1. Augmentation of Standard Antidepressant Therapy for Major Depressive Disorder Derek S. Mongold MD Assistant professor WVU School of medicine www.DerekMongold.com

3. Objectives Show why treatment of depression to remission is important. Set realistic expectations for treatment. Show alternative treatments for resistant major depressive disorder (MDD). www.DerekMongold.com

4. Outline Why should family docs care? Efficacy of treatment. Treatment resistance. STAR*D. Other augmenting agents. www.DerekMongold.com

5. What is Major Depressive Disorder? www.DerekMongold.com

7. Why Should Family Docs Care? www.DerekMongold.com

8. Why Should Family Docs Care? CAD: www.DerekMongold.com

9. Why Should Family Docs Care? CAD: SADHART trial 1 : – Greater baseline severity of MDD within a few weeks of hospitalization for ACS resulted in twice the risk of mortality (HR = 2.30). – Lack of improvement in MDD during antidepressant treatment resulted in twice the risk of mortality (HR = 2.39). www.DerekMongold.com

10. Why Should Family Docs Care? www.DerekMongold.com

11. Why Should Family Docs Care? MDD interacts with Diabetes 18. www.DerekMongold.com

12. Why Should Family Docs Care? MDD interacts with Diabetes 18. – Over 6 years, the relative risk for all cause mortality was: – Depression alone: – Diabetes alone: – Depression and Diabetes combined: www.DerekMongold.com

13. Why Should Family Docs Care? MDD interacts with Diabetes 18. – Over 6 years, the relative risk for all cause mortality was: – Depression alone: 1.76 – Diabetes alone: 1.71 – Depression and Diabetes combined:3.11 www.DerekMongold.com

14. Why Should Family Docs Care? COPD: www.DerekMongold.com

15. Why Should Family Docs Care? COPD: – Depressive symptoms at baseline almost double the odds of mortality 2. (OR = 1.93; 95% CI, 1.12-3.33; P<0.5). www.DerekMongold.com

16. Why Should Family Docs Care? Rehospitalization: www.DerekMongold.com

17. Why Should Family Docs Care? Rehospitalization: – MDD triples the odds of rehospitalization 3. (OR = 3.34; 95% CI, 1.20 – 9.25; P=0.02). www.DerekMongold.com

18. Why Should Family Docs Care? MDD is also a risk factor for developing: www.DerekMongold.com

19. Why Should Family Docs Care? MDD is also a risk factor for developing: – CAD. – Obesity. – DM-II. – Pulmonary disorders. – Neurodegenerative disorders. – Osteoporosis. www.DerekMongold.com

20. Why Should Family Docs Care? Patients with serious mental illness DIE 25 YEARS EARLIER than the general population. www.DerekMongold.com

21. Why Should Family Docs Care? Prevalence of major depressive disorder in primary care settings. www.DerekMongold.com

22. Why Should Family Docs Care? Prevalence of major depressive disorder in primary care settings 4. 5-13% in adults. 6-9% in older adults www.DerekMongold.com

23. Efficacy of Treatment www.DerekMongold.com

24. Efficacy of Treatment Question: What percent of patient’s are in remission after first line therapy? www.DerekMongold.com

25. Efficacy of Treatment Question: What percent of patient’s are in remission after first line therapy? Answer: 30-35% 5. www.DerekMongold.com

26. Efficacy of Treatment Question: How much response do you have to get to function normally? www.DerekMongold.com

27. Efficacy of Treatment

28. Question: How much response do you have to get to function normally? Answer: Complete remission is needed to function normally 6. www.DerekMongold.com

29. Efficacy of Treatment www.DerekMongold.com

30. Treatment Resistance Definition: www.DerekMongold.com

31. Treatment Resistance Definition: Not responding to two trials of antidepressants from different pharmacologic classes with adequate dose, duration, and compliance. www.DerekMongold.com

32. Treatment Resistance Prevalence: www.DerekMongold.com

33. Treatment Resistance Prevalence: – 2% of the US population 7. www.DerekMongold.com

34. Treatment Resistance Causes: www.DerekMongold.com

35. Treatment Resistance Causes: – Medication nonadherence. 30% discontinuation rate at 1 month. 50% discontinuation rate at 4 months. – Inadequate dose. – Inadequate duration of treatment. – Wrong diagnosis (eg. Bipolar disorder, substance induced mood disorder, adjustment D/O, Bereavement, personality D/O, etc.). www.DerekMongold.com

36. Treatment Resistance Final results of the STAR*D trail show that after 4 steps of treatment about 67% of patients can eventually attain remission of depression 8. www.DerekMongold.com

37. STAR-D 8 www.DerekMongold.com

39. STAR-D www.DerekMongold.com

40. STAR-D www.DerekMongold.com Citalopram Bupropion SR Sertraline Venlafaxine XR Cognitive Therapy (CT ) Citalopram + CT Citalopram + Bupropion SR Citalopram + Buspirone SwitchAugment/combine Switch Bupropion SR Venlafaxine XR Mirtazapine Nortriptyline Lithium + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram T 3 + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram Tryanylcypromine Mirtazapine + Venlafaxine SR Switch Augment 1 2 3 4

41. STAR-D Step 1:Response Rate – Citalopram (Celexa). www.DerekMongold.com

42. STAR-D Step 1:Response Rate – Citalopram (Celexa). (32.9%) www.DerekMongold.com

43. STAR-D Step 2a (switch):Response Rate – Bupropion SR (Wellbutrin). – Sertraline (Zoloft). – Venlafaxine (Effexor XR). Step 2b (Augment): – Citalopram + Bupropion SR. – Citalopram + Buspirone. www.DerekMongold.com

44. STAR-D Step 2a (switch):Response Rate – Bupropion SR (Wellbutrin).(25.5%) – Sertraline (Zoloft).(26.8%) – Venlafaxine (Effexor XR).(25.0%) Step 2b (Augment): – Citalopram + Bupropion SR.(39.0%) – Citalopram + Buspirone.(32.9%) www.DerekMongold.com

45. STAR-D Step 3a (Switch):Response Rate – Mirtazapine (Remeron). – Nortriptyline (Pamelor). Step 3b (Augment): – Lithium + Original antidepressant. – T3 + Original antidepressant. www.DerekMongold.com

46. STAR-D Step 3a (Switch):Response Rate – Mirtazapine (Remeron).(8.0%) – Nortriptyline (Pamelor).(12.4%) Step 3b (Augment): – Lithium + Original antidepressant.(13.2%) – T3 + Original antidepressant.(24.7%) www.DerekMongold.com

47. STAR-D Step 4 (Switch)Response Rate – Tranylcypromine (Parnate). – Mirtazapine + Venlafaxine SR. www.DerekMongold.com

48. STAR-D Step 4 (Switch)Response Rate – Tranylcypromine (Parnate).(13.8%) – Mirtazapine + Venlafaxine SR.(15.7%) www.DerekMongold.com

49. STAR-D www.DerekMongold.com

50. STAR-D www.DerekMongold.com 30% Dropout rate 40% Dropout rate n=65n=36

51. STAR-D www.DerekMongold.com Citalopram Bupropion SR Sertraline Venlafaxine XR Cognitive Therapy (CT ) Citalopram + CT Citalopram + Bupropion SR Citalopram + Buspirone SwitchAugment/combine Switch Bupropion SR Venlafaxine XR Mirtazapine Nortriptyline Lithium + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram T 3 + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram Tryanylcypromine Mirtazapine + Venlafaxine SR Switch Augment 1 2 3 4

52. STAR-D www.DerekMongold.com

53. Other Augmenting Agents www.DerekMongold.com

54. Atypical Antipsychotics Aripiprazole (Abilify): www.DerekMongold.com

55. Atypical Antipsychotics Aripiprazole (Abilify): – The first atypical antipsychotic approved in the US as add-on therapy. – At least 3 trials show its efficacy over placebo 9-11. – Added to patients failing to remit when taking antidepressant monotherapy (eg. During first failure). www.DerekMongold.com

56. Atypical Antipsychotics www.DerekMongold.com

57. Atypical Antipsychotics – Quetiapine (Seroquel XR): www.DerekMongold.com

58. Atypical Antipsychotics – Quetiapine (Seroquel XR): Two trials show better response and remission rates over placebo 12-13. However, the 150mg dose was barely significantly better in one trial and the 300mg dose was barely significantly better in one trial. Added to patients failing to remit when taking antidepressant monotherapy (eg. During first failure). www.DerekMongold.com

59. Atypical Antipsychotics www.DerekMongold.com

60. Atypical Antipsychotics – Olanzapine-Fluoxetine (Symbyax) 14 : www.DerekMongold.com

61. Atypical Antipsychotics – Olanzapine-Fluoxetine (Symbyax) 14 : At least 5 studies. Added after patient’s failed to respond to 2 different antidepressants in the current episode. Remission rate of 25.5% for Symbyax. – Fluoxetine (Prozac) alone (17.3%, P=.006). – Olanzapine (Zyprexa) alone (14.0%, P<0.001). www.DerekMongold.com

62. Other Antidepressants Mirtazapine (Remeron) 15 : www.DerekMongold.com

63. Other Antidepressants Mirtazapine (Remeron) 15 : – Patient’s received the following drug combinations:Remission Rates Fluoxetine (Prozac). Fluoxetine + Mirtazapine. Venlafaxine (Effexor) + Mirtazapine. Bupropion (Wellbutrin) + Mirtazapine. www.DerekMongold.com

64. Other Antidepressants Mirtazapine (Remeron) 15 : – Patient’s received the following drug combinations:Remission Rates Fluoxetine (Prozac).(25%) Fluoxetine + Mirtazapine.(52%) Venlafaxine (Effexor) + Mirtazapine.(58%) Bupropion (Wellbutrin) + Mirtazapine.(46%) www.DerekMongold.com

65. Other Antidepressants www.DerekMongold.com

66. Psychotherapy www.DerekMongold.com

67. Psychotherapy In the STAR*D trial 16, psychotherapy was either added to Citalopram (augmentation) or used alone after initial failure of Citalopram (switch). www.DerekMongold.com

68. Psychotherapy In the STAR*D trial 16, psychotherapy was either added to Citalopram (augmentation) or used alone after initial failure of Citalopram (switch). – Remission rate with augmentation: (29.4%). – Remission rate with switching to therapy: (41.9%). www.DerekMongold.com

69. Psychotherapy www.DerekMongold.com

70. Psychostimulants www.DerekMongold.com

71. Psychostimulants Dexamphetamine, methylphenidate, methlamphetamine, pemoline, Modafinil: www.DerekMongold.com

72. Psychostimulants Dexamphetamine, methylphenidate, methlamphetamine, pemoline, Modafinil: – A recent systematic review in the Cochrane Database fond only modest support for psychostimulents 17. – In the 3 small trials that showed short-term benefit, the improvement in depressive symptoms was of questionable clinical significance. – No benefit found for Modafinil. www.DerekMongold.com

73. Other Agents www.DerekMongold.com

74. Other Agents Insufficient evidence to recommend for or against. – Pindolol. – L-methylfolate (Deplin). – Estrogens. – Testosterone. www.DerekMongold.com

75. Conclusions www.DerekMongold.com

76. Conclusions Major depressive disorder is common and relevant to the family doctor’s practice. www.DerekMongold.com

77. Conclusions Major depressive disorder is common and relevant to the family doctor’s practice. Treatment resistance is a common phenomenon in Major depression. www.DerekMongold.com

78. Conclusions Major depressive disorder is common and relevant to the family doctor’s practice. Treatment resistance is a common phenomenon in Major depression. Several alternatives to first line treatment of major depressive disorder exist. www.DerekMongold.com

79. Review of Augmentation Strategies. www.DerekMongold.com

80. Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). www.DerekMongold.com

81. Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar). www.DerekMongold.com

82. Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar). Lithium. www.DerekMongold.com

83. Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar). Lithium. T 3 (Cytomel). www.DerekMongold.com

84. Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar). Lithium. T 3 (Cytomel). 2 nd generation antipsychotics. – Aripiprazole (Abilify). – Quetiapine SR (Seroquel XR). – Olanzapine + Fluoxetine (Symbyax). www.DerekMongold.com

85. Review of Augmentation Strategies. Mirtazapine (Remeron). www.DerekMongold.com

86. Review of Augmentation Strategies. Mirtazapine (Remeron). Psychotherapy. www.DerekMongold.com

87. Review of Augmentation Strategies. Mirtazapine (Remeron). Psychotherapy. Psychostimulats. www.DerekMongold.com

88. References 1. Glassman AH, Bigger JT Jr, Gaffney M. Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression: seven- year follow-up of SADHART participants. Arch Gen Psychiatry. 2009;66(9):1022-1029. 2. de Voogd JN, Wempe JB, Koeter GH, et al. Depressive symptoms as predictors of mortality in patients with COPD. Chest. 2009;135(3):619-625. 3. Kartha A, Anthony D, Manasseh CS, et al. Depression is a risk factor for rehospitalization in medical inpatients. Prim Care Companion J Clin Psychiatry. 2007:9(4):256-262. 4. O’Conner EA, Whitlock EP, Gaynes B, et al. Screening for Depression in Adults and Older Adults in Primary Care: An Updated Systematic Review. Rockville, MD: Agency for Healthcare Research and Quality: 2009. Evidence Report No. 75 AHRQ Publication No. 10-05143-EF-1. 5. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term out=comes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. 6. Thase ME. Update on partial response in depression. J Clin Psychiatry. 2009:70(suppl 6):4-9. 7. Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68(suppl 8):17-25. 8. US National Institutes of Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D). http://clinical trials.gov/show/NCT00021528. Published September 24,2009. 9. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of Aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(6):843-853. 10. Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of Aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(2):156-165. www.DerekMongold.com

89. References 11. Berman RM, Fava M, Thase ME, et al. Aripiprazole augmentation in major depressive disorder: a double blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr. 2009;14(4):197-2006. 12. Bauer M, Protorius HW, Constant EL, et al. Extended-release Quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo- controlled, double-blind study. J Clin Psychiatry. 2009;70(4):540-549. 13. El-Khalili N, Joyce M, Atkinson S, et al. Extended-release Quetiapine fumarate (Quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 14. Trivedi MH, Thase ME, Osuntokun O, et al. An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression. J Clin Psychiatry. 2009:70(3):387- 396. 15. Blier P, Qard HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288. 16. Tush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. 17. Candy B, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev. 2008;(2):CD006722. 18. Pan A, Lucas M, Sun Q, Van Dam RM, et al. Increased Mortality Risk in Women with Depression and Diabetes. JAMA Archives of General Psychiatry. 2011:68(1):42-50. www.DerekMongold.com

91. The Bluebird of Happiness long absent from his life, Ned is visited by the Chicken of Depression.

92. www.DerekMongold.com

94. Measurement-Based Care Defining and measuring therapeutic endpoints. Has been demonstrated to independently contribute to improved outcomes in MDD. Has been referred to as the “Standard of care”. www.DerekMongold.com

95. Measurement-Based Care Symptom Assessment Tools: www.DerekMongold.com

96. Measurement-Based Care Objective Symptom Assessment Tools: – 17-item Hamilton Depression Rating Scale (HDRS 17 ). – Toronto 7-item Hamilton Depression Rating Scale (HDRS 7 ). – Montgomery-Asberg Depression Rating Scale (MADRS). www.DerekMongold.com

97. Measurement-Based Care Subjective Symptom Assessment Tools: – Beck Depression Inventory (BDI). – 9-Item Patient Health Questionnaire (PHQ-9) www.DerekMongold.com

98. Measurement-Based Care Functional Assessment Tools: – Sheehan Disability Scale (SDS). – Social Adjustment Scale – Self Report (SAS-SR). www.DerekMongold.com

99. Measurement-Based Care Quality of Life Assessment Tools: – Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). – Quality of life in Depression Scale (QLDS). www.DerekMongold.com

100. Measurement-Based Care www.DerekMongold.com

101. Measurement-Based Care Who Cares? www.DerekMongold.com

102. Measurement-Based Care Who Cares? – Remission rates with first-line pharmacotherapy is 30-35%. – Patients have to wait 4-6 weeks to see if a patient will respond to a first-line treatment. www.DerekMongold.com

103. Measurement-Based Care Who Cares? – Emerging evidence shows that early (2week) improvement can be detected with depression rating scales. Symptomatic improvement at 2 weeks predicts remission at 6-8 weeks. Nonimprovement at week 2 may be a more robust negative predictor of nonremission at weeks 6-8. www.DerekMongold.com