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

2. Accreditation Statement Physician Credit Designation Statement PRIME Education, Inc. (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. PRIME® designates this live activity for a maximum of.50 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity. Physician Assistant Accreditation Statement AAPA accepts AMA Category 1 CME Credit™ for the PRA from organizations accredited by ACCME. Nurse Practitioner Accreditation Statement PRIME Education, Inc. (PRIME®) is accredited by the American Academy of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 060815. This program is accredited for.50 contact hour. Program ID# CER38. This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standards. Nurse Accreditation Statement PRIME Education, Inc. (PRIME®) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. PRIME® designates this activity for.50 contact hour. California Nurse Accreditation Statement PRIME® designates this educational activity for.50 contact hour for California nurses. PRIME® is accredited as an approver of continuing education in nursing by the California Board of Registered Nursing.

3. Disclosure Information Disclosure Policy PRIME Education, Inc (PRIME ® ) endorses the standards of the ACCME, as well as those of the AANP, ANCC and ACPE, that require everyone in a position to control the content of a CME/CE activity to disclose all financial relationships with commercial interests that are related to the content of the CME/CE activity. CME/CE activities must be balanced, independent of commercial bias and promote improvements or quality in healthcare. All recommendations involving clinical medicine must be based on evidence accepted within the medical profession. A conflict of interest is created when individuals in a position to control the content of CME/CE have a relevant financial relationship with a commercial interest which therefore may bias his/her opinion and teaching. This may include receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, stocks or other financial benefits. PRIME ® will identify, review and resolve all conflicts of interest that speakers, authors, course directors, planners, peer reviewers, or relevant staff disclose prior to an educational activity being delivered to learners. Disclosure of a relationship is not intended to suggest or condone bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. Disclosure information for speakers, authors, course directors, planners, peer reviewers, and/or relevant staff are provided with this activity. Presentations that provide information in whole or in part related to non FDA approved uses of drugs and/or devices will disclose the unlabeled indications or the investigational nature of their proposed uses to the audience. Participants should refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. Participants should verify all information and data before treating patients or employing any therapies prescribed in this educational activity. The opinions expressed in the educational activity are those of the presenting faculty and do not necessarily represent the views of PRIME ®, the ACCME, AANP, ACPE, ANCC and other relevant accreditation bodies.

4. Disclosure Information Program Disclosure Information Advisory BoardConsultant Grants/ Research Salary/ Contractual Supported Promotional Education Stock/Share holder Other Financial Support Bradley N Gaynes, MD, MPH Planner None Carolyn LePage, PhD, ARNP Planner None Barry UniversityNone Heidi Wynn Maloni, PhD, ANP-BC Planner None Name, credentials Speaker None Joyce M Knestrick, PhD, CRNP, FAANP Reviewer None Larry Culpepper, MD, MPH Reviewer None Merck for unbranded presentations re: federally supported research about approaches to reduce hospital readmissions NoneLabopharm Pamela Feinberg-Rivkin, RN, BSN, CCM, CRRN, ABDA, QRP Reviewer None Chris R Prostko, PhD Scientific Program Director None PRIME ® None Lynn Goldenberg, RN, BSN Director of Accreditation & Compliance None PRIME ® None

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 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. Pharmacotherapy management 1 st generation antidepressants Tricyclic antidepressants Monoamine oxidase inhibitors 2 nd generation antidepressants Selective serotonin reuptake inhibitors Selective serotonin and norepinephrine reuptake inhibitors Other 2 nd -generation antidepressants

7. Pharmacotherapy Efficacy of 1 st and 2 nd generation antidepressant mediations is similar, however: 1 st 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 2 nd 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 Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52 Suppl:28-34. TIME Episode of Depression Baseline Clinical Depression Treatment Begins SOME SYMPTOMS OF DEPRESSION Response Remission Sustained Remission RelapseRecurrence Unresolved Symptoms Acute phase Continuation phase Maintenance phase INCREASED SEVERITY 6-12 weeks4-9 months≥ 1 year

9. 2 nd Generation Antidepressants in U.S. Generic NameTrade Name*ClassLabeled UsesGeneric $ † Brand $ † Bupropion ‡ Wellbutrin, Wellbutrin SR, Wellbutrin XL OtherMDD, SAD53-166235-499 Citalopram ‡ CelexaSSRIMDD31-38127-143 DesvenlafaxinePristiqSSRIMDD-157 DuloxetineCymbaltaSSRIMDD, GAD, neuropathic pain, fibromyalgia-166-181 EscitalopramLexaproSSRIMDD, GAD-121-125 Fluoxetine ‡ Prozac, Prozac WeeklySSRIMDD, OCD, PMDD, panic d/o, bulimia nervosa22-136176-449 Mirtazapine ‡ Remeron, Remeron Soltab OtherMDD44-77124-190 Nefazodone ‡ SerzoneOtherMDD-65-70 Paroxetine ‡ Paxil, Paxil CRSSRIMDD, OCD, panic d/o, social anxiety d/o, GAD, PTSD, PMDD § 20-115130-163 Sertraline ‡ ZoloftSSRIMDD, OCD, panic d/o, PTSD, PMDD, social anxiety d/o 28-29146-152 Trazodone ‡ DesyrelOtherMDDNR Venlafaxine ‡ Effexor, Effexor XRSSRIMDD, GAD, panic d/o, social anxiety d/o II 88-129168-193 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 2 nd -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, KQ3 Acute Phase Response Remission KQ1, KQ3 Acute Phase Response Remission Final Health Outcomes Quality of Life Functional Capacity Final Health Outcomes Quality of Life Functional Capacity KQ2, KQ3 Continuation Phase Maintenance of response Maintenance of remission KQ2, KQ3 Continuation Phase Maintenance of response Maintenance of remission Adverse effects of treatment Second-Generation Antidepressants Treatment for MDD, dysthymia, or subsyndromal depressive disorders KQ4 KQ1, KQ2, KQ3, KQ5 Intermediate Outcomes 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 High High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Moderate Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate. Low Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient Evidence is either unavailable or does not permit estimation of an effect. Gartlehner G, et al. AHRQ. Pub No. 12-EHC012-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

14. Study Design Identification Screening Eligibility Included 6,353 identified (3,722 records remaining after eliminating duplicates) 3,722 abstracts screened 6,186 records from database search 167 records from other sources 2,265 excluded 1,457 full-text articles assessed for eligibility 228 studies (267 articles) included in qualitative synthesis 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. 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 1,190* 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

15. Overview of Findings of 2 nd - Generation Antidepressants Generally, 2 nd -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 2 nd - 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 2 nd - 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 2 nd - Generation Antidepressants Efficacy among all of the 2 nd -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 2 nd -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 Outcome of InterestStrength of Evidence Findings Comparative efficacy Moderate61 head-to head trials and 31 placebo-controlled trials indicate no substantial differences in efficacy exist among 2 nd -generation antidepressants Comparative effectiveness Moderate3 effectiveness trials (1 good) and indirect evidence from efficacy trials indicate no substantial differences in effectiveness among 2 nd -generation antidepressants Quality of lifeModerate18 trials indicate efficacy with respect to quality of life does not differ among 2 nd –generation antidepressants Onset of actionModerate 7 trials suggest mirtazapine has significantly faster onset of action than citalopram, fluoxetine, paroxetine, and sertraline. Whether this difference can be extrapolated to other 2 nd -generation antidepressants is unclear. Most other trials do not indicate a faster onset of action of one 2 nd -generation antidepressant compared with another 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy Insufficient No head-to-head evidence exists 5 placebo- controlled trials were insufficient to draw conclusions about comparative efficacy Comparative effectiveness InsufficientNo head-to-head evidence exists. One effectiveness trial provides mixed evidence about paroxetine versus placebo patients older than 60 showed greater improvement on paroxetine those younger than 50 did not show any difference Quality of lifeInsufficientNo Evidence Onset of actionInsufficientNo Evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacyLow 1 nonrandomized, open-label trial did not detect any difference between citalopram and sertraline Results from 2 placebo-controlled trials were insufficient to draw conclusions Comparative effectivenessInsufficientNo Evidence Quality of lifeInsufficientNo Evidence Onset of actionInsufficientNo Evidence 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 Outcome of InterestStrength of Evidence Findings Major depressive disorderInsufficientNo Evidence DysthymiaInsufficientNo Evidence Subsyndromal depressionInsufficientNo Evidence 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 Disorder, and Outcome of Interest Strength of Evidence Findings Major depressive disorder Moderate 2 trials indicate no differences in response to treatment exist between paroxetine IR & paroxetine CR 2 trials did not detect significant differences in maintenance of response and remission between fluoxetine daily and fluoxetine weekly Low1 trial reported higher response rates for venlafaxine XR than venlafaxine IR DysthymiaInsufficientNo Evidence Subsyndromal depression InsufficientNo Evidence 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 Disorder, and Outcome of Interest Strength of Evidence Findings Continuing initial medications ----------------------------------------------------------------------- Comparative efficacy Moderate6 efficacy trials and one naturalistic study; no significant differences exist between escitalopram and desvenlafaxine, escitalopram and paroxetine, fluoxetine and sertraline, fluoxetine and venlafaxine, fluvoxamine and sertraline, and trazodone and venlafaxine for preventing relapse or recurrence. Comparative effectiveness InsufficientNo Evidence Switching medications -------------------------------------------------------------------------------- Comparative efficacy InsufficientNo Evidence Comparative effectiveness InsufficientNo Evidence 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 Disorder, and Outcome of Interest Strength of Evidence Findings Comparative efficacy Low4 trials suggest no differences or only modest differences between SSRIs and venlafaxine Numerical trends favored venlafaxine over comparator drugs in three of these trials Differences were statistically significant in only one trial, which compared venlafaxine with paroxetine Comparative effectiveness Low2 effectiveness studies are conflicting 1 trial rated good; no significant differences in effectiveness exist among bupropion SR, sertraline, and venlafaxine XR 1 effectiveness trial found venlafaxine to be modestly superior to citalopram, fluoxetine, mirtazapine, paroxetine, and sertraline 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy for depression Moderate5 head-to-head trials suggest that efficacy does not differ substantially for treatment of depression in patients with accompanying anxiety. Comparative effectiveness for depression InsufficientNo evidence Comparative efficacy for anxiety Moderate8 head-to-head trials and three placebo-controlled trials suggest that no substantial differences in efficacy exist among 2 nd -generation antidepressants for treatment of accompanying anxiety symptoms. Comparative effectiveness for anxiety InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy for depression InsufficientResults from 1 head-to-head study are insufficient to draw conclusions about the comparative efficacy for treating depression in patients with coexisting insomnia Comparative effectiveness for depression InsufficientNo evidence Comparative efficacy for insomnia Low5 head-to-head trials suggest that no substantial differences in efficacy exist among second-generation antidepressants for treatment of accompanying insomnia. Results are limited by study design; differences in outcomes are of unknown clinical significance Comparative effectiveness for insomnia InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy for depression Insufficient Results from one placebo-controlled trial of bupropion XL are insufficient to draw conclusions about treating depression in patients with coexisting low energy Results from head-to-head trials are not available Comparative effectiveness for depression InsufficientNo evidence Comparative efficacy for low energy Insufficient Results from one placebo-controlled trial of bupropion XL are insufficient to draw conclusions about treating low energy in depressed patients Results from head-to-head trials are not available Comparative effectiveness for low energy InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy for depression Insufficient Results from 2 head-to-head trials are insufficient to draw conclusions about treating depression in patients with coexisting melancholia Results are inconsistent across studies Comparative effectiveness for depression InsufficientNo evidence Comparative efficacy for melancholia InsufficientNo evidence Comparative effectiveness for melancholia InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy for depression Insufficient 2 placebo-controlled trials are conflicting regarding the superiority of duloxetine over placebo. Results from head-to-head trials are not available Comparative effectiveness for depression InsufficientNo evidence Comparative efficacy for pain ModerateEvidence from 1 systematic review, 2 head-to-head trials (one poor), and 5 placebo-controlled trials indicate no difference in efficacy between paroxetine and duloxetine. Comparative effectiveness for pain InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy for depression InsufficientResults from 1 head-to-head trial are insufficient to draw conclusions about the comparative efficacy for treating depression in patients with coexisting psychomotor change Comparative effectiveness for depression InsufficientNo evidence Comparative efficacy for psychomotor change ModerateNo evidence Comparative effectiveness for psychomotor change InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy for depression InsufficientNo evidence Comparative effectiveness for depression InsufficientNo evidence Comparative efficacy for somatization ModerateResults from 1 head-to-head trial Are insufficient to draw conclusions about comparative efficacy for treating somatization Results indicate similar improvement in somatization Comparative effectiveness for somatization InsufficientEvidence from 1 open-label head-to-head trial is insufficient to draw conclusions about comparative efficacy for treating coexisting somatization in depressed patients Results indicate no difference in effectiveness 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 Outcome of InterestStrength of Evidence Findings Adverse-events profiles High92 efficacy trials and 48 studies of experimental or observational design show results are similar among 2nd- generation antidepressants. The incidence of specific adverse events differs across antidepressants Comparative risk of nausea and vomiting HighMeta-analysis of 15 studies indicates that venlafaxine has a higher rate of nausea and vomiting than SSRIs as a class. Comparative risk of weight change High7 trials indicate that mirtazapine leads to higher weight gains than citalopram, fluoxetine, paroxetine, & sertraline Comparative risk of GI adverse events Moderate 15 studies indicate that sertraline has a higher incidence of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine Results from 1 systematic review confirm some of these findings 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 Outcome of InterestStrength of Evidence Findings Comparative risk of somnolence Moderate6 trials indicate that trazodone has a higher rate of somnolence than bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine Comparative risk of discontinuation syndrome ModerateA good systematic review indicates that paroxetine and venlafaxine have the highest rates of discontinuation syndrome fluoxetine has the lowest Comparative risk of discontinuation of treatment HighMeta-analyses of numerous efficacy trials indicate that overall discontinuation rates are similar. Duloxetine and venlafaxine have higher rate of discontinuations due to adverse events than SSRIs as a class Venlafaxine has a lower rate of discontinuations because of lack of efficacy than SSRIs as a class 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 Outcome of InterestStrength of Evidence Findings Comparative risk of suicidality (suicidal thoughts and behavior) Insufficient11 observational studies (2 good quality), 5 meta- analyses or systematic reviews (4 good), and 1 systematic review yield conflicting information about the comparative risk of suicidality Comparative risk of sexual dysfunction High6 trials indicate that bupropion causes significantly less sexual dysfunction than escitalopram, fluoxetine, paroxetine, and sertraline ModerateAmong SSRIs, paroxetine has the highest rates of sexual dysfunction Comparative risk of seizures Insufficient3 studies (1 good observational design) yield conflicting information about the comparative risk of seizures Cardiovascular events Insufficient1 good observational study and 1 pooled analysis yield non-comparative or conflicting information about the comparative risk of CV 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 Outcome of InterestStrength of Evidence Findings Comparative risk of hyponatremia Insufficient No trials or observational studies assessing hyponatremia met criteria for inclusion in this review 1 cohort study not meeting inclusion criteria suggested that hyponatremia was more common in elderly patients treated with various antidepressants than in placebo-treated patients Comparative risk of hepatotoxicity Insufficient Evidence from existing studies is insufficient to draw conclusions about the comparative risk of hepatotoxicity Weak evidence indicates that nefazodone might have an increased risk of hepatotoxicity Comparative risk of serotonin syndrome Insufficient No trials or observational studies assessing serotonin syndrome were included in this review Numerous case reports of this syndrome exist but were not included in this review 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 Outcome of InterestStrength of Evidence Findings Comparative adherence in efficacy studies ModerateEfficacy studies indicate no differences in adherence Comparative adherence in effectiveness studies InsufficientEvidence from existing studies is insufficient to draw conclusions about adherence in real-world settings Comparative persistence InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative risk of harms ModerateFindings from 1 trial each indicate that no differences in harms exist between fluoxetine daily and fluoxetine weekly or between venlafaxine IR and venlafaxine XR. Low1 trial provides evidence that paroxetine IR leads to higher rates of nausea than paroxetine CR Comparative adherence Low1 trial provides evidence that fluoxetine weekly has better adherence rates than fluoxetine daily. Comparative persistence LowEvidence from 1 observational study indicates that prescription refills are more common with the extended- release than the immediate-release formulation of bupropion DysthymiaInsufficientNo evidence Subsyndromal depression InsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy Moderate11 trials indicate efficacy does not differ substantially among 2nd-generation antidepressants for treating MDD in patients age 60 years or older Insufficient No head-to-head evidence found for dysthymia or subsyndromal depression Results from 1 good placebo-controlled trial showed no difference between fluoxetine and placebo Comparative effectiveness InsufficientNo evidence in older patients with MDD Insufficient1 effectiveness study showed greater improvement with paroxetine vs. placebo in dysthymia patients older than 60 years; insufficient evidence to draw conclusions on comparative effectiveness Comparative harms Low6 studies indicate adverse events may differ somewhat across 2 nd -generation antidepressants in older adults. InsufficientNo head-to-head studies were found for dysthymia or subsyndromal depression.

40. Summary of Findings, KQ5: Subgroups– Sex Outcome of InterestStrength of Evidence Findings Comparative efficacy InsufficientNo evidence Comparative effectiveness InsufficientNo evidence Comparative harmsLow2 trials suggest differences between men and women in sexual side effects Subgroups– Race or Ethnicity Comparative efficacy InsufficientNo evidence Comparative effectiveness InsufficientNo evidence Comparative harmsInsufficientNo evidence 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 Outcome of InterestStrength of Evidence Findings Comparative efficacy Low A subgroup analysis of 1 trial indicates significantly greater response with venlafaxine XR than fluoxetine in patients with MDD and comorbid generalized anxiety disorder Insufficient Placebo-controlled trials assessed efficacy in patients with the following comorbidities: alcohol/substance abuse, Alzheimer’s disease/dementia, arthritis, diabetes, HIV/AIDS, multiple sclerosis, stroke, and vascular disease No head-to-head evidence exists on comparative efficacy Comparative effectiveness InsufficientNo evidence Comparative harmsInsufficientNo evidence 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 2 nd -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.

44. Thank you for the opportunity to share this information with you For CE/CME: – www. ce.effectivehealthcare.ahrq.gov/credit – Use code: CER38 For electronic copies of the clinician guide, the consumer guide, and the full systematic review – www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productID=862 www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productID=862 – For free print copies – AHRQ Publications Clearinghouse (800) 358-9295 We encourage you to visit AHRQ’s continuing education website regularly to participate in future programs.