1. Agency for Healthcare Research and Quality (AHRQ)
Second-Generation Antidepressants for Treating Adult Depression—An Update
Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
Second-Generation Antidepressants for Treating Adult Depression—An Update This slide set is based on the research presented in a comparative effectiveness review (CER), Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review, which was developed by the RTI International–University of North Carolina Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No I). The findings and conclusions in this document are those of the author(s), who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information presented here is intended to help health care decisionmakers—clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This information is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, that is, in the context of available resources and circumstances presented by individual patients.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at

2. Outline of Material 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
This slide talk is based on the research presented in the comparative effectiveness review (CER), Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review, which was developed by the RTI International–University of North Carolina Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No I). CERs represent systematic reviews of the literature and usually compare two or more types of treatments, such as different drugs, devices, or procedures for the same disease. The methods used to develop this CER followed the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ.
This presentation will briefly review the CER process, including the specific questions addressed in this CER and the results from this research. Finally, the data that are most applicable to clinicians and policy decisionmakers are presented.
References:
Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; Prepublication Draft Copy April Available at
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at

3. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development
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
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, who are 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 reviews and the full report, with references for included and excluded studies, are available at
The purpose of presentation is to help policymakers, clinicians, and patients make informed choices about the use of second-generation antidepressants. Given the prominent role of drug therapy in psychiatric disease and the prevalent use of these drugs, thi spresentation will summarize comparative data on the efficacy, effectiveness, and harms of 13 newer antidepressants: bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine. This presentation will evaluate evidence for these agents in treating patients with depressive syndrome, including major depressive disorder, dysthymic disorder, and subsyndromal depressive disorders, as defined by the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) when used in adults 18 years of age and older, including the elderly. The data from the comparative effectiveness review (CER) updates a previous report (January 2007) by including new evidence published since the latest date of publications in the original review. One new medication (desvenlafaxine) and comparisons of different formulations of the same chemical entity have been included. Additionally, the CER examined whether switching medications after a successful response to an initial medication increases the risk of relapse or recurrence. This question is especially relevant to patients who face changes in their insurance benefit when their insurers no longer cover the medication they are currently taking.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

4. Rating the Strength of Evidence From the Comparative Effectiveness Review
The strength of evidence was classified into four broad categories:
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 either is unavailable or does not permit a conclusion.
Rating the Strength of Evidence From the Comparative Effectiveness Review The Evidence-based Practice Center GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as 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), or insufficient (evidence either is unavailable or does not permit a conclusion). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication using the PICOTS (population, intervention, comparator, outcome, timing, and setting) framework.
References:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; Prepublication Draft Copy April Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

5. Background: Prevalence of Depressive Disorders
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
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.
References:
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; 2000.
Birnbaum HG, Ben-Hamadi R, Greenberg PE, et al. Determinants of direct cost differences among US employees with major depressive disorders using antidepressants. Pharmacoeconomics 2009;27(6): PMID:
Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry 2003 Dec;64(12): PMID:
Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289(23): PMID:
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:

6. Background: Treatment for Depression
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
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 and 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), and 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.
Reference:
Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry 2009 Aug;66(8): PMID:
Olfson M, Marcus SC. Arch Gen Psychiatry 2009 Aug;66(8): PMID:

7. Background: Antidepressant Medications
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
In general, the efficacies of first- and second-generation antidepressant medications are similar and have been reported to be somewhere around 60 percent. 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.
References:
Geddes JR, Freemantle N, Mason J, et al. Selective serotonin reuptake inhibitors (SSRIs) versus other antidepressants for depression. Cochrane Database Syst Rev 2007 Jul 18;(3):CD PMID:
Williams JW, Mulrow CD, Chiquette E, et al. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med 2000 May 2;132(9): PMID:
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:

8. Comparative Effectiveness Review on Second-Generation Antidepressants for Adults With Depression
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
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
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

9. Second-Generation Antidepressants Included in the 2011 Updated Review
Many second-generation drugs are now available generically, although newer agents such as desvenlafaxine (2008), duloxetine (2004), and escitalopram (2002) have remaining patent protection. Except for fluvoxamine (which is approved only for the treatment of obsessive-compulsive disorder), all second-generation antidepressants are approved for the treatment of major depressive disorder. This table summarizes the second-generation antidepressants that are available in the United States by their mechanism of action; it shows names, therapeutic class, and U.S. Food and Drug Administration–approved (labeled) uses. The mechanism of action of most second-generation antidepressants is poorly understood. In general, these drugs work through their effect on prominent neurotransmitters in the central nervous system. Although the drugs can be grouped as SSRIs, SNRIs, SSNRIs, and “other” antidepressants because of their primary mechanism of action, drugs within these groups are not homogenous, and the specific activity may differ among them.
Abbreviations: SNRI = serotonin and norepinephrine reuptake inhibitor; SSNRI = selective serotonin and norepinephrine reuptake inhibitors; SSRI = selective serotonin reuptake inhibitor
References:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Maj J, Palider W, Rawlow. Trazodone, a central serotonin antagonist and agonist. J Neural Transm 1979;44(3): PMID:
Stefanini E, Fadda F, Medda L, et al. Selective inhibition of serotonin uptake by trazodone, a new antidepressant agent. Life Sci 1976 Jun 15;18(12): PMID:
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46. Available at

10. Outcomes of Interest in Studies on Second-Generation Antidepressants for Depression
Health Outcomes
Safety 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
The health outcomes of interest from the included studies were response, remission, speed of response/remission, relapse, quality of life, functional capacity, and hospitalization. The safety and tolerability of second-generation antidepressants were measured by overall adverse events, withdrawals because of adverse events, serious adverse events, and specific adverse events (hyponatremia, seizures, suicide, hepatotoxicity, weight gain, gastrointestinal symptoms, sexual side effects, and others).
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

11. Overall Comparative Effectiveness
Overall Comparative Effectiveness of Second-Generation Antidepressants for Treating Major Depressive Disorder
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
In all, 91 RCTs (reported in 93 articles) compared the efficacy or effectiveness of one second-generation antidepressant with that for another for treating patients with major depressive disorder (MDD). Most subjects were younger than 60 years; 11 trials were conducted in populations 55 years of age or older. In general, studies enrolled patients according to a criteria-based diagnosis of MDD relating to the Diagnostic and Statistical Manual of Mental Disorders (either the revised third edition [DSM-III-R] or fourth edition [DSM-IV]) and a predefined cutoff point of a widely used depression scale (i.e., Hamilton Rating Scale for Depression [HAM-D] =18 or Montgomery-Asberg Depression Rating Scale [MADRS] =19). Most patients had moderate to severe depression as measured by a variety of scales. Most studies excluded patients who had additional axis I disorders, high suicidal risk, or progressive medical diseases or who used psychotherapy, electroconvulsive therapy, or psychotropic medications. In the majority of studies, the primary end points were either changes from baseline or rates of response or remission on investigator-rated diagnostic depression scales such as the HAM-D or MADRS. Changes on such diagnostic depression scales are generally viewed as intermediate outcomes rather than health outcomes, and they are not always reliably related to changes in health outcomes. Response or remission, even when deducted from such a scale (e.g., response is defined as a 50% improvement of scores on the HAM-D or the MADRS), can be seen as proxies to health outcomes. Therefore, reporting of outcomes is focused on differences in response or remission rates rather than differences in changes of scores.
This portion (slides 11–14) of the presentation addreses the comparative effectiveness of second-generation antidepressants for treating adults with MDD. The overall comparative effectiveness results will be addressed first, followed by the results from the immediate-release and extended-release formulations and the results related to treatment adherence and persistence.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

12. Overall Comparative Effectiveness of Second-Generation Antidepressants for Treating Adults With MDD
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
Efficacy and Effectiveness: Overall, 37 percent of patients did not respond during 6 to 12 weeks of treatment with second-generation antidepressants; 53 percent did not achieve remission. Ninety-one head-to-head trials (i.e., comparisons between medications conducted within trials) provided data on 40 of the potential comparisons between the 13 second-generation antidepressants addressed in this report. Many efficacy trials were not powered to detect statistically or clinically significant differences, leading to inconclusive results. Direct evidence from head-to-head trials was considered sufficient to conduct meta-analyses on the response to treatment (at least 50% improvement from baseline) for six drug-to-drug comparisons. Differences in efficacy reflected in some of these meta-analyses are of modest magnitude, and clinical implications remain to be determined. Findings from indirect comparisons yielded some statistically significant differences in response rates. The magnitudes of these differences, however, were small and are likely not to be clinically significant. Overall, the strength of the evidence supporting no substantial differences in efficacy and effectiveness among second-generation antidepressants for the treatment of major depressive disorder (MDD) in adults was graded as moderate.
Quality of Life: Quality of life or functional capacity was infrequently assessed, usually as a secondary outcome. Seventeen studies (3,960 patients), mostly of fair quality, indicated no statistical differences in efficacy with respect to health-related quality of life. The strength of evidence is moderate.
Speed of Response: Seven studies, all of fair quality and funded by the maker of mirtazapine, reported that mirtazapine had a significantly faster onset of action than citalopram, fluoxetine, paroxetine, and sertraline. The pooled number need to treat to yield one additional responder after 1 or 2 weeks of treatment is 7 (95-percent confidence interval, 5 to 12); after 4 weeks of treatment, however, most response rates were similar. The strength of evidence is moderate.
Age and MDD: Head-to-head trials provided mixed results on differences in benefits and harms in older adults with MDD. The majority of the trials found no differences in efficacy but suggested some differences in adverse events. Two trials comparing fluoxetine, paroxetine, and placebo reported conflicting results. One trial comparing escitalopram with fluoxetine found a significant difference favoring escitalopram over fluoxetine for efficacy; however, this trial also found neither to be significantly better than placebo. Strength of evidence is moderate for comparative efficacy; strength of evidence is low for harms.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

13. Immediate-Release Versus Extended-Release Formulations of Second-Generation Antidepressants for Adults With MDD
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
There were five head-to-head trials that investigated the comparative efficacy of daily versus weekly dosing and immediate-release versus extended-release formulations. Two of these trials compared fluoxetine daily with fluoxetine weekly; two good-quality trials assessed paroxetine IR (immediate release) versus paroxetine CR (controlled release); and one trial compared venlafaxine IR with venlafaxine XR (extended release). There were no studies on other medications, such as bupropion or fluvoxamine, that are available as both immediate-release and extended-release formulations.
Key Points
- Five head-to-head trials investigated the comparative efficacy of daily versus weekly dosing and immediate-release versus extended-release formulations.
- Two randomized controlled trials (RCTs) reported similar rates of maintenance of response and relapse for patients treated with fluoxetine daily or fluoxetine weekly during the continuation phase of therapy for major depressive disorder (MDD). The strength of evidence is moderate.
- One RCT and a pooled analysis of two identical RCTs did not find any differences in response rates in patients treated with paroxetine IR or paroxetine XR for acute-phase MDD. The strength of evidence is moderate.
- One RCT reported higher response rates for patients on venlafaxine XR than those on venlafaxine IR. The strength of evidence is low.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
MDD = major depressive disorder
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

14. Adherence and Persistence in Second-Generation Antidepressants for Adults With MDD
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.
Adherence and Persistence in Second-Generation Antidepressants for Adults With MDD
Adherence rates in efficacy trials range between 90 and 100 percent. Results from efficacy randomized controlled trials (RCTs) did not indicate any differences in adherence among second-generation antidepressants. The evidence, however, is limited to few comparisons for which the strength of the evidence is moderate. For the majority of possible comparisons among second-generation antidepressants, the strength of the evidence is insufficient to permit conclusions about the comparative adherence. Findings from highly controlled efficacy studies may have limited applicability to real-world practice, especially because of the overall short duration of these trials. The evidence is insufficient to permit conclusions about adherence and persistence in effectiveness studies.
Comparative Adherence and Persistence of Immediate-Release Versus Extended-Release Formulations: Three studies assessed the comparative adherence of immediate-release and extended-release formulations. Based on one open-label RCT, adherence to fluoxetine weekly was higher than to fluoxetine daily; the strength of evidence for this finding is low. The only double-blinded RCT available reported no significant differences in adherence between patients treated with paroxetine IR and those receiving paroxetine CR (93% vs. 96%) over a 25-week followup period; the strength of evidence for this finding is moderate. A retrospective cohort study, based on U.S. prescription data, showed higher refill persistence for prescriptions of bupropion XL than for those of bupropion SR; the strength of evidence for this finding is low.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

15. Maintaining Remission Treating Resistant or Refractory Depression
Comparative Effectiveness of Second-Generation Antidepressants in Continuation and Maintenance Phases
Preventing Relapse
Maintaining Remission
Treating Resistant or Refractory Depression
Comparative Effectiveness of Second-Generation Antidepressants in Continuation and Maintenance Phases
This portion (slides 15–16) of the presentation addresses two key aspects of treating patients with major depressive disorder (MDD). First, the research presented in this section addresses maintenance of remissions and prevention of relapses or recurrences for patients who have responded to antidepressant treatment; the second issue the research addresses focuses on ongoing depressive disease for those who have not responded to such therapy or who have experienced relapses or new episodes. For patients who have responded, two subquestions are important: the efficacy or effectiveness of (1) continuing the initial (existing) medication or (2) switching to a different one. For patients who have not responded to treatment, the studies focus on using different antidepressants.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

16. Maintaining Remission
Comparative Effectiveness of Second-Generation Antidepressants in Continuation and Maintenance Phases
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 the Continuation and Maintenance Phases
For maintaining remission, there is moderate-strength evidence that most second-generation antidepressants effectively maintain remission (prevent relapse and recurrence) with similar efficacy. When treating resistant or refractory depression, there is low-strength evidence that venlafaxine may be modestly superior to other selective serotonin reuptake inhibitors; however, results on comparative effectiveness are mixed.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

17. Effectiveness of Second-Generation Antidepressants in Treating Symptoms That May Accompany Depression
Anxiety
Pain
Insomnia
Low Energy
Psychomotor Change
Melancholia
Somatization
Effectiveness of Second-Generation Antidepressants in Treating Symptoms That May Accompany Depression
This portion (slides 17–18) of the presentation addresses the research focused on the comparative benefits of medications for patients with depression and an accompanying symptom cluster. Studies addressing seven symptom clusters were identified and included: anxiety, insomnia, low energy, pain, psychomotor change (retardation or agitation), melancholia (a depressive subtype that is a severe form of major depressive disorder with characteristic somatic symptoms), and somatization (physical complaints that are manifestations of depression rather than of an underlying physical illness). This set does not represent a complete list of symptoms that commonly accompany depression. For example, there were no included studies addressing appetite change—a common accompanying symptom reported by depressed patients.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

18. Effectiveness in Treating Symptoms That May Accompany Depression
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
Anxiety: Key Points
Eleven head-to-head trials and two placebo-controlled trials examined treatment of accompanying anxiety symptoms in patients with major depressive disorder. Of the 14 trials, 6 compared various selective serotonin reuptake inhibitors (SSRIs) with each other, 6 compared an SSRI with a serotonin norepinephrine reuptake inhibitor (SNRI) or another second-generation drug, and 2 compared an SSRI or another second-generation drug with placebo. The strength of evidence that antidepressants are equally efficacious in treating depression in anxious patients and in treating the accompanying anxiety was rated as moderate. There was insufficient evidence to determine the comparative efficacy of second-generation antidepressants for low energy, psychomotor changes, melancholia, or somatization.
Pain: Key Points
Pooled results of four head-to-head studies in the systematic review and meta-analysis showed that improvement in pain scores was similar for paroxetine and duloxetine. Six studies provided mixed evidence for efficacy of active drugs, when compared with placebo, for treatment of accompanying pain. Six trials compared duloxetine with placebo; three of these reported statistically greater pain improvement in at least one duloxetine treatment arm. One study compared paroxetine with placebo and found a statistically greater improvement for paroxetine when compared with placebo. Overall, mean differences in pain scores between groups were small and may not be clinically meaningful. There was moderate-strength evidence that paroxetine and duloxetine had similar efficacy for treating chronic pain in patients with depression.
Insomnia: Key Points
Six head-to-head trials provided mixed evidence about the effects of antidepressants on insomnia in patients with depression. Two trials reported greater improvement in sleep scores for trazodone than for fluoxetine and venlafaxine; however, neither of these trials analyzed a subgroup of patients with insomnia. One trial found that sleep scores worsened with fluoxetine treatment but not with nefazodone treatment. One trial each found no statistically significant differences for patients taking the following medications: escitalopram or fluoxetine; fluoxetine, paroxetine, or sertraline; and fluoxetine or mirtazapine. Two trials of fluoxetine supplemented with eszopiclone and compared with fluoxetine alone in depressed patients with insomnia showed an improvement in sleep for those receiving concomitant eszopiclone. A placebo-controlled study of bupropion XL found a small, statistically significant improvement in insomnia in patients taking bupropion. There was only low-strength evidence that several second-generation antidepressants are equally effective at treating insomnia symptoms in patients with depression.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

19. Comparative Harms of Second-Generation Antidepressants
Overall Comparative Harms
Specific Adverse Events by Drug
Risk of Severe Adverse Events
Comparative Harms of Second-Generation Antidepressants
This portion (slides 19–25) of the presentation addresses whether the medications differ in safety or adverse effects. Of interest, as before, are the following: the selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline); the selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) desvenlafaxine, duloxetine, mirtazapine, and venlafaxine; and all other second-generation agents (bupropion, nefazodone, and trazodone). Data included outcomes from head-to-head trials, placebo-controlled trials, and observational studies assessing the comparative harms of second-generation antidepressants. Observational studies were also included when the sample size was larger than 1,000 and the study duration at least 3 months. Comparisons across different drugs should be made with caution, given differences in assessment and reporting of adverse events across trials.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

20. Strength of Evidence: High Overall differences in formulations:
Overall Comparative Harms of Second-Generation Antidepressants for Adults With Major Depressive Disorder
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
Overall there is high-strength evidence that the rates of adverse events were similar among second-generation antidepressants, though incidence of specific adverse effects differed across antidepressants and will be addressed in the following slides. Research on comparative harms for the different formulations of second-generation antidepressants found that there was moderate-strength evidence that there were no differences in harms between fluoxetine daily and fluoxetine weekly or between venlafaxine immediate release and venlafaxine extended release.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

21. Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (1 of 3)
Adverse Effects
Outcome
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).
Diarrhea
Sertraline was associated with an 8-percent higher incidence of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine.
Moderate
Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (1 of 3)
There is high-strength evidence that venlafaxine has a 52-percent higher incidence of nausea and vomiting than selective serotonin reuptake inhibitors as a class. Low-strength evidence suggests that when used to treat major depressive disorder (MDD), paroxetine IR (immediate release) may lead to higher rates of nausea than paroxetine CR (controlled release). The strength of evidence was high that mirtazapine is associated with more weight gain than citalopram, fluoxetine, paroxetine, and sertraline (0.8–3.0 kg after 6–8 weeks). Sertraline was associated with an 8-percent higher incidence of diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine at a moderate strength of evidence.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

22. Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (2 of 3)
Adverse Effects
Outcome
Strength of Evidence
Somnolence
Trazodone 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
Low
Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (2 of 3)
The strength of evidence was moderate that trazodone was associated with a 16-percent higher incidence of somnolence than bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine. High-strength evidence suggests that bupropion had fewer sexual side effects than escitalopram, fluoxetine, paroxetine, and sertraline. Moderate-strength evidence indicated that paroxetine had the highest rate of sexual side effects when compared with selective serotonin reuptake inhibitors as a class (16% vs. 6%). However, there was some low-strength evidence that sexual side effects may occur at different rates between men and women.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
MDD = major depressive disorder
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

23. Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (3 of 3)
Adverse Effects
Outcomes
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
Specific Comparative Harms of Second-Generation Antidepressants for Adults With MDD (3 of 3)
When compared with most selective serotonin reuptake inhibitors, there was high-strength evidence that higher discontinuation rates due to adverse effects were seen with duloxetine (67% higher risk) and venlafaxine (40% higher risk). There was also high-strength evidence that venlafaxine had lower discontinuation rates due to lack of efficacy (35% lower risk).
The highest rates of withdrawal symptoms (headache, dizziness, light-headedness, nausea, and anxiety) were reported after discontinuation of paroxetine or venlafaxine, and fluoxetine had the lowest rate of withdrawal symptoms (moderate-strength evidence).
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
MDD = major depressive disorder; SSRI = selective serotonin reuptake inhibitor
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

24. Risks of Severe Adverse Events From Second-Generation Antidepressants for Adults With MDD
Severe Adverse Effects
Outcomes
Strength of Evidence
Suicidality
Evidence is insufficient to evaluate the comparative risk of suicidal thoughts and behavior.
Insufficient
Others
Evidence is insufficient to evaluate the comparative risk for rare but severe adverse effects such as seizures, cardiovascular events, hyponatremia, hepatotoxicity, and serotonin syndrome.
Risks of Severe Adverse Events From Second-Generation Antidepressants for Adults With MDD
Evidence is insufficient to evaluate the comparative risk of suicidal thoughts and behavior. Evidence is also insufficient to evaluate the comparative risk for other rare but severe adverse effects such as seizures, cardiovascular events, hyponatremia, hepatotoxicity, and serotonin syndrome.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
MDD = major depressive disorder
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

25. Noncomparative Evidence on Adverse Effects: Diabetes, Fractures, and Bleeding
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
Diabetes Mellitus
In a cohort of 165,958 patients with depression included in the U.K. General Practice Research Database, a total of 2,243 cases of incident diabetes mellitus and 8,963 matched comparison subjects were identified. This nested case-control study showed that recent long-term
use (>24 months) of antidepressants in moderate to high daily doses was associated with an increased risk of diabetes (incidence rate ratio (IRR), 1.84; 95-percent confidence interval [95% CI], 1.35 to 2.52). The study investigated tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, and other antidepressants. For users of SSRIs as a group, increased risk was observed only for recent long-term use of moderate to high daily doses (IRR, 2.06; 95% CI, 1.20 to 3.52). When individual antidepressants were analyzed, increased risk estimates only in long-term users were observed for recent use of fluvoxamine, paroxetine, and venlafaxine. Antidepressant treatment for shorter periods or with lower daily doses was not associated with an increased risk.
Fractures
A large, well-conducted case-control study, including 498,617 subjects (124,655 cases and 373,962 controls) from a Danish national prescription database, reported a significant dose-response relationship for citalopram, fluoxetine, and sertraline with respect to an increase of the risk of fracture. Among SSRIs, high-dose citalopram, fluoxetine, paroxetine, and sertraline were associated with the highest risk for hip fracture (odd ratio [OR], 1.98, 95% CI, 1.82 to 2.16) and other fractures except fractures of the forearms and spine (OR, 1.38; 95% CI, 1.33 to 1.44). Evidence regarding the impact of the duration of use on the risk of fractures was mixed for second-generation antidepressants. A Dutch case-control study that did not meet eligibility criteria reported an increase for nonvertebral fractures for SSRIs as a class.
Increased Risk of Bleeding
Evidence from three case-control studies indicated an increased risk of upper gastrointestinal tract bleeding during SSRI treatment. These studies did not meet eligibility criteria because they provided no information on the comparative risks among individual SSRIs.
References:
Andersohn F, Schade R, Suissa S, et al. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry 2009 May;166(5): PMID:
Barbui C, Andretta M, De Vitis G, et al. Antidepressant drug prescription and risk of abnormal bleeding: a case-control study. J Clin Psychopharmacol 2009;29(1):33-8. PMID:
de Abajo FJ, Garcia-Rodriguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal antiinflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008 Jul;65(7): PMID:
Targownik LE, Bolton JM, Metge CJ, et al. Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol 2009 Jun;104(6): PMID:
Vestergaard P, Rejnmark L, Mosekilde L. Selective serotonin reuptake inhibitors and other antidepressants and risk of fracture. Calcif Tissue Int 2008;82(2): PMID:
Ziere G, Dieleman JP, Van Der Cammen TJM, et al. Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol 2008;28(4): PMID:

26. Gaps in Knowledge (1 of 2)
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)
The research from the comparative effectiveness review identified these gaps in knowledge:
- The general efficacy of second-generation antidepressants for the treatment of 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.
- 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.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

27. Gaps in Knowledge (2 of 2)
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)
The research from the comparative effectiveness review identified these gaps in knowledge:
- 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 dose on the risk of relapse or recurrence.
- The effect of switching to a new drug after successful completion of acute-phase or continuation-phase treatment.
- 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.
Reference:
Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Comparative Effectiveness Review No. 46 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; December AHRQ Publication No. 12-EHC012-EF. Available at
Gartlehner G, Hansen RA, Morgan LC, et al. AHRQ Comparative Effectiveness Review No. 46.
Available at

28. What To Discuss With Your Patients About Second-Generation Antidepressants
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
In order to facilitate shared decisionmaking in discussions with your patients, here are a few topics to start the exchange of information:
- 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.