1. 1 Managing Depression in Primary Care: A Pragmatic Review of the Evidence Bradley N. Gaynes, MD, MPH Professor of Psychiatry University of North Carolina School of Medicine November 29, 2011

2. Objectives Identify key concepts of evidence-based depression care. Review screening with a depression instrument. Clarify key points in diagnosing depression. Examine a Measurement-Based Care approach to managing primary care depression. Provide prescription tips.

3. I. Key Concepts of Evidence-based Depression Care The USPSTF (2009) recommends screening adults for depression when staff-assisted depression care supports are in place to assure accurate diagnosis, effective treatment, and follow-up. (Grade B) The choice of screener is less important than finding one that works in your setting, and systematically applying it Major depression presenting for treatment in primary care settings is nearly identical to that presenting in psychiatric settings (Gaynes, 2007a)

4. Distribution of HAMD 17 by Setting Kolmogorov-Smirnov Two-Sample Test Statistic 0.81 p-value 0.52 Figure 1 (Gaynes, 2007a)

5. Key Concepts of Evidence-based Care Remission of a depression rather than merely response is the treatment goal. (Rush, 2007) Physicians should ensure maximal but tolerable doses for 6-8 weeks before deciding that an intervention has failed Identical remission rates can be achieved in primary and specialty settings when similar evidence-based care is provided (Gaynes, 2008)

6. Key Concepts of Evidence-based Care Should the first treatment fail, either switching treatment or augmenting the current treatment is reasonable. The likelihood of remission after two well- delivered medication trials substantially decreases.

7. Euthymia Symptoms Syndrome Treatment phases Progression to disorder Acute (6 to 12 wk) Continuation (4 to 9 mo) Maintenance (  1 y) Time Increased severity Relapse Remission Recurrence Relapse Response Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34. + + Treatment Phases of Major Depression

8. II. Screening with a Depression Instrument Objective: to identify and clarify cases of depressive illness Note that it can be used to monitor response to illness also Scoring is simple, and total score has clinical relevance

9. 9 Screening Can Improve Depression Outcome in Primary Care, But Only With Adequate Support Data Synthesis: Nine trials indicate that primary care depression screening and care management programs with staff assistance, such as case management or mental health specialist involvement, can increase depression response and remission. Benefit was not evident in screening programs without staff assistance in depression care. O’Connor et al, 2009

10. 10 How Do You Measure Depressive Severity?

11. Over the last 2 weeks how often have you been bothered by any of the following problems? Complete Questions 1 - 9 Initially then at all Critical Decision Points (CDPs) 0 Not at all 1 Several days 2 More than half the days 3 Nearly every day 1. Little interest or pleasure in doing things  2. Feeling down, depressed, or hopeless  3. Trouble falling/staying asleep, 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 could have noticed. Or the opposite-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. (if positive, complete the Suicide Risk Assessment)  ___ X 0 = ___ X 1 = ___ X 2 = ___ X 3 = Per Category ______ + ______ _ + _______ = PHQ-9 Total Score: ______

12. 12 PHQ-9 Score Depression Severity Proposed Treatment Actions 1 – 4None 5 – 9MildWatchful waiting; repeat PHQ-9 at follow-up 10 – 14ModerateTreatment plan, considering counseling, follow- up and/or pharmacotherapy 15 – 19 Moderately Severe Immediate initiation of pharmacotherapy and/or psychotherapy 20 – 27Severe Immediate initiation of pharmacotherapy and, if severe impairment or poor response to therapy, expedited referral to a mental health specialist for psychotherapy and/or collaborative management PHQ-9 Scores, Severity and Proposed Treatment Actions Kroenke, 2002

13. III. Clinical Review of Mania and Psychosis Mania: –“Has there ever been a period of 4 days or more when you were feeling so good, “high”, excited, or hyper that you got into trouble, or your family or friends worried about you, or a doctor said you were manic?” Psychotic symptoms: –“Has there even been a time when your mind seemed to be playing tricks on you, so that you heard voices or sounds others didn’t hear? Or saw things others didn’t see? Or were afraid there was someone out to harm you when others didn’t think so?”

14. Reprint permission granted by the Cartoon Bank.

15. IV. Overview of Measurement- Based Care of Depression Goals –Monitor depressive severity closely with PHQ-9 –Consider medication side effects –Make decisions at Critical Decision Points (CDPs) –Evidence-based treatment algorithm –Manage aggressively and treat to remission

16. How Does It Work? At each visit, measures taken on –Depressive severity, to assess RESPONSE –Side effects, to assess TOLERABILITY At CRITICAL DECISION POINTS, decisions about dose changes are made Algorithm is a guide; clinicians and patients make ultimate decision Goal is REMISSION

17. 17 How Do You Define Remission? No Response: PHQ-9 ≥ 10 Partial Response: PHQ-9 = 5-9 Remission:PHQ-9 < 5

18. How Often Does Patient Follow-up? Follow-up every 4 weeks within acute phase of treatment Telephone contact in between to check on tolerance, adherence (by physician extender) In person contact at Critical Decision Points, at which time the clinician can change dosing to general categories of Low, Medium, and High

19. 19

20. Antidepressant Dosing Range Total Daily Dose Range (mg) SSRITrade NameStarting-LowMiddleHigh Fluoxetine*Prozac10 qAM X 1 wk, then 20 qAM40 qAM60 qAM Sertaline*Zoloft50 qAM X 1 wk, then 100 qAM150 qAM200 qAM Paroxetine*Paxil10 qAM X 1 wk, then 20 qAM40 qAM60 qAM Citalopram*; Escitalopram Celexa; Lexapro 10 qAM X 1 wk, then 20qAM; 10 q AM 40 qAM; 20 q AM 40 qAM; 20 q AM Non-SSRI Buproprion SR* (avoid w/ seizure hx) Wellbutrin SR150 qAM X 1 wk, then 100 BID 150 BID200 BID Mirtazapine*Remeron15 qHS X 1k, then 30 qHS45 qHS60 qHS Venlafaxine* XREffexor XR37.5 qAM X 1 wk, then 75 qAM X 1wk, then 150 qAM 225 qAM300 qAM * = generic available

21. Which Antidepressant Do You Use First? It does not matter, assuming patient: –has NOT already demonstrated failure to respond to an adequate trial of that medication –Has not demonstrated intolerance of the medicine –Is not on medications with problematic drug interactions

22. Do Medications Differ in Treating Major Depressive Disorder? 72 head-to-head trials (including 3 effectiveness trials) on 16,780 patients 18 studies assessed quality of life We conducted 4 meta-analyses and 62 adjusted indirect comparisons –Outcome of interest: response to treatment Gartlehner, 2007

23. Major Depressive Disorder: Evidence Similar Efficacy Overall, no substantial differences in efficacy Statistically significant results from meta-analyses: modest and likely not clinically important No differences in quality of life Strength of evidence: moderate

24. Tolerability and Discontinuation Rates Are Also Similar Overall discontinuation rates do not differ significantly among drugs Venlafaxine has higher discontinuation rates because of adverse events but lower discontinuation rates because of lack of efficacy than SSRIs. Strength of evidence: high

25. General Adverse Events Similar However, incidence of specific adverse events can differ significantly among drugs –Nausea and vomiting: higher rates with venlafaxine than with SSRIs –Somnolence: higher rates with trazodone than with other drugs –Diarrhea: higher rates with sertraline than with other drugs –Weight gain: higher rates with mirtazapine than with SSRIs

26. Severe Adverse Events: Sexual Dysfunction Differs Fewer sexual side effects for bupropion than for fluoxetine, paroxetine, and sertraline Among SSRIs, highest rate for paroxetine Strength of evidence: moderate

27. Selection of Antidepressant is Primarily Guided by Side Effects No difference among antidepressant in terms of likelihood of remission or response BUT, they do differ by side effect

28. 28 What Do You Do If Patient Endorses Suicidal Ideation?

29. 29 First, clarify whether the ideation is active or passive currently Current vs. not: –Are you having these thoughts right now? When did you last have them? Active vs. Passive: –Do you have thoughts you’d be better off dead, or are you having thoughts of harming or killing yourself? IF active suicidal ideation currently, you need to further assess plans and intent

30. 30 Next, assess intent and plan Do you have any plans on how you would harm yourself? IF yes, what have you thought about? Have you actually done anything to hurt yourself?

31. 31 Key demographic risk factors for completed suicides Age, noteworthy in two groups –Individuals aged 65 and older, especially white males over 85 years (59/100,000) –Adolescents and young adults aged 15-24 years, for whom it is the third leading cause of death (10.3/100,000) Single or living alone Male sex

32. 32 Other key variables to consider Past psychiatric hospitalizations Past suicide attempts Family history of suicide attempts History of substance use (impulsivity) Any other history of impulsivity Availability of social support Access to means to harm self Why now? Is there a crisis? Hopelessness

33. 33 Assessment of Suicide Risk RiskDescriptionAction Low RiskNo current thoughts, no major risk factors Continue follow-up visits and monitoring Intermediate RiskCurrent thoughts, but no plans, with or without risk factors Assess suicide risk carefully at each visit and contract with patient to call you if suicide thoughts become more prominent; Consider referral to mental health professional Acute/High RiskCurrent thoughts with plansEmergency management by qualified expert; referral to Emergency room or psychiatric hospital for continued evaluation and management MacArthur Foundation Toolkit. http://www.depression-primarycare.org/clinicians/toolkits/

34. How Well Does It Work in Primary Care?

35. Minimal Difference in Treatment Characteristics Gaynes et al, 2008

36. Similar Outcomes in Primary Care and Psychiatric Care Settings (N = 2876) Gaynes et al, 2008

37. What else have STAR*D and MBC Demonstrated?

38. Providing An Adequate Trial is Key From treatment initiation, physicians should ensure maximal but tolerable doses for 6-8 weeks before deciding that an intervention has failed.

39. 39 Psychotherapy Is A Reasonable Option If Available For most presentations, an antidepressant and an evidence-based psychotherapy produce equivalent outcomes However, for a severe depression, a medication produces quicker improvement.

40. 40 Does Collaborative Care Improve Comorbid Medical Illness? In DM, compared with controls, patients in the intervention group had –Greater overall 12-month improvement across glycated hemoglobin levels (difference, 0.58%) –LDL cholesterol levels (difference, 6.9 mg per deciliter [0.2 mmol per liter]) –Systolic blood pressure (difference, 5.1 mm Hg) –SCL-20 depression scores (difference, 0.40 points) (P<0.001).

41. 41 What If The Initial Attempt Doesn’t Produce Remission? Might add Bupropion up to 400 mg/day SR (or 450 mg/day XL) –For SR, add 75 mg/day for first week, and if tolerated increase to 150 mg/day (low dose) –Increase per protocol to middle range (300 mg/day in BID dosing) or high range (400 mg/day in BID dosing) at Critical Decision Points. No single dosage should exceed 200 mg. Might add Mirtazapine –15mg (low); 30 mg (medium); 45 mg (high)

42. Gaynes, 2007b With persistence and the provision of MBC, there is hope

43. Prescription Tips All antidepressant medications have a similar likelihood of being effective; selection is based primarily on the wish to benefit from (or avoid) particular side effects. If a patient has a substantial amount of coexisting anxiety, start the dose a little lower but know that the ultimate dose may need to be on the higher end. The first 4-6 weeks of antidepressant treatment is the time period when patients are at greatest risk to stop medications prematurely; monitor closely during this time.

44. Prescription Tips If a patient has a partial but less than complete response, adding a 2 nd psychiatric medication to augment the response is a reasonable strategy After two failures to remit with an adequate trial, consider psychiatric consultation

45. Summary The PHQ-9 is an easy to use, effective tool to both identify patients with major depression and to monitor their response to treatment. After a positive screen, physicians should clinically confirm a diagnosis of MDD. Physicians should ensure maximal but tolerable doses for at least 8 weeks before deciding that an intervention has failed. Remission is the goal of treatment.

46. Summary (cont) Should the first treatment fail, either switching treatment or augmenting the current treatment is reasonable. The likelihood of remission after two well- delivered medication trials substantially decreases. –Such patients likely require more complicated regimens. –Given the thin existing database, these patients are best referred to psychiatrists for more complex treatments.

47. References Gartlehner G, Hansen R, Thieda P, et al. Comparative Effectiveness of Second- generation Antidepressants in the Pharmacologic Treatment of Depression. Agency for Healthcare Research and Quality. Available at: http://effectivehealthcare.ahrq.gov/reports/topic.cfm?topic=8&sid=39&rType=3. http://effectivehealthcare.ahrq.gov/reports/topic.cfm?topic=8&sid=39&rType=3 Gaynes BN, Rush AJ, Trivedi MH, et al. (2007). Major Depression Symptoms in Primary Care and Psychiatric Care Settings: A Cross-Sectional Analysis. Ann Fam Med, 5(2):126-134. Gaynes BN, Rush AJ, Trivedi MH, et al. (2008). Primary vs. Specialty Care Outcomes for Depressed Outpatients Managed with Measurement-Based Care: Results from STAR*D. Journal of General Internal Medicine, 23(5), 551-560. Katon WJ, Lin EHB, Korff MV, et al. Collaborative Care for Patients with Depression and Chronic Illnesses. N Engl J Med 2010; 363:2611-2620 Kupfer, DJ. (1991). Long-Term Treatment of Depression. Journal of Clinical Psychiatry. 52 (5 suppl), 28-34. Kroenke K, Spitzer R. (2002). The PHQ-9: A new depression diagnostic and severity measure. Psychiatric Annals. 32(9). 508- 515. O’Connor EA, Whitlock EP, Beil TL, and Gaynes BN. Screening for Depression in Adult Patients in Primary Care Settings: A Systematic Evidence Review. Ann Intern Med. 2009;151:793-803. Rush AJ. STAR*D: what have we learned? Am J Psychiatry. Feb 2007;164(2):201- 204. U.S. Preventive Services Task Force. Screening for depression in adults: U.S. preventive services task force recommendation statement. Ann Intern Med. 2009 Dec 1;151(11):784-92.