Second-Generation Antidepressants for Treating Adult Depression—An Update Prepared for: Agency for Healthcare Research and Quality (AHRQ)

 The comparative effectiveness review (CER) process  Background  Questions addressed in the CER on second-generation antidepressants for adults with major depressive disorder (MDD):  Overall comparative effectiveness of treatments for MDD  Treating patients with unresponsive or recurrent disease  Treating symptoms that accompany depression  Comparative adverse effects  Evidence available on effectiveness and adverse effects in different patient subpopulations  Conclusions Outline of Material

 Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report are available at Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the Comparative Effectiveness Review Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Depressive disorders such as major depressive disorder (MDD), dysthymia, and subsyndromal depression may be serious, disabling illnesses.  MDD affects more than 16 percent of adults at some point during their lifetimes.  In 2000, the economic burden of depressive disorders in the United States was estimated to be $83.1 billion. Likely, this number has increased during the past 10 years. More than 30 percent of these costs are attributable to direct medical expenses. Background: Prevalence of Depressive Disorders American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Text rev Birnbaum HG, Ben-Hamadi R, Greenberg PE, et al. Pharmacoeconomics 2009;27(6): PMID: Greenberg PE, Kessler RC, Birnbaum HG, et al. J Clin Psychiatry 2003 Dec;64(12): PMID: Kessler RC, Berglund P, Demler O, et al. JAMA 2003;289(23): PMID:

 Pharmacotherapy dominates the medical management of depressive disorders, including first-generation and the more recently developed second-generation antidepressants.  First-generation antidepressants include:  Tricyclic antidepressants  Monoamine oxidase inhibitors  Second-generation antidepressants dominate the medical management of depressive disorders and include:  Selective serotonin reuptake inhibitors (SSRIs)  Serotonin and norepinephrine reuptake inhibitors (SNRIs)  Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs)  Other drugs with related mechanisms of action that selectively target neurotransmitters  The mechanism of action of most of these agents is poorly understood, but they most likely work through their effects on neurotransmitters such as serotonin, norepinephrine, or dopamine in the central nervous system. Background: Treatment for Depression Olfson M, Marcus SC. Arch Gen Psychiatry 2009 Aug;66(8): PMID:

 In general, the efficacies of first- and second-generation antidepressant medications are similar.  However, first-generation antidepressants often produce multiple side effects that many patients find intolerable, and the risk for harm when taken in overdose or in combination with certain medications is high.  Because of their relatively favorable side-effect profile, the second-generation antidepressants play a prominent role in managing patients with major depressive disorder and are the focus of this presentation. Background: Antidepressant Medications Geddes JR, Freemantle N, Mason J, et al. Cochrane Database Syst Rev 2007 Jul 18;(3):CD PMID: Williams JW, Mulrow CD, Chiquette E, et al. Ann Intern Med 2000 May 2;132(9): PMID:

 A systematic review of 248 clinical studies published between January 1980 and January 2011 sought to determine the effectiveness, benefits, and adverse effects of second-generation antidepressants for adults with depression.  This presentation is provided to assist in decisionmaking and should not be construed to represent clinical recommendations or guidelines. The full report is available at ahrq.gov/secondgenantidep.cfm. Comparative Effectiveness Review on Second-Generation Antidepressants for Adults With Depression Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

Second-Generation Antidepressants Included in the 2011 Updated Review Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

Health OutcomesSafety and Tolerability Response Remission Speed of response/remission Relapse Quality of life Functional capacity Hospitalization Overall adverse effects Withdrawals Serious adverse events Specific adverse events including: Hyponatremia Seizures Suicide Hepatotoxicity Weight gain Gastrointestinal symptoms Sexual side effects Others Outcomes of Interest in Studies on Second- Generation Antidepressants for Depression Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Overall Comparative Effectiveness  Immediate-Release and Extended-Release Formulations  Treatment Adherence and Persistence Overall Comparative Effectiveness of Second-Generation Antidepressants for Treating Major Depressive Disorder Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Overall, second-generation antidepressants have similar efficacy, effectiveness, and effects on quality of life (37% did not respond during 6 to 12 weeks of treatment; 53% did not achieve remission). Strength of Evidence: Moderate  Mirtazapine has a faster onset of action (1 – 2 weeks) than do citalopram, fluoxetine, paroxetine, and sertraline; however, response rates were similar after 4 weeks of treatment. Strength of Evidence: Moderate  Elderly patients (≥60 years) with major depressive disorder (MDD) had similar efficacy with second-generation antidepressants. Strength of Evidence: Moderate  Elderly patients (≥60 years) with MDD may experience some differences in adverse events from these drugs. Strength of Evidence: Low Overall Comparative Effectiveness of Second-Generation Antidepressants for Treating Adults With MDD Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Fluoxetine daily and fluoxetine weekly have similar response and remission rates. Strength of Evidence: Moderate  Paroxetine IR (immediate release) and paroxetine CR (controlled release) have similar response rates. Strength of Evidence: Moderate  One trial reported higher response rates for venlafaxine XR (extended release) than venlafaxine IR. Strength of Evidence: Low Immediate-Release Versus Extended-Release Formulations of Second-Generation Antidepressants for Adults With MDD Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at MDD = major depressive disorder

 Adherence rates were similar (strength of evidence: moderate) for the following comparisons:  Citalopram versus sertraline  Bupropion SR versus fluoxetine, paroxetine, or sertraline  Bupropion versus trazodone  Paroxetine IR versus paroxetine CR  Adherence rates in patients with major depressive disorder (MDD) were higher for fluoxetine weekly versus daily.  Strength of Evidence: Low  Adherence rates were similar in patients treated with paroxetine IR and those receiving paroxetine CR.  Strength of Evidence: Moderate  Patients with MDD refilled prescriptions for bupropion XL more frequently than for bupropion SR.  Strength of Evidence: Low Adherence and Persistence in Second-Generation Antidepressants for Adults With MDD Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Preventing Relapse  Maintaining Remission  Treating Resistant or Refractory Depression Comparative Effectiveness of Second-Generation Antidepressants in Continuation and Maintenance Phases Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Maintaining Remission  Most second-generation antidepressants effectively maintain remission (prevent relapse and recurrence) with similar efficacy. Strength of Evidence: Moderate  Resistant or Refractory Depression  Venlafaxine may be modestly superior to other selective serotonin reuptake inhibitors; however, results on comparative effectiveness are mixed. Strength of Evidence: Low Comparative Effectiveness of Second-Generation Antidepressants in Continuation and Maintenance Phases Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Anxiety  Pain  Insomnia  Low Energy  Psychomotor Change  Melancholia  Somatization Effectiveness of Second-Generation Antidepressants in Treating Symptoms That May Accompany Depression Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Second-generation antidepressants have similar efficacy for treating depression in patients who also have anxiety. Strength of Evidence: Moderate  Improvements in anxiety scores were similar among second-generation antidepressants for patients with depression. Strength of Evidence: Moderate  Paroxetine and duloxetine showed similar improvements in pain scores in patients with depression. Strength of Evidence: Moderate  Several second-generation antidepressants are equally effective in treating insomnia symptoms in patients with depression. Strength of Evidence: Low  There was insufficient evidence to determine the comparative efficacy of second-generation antidepressants in treating low energy, psychomotor changes, melancholia, or somatization. Effectiveness in Treating Symptoms That May Accompany Depression Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Overall Comparative Harms  Specific Adverse Events by Drug  Risk of Severe Adverse Events Comparative Harms of Second-Generation Antidepressants Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 Overall rates of adverse events were similar among second-generation antidepressants, though incidence of specific adverse effects differed across antidepressants. Strength of Evidence: High  Overall differences in formulations:  No differences in harms were found between fluoxetine daily and fluoxetine weekly or between venlafaxine IR and venlafaxine XR. Strength of Evidence: Moderate Overall Comparative Harms of Second-Generation Antidepressants for Adults With Major Depressive Disorder Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (1 of 3) Adverse EffectsOutcome Strength of Evidence Nausea and Vomiting Venlafaxine has a 52-percent higher incidence than selective serotonin reuptake inhibitors as a class. When used to treat major depressive disorder, paroxetine IR may lead to higher rates of nausea than paroxetine CR. High Low Weight Gain Mirtazapine is associated with more weight gain than citalopram, fluoxetine, paroxetine, and sertraline (0.8–3.0 kg after 6–8 weeks). High DiarrheaSertraline was associated with an 8-percent higher incidence of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine. Moderate Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (2 of 3) Adverse EffectsOutcome Strength of Evidence SomnolenceTrazodone was associated with a 16-percent higher incidence of somnolence than bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine. Moderate Sexual Dysfunction Bupropion had fewer sexual side effects than escitalopram, fluoxetine, paroxetine, and sertraline. Paroxetine had the highest rate of sexual side effects when compared with selective serotonin reuptake inhibitors as a class (16% vs. 6%). Sexual side effects may occur at different rates between men and women. High Moderate Low Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at MDD = major depressive disorder

Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (3 of 3) Adverse EffectsOutcomes Strength of Evidence Discontinuation Rates When compared with most SSRIs, higher discontinuation rates due to adverse effects were seen with duloxetine (67% higher risk) and venlafaxine (40% higher risk). Venlafaxine had lower discontinuation rates due to lack of efficacy (35% lower risk). High Withdrawal Symptoms The highest rates of withdrawal symptoms (headache, dizziness, light-headedness, nausea, and anxiety) were reported after discontinuation of paroxetine or venlafaxine. Fluoxetine had the lowest rate of withdrawal symptoms. Moderate Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at MDD = major depressive disorder; SSRI = selective serotonin reuptake inhibitor

Risks of Severe Adverse Events From Second- Generation Antidepressants for Adults With MDD Severe Adverse EffectsOutcomes Strength of Evidence SuicidalityEvidence is insufficient to evaluate the comparative risk of suicidal thoughts and behavior. Insufficient OthersEvidence is insufficient to evaluate the comparative risk for rare but severe adverse effects such as seizures, cardiovascular events, hyponatremia, hepatotoxicity, and serotonin syndrome. Insufficient Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at MDD = major depressive disorder

 Unrated evidence on second-generation antidepressants shows:  An increased risk for diabetes in patients on recent long- term use (>24 months) of moderate to high doses of fluvoxamine, paroxetine, or venlafaxine.  An increased risk for fractures (hip and other fractures, except fractures of the forearms or spine) for patients on high-dose citalopram, fluoxetine, paroxetine, and sertraline.  An increased risk for upper gastrointestinal tract bleeding during treatment with selective serotonin reuptake inhibitors. Noncomparative Evidence on Adverse Effects: Diabetes, Fractures, and Bleeding

 The general efficacy of second-generation antidepressants for treating dysthymia and subsyndromal depression.  Differences in benefits and harms in subgroups such as the very elderly or patients with common comorbidities.  The most appropriate duration of antidepressant treatment for maintaining remission.  The effect of drug dosage on the risk of relapse or recurrence. Gaps in Knowledge (1 of 2) Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 The most effective second-generation antidepressant in patients who either did not respond or could not tolerate a first-line treatment.  How combinations of antidepressants compare with monotherapy in treatment-resistant depression.  How outcomes of second-generation antidepressants differ in populations with accompanying symptoms such as anxiety, insomnia, pain, or fatigue.  The comparative risks of second-generation antidepressants with respect to rare but serious adverse effects such as suicidality, hyponatremia, hepatotoxicity, seizures, cardiovascular adverse events, and serotonin syndrome. Gaps in Knowledge (2 of 2) Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

 The benefits of the different second-generation antidepressants for treating their specific symptoms.  How they will know if their medication is working.  How to identify the potential adverse effects of the medications and how to handle them.  How long they may need to take their current antidepressant.  The importance of adhering to their treatment regimens and what to expect if they stop taking their medications such as withdrawal or discontinuation syndrome.  To always consult their health care provider before discontinuing any medication.  How their medications will affect the symptoms that may be accompanying their depression such as anxiety, insomnia, or chronic pain.  Their comorbidities and the medications they may be taking for them and how these may influence their depression-related outcomes. What To Discuss With Your Patients About Second-Generation Antidepressants