Intended for healthcare professionals


Choosing a second generation antidepressant for treatment of major depressive disorder

BMJ 2012; 344 doi: (Published 14 February 2012) Cite this as: BMJ 2012;344:e1014
  1. Helen Lester, professor of primary care1,
  2. Simon Gilbody, professor of psychological medicine and health services research2
  1. 1University of Birmingham, Birmingham B15 2TT, UK
  2. 2University of York and HYMS, York, UK
  1. h.e.lester{at}

Involve patients in decision because drugs have similar efficacy but side effect profiles differ

Depression is a major cause of disability worldwide,1 with costs and consequences at the level of the individual, the family, and society.2 Effective treatments—both drug based and psychological—are much needed. A variety of antidepressants have been shown to be effective in clinical trials, and primary care and secondary care clinicians seem to have almost too much choice. However, recent meta-analyses of the comparative efficacy and safety of second generation antidepressants have reached conflicting conclusions, muddying the therapeutic waters. The most recent meta-analysis found little difference in efficacy among second generation antidepressants,3 whereas an earlier one found that escitalopram and sertraline had the best efficacy to acceptability ratio.4 National Institute for Health and Clinical Excellence guidance in England and Wales suggests that the first choice antidepressant should be a generic selective serotonin reuptake inhibitor (SSRI).5

The most recent meta-analysis reviewed 234 studies (including 118 head to head drug trials) published between 1980 and August 2011 and focused on the benefits and harms of 13 pharmacologically different second generation antidepressants for treating major depressive disorder.[3] Their method included inviting key stakeholders to help the study team refine their review questions and they sought unpublished research in this area, which is bedevilled by publication bias and conflicts of interest. Just under two thirds of the patients responded to treatment by 12 weeks and just under half achieved full remission. This provides evidence that antidepressants are an effective treatment for depression and counters recent claims of low effect sizes or no effect for people with anything less than very severe depression.6

The study highlighted important limitations in the primary research. Most of the trials recruited highly selected populations and the analysis did not include studies conducted in patients older than 65, which limited the transferability of research to older adults. In addition, no studies directly compared the efficacy, effectiveness, and harms between subgroups and the general population.

The meta-analysis found no clinically important differences between drugs in efficacy or effectiveness in acute, continuation, and maintenance phases of major depressive disorder, although small differences were noted in how quickly different drugs started to work and their side effect profiles. For example, nearly two thirds of patients had at least one adverse event, but effects varied between drugs. A low incidence of sexual dysfunction was seen for bupropion but the incidence was high for paroxetine; mirtazapine was more likely to lead to weight gain but had a faster onset of action than citalopram, fluoxetine, paroxetine, and sertraline; trazadone had a greater sedative effect and sertraline had a higher incidence of diarrhoea than comparator drugs; and venlafaxine (a serotonin noradrenaline (norepinephrine) reuptake inhibitor) had a higher incidence of nausea and vomiting than SSRIs as a class. In short, the drugs were “the same but different,” in that each seemed to work, with minimal differences in efficacy, and no drug was without problems, although side effects differed.

What are the lessons for clinicians? The authors of this high quality meta-analysis focused on clinical rather than statistical significance. Although similarly effective, the newer antidepressants offer different therapeutic options in practice. In the absence of an obvious best treatment, the clinical consultation needs to focus discussing side effects with patients so that they can make an informed choice.

Clinicians might take a moment to reflect on advances in, and limitations of, drug treatments for depression. It is now 25 years since the first SSRI, fluoxetine (Prozac), was licensed. Second generation antidepressants were hailed as a major advance over first generation ones. Systematic reviews have since shown that the benefits of second generation drugs over first generation ones are smaller than originally envisaged.7 Each subsequent second generation drug has been marketed as an important advance over previous ones. The findings of the recent meta-analysis suggest a limited or non-existent incremental benefit of each new antidepressant. Newer drugs are unlikely to be of sufficient additional benefit to make them cost effective compared with older second generation drugs. Many second generation agents are now off patent, and cost conscious prescribing should give primacy to generic preparations where possible.

Evidence from randomised trials and observational studies indicates that overall rates of discontinuation of antidepressants are high and adherence rates are poor, which reduces the effectiveness of these drugs. Collaborative care tackles these problems by integrating shared decision making with medication management, where case managers check patients’ understanding and worries about drugs and liaise closely with general practitioners if problems arise. This approach increases the use of antidepressants and improves patient outcomes, according to a large body of evidence from more than 36 randomised trials.8 In the long term, better services may have more effect on improving care than choice of antidepressant.

Nearly 40 years ago, when reviewing which form of psychotherapy was the most effective, researchers arrived at the so called dodo verdict: “Everybody has won and all must have prizes” (from Lewis Carroll’s Alice’s Adventures in Wonderland).9 The same verdict seems appropriate for second generation antidepressants. The immediate challenge is not to try to work out which drug is best but to make the most of what is available through cost conscious prescribing and shared decision making.


Cite this as: BMJ 2012;344:e1014


  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: they had financial support from the UK National Institute of Health Research to support research on the management of depression in primary care; no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; not externally peer reviewed.


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