Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative

1. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review First Last, Credentials

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5. Learning Objectives Upon completion of this activity, the participant is expected to be able to: Compare the effectiveness and efficacy of antidepressants in treating depressive symptoms in adults Assess the benefits and harms of antidepressants among certain adult patient subgroups Apply the findings of the systematic review to improve outcomes for adult patients through patient-centered care

6. Background: Depression • Pharmacotherapy management • 1st generation antidepressants • Tricyclic antidepressants • Monoamine oxidase inhibitors • 2nd generation antidepressants • Selective serotonin reuptake inhibitors • Selective serotonin and norepinephrine reuptake inhibitors • Other 2nd-generation antidepressants • Depressive disorders: • Major depressive disorder (MDD) • Dysthymia • Subsyndromal depression (including minor depression) • Most prevalent: MDD • Affecting 16% (lifetime) of US adults • Economic burden (2000): $83.1 billion – 30% of cost is direct medical expenses Egan BM, et al. JAMA. 2010;303:2043-2050. Law, MR et al. BMJ. 2003;326:1427-1431.

7. Pharmacotherapy • Efficacy of 1st and 2nd generation antidepressant mediations is similar, however: • 1st generation antidepressants often • Produce multiple side effects patients find intolerable • Have risk for harm when taken in overdose or in combination with certain other meds • 2nd generation antidepressants are the focus of this review because they • Have relatively favorable side-effect profile • Play a prominent role in management of patients with MDD Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

8. Phases of Treatment for Clinical Depression TIME Episode of Depression Remission Sustained Remission INCREASED SEVERITY Baseline Unresolved Symptoms SOME SYMPTOMS OF DEPRESSION Response Treatment Begins Clinical Depression Relapse Recurrence Acute phase Continuation phase Maintenance phase 6-12 weeks 4-9 months ≥ 1 year Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52 Suppl:28-34.

9. 2nd Generation Antidepressants in U.S. Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

10. Key Questions: KQ1a – KQ2b Do commonly used medications for depression differ in efficacy or effectiveness in treating depressive symptoms? (KQ1a) If a patient has responded to one agent in the past, is that agent better than current alternatives at treating depressive symptoms? (KQ1b) Are there any differences in efficacy or effectiveness between immediate-release and extended-release formulations of second-generation antidepressants? (KQ1c) For responders to antidepressant treatment, do 2nd-generation antidepressants differ in efficacy or effectiveness for preventing relapse (i.e., continuation phase) or recurrence (i.e., maintenance phase) when a patient continues the drug they initially responded to or switches to a different antidepressant? (KQ2a) For adults with a depressive syndrome that has not responded to acute antidepressant treatment or has relapsed (continuation phase) or recurred (maintenance phase), do alternative second-generation antidepressants differ in their efficacy or effectiveness? (KQ2b) Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm. .

11. Key Questions: KQ3-KQ5 With accompanying symptoms such as anxiety, insomnia, and neurovegetative symptoms, do medications or combinations of medications differ in efficacy or effectiveness for treating the depressive episode or for treating the accompanying symptoms? (KQ3) For adults with a depressive syndrome, do commonly used antidepressants differ in safety, adverse events, or adherence? (KQ4a) Are there any differences in safety, adverse events, or adherence between immediate-release and extended-release formulations of second-generation antidepressants? (KQ4b) How do the efficacy, effectiveness, or harms of treatment with antidepressants for a depressive syndrome differ for the following subpopulations? • Elderly or very elderly patients • Other demographic groups (defined by age, ethnic or racial group, and sex) • Patients with medical comorbidities (e.g., IHD, cancer) • Patients with psychiatric and behavioral comorbidities (e.g., substance abuse disorders) • Patients taking other medications Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm. .

12. Framework for the Comparative Effectiveness Update of Second-Generation Antidepressants KQ1, KQ2, KQ3, KQ5 Intermediate Outcomes Treatment for MDD, dysthymia, or subsyndromal depressive disorders • KQ1, KQ3 • Acute Phase • Response • Remission • KQ2, KQ3 • Continuation Phase • Maintenance of response • Maintenance of remission • Final Health Outcomes • Quality of Life • Functional Capacity Second-Generation Antidepressants KQ4 Adverse effects of treatment Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

13. Grading the Strength of Evidence Ratings based on GRADE(Grading of Recommendations Assessment, Development, and Evaluation) framework Considerations: number of studies, the size of the studies, strength of study design, and the quality of individual studies Strength of evidence classified into 4 categories: e Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

14. 6,186 records from database search 167 records from other sources Study Design Identification 6,353 identified (3,722 records remaining after eliminating duplicates) 2,265 excluded 3,722 abstracts screened Screening • 1,190* full-text articles excluded: • 7 Foreign languages • 10 Too short of duration • 84 Wrong population • 142 Wrong drug • 197 Wrong outcome • 260 Wrong publication • 279 Does not address outcomes of interest • 464 Wrong design • 79 Poor quality • * Multiple exclusion reasons are possible for each article 1,457 full-text articles assessed for eligibility 228 studies (267 articles) included in qualitative synthesis Eligibility Included 92 studies included in quantitative synthesis • Strength of evidence grades (high, moderate, low, or insufficient) based on methods guidance for the EPC program; outcomes for which we have no studies are designated no evidence. • Good, fair, or poor designations relate to quality grades given to each study; see Methods chapter of main report. We provide the designations only for good (or poor) studies; the remaining studies are all of fair quality.

15. Overview of Findings of 2nd-Generation Antidepressants • Generally, 2nd-generation antidepressants have similar effectiveness • 37% of patients with no improvement • 53% had only partial improvement • 25% - 33% improved with addition or substitution of a different drug if the first drug = no improvement • These medications worked at different rates • 7 studies funded by the manufacturer of mirtazapine suggested that it worked faster than citalopram, fluoxetine, paroxetine, or sertraline Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

16. Overview of Findings of 2nd- Generation Antidepressants • Average of 63% experienced ≥ 1 side effect • Most common are nausea and vomiting, constipation, diarrhea, dizziness, headache, and sleeplessness • Venlafaxine, an SNRI, associated with a higher incidence of nausea and vomiting than SSRIs. • Venlafaxine more likely than SSRIs to be discontinued due to adverse events, but less likely to be discontinued because of lack of efficacy • Sertraline more likely to cause diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, or venlafaxine SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

17. Overview of Findings of 2nd- Generation Antidepressants Mirtazapine led to higher weight gains than fluoxetine, paroxetine, venlafaxine, or trazodone. Trazodone showed higher rates of sleepiness than bupropion, fluoxetine, mirtazapine, paroxetine, or venlafaxine. Paroxetine and venlafaxine had the highest rates of discontinuation syndrome—a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRIs or SNRIs. Fluoxetine produced the lowest rates of the syndrome. Bupropion less likely to cause sexual dysfunction than fluoxetine, paroxetine, or sertraline. Paroxetine had higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline. Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

18. Overview of Findings of 2nd-Generation Antidepressants Efficacy among all of the 2nd-generation medications did not differ substantially for treatment of depression in patients with accompanying anxiety Efficacy among all of the medications did not differ between people older than 55 years or those with type 2 diabetes. No evidence addressed how 2nd-generation antidepressants compare when a patient responds to one agent and then is required to switch to a different agent (e.g., because of changes in health insurance benefits). Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

19. Summary of Findings, KQ 1a: Major Depressive Disorder Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

20. Summary of Findings, KQ 1a: Dysthymia Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

21. Summary of Findings, KQ 1a: Subsyndromal Depression Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

22. Summary of Findings, KQ 1b: Greater Efficacy/Effectiveness with Previously Effective Medications Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

23. Summary of Findings, KQ1c: Efficacy/Effectiveness - IR vs. XR CR = controlled release; IR = immediate release; XR = extended release Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

24. Summary of Findings, KQ2a: Maintenance of Response or Remission Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

25. Summary of Findings, KQ2b: Achieving Response in Unresponsive or Recurrent Disease Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

26. Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Anxiety Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

27. Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Insomnia Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

28. Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Low Energy Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

29. Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Melancholia Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

30. Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Pain Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

31. Summary of Findings, KQ3: Treatment of Depression in Patients With Psychomotor Change Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

32. Summary of Findings, KQ3: Treatment of Depression in Patients With Accompanying Somatization Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

33. Summary of Findings, KQ4a: Risk of Harms – General Tolerability Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

34. Summary of Findings, KQ4a: Risk of Harms – General Tolerability continued Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

35. Summary of Findings, KQ4a: Risk of Harms – Severe Adverse Events Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

36. Summary of Findings, KQ4a: Risk of Harms – Severe Adverse Events continued Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

37. Summary of Findings, KQ4a: Risk of Harms – Adherence Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

38. Summary of Findings, KQ4b: Differences of Harms – MDD Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

39. Summary of Findings, KQ5: Subgroups– Age

40. Summary of Findings, KQ5: Subgroups– Sex Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

41. Summary of Findings, KQ5: Subgroups– Comorbidities Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

42. Clinical Bottom Line:Limitations Most trials were conducted in highly selected populations Publication bias might affect the estimates of some comparisons Mixed-treatment comparisons cannot conclusively exclude differences in efficacy. Evidence within subgroups was limited Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

43. Clinical Bottom Line:Conclusion Current evidence does not warrant recommending a particular 2nd-generation antidepressant on the basis of differences in efficacy Differences in onset of action and adverse events may be considered when choosing a medication Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

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