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Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007-.

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Comparative Effectiveness Review Summary Guides for Clinicians [Internet].

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Second-Generation Antidepressants for Treating Adult Depression: An Update


Baylor College of Medicine, Houston, Texas

Issued: .

Focus of Research for Clinicians

As an update to a 2007 report, a systematic review of 248 clinical studies published between January 1980 and January 2011 examined the comparative effectiveness, benefits, and adverse effects of second-generation antidepressants for adults with depression. This review did not cover nonpharmaceutical treatments for depression, the comparative effectiveness of first-generation antidepressants, or the use of second-generation antidepressants in treating other axis 1 disorders including substance use disorders, bipolar disorder, bulimia nervosa, or schizophrenia. The full report is available at This summary is provided to inform discussions of options with patients and to assist in decisionmaking along with consideration of a patient’s values and preferences. Reviews of evidence should not be construed to represent clinical recommendations or guidelines.


Depressive disorders, including major depressive disorder (MDD), dysthymia, and subsyndromal depression, affect approximately one in five people in the United States. Pharmacotherapy dominates the medical management of depressive disorders. Most first- and second-generation antidepressants both have about a 60-percent response rate when used to treat adults with MDD. However, first-generation antidepressants often have intolerable side effects and a high risk for harm when taken in excess or in combination with certain medications. Second-generation antidepressants have a more favorable side-effect profile and thus play a prominent role in managing patients with MDD.

The 2007 comparative effectiveness review on second-generation antidepressants summarized the available evidence on 12 medications (see Table 1) and their comparative efficacy, effectiveness, and adverse effects for treating adults with depression, maintaining remission, and treating accompanying symptoms such as anxiety, insomnia, and chronic pain. This updated review includes additional comparative data, one new medication, and additional studies on formulas of included medications.

Table 1. List of Second-Generation Antidepressants Included in the 2011 Updated Review.

Table 1

List of Second-Generation Antidepressants Included in the 2011 Updated Review.


New evidence included in the current review continues to support the original conclusions from the 2007 review, namely that second-generation antidepressants used to treat MDD in adults have similar effectiveness, efficacy, and effects on quality of life. Some clinically significant differences among individual drugs do exist with respect to onset of action and adverse effects, which may affect treatment choices. For example, mirtazapine has a faster onset of action but is associated with greater weight gain. Also, bupropion has fewer sexual side effects than many comparators. More research is needed to evaluate whether the benefits or adverse effects of second-generation antidepressants differ in subgroups or in populations with accompanying symptoms such as anxiety, insomnia, or chronic pain.

Clinical Bottom Line

Major Depressive Disorder

Overall, second-generation antidepressants have similar efficacy, effectiveness, and effects on quality of life. Image clindep2fu2.jpg

Elderly patients (≥60 years) with MDD had similar efficacy with second-generation antidepressants Image clindep2fu2.jpg but may experience differences in adverse effects Image clindep2fu3.jpg

Mirtazapine has a faster onset of action (1–2 weeks) than do citalopram, fluoxetine, paroxetine, and sertraline; however, response rates were similar for these drugs after 4 weeks of treatment. Image clindep2fu2.jpg

Fluoxetine daily and fluoxetine weekly have similar response and remission rates. Image clindep2fu2.jpg

Paroxetine IR (immediate release) and paroxetine CR (controlled release) have similar response rates. Image clindep2fu2.jpg

One trial reported higher response rates for venlafaxine XR (extended release) than venlafaxine IR. Image clindep2fu3.jpg

Adults With Dysthymia or Subsyndromal Depression

For adults with subsyndromal depression, limited evidence supports no difference in comparative efficacy between citalopram and sertraline. Image clindep2fu3.jpg

Evidence is unavailable or inconclusive regarding all other outcomes for treatment of dysthymia or subsyndromal depression with second-generation antidepressants. Image clindep2fu4.jpg

Maintaining Remission

Most second-generation antidepressants effectively maintain remission (prevent relapse and recurrence) with similar efficacy. Image clindep2fu2.jpg

Resistant or Refractory Depression

Venlafaxine may be modestly superior to other selective serotonin reuptake inhibitors (SSRIs); however, results on comparative effectiveness are mixed. Image clindep2fu3.jpg

Treatment for Symptoms That May Accompany Depression


Second-generation antidepressants have similar efficacy for treating depression in patients who also have anxiety. Image clindep2fu2.jpg

Improvements in anxiety scores were similar among second-generation antidepressants in adults with depression. Image clindep2fu2.jpg


Paroxetine and duloxetine showed similar improvements in pain scores for patients with depression. Image clindep2fu2.jpg


Several second-generation antidepressants are equally effective at treating insomnia symptoms in patients with depression. Image clindep2fu3.jpg

Adherence and Persistence

Adherence rates were similar for the following comparisons ( Image clindep2fu2.jpg):

Adherence rates in patients with MDD were higher for fluoxetine weekly versus fluoxetine daily. Image clindep2fu3.jpg

Patients with MDD refilled prescriptions for bupropion XL more frequently than for bupropion SR. Image clindep2fu3.jpg

Comparative Adverse Effects

Overall rates of adverse effects were similar among second-generation antidepressants, though incidence of specific adverse events differed across antidepressants. Image clindep2fu1.jpg

Overall differences in formulations

No differences in harms were found between fluoxetine daily and fluoxetine weekly or between venlafaxine IR and venlafaxine XR. Image clindep2fu2.jpg

Nausea and vomiting

Venlafaxine has a 52-percent higher incidence than SSRIs as a class. Image clindep2fu1.jpg

Paroxetine IR may lead to higher rates of nausea than paroxetine CR. Image clindep2fu3.jpg

Weight gain

Mirtazapine is associated with more weight gain than are citalopram, fluoxetine, paroxetine, and sertraline (0.8–3.0 kg after 6–8 weeks). Image clindep2fu1.jpg


Sertraline was associated with an 8-percent higher incidence of diarrhea than were bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine. Image clindep2fu2.jpg


Trazodone was associated with a 16-percent higher incidence of somnolence than were bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine. Image clindep2fu2.jpg

Discontinuation rates

Higher discontinuation rates due to adverse effects were seen with duloxetine (67% higher risk) and venlafaxine (40% higher risk) when compared with most SSRIs. Image clindep2fu1.jpg

Venlafaxine had lower discontinuation rates due to lack of efficacy (35% lower risk). Image clindep2fu1.jpg

Withdrawal symptoms

The highest rates of withdrawal symptoms (headache, dizziness, light-headedness, nausea, and anxiety) were reported after discontinuing paroxetine or venlafaxine. Image clindep2fu2.jpg

Fluoxetine had the lowest rate of withdrawal symptoms. Image clindep2fu2.jpg

Sexual dysfunction

Bupropion had fewer sexual side effects than escitalopram, fluoxetine, paroxetine, and sertraline. Image clindep2fu1.jpg

Paroxetine had the highest rate of sexual side effects when compared with SSRIs as a class (16% vs. 6%). Image clindep2fu2.jpg

Sexual side effects may occur at different rates between men and women. Image clindep2fu3.jpg


Evidence is insufficient to evaluate the comparative risk of suicidal thoughts and behavior. Image clindep2fu4.jpg

Severe adverse effects

Evidence is insufficient to evaluate the comparative risk for rare but severe events such as seizures, cardiovascular events, hyponatremia, hepatotoxicity, and serotonin syndrome. Image clindep2fu4.jpg

Noncomparative Evidence for 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 forearm or spine) for patients on high-dose citalopram, fluoxetine, paroxetine, and sertraline.
  • An increased risk for upper gastrointestinal tract bleeding during SSRI treatment.

Strength of Evidence Scale

High: Image clindep2fu1.jpgThere is high confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate: Image clindep2fu2.jpgModerate 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: Image clindep2fu3.jpgLow confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.
Insufficient: Image clindep2fu4.jpgEvidence either is unavailable or does not permit estimation of an effect.

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 dosage on the risk of relapse or recurrence.
  • The effect of switching to a new drug after successful completion of acute- or continuation-phase treatment.
  • The most effective second-generation antidepressant in patients who either did not respond to 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.

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 medicines, including the risk of 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 other medications they may be taking and how these may influence their depression-related outcomes.

Resource for Patients

Medicines for Treating Depression, A Review of the Research for Adults is a free companion to this clinician research summary that is written specifically for patients. It can help patients talk with their health care professionals about treatments for depression and related symptoms. It provides information about:

  • Antidepressants available for treating adults with depression
  • Side effects related to medications used to treat depression
  • Questions for patients to ask their health care providers

Ordering Information

For electronic copies of Medicines for Treating Depression, A Review of the Research for Adults, this clinician research summary, and the full systematic review, visit To order free print copies, call the AHRQ Publications Clearinghouse at 800-358-9295.


The information in this summary is based on 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. 290-2007-10056-I for the Agency for Healthcare Research and Quality, December 2011. Available at This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX.

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