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Second-Generation Antidepressants for Treating Adult Depression: An Update

Clinician Summary – Jul. 30, 2012

Second-Generation Antidepressants for Treating Adult Depression: An Update


Table of Contents

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.


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
Adults With Dysthymia or Subsyndromal Depression
Maintaining Remission
Resistant or Refractory Depression
Treatment for Symptoms That May Accompany Depression
  • Second-generation antidepressants have similar efficacy for treating depression in patients who also have anxiety. evidence medium
  • Improvements in anxiety scores were similar among second-generation antidepressants in adults with depression. evidence medium
  • Paroxetine and duloxetine showed similar improvements in pain scores for patients with depression. evidence medium
  • Several second-generation antidepressants are equally effective at treating insomnia symptoms in patients with depression. evidence low
Adherence and Persistence
Comparative Adverse Effects
  • Overall rates of adverse effects were similar among second-generation antidepressants, though incidence of specific adverse events differed across antidepressants. evidence high
Overall differences in formulations
Nausea and vomiting
Weight gain
Discontinuation rates
Withdrawal symptoms
Sexual dysfunction
Severe adverse effects
Confidence Scale

High: evidence high

There 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: evidence medium

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: evidence low

Low 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: evidence insufficient

Evidence either is unavailable or does not permit estimation of an effect.

Noncomparative Evidence for Diabetes, Fractures, and Bleeding
Unrated evidence on second-generation antidepressants shows:

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

Generic Name U.S. Trade Namea Labeled Usesb Therapeutic Classification
a CR = controlled release; SR = sustained release; XL or XR = extended release

b GAD = generalized anxiety disorder; MDD = major depressive disorder; OCD = obsessive-compulsive disorder; PMDD = premenstrual dysphoric disorder; PTSD = post-traumatic stress disorder; SNRI = serotonin and norepinephrine reuptake inhibitor; SSNRI = selective serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor

c A generic is available for some dosage forms.

d Desvenlafaxine was not included in the 2007 report but is included in the 2011 updated review.

e Only generic nefazodone is available in the United States.

f Only Paxil CR (not Paxil) is approved for treating PMDD.

g Only Effexor XR (not Effexor) is approved for treating GAD and social anxiety disorder.
Bupropionc Wellbutrin®; Wellbutrin SR®; Wellbutrin XL® MDD; seasonal affective disorder Other
Citalopramc Celexa® MDD SSRI
Desvenlafaxined Pristiq® MDD SNRI
Duloxetine Cymbalta® MDD; GAD; neuropathic pain; fibromyalgia SSNRI
Escitalopram Lexapro® MDD; GAD SSRI
Fluoxetinec Prozac®; Prozac Weekly® MDD; OCD; PMDD; panic disorder; bulimia nervosa SSRI
Fluvoxaminec Luvox® OCD SSRI
Mirtazapinec Remeron®; Remeron SolTab® MDD Other
Nefazodonec Serzone®e MDD Other
Paroxetinec Paxil®; Paxil CR®f MDD; OCD; panic disorder; social anxiety disorder; GAD; PTSD; PMDDf SSRI
Sertralinec Zoloft® MDD; OCD; panic disorder; PTSD; PMDD; social anxiety disorder SSRI
Trazodonec Desyrel® MDD Other
Venlafaxinec Effexor®; Effexor XR® MDD; GAD;g panic disorder; social anxiety disorderg SNRI

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


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. It was written by Andrea Humphries, Ph.D., Thomas Workman, Ph.D., Rayan Al Jurdi, M.D., and Michael Fordis, M.D.