who had smoked for more than 30 years. Moreover, Key messages breast cancer will occur eight years earlier in smokers than in non-smokers. This finding could support the * Breast cancer is the commonest cancer in women throughout the world, hypothesis ofa direct carcinogenic effect oftobacco. and its incidence is increasing * It has been suggested that smoking protects against breast cancer because This study was financially supported by the Niels Jensen of an antioestrogenic effect Foundation and Hj0rring District Hospital. * This study shows, however, that women who have smoked for more than 1 MacMahon B, Trichopoules D, Cole P, Brown J. Cigarette smoking and 30 years have an increased risk ofdeveloping breast cancer urinary estrogens. NEnglJMed 1982;307:1062-5. 2 Baron JA, LaVecchia C, Levi F. The antiestrogenic effect of cigarette smoking * Moreover, smokers with breast cancer were eight years younger than in women. Amy Obstet Gynecol 1990;162:502-14. non-smokers with breast cancer 3 Petrakis NL, Maack CA, Lee RE, Jyon M. Mutagenic activity in nipple aspirates ofhuman breast fluid. Cancer Res 1980;40:188-9. 4 Hiatt RA, Fireman BH. Smoking, menopause, and breast cancer. J Natl Cancer Inst 1986;76:833-8. than those in 5 Palmer JR, Rosenberg L. Cigarette smoking and the risk of breast cancer. included our model-for example, EpidemiolRev 1993;5:145-56. alcohol, diet, body size, and use of oral contraception 6 Hosmer DW, Lemeshow S. Applied logistic regression. New York: John Wiley, -have been studied extensively.' 02 The associations 1989. 7 Osler M. Danskernes rygevaner [Smoking habits of Danes]. Dansk Institut for between these factors and breast cancer, however, are Klinisk Epidemiologi: Copenhagen, 1992. often weak and inconsistent. Although confounding 8 Krall EA, Valadian I, Dwyer JT, Gardener J. Accuracy of recalled smoking data. Am yPublic Health 1989;79:200-6. cannot be ruled out as an explanation ofour results, it is 9 Vogt TM, Steve S, Widdenson G, Hulley SB. Expired air carbon monoxide not likely that an inverse relation exists between and serum thiocyanate as objective measures of cigarette consumption. Am I smoking and breast cancer. Public Health 1977;67:545-9. 10 Hunter DJ, Willett WC. Diet, body size, and breast cancer. Epidemiol Rev 1993;15:1 10-32. CONCLUSION 11 Malone KE, Daling JR, Weiss NS. Oral contraceptives in relation to breast cancer. Epidemiol Rev 1993;15:80-97. In conclusion, nothing in the present study suggests 12 Roth HD, Levy PS, Shi L, Post E. Alcoholic beverages and breast cancer: that smoking protects against breast cancer-rather, some observations on published case-control studies. J Clin Epidemiol the opposite. Smoking seemed to increase the risk of 1994;47:207-16. developing cancer to a modest extent among women (Accepted 11April 1995) Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants: a meta-analysis I M Anderson, B M Tomenson Abstract the selective serotonin reuptake inhibitors-compared Objective-To assess treatment discontinuation with the cheaper, first generation tricyclic antidepres- rates with selective serotonin reuptake inhibitors sants.' 2 Both groups of drugs are of comparable compared with tricyclic antidepressants. efficacy,3-5 so that cost effectiveness hinges on toler- Design-Meta-analysis of 62 randomised con- ability and safety. Tricyclic antidepressants are much trolled trials. cheaper per tablet than selective serotonin reuptake Subjects-6029 patients with major unipolar inhibitors. But if compliance is poorer tricyclic anti- depression. depressants may prove more expensive overall because Main outcome measures-Pooled risk ratios for of costs incurred through treatment failure (for drop out rates with respect to all cases of discon- example, costs of extra treatment, time off work, tinuation and those due to side effects and treatment sickness benefit, etc).6 failure. One way of assessing relative tolerability is to Results-The total discontinuation rate was 10% measure discontinuation rates in randomised, double lower with selective serotonin reuptake inhibitors blind, parallel comparative trials. Though this is fairly than with tricyclic antidepressants (risk ratio 0 90; crude,7 it provides an objective measure of the propor- 95% confidence interval 0.84 to 0.97) and the drop tion of patients who persist with each treatment during out rate due to side effects was 25% lower (risk ratio the study. In an influential meta-analysis, Song et al 075; 066 to 0 84). There was no significant differ- found that efficacy and drop out rates did not differ ence between drug classes in the drop out rates for between tricyclic antidepressants and selective sero- treatment failure. The risk ratios for drop out did tonin reuptake inhibitors and concluded that the not differ significantly between individual selective increasing use of the newer drugs as first line treatment serotonin reuptake inhibitors. was not warranted.4 Their analysis was weakened by Conclusions-Selective serotonin reuptake the inclusion of non-tricyclic, second generation anti- inhibitors are better tolerated than tricyclic anti- depressants in the tricyclic group (table I), accounting depressants as measured by total numbers of drop for about a quarter of the studies they analysed. These University ofManchester outs. The definite advantage to selective serotonin drugs generally have a better side effect profile than the Department ofPsychiatry, reuptake inhibitors is explained by fewer drop outs tricyclic antidepressants8 but are infrequently used Rawnsley Building, due to side effects. The overall difference, however, in practice.9 Hence the clinical relevance of their Manchester Royal is comparatively small and may not be clinically inclusion in the meta-analysis can be questioned. Infirmary, Manchester relevant. Analyses of cost effectiveness should not Montgomery et al confined their meta-analysis to M13 9WL studies including tricyclic antidepressants and found I M Anderson, senior lecturer overestimate the advantage to selective serotonin reuptake inhibitors. that selective serotonin reuptake inhibitors caused B M Tomenson, statistician significantly fewer drop outs due to side effects Correspondence to: whereas there was no difference in drop outs due to Dr Anderson. Introduction inefficacy.7 Unfortunately, given that discontinuation There is debate about the cost effectiveness of due to side effects accounts for only 30-50% of drop BMJ 1995;310:1433-8 newer, more expensive antidepressants-especially outs,42727 they failed to analyse total drop out rates. BMJ voLuME310 3JUNE1995 1433 Possibly more prominent side effects could lead to a The main objective of this meta-analysis was to greater attribution of discontinuation to adverse effects discover whether the overall discontinuation rate with without changing the number of patients who in fact selective serotonin reuptake inhibitors is different stopped treatment. It is therefore very important to from that with tricyclic antidepressants. Drop outs analyse both the total number of drop outs and the due to side effects and treatment failure were also discontinuations that may be attributable to side analysed. effects or treatment failure. TABLE i-Papers included in meta-analysis of total drop outs by Song et aP but excludedfrom this analysis Methods for reasons stated Potential studies testing five selective serotonin Study Comparator antidepressant Reason for exclusion reuptake inhibitors (fluoxetine, fluvoxamine, paroxe- against a tricyclic anti- Debus et al, 1988'0 Trazodone Non-tricyclic antidepressant tine, sertraline, or citalopram) deJonghe et al, 1991" Maprotiline Non-tricyclic antidepressant depressant in patients with the equivalent of major de Jonghe et al, 1991' Matroptiline Non-tricyclic antidepressant unipolar depressive illness were identified from Dorman, 1992"3 Mianserin Non-tricyclic antidepressant Falk et al, 1989"4 Trazodone Non-tricyclic antidepressant previous meta-analyses and reviews and by manual Feighner et al, 1989"5 Imipramine Total drop outs not reportedt cross referencing and a Medline search in June 1993. Feighner et al, 1991"6 Bupropion Non-tricyclic antidepressant Ferreri, 1989" Amineptine Non-tricyclic antidepressant We identified 81 reports of double blind randomised Laakmann etal, 1988"1 Amitriptyline Conflicting numbers reported controlled trials in depressed patients. We were careful Mertens and Pintens, 1988"4 Mianserin Non-tricyclic antidepressant to avoid duplication and whenever possible for multi- Muijen et al, 1988"0 Mianserin Non-tricyclic antidepressant Perez and Ashford, 1990"' Mianserin Non-tricyclic antidepressant centre studies used the combined multicentre report; Perry et al, 1989"1 Trazodone Non-tricyclic antidepressant in two exceptions there was lack of information about Phanjoo et al, 1991"3 Mianserine Non-tricyclic antidepressant Poelinger and Haber, 1989"4 Maprotiline Non-tricyclic antidepressant drop outs.28 29 This left 71 studies, ofwhich 62 provided Taneri and Kohler, 19892" Nomifensine Non-tricyclic antidepressant adequate information on the total number of drop outs and a further two reported only drop outs due to side tReported only drop outs due to side effects. TABLE ni-Discontinuation rates in double blind randomised studies in major depression comparing selective serotonin reuptake inhibitors with tricyclic antidepressants Drop outs due to Drop outs due to No of patients Total drop outs side effects failure Serotonin Study