Authors' objectives

To determine whether high doses of antidepressants (both traditional and newer) are more effective than low doses, and how safety is affected by dose.

Searching

MEDLINE, Current Contents and the Cochrane Controlled Trials Register (CCTR) were searched. The years searched are not given, but some keywords are listed. References of retrieved papers and published literature reviews were examined, and many individual authors were contacted.

Study selection

Assessment of study quality

The Jadad checklist was used to assess methodological quality (see Other Publications of Related Interest no.1). Two reviewers scored each paper independently.

Data extraction

Data extraction was independently performed by two reviewers who were blind to the authors and journal title as well as to the type of drug and dose used. Disagreements between reviewers were solved through discussion. Data were extracted on: year of publication, setting, age, gender, diagnosis, duration of treatment, drop-outs, type and dose of antidepressant, concurrent medication or psychological treatment, outcomes.

Methods of synthesis

Results of the review

Thirty-three studies (n = 6842) were included.

Jadad quality score was 1 for one study, 2 for 11 studies, 3 for 15 studies and 4 for 6 studies.

None of the independent variables considered (antidepressant class, Jadad quality score, proportion of females, sample size, duration of treatment) were significant in the regression analysis and so were not included in the final regression model.

Percentage improvement: placebo 34.8 (95% CI: 25.4-44.3); <100mg 46.0 (95% CI: 36.9-55.1); 100-200mg 53.3 (95% CI: 48.0-58.5); 201-250mg 46.3 (34.9-57.7); >250mg 48.3 (95% CI: 37.0-59.7).

Adverse event rate (events/ week): placebo 0.22 (95% CI: 0.13-0.33); <100mg 0.22 (95% CI: 0.13-0.33); 100-200mg 0.30 (95% CI: 0.21-0.39); 201-250mg 0.36 (0.23-0.52); >250mg 0.48 (0.32-0.67).

Authors' conclusions

The dose level 100-200mg imipramine equivalents showed an average improvement of 53% by intention to treat. Higher doses were not accompanied by increased efficacy while lower doses showed reduction in efficacy. Adverse events significantly increased with dose. With a low dose of antidepressants, clinicians trade off a slightly reduced chance of improvement for a higher chance of avoiding adverse reactions.

CRD commentary

The review question is clearly stated and inclusion criteria are specific. The literature search is not well reported and it is unclear whether there were any language restrictions which could have led to studies being missed. It is unclear whether an attempt was made to find unpublished studies (although authors were contacted); if not, publication bias may result. Study details are not presented. Heterogeneity was investigated by including possible sources in a regression model and these were not found to be significant. Validity was assessed but, again, results are not presented. The authors' conclusions follow from the results but should be treated with some caution given the above limitations.

Implications of the review for practice and research

Research: The authors state that more research is needed on cheaper and, perhaps, more effective interventions aimed at retaining depressed patients on treatment, by managing adverse reactions and improving the therapeutic relationship between patient and physician.

Bibliographic details

Bollini P, Pampallona S, Tibaldi G, Kupelnick B, Munizza C. Effectiveness of antidepressants: meta-analysis of dose-effect relationships in randomised clinical trials. British Journal of Psychiatry 1999; 174: 297-303. [PubMed: 10533547]

Other publications of related interest

1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.

This additional published commentary may also be of interest. Goodwin GM. Review: lower doses of antidepressant drugs are effective and have fewer adverse effects in depression. Evid Based Med 2000;5:22.

Indexing Status

Subject indexing assigned by NLM

MeSH

Age Factors; Antidepressive Agents /administration & dosage; Depressive Disorder /drug therapy; Dose-Response Relationship, Drug; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

AccessionNumber

11999000941

Database entry date

31/03/2001

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.