depression found shortterm improvement in depression symptoms and fatigue (54). A second review of 19 controlled trials on adults older than 65 years supported this recommendation for methylphenidate; however, dosing, when to initiate therapy, and how to monitor side effects remains unclear (55).

90 minutes each morning) for winter depression (59), yoga, self-help books, exercise (60), relaxation therapy (61), and acupuncture seem useful. What are the common adverse effects of antidepressant drugs and how should clinicians manage these effects? Specific types of side effects are more common with particular drugs and should guide choice of medications (Table 3). Sexual side effects of SSRIs include decreased libido or interest (men and women), anorgasmia (women), and delayed ejaculation (men). To address these side effects, consider pretreatment counseling, switching to a drug with a different mechanism of action (for example, bupropion or mirtazapine), or using sildenafil for SSRI-associated erectile dysfunction if no contraindications (62). Switching to bupropion can reduce undesired weight gain. Agitation or excessive activation, most commonly with fluoxetine, warrants switching to another SSRI and considering mixed mania. Adding a low-dose tricyclic agent, mirtazapine, trazodone, or a sedative-hypnotic may reduce insomnia early in the course of treatment. During SSRI initiation, clinicians may also provide a short course of benzodiazepines to counter anxiety with major depression or early SSRI treatment. SSRIs are associated with hyponatremia in elderly persons (63) and may promote osteoporosis (64).
Analysis from the Womens Health Initiative found that although antidepressant use did not increase the risk for coronary heart disease, SSRI use was associated with an increased risk for hemorrhagic and fatal stroke and that both SSRI and TCA were associated with increased mortality (65). Conversely, OConnor and colleagues studied 1006 patients with clinical heart failure and reported that depression, and not antidepressant use, was associated with increased mortality (66).

Studies are conflicting about the effectiveness of adding thyroid hormone (triiodothyronine [T3] and levothyroxine [T4]) to antidepressants. (56, 57). More research is needed before these therapies can be recommended for use in primary care. Augmentation with other nontraditional agents has also shown mixed results: omega-3 fatty acids added to sertraline in patients with coronary heart disease did not improve depressive outcomes (58), whereas light therapy (6000 to 10 000 lux for 30 to

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When should clinicians consult a psychiatrist for help in managing drug therapy? Treatment-resistant depression is common and may require psychiatric consultation. Referral may be necessary for patients who have not responded to agents familiar to the primary care provider, have repeated failures, or have side effects that are difficult to manage. The threshold for referral should be lower for more severely impaired patients. The Agency for Healthcare Research and Policy recommends a psychiatric consult for severe symptoms; heightened suicide risk; comorbid, psychiatric, or substance abuse problems; or lack of response to appropriate treatment (27). Electroconvulsive therapy can be considered for depressed patients who have psychotic features, suicidal thoughts, no response to antidepressants, or who cannot tolerate antidepressants. Electroconvulsive therapy should be managed by a psychiatrist (7). When should clinicians consider hospitalizing depressed patients? Hospitalization should be considered for significant suicidal ideation or intent without safeguards in the family environment, express intent to hurt others, requirement for close observation (to assess self-care and adherence), detoxification or substance abuse treatment, electroconvulsive therapy candidates, or dysfunctional family systems worsening the depressive disorder or interfering with treatment. When a patients life is in jeopardy, hospitalization against their wishes is necessary. The conditions of such involuntary hospitalization are governed by state-specific legal requirements. What should clinicians advise patients about complementaryalternative treatments for depression? St. Johns wort (Hypericum) may be beneficial for subsyndromal

depression or for patients who are unwilling or cannot take conventional therapy for mild depression.
A Cochrane review suggests that Hypericum extracts are as effective as standard antidepressants for mild depression and have fewer side effects (67).
66. OConnor CM, Jiang W, Kuchibhatla M, et al. Antidepressant use, depression, and survival in patients with heart failure. Arch Intern Med. 2008;168:2232-7. [PMID:19001200] 67. Linde K, Berner MM, Kriston L. St Johns wort for major depression. Cochrane Database Syst Rev. 2008:CD000448. [PMID:18843608] 68. Obach RS. Inhibition of human cytochrome P450 enzymes by constituents of St. Johns Wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther. 2000;294:88-95. [PMID:10871299] 69. de Maat MM, Hoetelmans RM, Math RA, et al. Drug interaction between St Johns wort and nevirapine. AIDS. 2001;15:420-1. [PMID:11273226] 70. Ondrizek RR, Chan PJ, Patton WC, et al. Inhibition of human sperm motility by specific herbs used in alternative medicine. J Assist Reprod Genet. 1999;16:8791. [PMID:10079411] 71. Pies R. Handbook of Essential Psychopharmacology, second ed. American Psychiatric Publishing; 2005. 72. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354:579-87. [PMID:16467545] 73. U.S. Food and Drug Administration. FDA Public Health Advisory: Treatment Challenges of Depression in Pregnancy. 2006. Accessed at www.fda.gov/Drugs/ DrugSafety/PublicHealthAdvisories/ucm124348.ht m on 25 March 2010. 74. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165:749-52. [PMID: 18381907]

St. Johns wort should not be used for moderate-to-severe major depression, because of lack of benefit. Although St. Johns wort has mixed results in randomized, placebocontrolled trials, serious adverse effects are uncommon. Many trials with positive findings have used standardized doses of 0.3% hypericin, 300 mg three times a day (67). There are important caveats to the use of St Johns wort. To avoid symptoms of serotonin excess, do not use with SSRIs. Through activation of the cytochrome P450 system, St. Johns wort may reduce plasma concentration of digoxin, theophylline, simvastatin, and warfarin (68). Severe drug interactions have also been reported with antiretroviral therapy; St. Johns wort can decrease concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (69). At high concentrations, St. Johns wort may harm sperm cells and lead to decreased fertility (70). The National Institute of Healths National Center for Complementary and Alternative Medicine is a good resource for more information (http:// nccam.nih.gov/health/stjohnswort). If a patient relapses after cessation of depression treatment, should clinicians resume previously effective therapy or select a new therapy? Recurrence of major depression requires long-term maintenance therapy with the same antidepressant that previously led to remission. Lifetime therapy may be required for patients with 3 or more depressive episodes or with first recurrence and risk factors for more recurrences (family history of

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bipolar disorder, recurrence <1 year, onset in adolescence, severe depression, suicide attempt, and sudden onset of symptoms) (71). How should clinicians advise women receiving drug therapy for depression who are or who wish to become pregnant? In 2006, the FDA issued a warning concerning SSRI use during pregnancy. A casecontrol study showed that persistent pulmonary hypertension was 6 times more common in babies whose mothers received an SSRI after the 20th week of gestation than in those whose mothers did not (72). The absolute risk for persistent pulmonary hypertension was low (about 6 to 12 per 1000 women). However, this study adds to concerns from previous reports that infants of mothers taking SSRIs late in pregnancy may have irritability, difficulty feeding, and (in very rare cases) difficulty breathing. The teratogenic potential of SSRIs is probably low overall, but 2 epidemiologic studies of paroxetine in early pregnancy prompted the FDA in late 2005 to order a change

in labeling for this agent (73). Paroxetine is the only SSRI with a class D rating for pregnancy; all others are class C.
A recent review of over 3000 births to women receiving paroxetine during the first trimester showed no increase in cardiac malformations (74).

Stopping antidepressants carries its own risks.

In 201 pregnant women with history of major depression before pregnancy, relapse of depression was more common in those who stopped their medication than in those who continued (68% vs. 26%, hazard ratio, 5.0; P < 0.001) (75).

Tricyclic antidepressants are not strictly contraindicated in pregnancy. However, the neonatal withdrawal syndrome may occur, and these drugs should be tapered before delivery (71). If a TCA is chosen, desipramine or nortriptyline may be preferred, because they cause fewer side effects and because drug levels can be monitored (76). Clinicians should help patients make an informed decision and should check for signs of postpartum depression 4 to 6 weeks after delivery.

Treatment... Primary care physicians play an important role in treating affective disorders. Depression is highly treatable and has many treatment options; clinicians familiar with 2 SSRIs (such as citalopram, sertraline), an SNRI (such as extended-release venlafaxine), and sustained-release bupropion are well equipped to treat most cases. However, clinicians should not hesitate to refer patients to a psychiatrist for evaluation or comanagement. Familiarity with local psychotherapy options and options for addressing common side effects is also helpful.

CLINICAL BOTTOM LINE

Practice Improvement

What can clinicians do to encourage adherence to therapy for patients with depression? Patient education and slowly increasing medication doses to minimize side effects are the first lines of defense against nonadherence to antidepressant therapy.

Among 155 depressed patients, those receiving the following educational messages were more likely to adhere to therapy during the first month: take the medication daily, antidepressants must be taken for 2 to 4 weeks for a noticeable effect, continue to take medicine even if feeling better, do not stop taking antidepressant medication without

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checking with the physician, and resolve questions regarding antidepressants and potential side effects with the physician (45).

A meta-analysis of 37 RCTs showed that collaborative care is more effective than standard care in improving depression outcomes (83).

Nonadherence often begins in the first weeks of therapy and is related to beliefs about the illness, concerns over side effects, ineffectiveness of treatment, cost of medications, and diverse cultural and attitudinal factors (77). Clinicians should routinely ask patients and their families about their beliefs. Personalizing educational messages to address the patients beliefs will enhance the benefit. Whenever possible, family involvement may improve acceptance of and support for the patients condition and may enhance response. Patients and their families should receive appropriate written and electronic patient education materials about depression and its management. Clinicians can improve the effect of printed material by intensive reinforcement of key educational messages (45). How can primary care practices improve depression care? Improving outcomes in depression care requires systems change (78). Elements shown to support improvement include collaborative care involving primary care clinicians and mental health specialists, systematic tracking of outcomes with decision support, and use of nurses or office staff to coordinate follow-up (79, 80). Recommendations to adopt screening strategies using questionnaires without organizational enhancements may not be justified (81). Changing physician behavior requires structured interventions that operate independently of physician initiation. Most collaborative care models require additional resources, but some are cost-saving (82), and overall costs seem commensurate with demonstrated benefit. Implementation of these approaches requires initiative at the level of the health care delivery system rather than in the doctor-patient relationship.

What criteria are used to judge the quality of depression care? The Ambulatory Care Quality Alliance has adopted 2 antidepressant medication management measures developed by the National Committee for Quality Assurance: antidepressant therapy for at least 12 weeks after the initial diagnosis and treatment and continuous anti depressant therapy for at least 6 months after the initial diagnosis and treatment. For more information, see www.aqaalliance.org/ performancewg.htm.
A study of 1299 patients in a primary care HMO compared usual care with 2 qualityimprovement programs: one offered medication-focused management, and the other emphasized psychotherapy. Both interventions showed benefit versus usual care at 6 and 12 months, but only the psychotherapy intervention showed a persistent benefit at 24 months in both clinical outcomes and mental healthrelated quality of life (84).

What do professional organizations recommend regarding screening for and managing depression? In 2009, the U.S. Preventive Services Task Force issued guidelines on screening for depression (www.ahrq .gov/clinic/uspstf/ix.htm). The Task Force recommends screening adults in clinical practices with staffassisted depression care supports. The Task Force also issued a guideline on screening for suicide risk in 2004 (www.ahrq.gov/clinic/uspstf /uspssuic.htm). The American Psychiatric Association published its Practice Guideline for the Treatment of Patients with Major Depressive Disorder in 2002, and a third edition is under development (www.psych.org/psych _pract/treatg/pg/MDD2e_05-15 -06.pdf ). Updates to this guideline

75. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295:499-507. [PMID:16449615] 76. Miller LJ. Psychiatric medication during pregnancy: understanding and minizing risks. Psychiatr Ann. 1994;24:69-75. 77. Delgado PL. Approaches to the enhancement of patient adherence to antidepressant medication treatment. J Clin Psychiatry. 2000;61 Suppl 2:6-9. [PMID:10714617] 78. Ong MK, Rubenstein LV. Wishing upon a STAR*D: the promise of ideal depression care by primary care providers. Psychiatr Serv. 2009;60:1460-2. [PMID: 19880461] 79. Gilbody S, Bower P, Fletcher J, et al. Collaborative care for depression: a cumulative meta-analysis and review of longer-term outcomes. Arch Intern Med. 2006;166:231421. [PMID:17130383] 80. Weissman MM, Olfson M. Translating intergenerational research on depression into clinical practice. JAMA. 2009;302:2695-6. [PMID:20040558] 81. Gilbody S, Sheldon T, House A. Screening and case-finding instruments for depression: a metaanalysis. CMAJ. 2008;178:997-1003. [PMID:18390942] 82. Unutzer J, Katon WJ, Fan MY, et al. Longterm cost effects of collaborative care for late-life depression. Am J Manag Care. 2008;14:95-100. [PMID: 18269305] 83. Bower P, Rowland N. Effectiveness and cost effectiveness of counselling in primary care. Cochrane Database Syst Rev. 2006;3:CD001025. [PMID:16855955] 84. Sherbourne CD, Wells KB, Duan N, et al. Long-term effectiveness of disseminating quality improvement for depression in primary care. Arch Gen Psychiatry. 2001;58:696-703. [PMID:11448378]

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are available (www.psych.org/psych _pract/treatg/pgMDDWatch.pdf ). The MacArthur Initiative in Depression and Primary Care, in collaboration with Dartmouth College and Duke University, has expanded the work of the AHRQ by developing a comprehensive Web site that offers provider guidelines and patient education resources

covering all aspects of depression management. It can be accessed at www.depression-primarycare.org. Pharmacologic therapy of major depression and dysthymia is covered in clinical guidelines from the American College of Physicians that were issued in 2008 (www .annals.org/cgi/content/149/ 10/725.abstract).

in the clinic

PIER Modules
http://pier.acponline.org/physicians/diseases/d954/d954.html Access the PIER module on depression from the American College of Physicians. PIER modules provide an evidence-based, electronic resource for clinical recommendations and links to patient information materials at the point of care.

Tool Kit
Depression

Depression Scales
www.chcr.brown.edu/pcoc/cesdscale.pdf Center for Epidemiological Studies Depression Scale http://healthnet.umassmed.edu/mhealth/ZungSelfRatedDepressionScale.pdf Zung Self-Depression Scale www.stanford.edu/~yesavage/GDS.html Geriatric Depression Scale www.nelmh.org/downloads/other_info/hopkins_symptom_checklist.pdf Hopkins Symptom Checklist www.aap.org/practicingsafety/Toolkit_Resources/Module2/EPDS.pdf Edinburgh Postnatal Depression Scale

Patient Information
www.doctorsforadults.com/images/healthpdfs/depression.pdf Downloadable brochure on depression and how internists can help. www.depression-primarycare.org Patient education handouts on depression symptoms, management, medications, and psychological counseling. www.annals.org/intheclinic/toolkit-depression.html Download an electronic copy of the patient information sheet on the next page for duplication and use in your office www.nlm.nih.gov/medlineplus/depression.html Public-oriented information on depression, including educational information from the National Institutes of Mental Health and other organizations, recent studies, and news. Many resources are available in Spanish.

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THINGS YOU SHOULD KNOW ABOUT DEPRESSION

Depression makes you feel sad and makes it hard to do or enjoy anything. Talking to a therapist or taking the right medicine can make you feel better.

In the Clinic Annals of Internal Medicine

What You Can Do

Dont be afraid to ask for help. If the doctor gives you medicine, take it every day. Dont expect your medicine to work for 2 to 4 weeks after you start it. Keep taking your medicine even if you feel better. Dont stop your medicine without checking with your doctor. Expect to take your medicine for at least 6 months. See the doctor 1 to 2 weeks after you start medicine and then again in 6 weeks. Ask your doctor about side effectsputting on weight, feeling nervous, or having trouble with sex. Ask your doctor about the right people to talk to and how your family can help you. If you feel bad or need help, call your doctor or 911 or go to the emergency room right away. Your medicines have too many side effects You are having strange thoughts or big mood swings

Ask your doctor about seeing a specialist if:

Your medicines dont seem to be working

You feel you may hurt yourself or other people You are drinking too much or taking street drugs

For More Information

www.nlm.nih.gov/medlineplus/depression.html

MedlinePLUS
www.nami.org/Template.cfm?Section=By_Illness/TaggedPage/ TaggedPageDisplay.cfm

National Alliance on Mental Illness

www.nimh.nih.gov/publicat/depression.cfm

National Institutes of Mental Health

www.fda.gov

U.S. Food and Drug Administration (search for depression drugs)

www.cancer.gov/espanol/pdq/cuidados-medicos-apoyo/depresion/ patient/

National Cancer Institute (Spanish)

Patient Information

CME Questions
1. A 25-year-old woman is evaluated for a 2month history of feeling down and hopeless after her fianc ended their engagement. She believes that the broken engagement was somehow her fault. The patient also reports spending less time with friends, restricting previously enjoyable social activities, and having difficulty concentrating. During the past week, she has been thinking increasingly about ending her life and has been fingering a knife when at home alone while contemplating cutting her wrists. She lives at home with her mother and two sisters, who are concerned and have expressed feelings of support and willingness to help. The patient is willing to make a no-harm contract of calling or going to the emergency department if suicidal feelings intensify. She has no history of suicide attempts. Medical history is unremarkable, and she takes no medications. Her father committed suicide several years ago. Findings on physical examination are unremarkable. Which is the most appropriate initial care for this patient? and reports that she is tolerating the medication well but has no significant change in symptoms, which is validated with a standardized symptom assessment tool. The sertraline is therefore increased to 100 mg/d. Six weeks later, she again reports no side effects and no improvement. Which is most appropriate at this time? sexual dysfunction manifested by bothersome anorgasmia. She is also overweight and is worried about gaining more weight. Blood pressure is 140/80 mm Hg. Her body mass index is 29 kg/m2. The remainder of the physical examination is normal. Which is the most appropriate alternative treatment option for this patients depression?

A. Add methylphenidate B. Discontinue sertraline and begin citalopram C. Reassess in 4 weeks D. Refer for electroconvulsive therapy
3. A 72-year-old woman is evaluated for a 4-month history of insomnia, with difficulty falling asleep. The patient was the major caretaker for her husband, who had advanced heart failure and died suddenly 4 months ago. She has lost 3.6 kg (8 lb) and does not have much of an appetite. The patient used to volunteer at the hospital, but she does not enjoy going there any more. She also does not have much energy. The patient is tearful and says that nearly everything reminds her of her husband. Medical history is otherwise unremarkable. The physical examination is unremarkable. Which is the most appropriate management option for this patient?

A. B. C. D.

Bupropion Citalopram Fluoxetine Mirtazapine

A. Corroborate her account by contacting her former fianc B. Reassurance and careful follow-up and observation C. Start an antidepressant and follow up in 2 weeks D. Urgent mental health referral
2. A 70-year-old woman is evaluated because of depressed mood, anhedonia, decreased appetite, impaired sleep, and decreased energy. Although the patient feels somewhat hopeless about the future, she adamantly states that she would never take her own life. Her judgment seems intact. Medical history is unremarkable, and she has not had previous episodes of depression. She is taking no medications. Findings on physical examination are unremarkable. Sertraline, 50 mg/d, is begun. The patient returns for a follow-up visit 5 weeks later

A. B. C. D.

Begin dextroamphetamine Begin mirtazapine at bedtime Begin zolpidem at bedtime Reassure the patient and schedule a follow-up appointment in 3 months

5. A 29-year-old woman has an 8-month history of insomnia, difficulty concentrating, fatigue, and irritability. She has trouble falling asleep, awakens after 2 or 3 hours, and has difficulty returning to sleep. The patient is concerned that her impaired concentration is interfering with her work as an attorney and has tried to compensate by spending long hours in the office. Her social activities have decreased because of the extended work hours. She broke up with her boyfriend several months ago and is concerned that she will soon be 30 years old and that her biological clock is ticking. She frequently lies awake in bed wondering if she will make partner at her law firm as well as whether she will ever get married and have children. She has occasional episodes of crampy abdominal pain, but her appetite is unchanged and her weight has been stable. Findings on physical examination are unremarkable. Body mass index is 24 kg/m2. Results of routine laboratory studies, including thyroid function tests, are normal. The patient refuses to see a psychotherapist because she finds talk therapy difficult. Which is the most appropriate pharmacologic agent at this time?

4. A 37-year-old woman is evaluated in the office for major depression that was diagnosed 3 months ago and treated with sertraline. Five weeks after initiation of treatment, she had no suicidal ideation, and her depressive symptoms had improved, with a 5-point decrease in her Patient Health Questionnaire (PHQ-9) score. During todays visit, she reports that her depressive symptoms have continued to improve, although she has experienced

A. B. C. D.

Alprazolam Imipramine Quetiapine Sertraline

Questions are largely from the ACPs Medical Knowledge Self-Assessment Program (MKSAP, accessed at http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/ to obtain up to 1.5 CME credits, to view explanations for correct answers, or to purchase the complete MKSAP program.

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