Second-Generation Antidepressants: Which one is better? Comparing Benefits & Harms.


Second-Generation Antidepressants: Which one is better? Comparing Benefits & Harms.


Two important studies have reviewed the comparative efficacy of second generation antidepressants, but their results were contradictory:-

(1) Study done by Cipriani et al (Lancet. 2009;373:746-58) compared effectiveness of 12 second generation antidepressants and concluded that their efficacy does not differ substantially

(2) Whereas MANGA (Multiple MetaAnalyses of New Generation Antidepressants) study group reported that escitalopram and sertraline have best efficacy/acceptability ratio compared with other second-generation antidepressants (PubMed PMID: 20704050).


Gartlehner et al published an updated meta-analysis of 234 studies (Ann Intern Med. 2011;155:772-785) to answer this question. The  next section will summarize the results of this meta-analysis:-


Acute Phase Treatment of Major Depression Disorder


(a) Overall comparative efficacy and effectiveness was similar among second-generation antidepressants (Strength of Evidence: Moderate).

(b) Meta-analyses of head-to-head trials showed:

  • Escitalopram > Citalopram (statistically significant response rate): largest relative difference with modest absolute difference.
  • Sertraline > Fluoxetine (statistically significant response rate).
  • Venlafaxine > Fluoxetine (statistically significant response rate): largest relative difference with modest absolute difference.


(c) Onset of action:

  • Mirtazapine > Citalopram, Fluoxetine, Paroxetine, and Sertraline: statistically significant (Strength of Evidence: Moderate). Note: All these studies were funded by maker of Mirtazapine. 


Maintaining response or remission:


(a) Meta-analyses of head-to-head trials showed No statistically significant differences in preventing relapse or recurrence between: (Strength of Evidence: Moderate)

  • Escitalopram and Paroxetine.
  • Fluoxetine and Sertraline.
  • Fluoxetine and Venlafaxine (Note: 1 study found shorter time for recurrence with Fluoxetine vs Venlafaxine).
  • Fluvoxamine and Sertraline.
  • Trazodone and Venlafaxine.


Treatment Resistant Depression:


(a) Efficacy:

  • Venlafaxine > Citalopram, Fluoxetine, and Paroxetine (Strength of Evidence: Low)


(b) Effectiveness: conflicting results (Strength of Evidence: Low)

  • One trail showing no significant difference between sustained-release bupropion, sertraline, and extended-release venlafaxine (good quality trial).
  • One trial showed venlafaxine > citalopram, fluoxetine, mirtazapine, paroxetine, and sertraline (fair quality trial).


Treating Depression with Comorbid Symptoms Cluster:


(a) Anxiety: No substantial difference in efficacy for depression and accompanying anxiety treatment. (Strength of Evidence: Moderate)

(b) Insomnia:

  • No substantial difference found- Results are limited by study design. (Strength of Evidence: Low)
  • 2 studies suggested greater improvement in sleep scores with trazodone > fluoxetine and venlafaxine.


(c) Low Energy: 1 placebo-controlled trial of bupropion XL is insufficient to draw conclusions.

(d) Melancholia: No evidence found. 

(e) Pain:

  • 2 fair-quality placebo-controlled studies showed conflicting results about superiority of duloxetine over placebo for depression.(Strength of Evidence: Insufficient)
  • No difference in efficacy found between paroxetine and duloxetine for pain management. (Strength of Evidence: Moderate)


Comparing Adverse Events:


(a) Nausea and vomiting:

  • Venlafaxine > other SSRIs medications. (Strength of Evidence: High)


(b) Diarrhea:

  • Sertraline > bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, and venlafaxine. (Strength of Evidence: Moderate)


(c) Weight changes:

  • Mirtazapine > citalopram, fluoxetine, paroxetine, and sertraline. (Strength of Evidence: Moderate)


(d) Somnolence:

  • Trazodone > bupropion, fluoxetine, mirtazapine, paroxetine, and venlafaxine. (Strength of Evidence: Moderate)


(e) Discontinuation Syndrome:

  • Highest: Paroxetine and Venlafaxine. (Strength of Evidence: Moderate)
  • Lowest: Fluoxetine.


(f) Suicidality: Insufficient evidence

  • No specific medication is at increased risk.


(g) Sexual adverse events:

  • Least for: Bupropion (compared to escitalopram, fluoxetine, paroxetine, and sertraline) (Strength of Evidence: High)
  • Higher for: Paroxetine (ejaculatory dysfunction).


(h) Cardiovascular adverse events:

  • Venlafaxine might cause an increased risk (Note: insufficient evidence)


(i) Seizures:

  • Increased risk: Bupropion (Note: insufficient evidence)


(j) Hepatotoxicity:

  • Increased risk: Nefazodone (Note: insufficient evidence)



  1. No substantial differences found in efficacy for the treatment of major depression disorder
  2. The differences in onset of action, adverse events, and some measures of health-related quality of life may be clinically relevant and influence the choice of a medication.
  3. This meta-analysis contradicts the MANGA study report of superior efficacy for escitalopram and sertraline.

This article is available as full PDF atAnn Intern Med. 2011;155:772-785 


Please do post your questions or comments below. 

Dr. Harvinder Singh, M.D. (Admin)

Enroll in our online course to have access to all important clinically relevant psychiatry topics in one place.

Related Articles