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2. © 2017 American College of Physicians
The information contained herein should never be used as a substitute for clinical judgment.

3. What Treatment Should I Offer This Patient with Depression?
March 2, 2017
Gerald Smetana, MD, MACP
Roscoe Brady, MD, PhD
Risa Burns, MD, MPH
Deborah Cotton, MD, MPH
The Series Editors have no conflicts of interest to disclose.

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5. Risa Burns, MD
Gerald Smetana, MD, MACP Roscoe Brady, MD, PhD
Deborah Cotton, MD, MPH

6. OUR PATIENT Medical History
Mr. Y is a 64 yo man whose depression has been slowly worsening over the past two years.
His depression was precipitated by “trying out” retirement and more recently the presidential election.
He first experienced depression as a young adult which improved once he found a rewarding career.
He has an extensive family history of depression with multiple family members on anti-depressant medications.
His past medical history is noteworthy only for a vestibular schwannoma.

7. Mr. Y is married and lives with his wife.
OUR PATIENT
Social History
Mr. Y is married and lives with his wife.
He does not smoke or drink alcohol.
To help treat his depression, he increased his exercise regimen to 4 times per week which he thinks improved his symptoms.

8. OUR PATIENT Physical Examination, Assessment and Plan
On exam Mr. Y displayed a sad affect but demonstrated good insight. His PHQ-9 score was 9.
He was felt to be experiencing mild to moderate depression.
He was wary of starting medications and preferred seeing a therapist.
His PCP helped him identify a therapist but at a follow-up visit 2 weeks later he had not improved.
He remained wary of medications and wanted to keep seeing the therapist. He felt that his depression would improve if only he could find something meaningful to do.

9. MR. Y’S STORY

10. Would you start this patient on an anti-depressant medication?
Would you start this patient on an anti-depressant medication?

11. DEPRESSION
Depression is a major public health problem and a common cause of disability.
The lifetime prevalence in the United States is estimated to be 16%.
To meet the American Psychiatric Association’s diagnostic criteria for Major Depressive Disorder (MDD), a person must:
experience five or more symptoms for a continuous period of at least two weeks
the symptoms must represent a change from prior functioning
at least one symptom must be either depressed mood or loss of interest or pleasure

12. DEPRESSION The symptoms of depression include: depressed mood
diminished interest or pleasure in activities
weight loss or decrease in appetite
insomnia or hypersomnia
psychomotor agitation or retardation
fatigue or loss of energy
feelings of worthlessness or excessive guilt

13. DEPRESSION - Treatment
Treatment options for MDD include:
Psychotherapy or cognitive behavioral therapy (CBT)
Complementary and alternative medicines (CAM)
Pharmacotherapy with second generation anti-depressants (SGAs)
Response to treatment can be quantified using the PHQ-9 or the Hamilton Depression Rating Scale (HAM-D). HAM-D is commonly used in research studies and a score < 7 is thought to be normal while a score > 20 represents moderate to severe depression.
Regardless of treatment type response rates are modest:
Only 60% of patients treated with an SGA respond
response is defined as > 50% improvement in HAM-D scores
Only 30% achieve remission
remission is defined as HAM-D score < 7

14. THE GUIDELINE
*Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians.
Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A
Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

15. THE GUIDELINE
The Guideline summarized and graded the evidence on the comparative effectiveness and safety of non-pharmacologic interventions and SGAs alone or in combination.
The evidence review was conducted by the Agency for Healthcare Research and Quality (AHRQ).
The review examined response and remission rates as well as harms or adverse events (AE).
The treatment options included psychotherapy, CBT, CAM, exercise, and SGAs.
*Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians.
Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A
Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

16. THE GUIDELINE
The evidence review compared the effectiveness of SGAs with non-pharmacologic interventions as initial treatment.
There were 43 head-to-head trials whose results are summarized on the upcoming slides.
There was no statistically significant difference in efficacy between SGAs and most other treatments for adult outpatients with mild to severe MDD.
Rates of AE and discontinuation were generally higher in patients treated with SGAs though the strength of the evidence for this finding was generally low.
*Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians.
Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A
Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

17. Comparison of response rates of SGAs and other interventions
THE GUIDELINE
Comparison of response rates of SGAs and other interventions
SGA: second-generation antidepressant
CBT: cognitive behavioral therapy
CAM: complementary and alternative medicine
SOE: strength of evidence.
*: Estimate is based on trial with lowest risk of bias
*Gartlehner G, Gaynes BN, Amick HR, Asher GN, Morgan LC, Coker-Schwimmer E, et al.
Comparative Benefits and Harms of Antidepressant, Psychological, Complementary, and
Exercise Treatments for Major Depression: An Evidence Report for a Clinical Practice
Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

18. Comparison of remission rates of SGAs and other interventions
THE GUIDELINE
Comparison of remission rates of SGAs and other interventions
SGA: second-generation antidepressant; CBT: cognitive behavioral therapy; CAM: complementary and alternative medicine; SOE: strength of evidence.
*: Estimate is based on trial with lowest risk of bias
*Gartlehner G, Gaynes BN, Amick HR, Asher GN, Morgan LC, Coker-Schwimmer E, et al.
Comparative Benefits and Harms of Antidepressant, Psychological, Complementary, and
Exercise Treatments for Major Depression: An Evidence Report for a Clinical Practice
Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

19. THE GUIDELINE
Comparison of discontinuation rates due to AE between SGAs and other interventions
SGA: second-generation antidepressant; CBT: cognitive; behavioral therapy; CAM: complementary and alternative medicine; SOE: strength of evidence.
*: Estimate is based on trial with lowest risk of bias
*Gartlehner G, Gaynes BN, Amick HR, Asher GN, Morgan LC, Coker-Schwimmer E, et al.
Comparative Benefits and Harms of Antidepressant, Psychological, Complementary, and
Exercise Treatments for Major Depression: An Evidence Report for a Clinical Practice
Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

20. THE GUIDELINE
For patients who did not achieve remission with initial treatment, the evidence review examined the comparative effectiveness of augmentation of the original SGA or switching to a different SGA or a non-pharmacologic treatment.
Only 2 trials addressed the comparative benefits and harms of these strategies.
The evidence review found that none of the second-step treatment strategies had greater efficacy or risk of harm than another.
*Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians.
Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A
Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164: c

21. THE GUIDELINE
In summary, given that the evidence review found that SGAs and CBT are similarly effective and that CBT has no more and probably fewer adverse effects, the ACP recommends that clinicians select between either SGAs or CBT to treat patients with major depressive disorder after discussing treatment effects, adverse effects, cost, accessibility and patient preferences.
*Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians.
Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A
Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

22. A DEBATE
In order to structure a debate between our discussants, we mutually agreed on the following key questions to consider when applying this guideline to clinical practice in general and Mr. Y in particular:
Question 1: What is the comparative effectiveness and what are the harms of the available pharmacologic and non-pharmacologic therapies for major depressive disorder?
Question 2: How do you help a patient choose between the available therapies while considering the cost, efficacy, harms and availability of services?
Question 3: What treatment options are available for a patient with depression who did not have an adequate response to their initial therapy?

23. Deborah Cotton, MD, MPH (Moderator)
Professor of Medicine, Boston University School of Medicine
Deputy Editor, Annals of Internal Medicine
Gerald Smetana, MD, MACP
Division of General Medicine and Primary Care, BIDMC
Professor of Medicine, Harvard Medical School
Roscoe Brady, MD, PhD
Division of Psychiatry, BIDMC
Assistant Professor of Psychiatry, Harvard Medical School

24. Gerald W. Smetana, MD, MACP Primary Care Viewpoint

25. Question 1: What is the comparative effectiveness and what are the harms of the available pharmacologic and non- pharmacologic therapies for major depressive disorder?

26. ACP Bottom Line: No Difference in Response or Remission Between SGA and Non-Pharm Rx
*Gartlehner G, Gaynes BN, Amick HR, Asher GN, Morgan LC, Coker-Schwimmer E, et al.
Comparative Benefits and Harms of Antidepressant, Psychological, Complementary, and
Exercise Treatments for Major Depression: An Evidence Report for a Clinical Practice
Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

27. Remember: ACP Recommends CBT as a Potential First Line Rx for Depression! Why Not?

28. St. John’s Wort as Effective as SGAs vs. Placebo OR 1. 54 vs. SGA OR 1
*Apaydin EA, Maher AR, Shanman R, Booth MS, Miles JN, Sorbero ME, et
al. A systematic review of St. John's wort for major depressive disorder.
Syst Rev. 2016;5:148.

29. Response Rates: Acupuncture Does not Differ from Antidepressant Rx
*Reprinted from Journal of Affective Disorders, Vol 124, Zhang ZJ, Chen HY, Yip KC, Ng R, Wong VT.
The effectiveness and safety of acupuncture therapy in depressive disorders: systematic review
and meta-analysis. pp 9-21, Copyright 2009, with permission from Elsevier.

30. ACP: Trend Towards Lower D/C Rates Due to Adverse Events for Counseling and Some CAM Rx’s
*Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians.
Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A
Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164:

31. Adverse Events Much Less Common for Acupuncture and St
Adverse Events Much Less Common for Acupuncture and St. John’s Wort than for SGAs
SGA (SSRIs as example)
Any (40%)*
Nausea (10%)
Headaches (10%)
Sweatiness (10%)
Insomnia (15%)
Sexual side effects (up to 50%)
Can induce manic episode if bipolar
Serotonin syndrome due to drug interactions
Acupuncture
Any (10%)*
Pain at needle sight
Dizziness
St John’s Wort
Rates similar to placebo**
GI, dizziness, sedation, photosensitivity, dry mouth rarely
interactions
*Zhang ZJ, Chen HY, Yip KC, Ng R, Wong VT. The effectiveness and
safety of acupuncture therapy in depressive disorders: systematic review
and meta-analysis. J Affect Disord. 2010;124:9-21.
**Knüppel L, Linde K. Adverse effects of St. John's Wort: a systematic
review. J Clin Psychiatry. 2004;65:

32. 17 trials in primary care settings
Dr. Brady Will State that Trials Do Not Reflect Real World and Only 3 are in PCP Settings: Is This Accurate?
17 trials in primary care settings
ACP: SGA vs. psychological interventions: 5 trials in primary care settings
16% drop out rate
ACP: SGA vs. CAM therapies 12 of 20 trials in primary care settings
Does not indicate near perfect participation

33. Dr. Brady Will Cite “3” Primary Care Trials in Favor of SGAs: How Were These Actually Conducted?
Miranda (2003):
Low income young minority women recruited from WIC food subsidy programs, not primary care settings
83% of women randomized to community health counseling did not attend a single visit
Not a representative sample
Revicki (2005): Same cohort as Miranda. No new data
Kendrick (2009):
Supportive care vs. supportive care + SSRI
Supportive care = PCP follow up with no counseling
Essentially a trial of SSRI vs. placebo
*Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study. Health Technol Assess. 2009;13:1-159.
*Revicki DA, Siddique J, Frank L, Chung JY, Green BL, Krupnick J, et al Cost-effectiveness of evidence-based pharmacotherapy or cognitive behavior therapy compared with community referral for major depression in predominantly low-income minority women. Arch Gen Psychiatry. 2005;62:
*Miranda J, Chung JY, Green BL, Krupnick J, Siddique J, Revicki DA, et al. Treating depression in predominantly low- income young minority women: a randomized controlled trial. JAMA. 2003;290:57-65.

34. Question 2: How do you help a patient choose between the available therapies while considering the cost, efficacy, harms and availability of services?

35. Shared Decision Making
What does your patient fear most?
What adverse events would be tolerable as opposed to disabling or unacceptable?
Will your patient live with minor SGA side effects?
Is there a need for a rapid treatment response due to severe depression?
Philosophy about “natural” Rx vs. prescriptions
Is a 2-6 month Rx window acceptable?
Does your patient have time and/or finances for the costly and/or time consuming options?

36. Problems with SGA as 1st Line Rx
May take 8-12 weeks to work
High side effect burden
40% adverse event rate
Sleep disturbances, weight gain common
Night sweats may be troubling
High dropout rate
May need to try more than 1 SGA to achieve response
Two or more drugs commonly required
Not a “natural” Rx

37. Pros and Cons: Counseling
Response rates comparable to SGA
Free of adverse events
Durable when patient applies tools learned for life long change
“Natural” Rx
CONS
Stigma of Rx
Time consuming - multiple visits per week/month
Expensive - $ per hour common
Health insurance covers most of cost but with caps on visits per year
Not always readily available

38. Are Mr. Y’s Concerns about Antidepressants Valid?
SGA are not “addicting” in the usual sense
Some patients do in fact become dependent in the sense that they relapse off the drug or worry about this potential and don’t want a drug free trial
Some patients will require lifelong Rx
Mr. Y is correct that side effects are common, often troubling, and frequently lead to Rx discontinuation
Personality change? Usually in a positive fashion
Some patients feel “numb” or apathetic on Rx

39. Question 3: What treatment options are available for a patient with depression who did not have an adequate response to their initial therapy?

40. STAR*D: Augmentation with Cognitive Therapy Does Not Differ from Adding 2nd Med, although Slower
Response Rates P=0.17
Meds:
Buspirone or
Bupropion
*Thase ME, Friedman ES, Biggs MM, Wisniewski SR, Trivedi MH, Luther JF, et al.
Cognitive therapy versus medication in augmentation and switch strategies as
second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:

41. STAR*D: Switch to Cognitive Therapy Equally Effective as Switch to New Medication
Meds:
Bupropion
Sertraline
Venlafaxin
Response Rates P=0.74
*Thase ME, Friedman ES, Biggs MM, Wisniewski SR, Trivedi MH, Luther JF, et al.
Cognitive therapy versus medication in augmentation and switch strategies as
second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:

42. What to Recommend for Mr. Y?
As no SI, no disabling depression, there is no urgency for rapid Rx response
Continue therapy for at least 2-3 months
Work with therapist with expertise in CBT
If no response, choices would be addition of acupuncture or St. John’s Wort if continues to be skeptical of medications
Consider SGA depending on patient preferences and shared decision making. More potential for side effects than other Rx

43. Roscoe Brady, MD, PhD
Psychiatry Viewpoint

44. Question 1: What is the comparative effectiveness and what are the harms of the available pharmacologic and non- pharmacologic therapies for major depressive disorder?

45. A Problem With Clinical Trials: They occur under idealized conditions
An example:
Trial of CBT vs. SGA. Of 56 patients allocated to the CBT trial arm, 55 engaged in CBT. Fully 90% completed treatment.
Does that match the Primary Care experience of referring patients to CBT? Or acupuncture? Or exercise?
What if we incorporate access to treatments into the trial?
*David D, Szentagotai A, Lupu V, Cosman D. Rational emotive behavior therapy,
cognitive therapy, and medication in the treatment of major depressive
disorder: a randomized clinical trial, posttreatment outcomes, and six-month
follow-up. J Clin Psychol. 2008;64:

46. Clinical Trial Structure
The “Trial Space”
Access: Not assessed. Almost all enter intervention
Tolerability: 90% Completion In All Arms
SGA
Recruitment
Assessment
Enrollment
Randomization
Other Therapy
Efficacy:
CBT = SGA
CBT

47. “Practical Clinical Trial” Structure Efficacy (Response/ Remission)
The “Practical Trial Space”
Accessibility
Tolerability
SGA
Prescribe
Recruitment
Assessment
Enrollment
Efficacy (Response/ Remission)
Randomization
Refer
CBT
Recommend
“Other”

48. Results of two RCTs in the primary care setting comparing PCPs Prescribing SGAs vs PCPs Referring to Other Treatment
Miranda et al, RCT of young women with depression seen in primary care and randomized to either:
1) Prescribed SGA or
2) Enroll in a trial of CBT
3) Referred to Community Mental Health Center
Patients treated with SGA twice as likely to achieve remission compared to those referred to other mental health providers. This intervention was also more cost effective than referral.
*Miranda J, Chung JY, Green BL, Krupnick J, Siddique J, Revicki DA, et al. Treating depression in predominantly low-income young minority women: a randomized controlled trial. JAMA. 2003;290:57-65.
*Revicki DA, Siddique J, Frank L, Chung JY, Green BL, Krupnick J, et al. Cost-effectiveness of evidence-based pharmacotherapy or cognitive behavior therapy compared with community referral for major depression in predominantly low-income minority women. Arch Gen Psychiatry. 2005;62:

49. Results of two RCTs in the primary care setting comparing PCPs Prescribing SGAs vs PCPs Referring to Other Treatment
Kendrick et al, RCT of patients with depression seen by general practitioners in the UK and randomized to either:
1) Supportive Care (defined as frequent follow-up plus counselling, referral to psychotherapy, exercise regimens, i.e. anything other than SSRI)
2)Supportive Care PLUS treatment with SSRI
Supportive Care PLUS SSRI is both more efficacious and cost effective than Supportive Care Alone.
*Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study. Health Technol Assess ;13:1-159.

50. Summary
SGAs and CBT are comparable in effectiveness in trials that have near 100% entry into treatment and 90% adherence to a full course of therapy.
When you incorporate real world conditions i.e. Compare PCP prescribed SGA versus PCP referred alternative treatments,
Prescribing an SGA is more efficacious and cost-effective than referral to other treatments, despite differences in tolerability.

51. Question 2: How do you help a patient choose between the available therapies while considering the cost, efficacy, harms and availability of services?

52. Make sure you and the patient have the same understanding of their options: What are the risks, costs, and efficacy?
What treatments can they access?
How much time do you have (i.e. how severe is the depressive episode)?
When and how will you evaluate the efficacy of your intervention?

53. Question 3: What treatment options are available for a patient with depression who did not have an adequate response to their initial therapy?

54. What are the key questions to ask:
1) Was the initial treatment non-pharmacologic?
Supplement with SGA.
How to choose the next SGA.
This is a good time to revisit the patient’s understanding of their options.
2) Was the initial treatment a SGA?
Should you switch to a different SGA?
Should you supplement with another SGA?
Should you refer to CBT?
How to decide on the next best step:
The patient did not get to remission but did they respond?
What is the patient’s preference?
RCTs suggest switching within class (e.g. SSRI to SSRI) and switching to a different class (e.g. SSRI to SNRI) are equally efficacious.

55. After two failed trials of a SGA:
Refer to psychiatric prescriber (i.e. a psychiatrist or advanced practice nurse). Subsequent trials have a low chance of resulting in remission.
Specialty care allows for closer follow-up and more time to evaluate for other psychiatric illness such as a substance use disorder, bipolar disorder, or post-traumatic stress disorder.
*Rush AJ. STAR*D: what have we learned? Am J Psychiatry. 2007;164:

56. Specific Recommendations for Mr. Y
Psychoeducation: Mr. Y’s is concerned about becoming addicted to antidepressants. He should be reassured that antidepressant medications are not addictive. We can then re-assess the patient’s stance on different treatment options.
Psychotherapy: Mr. Y has a history of engaging in psychotherapy, making it a part of his life for years and likely benefitting from it. He also has succeeded in engaging with a therapist in his current depressive episode. Is he as likely to benefit from this as a SGA? Unclear (e.g. Williams et al.)
Evaluation for treatment response: If he did not achieve remission by a week follow-up, I would recommend adding an SGA at that time.
*Williams JW Jr, Barrett J, Oxman T, Frank E, Katon W, et al. Treatment of dysthymia and minor depression in primary care: A randomized controlled trial in older adults. JAMA. 2000;284:

57. Dr. Smetana & Dr. Brady

58. 2nd Audience Vote
Will Go Here

59. Would you start this patient on an anti-depressant medication?
Would you start this patient on an anti-depressant medication?

60. Gerald Smetana, MD & Roscoe Brady, MD, PhD Last Minute Productions
We would like to thank…
Our Patient, Mr. Y.
Gerald Smetana, MD & Roscoe Brady, MD, PhD
Last Minute Productions
BIDMC Media Services
Kendra McKinnon
Anjala Tess, MD
Eileen Reynolds, MD
Gerald Smetana, MD
Risa Burns, MD, MPH
Deborah Cotton, MD, MPH

61. © 2017 American College of Physicians
The information contained herein should never be used as a substitute for clinical judgment.