Comparative efficacy and risk of harms of immediate- versus extended-release second-generation antidepressants: A systematic review with network meta-analysis

Barbara Nussbaumer, Laura C. Morgan, Ursula Reichenpfader, Amy Greenblatt, Richard A. Hansen, Megan Van Noord, Linda Lux, Bradley N. Gaynes, Gerald Gartlehner

Research output: Contribution to journalReview articlepeer-review

16 Scopus citations


Background: Major depressive disorder (MDD) has detrimental effects on an individual's personal life, leads to increased risk of comorbidities, and places an enormous economic burden on society. Several 'second-generation' antidepressants are available as both immediate-release (IR) and extended-release formulations. The advantage of extended-release formulations may be the potentially improved adherence and a lower risk of adverse events. Objective: We conducted a systematic review to assess the comparative efficacy, risk of harms, and patients' adherence of IR and extended-release antidepressants for the treatment of MDD. Data Source: English-language abstracts were retrieved from PubMed, EMBASE, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to October 2012, as well as from reference lists of pertinent review articles and grey literature searches. Eligibility Criteria: We included head-to-head randomized controlled trials (RCTs) of at least 6 weeks' duration that compared an IR formulation with an extended-release formulation of the same antidepressant in adult patients with MDD. We also included placebo-controlled trials to conduct a network meta-analysis. To assess harms and adherence, in addition to RCTs, we searched for observational studies with ≥1,000 participants and a follow-up of ≥12 weeks. Study Appraisal and Synthesis Methods: We dually reviewed abstracts and full texts and assessed quality ratings. Lacking head-to-head evidence for many comparisons of interest, we conducted network meta-analyses using Bayesian methods. Our outcome measure of choice was response on the Hamilton Depression Rating Scale. Results: We located seven head-to-head trials and 94 placebo- and active-controlled trials for network meta-analysis. Overall, our analyses indicate that IR and extended-release formulations do not differ substantially with respect to efficacy and risk of harms. The evidence is mixed with respect to differences in adherence, indicating lower adherence for IR formulations. Limitations: The lack of head-to-head comparisons for many drugs compromises our conclusions. Network meta-analyses have methodological limitations that need to be taken into consideration when interpreting findings. Conclusion: Available evidence currently shows no clear differences between the two formulations and therefore we cannot recommend a first choice. However, if adherence or compliance with one medication is an issue, then clinicians and patients should consider the alternative medication. If adherence or costs are a problem with one formulation, consideration of the other formulation to provide an adequate treatment trial is reasonable.

Original languageEnglish (US)
Pages (from-to)699-712
Number of pages14
JournalCNS Drugs
Issue number8
StatePublished - Aug 2014
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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