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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 [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Dec. (Comparative Effectiveness Reviews, No. 46.)

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Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review [Internet].

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Axis I psychiatric disorders such as depressive disorder can be serious disabling illnesses.1 Combined, they affect approximately one in five Americans.2 Major depressive disorder (MDD) is the most prevalent, affecting more than 16 percent (lifetime) of U.S. adults.3 The U.S. economic burden of depressive disorders is estimated to be more than $83 billion annually.4 More than 30 percent of these costs were attributable to direct medical expenses. Projected depression-related U.S. workforce productivity losses are estimated to be $24 billion annually.5

Pharmacotherapy is the primary treatment for the medical management of depression. As of 2005, an estimated 27 million Americans were treated with antidepressants.6 Antidepressants include first-generation drugs such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs); they also include newer drugs referred to here as second-generation antidepressants. Compared with the first-generation antidepressants, the second-generation antidepressant have similar efficacy.7, 8 However, first-generation drugs often are accompanied by multiple side effects that many patients find intolerable. For example, TCAs tend to cause anticholinergic effects including dry mouth and eyes, urinary hesitancy, and sometimes retention and constipation. In addition, TCAs have a high rate of lethality when overdose occurs. MAOIs can produce a potentially lethal hypertensive crisis if taken along with particular medications or with certain foods or dietary supplements containing excessive amounts of tyramine. Thus, first-generation antidepressants are no longer agents of choice in many circumstances.

Second-generation antidepressants now account for the majority of antidepressant prescribing. These drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other drugs with related mechanisms of action that selectively target neurotransmitters. In 2009, these drugs accounted for $9.9 billion in sales in the United States, ranking as the fourth top-selling therapeutic class of prescription drugs.9

Many second-generation drugs are now available generically, although newer agents such as desvenlafaxine (2008), duloxetine (2004), and escitalopram (2002) have remaining patent protection. Figure 1 illustrates the timing of approvals for second-generation antidepressant drug by the U.S. Food and Drug Administration (FDA) for the United States over the past three decades.

Figure 1 illustrates the timing of approvals for second-generation antidepressant drug by the U.S. Food and Drug Administration for the United States over the past three decades. Between 1980 and 1990, trazadone, buproprion and fluoxetine were approved; followed by sertraline, paroxetine, venlafaxine, nefazodone and mirtazapine between 1990 and 2000. From 2000 to 2010, citalopram, fluvoxamine, escitalopram; duloxetine and desvenlafaxine were approved.

Figure 1

Second-generation antidepressant approvals.

Except for fluvoxamine (which is approved only for the treatment of obsessive-compulsive disorder), all second-generation antidepressants are approved for the treatment of MDD. Table 1 summarizes the second-generation antidepressants that are available in the United States by mechanism of action; it shows names, all dosage forms, therapeutic class, and FDA-approved (labeled) uses.

Table 1. Second-generation antidepressants approved for use in the United States.

Table 1

Second-generation antidepressants approved for use in the United States.

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 (selective serotonin norepinephrine reuptake inhibitors), 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.

The six SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) act by selectively inhibiting the reuptake of serotonin 5-HT at the presynaptic neuronal membrane. Reuptake inhibition has the effect of increasing the levels of serotonin made available to improve the transmission of neural signals at the synapse. The three SNRIs (desvenlafaxine, mirtazapine, and venlafaxine) are potent inhibitors of serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Mirtazapine differs from desvenlafaxine and venlafaxine in that it is believed to enhance central noradrenergic and serotonergic activity as a 5-HT2 and 5-HT3 receptor antagonist. However, we classify them together because of overlap in the affected neurotransmitters. Duloxetine selectively inhibits serotonin and norepinephrine; we refer to it as an SSNRI although it also could be grouped with the SNRIs.

The three remaining drugs, classified as other, are believed to work in related ways through their effects on serotonin, norepinephrine, and dopamine. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine; its primary mechanism of action is believed to be dopaminergic and noradrenergic. Nefazodone is believed to inhibit neuronal uptake of serotonin and norepinephrine. Trazodone appears to produce its primary effect by selectively inhibiting serotonin reuptake, but it also causes adrenoreceptor subsensitivity and induces significant changes in 5-hydroxytryptamine (5-HT) presynaptic receptor adrenoreceptors. At low doses, it appears to act as a serotonin antagonist and at higher doses as an agonist.10, 11

Purpose of This Report

The purpose of this review 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, our goal is to 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. We evaluate evidence for these agents in treating patients with depressive syndrome, including MDD, dysthymic disorder, and subsyndromal depressive disorders, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).1 We focus this review on these disorders in adults 18 years of age and older, including the elderly.

This report updates our previous report (January 2007)12 by including new evidence published since the latest date of publications in the original review. We have included one new medication (desvenlafaxine). In addition to reviewing new comparative evidence, we extend our prior analyses by comparing different formulations of the same chemical entity (Table 2). We also examine 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.

Table 2. Usual dosing range and frequency of administration for adults.

Table 2

Usual dosing range and frequency of administration for adults.

We address several areas that are relevant for clinicians and policymakers that previous reports have not covered. First, we consider whether differences exist when comparing efficacy, effectiveness, or adverse events for immediate-release products with those factors for extended-release products. The distinction in immediate-release versus extended-release has implications for the number of times per day (or per week) patients need to take the medication. This factor influences dosing and medication adherence, which could be related to differences in effectiveness or tolerability. This question is particularly relevant to bupropion, fluoxetine, fluvoxamine, mirtazapine, paroxetine, and venlafaxine because these products come in multiple formulations.

Second, we consider treatment in the continuation and maintenance phases of depression, not simply the acute phase of treatment (see Figure 2). Among patients who have already responded to acute-phase treatment or who have maintained a response through continuation-phase treatment, we consider how treatments compare for preventing relapse or recurrence. We consider this question for patients who continue on the drug they initially responded to, as well as for patients who switch to a different antidepressant during the continuation or maintenance phase. The latter question may apply to patients who experience a change in insurance benefit and have to switch treatment because a drug is no longer covered by insurance or the cost is now prohibitive. These considerations are especially important to the initial treatment selection and the ongoing management of depression for several reasons.

Figure 2 displays the phases of treatment for major depression with response to initial treatment. Among people who do receive adequate treatment, the normal course of treatment consists of an acute phase lasting 6 to 12 weeks with the goal of remission, meaning a complete resolution of the depressive episode. This is followed by a continuation phase of treatment during which the treatment goal is continued absence of depressive symptoms (i.e., relapse prevention) for an additional 4 to 9 months such that the patient's episode can be considered completely resolved. A maintenance phase lasting an additional one or more years is recommended in patients who have had two or more previous episodes of depression to prevent the recurrence of a new depressive episode.

Figure 2

Phases of treatment for major depression. Source: Re-created based on Kupfer, 1991. Tx1=treatment attempt 1; dashed lines indicate hypothetical worsening of depressive severity.

First, clinical decisions will differ depending on where patients are in the trajectory of their treatment. The American College of Physicians (ACP) recommends that when clinicians are initially treating patients with acute major depressive disorders, they should first select an antidepressant on the basis of adverse-event profiles, cost, and patient preferences.14 Once an initial medication is selected, the ACP guidelines recommend that clinicians assess the patients' status, therapeutic response, and adverse effects on a regular basis, beginning 1 to 2 weeks after initiation of therapy. If patients do not have an adequate response to pharmacotherapy within 6 to 8 weeks, then clinicians should modify the treatment. If an adequate response is achieved, then patients should remain on the same antidepressant during a continuation phase that lasts at least 4 to 9 months. Finally, clinicians should consider a maintenance phase lasting an additional 1 or more years for patients who have had two or more previous episodes of depression.14-16

We consider all three phases of depression management (Figure 2):

  • Acute phase, first phase of depression management, usually 6 to 12 weeks;
  • Continuation phase, second phase of depression management, during which the treatment goal is ongoing absence of depressive symptoms for an additional 4 to 9 months such that the patient's episode can be considered completely resolved (i.e., relapse prevention); and
  • Maintenance phase third phase of depression management frequently a multiyear period during which the treatment goal is preventing the recurrence of a new, distinct episode (ie recurrence prevention)

Following this categorization allows us to make the clinically relevant distinction between relapse and recurrence We define relapse as the return of depressive symptoms during the acute or continuation phases so it is considered part of the same depressive episode We define recurrence as the return of depressive symptoms during the maintenance phase so it is considered a new distinct episode.

This distinction is critical to determining long-term treatment plans If an individual has a single episode of MDD that has resolved treatment recommendations may or may not include continued medication treatment. If, however, an individual has a diagnosis of recurrent MDD, the recommendation for continued treatment may be years.15, 16 In addition, this categorization can frame decisions about depression management into best treatments for immediate resolution of depressive symptoms (acute phase) and those best for ongoing management once symptoms have resolved (continuation and maintenance phases). Of note, the latter two phases involve a treatment period that is much longer than that for the first phase.

Finally, we review the data addressing whether the presence of accompanying symptoms, such as anxiety and insomnia, might affect outcomes. For example, MDD is frequently associated with concurrent anxiety. If certain antidepressants can treat such a depression more successfully than other agents, or if they can mitigate the specific concurrent anxiety symptoms, these agents might be preferred choices. Such data could guide clinicians on how better to target antidepressant selection and steer policymakers toward the best available agents.

Scope and Key Questions

This review compares the efficacy, effectiveness, and harms of second-generation antidepressant medications. To that end, we address the following Key Questions:


For adults with major depressive disorder (MDD), dysthymia, or subsyndromal depressive disorders, do commonly used medications for depression differ in efficacy or effectiveness in treating depressive symptoms?


If a patient has responded to one agent in the past, is that agent better than current alternatives at treating depressive symptoms?


Are there any differences in efficacy or effectiveness between immediate-release and extended-release formulations of second-generation antidepressants?


For adults with a depressive syndrome that has responded to antidepressant treatment, do second-generation antidepressants differ in their efficacy or effectiveness for preventing relapse (i.e., continuation phase) or recurrence (i.e., maintenance phase) when a patient

  • Continues the drug to which they initially responded, or
  • Switches to a different antidepressant?

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?


In depressed patients with accompanying symptoms such as anxiety, insomnia, and neurovegetative symptoms, do medications or combinations of medications (including a tricyclic in combination with a second-generation antidepressant) differ in their efficacy or effectiveness for treating the depressive episode or for treating an accompanying symptoms?


For adults with a depressive syndrome, do commonly used antidepressants differ in safety, adverse events, or adherence? Adverse effects of interest include but are not limited to nausea, diarrhea, headache, tremor, daytime sedation, decreased libido, failure to achieve orgasm, nervousness, insomnia, and more serious events including suicide.


Are there any differences in safety, adverse events, or adherence between immediate-release and extended-release formulations of second-generation antidepressants?


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 groups, and sex)
  • Patients with medical comorbidities (e.g., ischemic heart disease, cancer)
  • Patients with psychiatric and behavioral comorbidities (e.g., substance abuse disorders)
  • Patients taking other medications

Throughout this report, we highlight effectiveness studies conducted in primary-care or office-based settings that use less-stringent eligibility criteria, assess health outcomes, and have longer follow-up periods than most efficacy studies.17 We deemed studies that met at least six of seven predefined criteria as effectiveness studies (Table 3).18 Their results are more applicable to the average patient than are results from highly selected populations in efficacy studies.

Table 3. Criteria for effectiveness studies.

Table 3

Criteria for effectiveness studies.

For each Key Question, we evaluated specific outcome measures (where appropriate), as reported in Table 4. For efficacy and effectiveness, we focused on head-to-head trials comparing one second-generation antidepressant with another. This kind of information constitutes “direct” evidence. When sufficient head-to-head evidence was unavailable, we evaluated placebo-controlled evidence. Comparisons made using this kind of information constitute “indirect” evidence. Finally, we included observational studies to assess relapse or recurrence prevention, second-line treatment, and safety and tolerability.

Table 4. Outcome measures and study eligibility criteria.

Table 4

Outcome measures and study eligibility criteria.

To evaluate comparative evidence, we compared a large range of doses within and across studies. Because a reference standard does not exist for making dose comparisons across drugs, we use a comparative dose classification system to identify gross inequities in drug-dose comparisons.19 This classification provides a rough mechanism to determine whether doses are relatively similar when making head-to-head comparisons. The dose classification is rooted primarily in the dosing range suggested in the FDA-approved labeling; we also made some adjustments to this range to reflect clinical practice patterns that might not have been considered in the FDA-reviewed studies. The usual dosing range is divided by the upper and lower quartile to create three levels (Table 5).

Table 5. Comparative dose classification of second-generation antidepressants.

Table 5

Comparative dose classification of second-generation antidepressants.

Organization of the Report

The remainder of this comparative effectiveness review describes our methods to review and synthesize this literature, presents our results by Key Question, and discusses the implications of those results for clinical applications and future research. Appendix A describes our search strategy; Appendix B lists excluded studies; Appendix C presents evidence tables; Appendix D provides characteristics of studies with poor internal validity; Appendix E contains studies included in our mixed-treatment comparison; Appendix F contains a bibliography of articles by database searched; Appendix G exhibits evidence profiles for grading the strength of evidence for main outcomes for each Key Question. Appendix H presents our review and abstraction forms, including the quality assessment criteria.

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