Research reportSelective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability
Introduction
The selective serotonin reuptake inhibitors (SSRIs) are increasingly becoming the agents of first choice in the treatment of depression, replacing the well established tricyclic antidepressants (TCAs) probably because of their better side-effect profile and safety. The number of prescriptions issued by general practitioners for the treatment of depression increased by 33% between 1993 and 1995 (Donoghue et al., 1996). The increase in prescription rates of TCAs was 12.4%, while prescriptions of SSRIs increased by 133.8% during that time. An analysis of the prescribing patterns of psychiatrists in the USA, working in out-patient private clinics, revealed that in 1993–1994, psychiatric patients were 2.3-times more likely to receive an antidepressant than in 1985 (Olfson et al., 1998). SSRIs accounted for approximately half of all prescriptions.
SSRIs are more expensive than TCAs. The cost implications of the increasing use of SSRIs is large (Effective Health Care Bulletin, 1993) and has led to a heated debate over the cost-effectiveness of this change in prescribing pattern (Hotopf et al., 1996). There are now data from a large number of randomised controlled trials (RCTs) comparing SSRIs and TCAs and many meta-analyses have been carried out (e.g., Song et al., 1993, Anderson and Tomenson, 1994, Anderson and Tomenson, 1995, Montgomery et al., 1994, Hotopf et al., 1997, Steffens et al., 1997). The available randomised controlled trials have serious limitations in helping to cast light on cost-effectiveness issues because they are nearly all short-term treatment studies, whereas guidelines indicate the need to continue treatment for many months (Paykel and Priest, 1992, Montgomery et al., 1993) and they are artificial compared to treatment that occurs in everyday practice. However, it is important to inform the debate with the best evidence on efficacy and tolerability available from RCTs in order to guide clinicians’ choice and, arguably, as one basis for cost-effectiveness analyses. In spite of the plethora of meta-analyses that have been published, few have examined clinically important questions related to subgroups of patients and drugs which may provide guidance in treating individual patients with specific antidepressants. In a previous meta-analysis comparing TCAs (and maprotiline) with SSRIs, we detected no difference in efficacy in the overall analysis. However, SSRIs appeared less effective than some individual TCAs, and in hospitalised patients (Anderson and Tomenson, 1994). In a second meta-analysis which addressed the issue of relative tolerability, we found that fewer patients receiving SSRIs dropped out of treatment than those receiving TCAs, and that the main reason for discontinuation was attributed to side effects (Anderson and Tomenson, 1995), although the size of the effect was relatively small.
This meta-analysis was carried out because of the importance of updating previous studies given the significant increase in the number of trials comparing SSRIs and TCAs since our previous studies; a larger data-set allows more confident estimates of effect and reduces the likelihood of chance findings. It also seems unlikely that many more RCTs of this nature will be carried out so we are probably close to having as much data as will be available. Our previous studies raised important questions with regard to certain types of patients and a possible greater efficacy of specific TCAs. The larger number of studies allows further exploratory analysis of subgroups of trials in order to address these clinically important questions.
Section snippets
Selection of studies
Randomised controlled trials investigating the efficacy of SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) against a TCA in patients with unipolar major depressive illness were identified from previous meta-analyses and reviews, by manual cross-referencing and a MEDLINE search up to May 1997 (search terms: drug name; randomised controlled trial; controlled trial; depression and variants) with no language restrictions. The TCAs investigated included clomipramine,
All SSRIs versus TCAs
A total of 10 706 patients from 102 studies were included in the efficacy analyses, of whom 5533 received an SSRI and 5173 a TCA. The results are displayed in Fig. 1. There were no significant differences in efficacy between the SSRIs and the TCAs in the total patient population or in the subgroups which considered older and younger patient populations, high- and low-severity groups, and high- and low-dose TCA groups. In addition, no significant difference in efficacy between the drug classes
Discussion
The efficacy of the SSRIs as a group does not differ significantly from that of the TCAs as a group. This finding is consistent with previous meta-analyses (Anderson and Tomenson, 1994, Song et al., 1993) and studies investigating individual SSRIs (Ottevanger, 1991, Pande and Sayler, 1993). However, the TCAs demonstrated greater efficacy in hospitalised patients, although this benefit of TCAs was not observed in patients with more severe forms of depression as measured by an initial high HAMD
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