Current issues of ACP Journal Club are published in Annals of Internal Medicine


Review: Selective serotonin reuptake inhibitors have comparable effectiveness and acceptability to tricyclic antidepressants in the initial treatment of depression

ACP J Club. 1993 Sept-Oct;119:45. doi:10.7326/ACPJC-1993-119-2-045

Source Citation

Song F, Freemantle N, Sheldon TA, et al. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. BMJ. 1993 Mar 13;306:683-7.



To compare the efficacy and acceptability of selective serotonin reuptake inhibitors with tricyclic and related antidepressants in the first-line treatment of depression using meta-analysis.

Data sources

Relevant citations were identified by searching MEDLINE and Index Medicus, by manual cross-referencing, and by discussion with experts.

Study selection

Randomized controlled trials comparing serotonin reuptake inhibitors with tricyclic or related antidepressants using a double-blind design were included.

Data extraction

63 trials met the selectioncriteria. The mean difference in Hamilton scores between patients treated with serotonin reuptake inhibitors and those treated with tricyclic or related antidepressants was calculated for each of the 55 trials using the Hamilton depression-rating scale. A pooled estimate of the treatment difference was calculated. Dropout rates were used to assess acceptability. A pooled estimate of the overall odds ratio (OR) for dropouts was calculated from the 58 trials that reported these data. The main subjective reason given by patients for discontinuing therapy was also recorded when available.

Main results

Among the 20 trials reporting the standard deviation for the Hamilton score, no difference was found in mean improvement in Hamilton score when comparing the serotonin group with the tricyclic and related antidepressants group (standardized difference 0.004, 95% CI -0.096 to 0.105). Weighted average standard deviations were ascribed to the remaining 33 trials that used the 17- or 21-item Hamilton scale, and the results indicated that the serotonin group was not better than the tricyclic group when evaluating improvement in mean Hamilton score (17-item scale mean difference 0.727, CI 0.083 to 1.370, in favor of the tricyclic group; 21-item scale 0.147, CI -0.597 to 0.891). The pooled dropout rate was 32% in the serotonin group and 33% in the tricyclic and related antidepressant group (OR 0.95, CI 0.816 to 1.107). The 2 most commonly cited reasons for dropout were lack of efficacy and side effects. No difference existed between treatment groups in dropouts attributed to lack of efficacy, but slightly more dropouts were attributed to side effects in the tricyclic group.


Selective serotonin reuptake inhibitors have comparable effectiveness and acceptability to tricyclic and related antidepressants in the first-line treatment for depression.

Source of funding: {UK Department of Health}*

For article reprint: Mr. T.A. Sheldon, Centre for Health Economics, University of York, York YO1 5DD, United Kingdom. FAX 44-904-433-644.

* Information supplied by author.


In 1993, Song and colleagues published a meta-analysis pooling 63 trials that compared tricyclic antidepressants with selective serotonin reuptake inhibitors. They concluded that there was no difference in effectiveness. Their only noteworthy finding was that although no difference existed in the pooled dropout rate, more people on tricyclic antidepressants reported dropping out because of adverse effects. Since then, at least 5 additional meta-analyses have been published on the same issue. A recent review by the Canadian Coordinating Office for Health Technology Assessment also found no difference in efficacy or in dropout rates (1). This review shows that the drugs differ in adverse effects, with tricyclic antidepressants causing more dry mouth, constipation, and dizziness, but less nausea, diarrhea, anxiety, agitation, and insomnia. Although additional meta-analyses will undoubtedly be done to clarify this issue even further, several much more important questions remain. From the system perspective, is there a difference in cost effectiveness between tricyclic antidepressants and selective serotonin reuptake inhibitors? Given that most of the original studies were done in mental health settings, is there a difference between the classes in patients treated in the primary care setting? Finally, and most importantly, how can we ensure that more depressed patients get these effective treatments? A recent analysis of depressed persons in the United States and Canada found that only 7% to 15% received appropriate management (2). This was because only 30% to 55% saw a provider (either primary care or mental health care) about a mental problem, and only 25% of obese patients received appropriate management. Ongoing studies are examining whether quality improvement methods can help medical systems be more effective at delivering this much-needed form of effective treatment.

Scott E. Sherman, MD, MPH
VA Center for the Study of Healthcare Provider BehaviorSepulveda, California, USA


1. Trinidade E, Menon D. Selective serotonin reuptake inhibitors (SSRIs) for major depression. Part I: Evaluation of the clinical literature. Ottawa: Canadian Coordinating Office for Health Technology Assessment, 1997. Report 3E.

2. Katz SJ, Kessler RC, Lin E, Wells KB. Medication managmeent of depression in the United States and Ontario. J Gen Intern Med. 1998;13:77-85.