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Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis

BMJ 2003; 326 doi: (Published 10 May 2003) Cite this as: BMJ 2003;326:1014
  1. Steve MacGillivray, research fellow (s.a.macgillivray{at},
  2. Bruce Arroll, associate professor of general practiced,
  3. Simon Hatcher, senior lecturer in psychiatrye,
  4. Simon Ogston, lecturer in medical statisticsa,
  5. Ian Reid, professor of psychiatryb,
  6. Frank Sullivan, professor of primary carec,
  7. Brian Williams, senior lecturer in behavioural sciencea,
  8. Iain Crombie, professor of epidemiology and public healtha
  1. a Department of Epidemiology and Public Health, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY
  2. b Department of Psychiatry, Ninewells Hospital and Medical School
  3. c Tayside Centre for General Practice, Ninewells Hospital and Medical School
  4. d Department of General Practice, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1, New Zealand
  5. e Division of Psychiatry, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92010
  1. Correspondence to: S MacGillivray
  • Accepted 19 March 2003


Objective: To compare the efficacy and tolerability of tricyclic antidepressants with selective serotonin reuptake inhibitors in depression in primary care.

Design: Systematic review and meta-analysis of randomised controlled trials.

Data sources: Register of the Cochrane Collaboration's depression, anxiety, and neurosis group. Reference lists of initial studies and other relevant review papers. Selected authors and experts.

Selection of studies: Studies had to meet minimum requirements on: adequacy of sample size, adequate allocation concealment, clear description of treatment, representative source of subjects, use of diagnostic criteria or clear specification of inclusion criteria, details regarding number and reasons for withdrawal by group, and outcome measures described clearly or use of validated instruments.

Main outcome measures: Standardised mean difference of final mean depression scores and relative risk of response when using the clinical global impression score. Relative risk of withdrawing from treatment at any time, and the number withdrawing due to side effects.

Results: 11 studies (2951 participants) compared a selective serotonin reuptake inhibitor with a tricyclic antidepressant. Efficacy between selective serotonin reuptake inhibitors and tricyclics did not differ significantly (standardised weighted mean difference, fixed effects 0.07, 95% confidence interval −0.02 to 0.15; z=1.59, P<0.11). Significantly more patients receiving a tricyclic withdrew from treatment (relative risk 0.78, 95% confidence interval 0.68 to 0.90; z=3.37, P<0.0007) and withdrew specifically because of side effects (0.73, 0.60 to 0.88; z=3.24, P<0.001). Most studies included were small and supported by commercial funding. Many studies were of low methodological quality or did not present adequate data for analysis, or both, and were of short duration, typically six to eight weeks.

Conclusion: The evidence on the relative efficacy of selective serotonin reuptake inhibitors and tricyclic antidepressants in primary care is sparse and of variable quality. The study setting is likely to be an important factor in assessing the efficacy and tolerability of treatment with antidepressant drugs.

What is already known on this topic

What is already known on this topic Previous meta-analyses have included comparatively large numbers of secondary care based studies that indicate no significant differences in efficacy between selective serotonin reuptake inhibitors and tricyclics

Previous meta-analyses are conflicting regarding the relative tolerability between selective serotonin reuptake inhibitors and tricyclics, but do suggest a small but significant difference in favour of selective serotonin reuptake inhibitors

Such meta-analyses show notable heterogeneity

What this study adds

What this study adds Selective serotonin reuptake inhibitors are better tolerated than tricyclics by primary care patients and may be better tolerated by primary care patients than secondary care patients

Study setting seems to be important and should be considered before licences are given to specific antidepressants

Although there are limited high quality data, available evidence shows that the most commonly prescribed classes of antidepressants in primary care (selective serotonin reuptake inhibitors and tricyclics) are equally effective in the short term for primary care patients, but the literature has many gaps


  • Funding Chief Scientist Office (Scotland) grant number CZG/3/2/101.

  • Competing interests SM has been reimbursed by GlaxoSmithKline for attending and speaking at conferences. SM and BW have received an unconditional educational grant from Eli-Lilly and are also involved in research unconditionally funded by GlaxoSmithKline. ICR has received research funding from Wyeth, Organon, and GlaxoSmithKline, and consultancy fees from Janssen, Organon and Eli-Lilly. FS is a member of the Medicines Monitoring Unit (MEMO) executive in the University of Dundee, which accepts unrestricted educational grants from pharmaceutical companies.

  • Embedded Image References to included and excluded studies appear on

  • Accepted 19 March 2003
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