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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Comparative risk for harms of second-generation antidepressants: a systematic review and meta-analysis

G Gartlehner, P Thieda, RA Hansen, BN Gaynes, A DeVeaugh-Geiss, EE Krebs, and KN Lohr.

Review published: 2008.

Link to full article: [Journal publisher]

CRD summary

The review assessed the comparative harms of second-generation antidepressants for the treatment of major depressive disorder. The authors concluded that adverse event profiles were similar between different second-generation antidepressants, but that the frequency of specific adverse events differed between drugs. This review was generally well conducted and the conclusion is likely to be reliable.

Authors' objectives

To assess the comparative harms of second-generation antidepressants for the treatment of major depressive disorder.

Searching

MEDLINE, EMBASE, PsycLIT, The Cochrane Library, International Pharmaceutical Abstracts and the Centre for Drug Evaluation and Research database were searched from 1980 to April 2007 for studies published in English. Search terms were reported. Reference lists of relevant publications were screened. Pharmaceutical manufactures were contacted for relevant studies.

Study selection

Experimental and observational studies that compared at least two second-generation antidepressants in adult patients with major depressive disorder over a period of at least six weeks were eligible for inclusion. Only observational studies with a large sample size of at least 100 patients were eligible for inclusion. Eligible antidepressants included bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone and venlafaxine. The review outcomes were overall rate of adverse events, discontinuation rate due to adverse events and specific and severe adverse events.

Most included studies were randomised controlled trials (RCTs). Most studies assessed adverse events using patient self-reporting together with regular clinical examinations. Adverse events were rarely prespecified in the included studies.

Two reviewers independently assessed studies for inclusion. Any disagreement was resolved by consensus or a third reviewer.

Assessment of study quality

Quality of RCTs was assessed using the following criteria: randomisation, allocation concealment, comparability of baseline characteristics, withdrawals and analysis of intention-to-treat. Quality of observational studies was assessed using the following criteria: selection of cases or cohorts and controls, adjustment for confounders, methods of outcome assessment and length of follow-up. Studies with a serious flaw in one or more categories were classified as poor quality.

The authors did not state how many reviewers performed the validity assessment.

Data extraction

Data on the outcomes of interest were extracted in structured forms. One reviewer extracted the data. One reviewer checked data for completeness and accuracy.

Methods of synthesis

The studies were combined in a narrative synthesis for most outcomes. When data from RCTs were sufficient, studies were combined in meta-analyses using random-effects models. Pooled relative risks (RRs) for dichotomous outcomes, with 95% confidence intervals (CIs), were calculated. Number needed-to-harm (NNH) with 95% CI was calculated. Statistical heterogeneity was investigated using I2 statistics. If I2 was 60% or more, sensitivity analyses were conducted according to population characteristics, dosage or drug formulation. Publication bias was assessed using funnel plots and Kendall's tests.

Results of the review

One hundred and four studies were included in the review, including 83 RCTs (n>17,000) and 21 observational studies (n>740,000). Studies with poor quality were excluded from analyses; the number of studies with poor quality was not reported.

When the studies were pooled, venlafaxine was significantly associated with a higher rate of nausea and vomiting compared with selective serotonin reuptake inhibitors (RR 1.53, 95% CI 1.26 to 1.86 and NNH 9, 95% CI 6 to 23; 17 RCTs) and a higher discontinuation rate due to adverse events (RR 1.42, 95% CI 1.15 to 1.75).

Compared with other second-generation antidepressants, sertraline was associated with a higher incidence (8%, 95% CI 3% to 11%) of diarrhoea; mirtazapine and paroxetine were associated with higher weight gains. Paroxetine was associated with a higher incidence of sexual dysfunction and bupropion with a lower incidence. There was insufficient evidence to draw firm conclusions about the risk for serious adverse events such as suicidality, hyponatremia and seizures.

Sensitivity analyses of drug formulation significantly altered the results for the outcome of nausea and vomiting. The result of publication bias assessment was not reported.

Authors' conclusions

Adverse event profiles were similar between different second-generation antidepressants, but the frequency of specific adverse events differed between drugs.

CRD commentary

This review's inclusion criteria were clear. A number of relevant databases were searched. Efforts were made to find published and unpublished studies to minimise the risk of publication bias. Publication bias was evaluated, but the result was not presented in the report. Language restrictions were applied (English only), which increased the possibility of language bias. Steps were taken to minimise bias by having more than one reviewer undertake the study selection and data extraction, but it was unclear whether the process of validity assessment was also performed in duplicate. Relevant criteria were used to examine study quality. A narrative synthesis for most outcomes was appropriate given the diversity of included studies. For RCTs with sufficient data, appropriate statistical methods were used to pool the results and statistical heterogeneity was assessed. This review was generally well conducted and the authors' conclusions are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that different frequencies of specific adverse events between second-generation antidepressants could influence the choice of a treatment.

Research: The authors stated that large and well-conducted observational studies were required to assess the comparative risk of severe adverse events between second-generation antidepressants. Such studies should evaluate whether elderly patients or patients with chronic diseases had an increased risk of severe adverse events of second-generation antidepressants.

Funding

Agency for Healthcare Research and Quality to the RTI International-University of North Carolina Evidence-based Practice Centre (contract no. 290-02-0016). Some personal financial relationships with a number of pharmaceutical companies were declared by the authors.

Bibliographic details

Gartlehner G, Thieda P, Hansen RA, Gaynes BN, DeVeaugh-Geiss A, Krebs EE, Lohr KN. Comparative risk for harms of second-generation antidepressants: a systematic review and meta-analysis. Drug Safety 2008; 31(10): 851-865. [PubMed: 18759509]

Other publications of related interest

Hansen RA, Gaynes BN, Gartlehner G, Moore CG, Tiwari R, Lohr KN. Efficacy and tolerability of second-generation antidepressants in social anxiety disorder. International Clinical Psychopharmacology 2008; 23(3): 170-179.

Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Annals of Internal Medicine 2005; 143(6): 415-426.

Krebs EE, Gaynes BN, Gartlehner G, Hansen RA, Thieda P, Morgan LC, DeVeaugh-Geiss A, Lohr KN. Treating the physical symptoms of depression with second-generation antidepressants: a systematic review and metaanalysis. Psychosomatics 2008; 49(3): 191-198.

Indexing Status

Subject indexing assigned by NLM

MeSH

Adult; Antidepressive Agents, Second-Generation /adverse effects /therapeutic use; Blood Pressure /drug effects; Depressive Disorder, Major /drug therapy /psychology; Humans; Nausea /chemically induced; Risk Assessment /methods /statistics & numerical data; Seizures /chemically induced; Sexual Dysfunction, Physiological /etiology; Sexual Dysfunctions, Psychological /etiology; Treatment Outcome; Vomiting /chemically induced

AccessionNumber

12009100796

Database entry date

25/11/2009

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18759509