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To review data on the efficacy and effectiveness of second-generation antidepressants for preventing major depression relapse and recurrence during continuation and maintenance phase treatment, respectively.
MEDLINE®, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts were searched from January 1980 through April 2007 for reviews, randomized controlled trials, meta-analyses, and observational studies. Two persons independently reviewed abstracts and full text articles using a structured data abstraction form to ensure consistency in appraisal and data extraction.
Four comparative trials and 23 placebo controlled trials that addressed relapse or recurrence prevention were included. Results of comparative trials have not demonstrated statistically significant differences between duloxetine and paroxetine, fluoxetine and sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine. Pooled data for the class of second-generation antidepressants compared with placebo suggest a relatively large effect size that persists over time. The number needed to treat to prevent one additional relapse or recurrence is 5 (95% CI 4 to 6). Differences in the length of open-label treatment prior to randomization, drug type, and trial duration did not affect pooled estimates of relapse rates (P = 0.716, P = 0.507, and P = 0.480, respectively). Across all trials, 7% of patients randomized to active treatment and 5% of patients randomized to placebo discontinued treatment because of adverse events.
This review demonstrates the overall benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants, and stresses the need for additional studies on comparative differences among drugs.
Antidepressants commonly are used as first-line treatment for major depressive disorder (MDD). On average, approximately 60% of patients respond to acute-phase treatment with second-generation antidepressants such as bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine (1). Once a patient demonstrates an appropriate response to an antidepressant, ongoing treatment is recommended.
Treatment guidelines for MDD (2, 3) suggest an acute-phase treatment duration of 6 to 12 weeks. For patients who demonstrate an adequate response (usually defined as remission) to acute-phase treatment, continuation-phase treatment of 4 to 9 months is recommended. The goal of continuation-phase treatment is enduring absence of depressive symptoms so the patient’s episode can be considered completely resolved. Effective continuation-phase treatment prevents relapse - the return of depressive symptoms during the current depressive episode. Following successful continuation-phase treatment, a maintenance-phase treatment to prevent recurrence of a new, distinct episode is considered. For those with a history of recurrent MDD, maintenance-phase treatment can frequently last for years.
To date, two reviews have systematically assessed relapse prevention during continuation and maintenance treatment (4, 5). However, these reviews included all antidepressants rather than just second-generation antidepressants; they are also limited by the dates of their literature searches (searches censored at 1987 (4) and 2000 (5) and therefore do not include more recent studies). A more recent review by Zimmerman and colleagues (2007) focused on second-generation antidepressants, although the intent of this review was to illustrate how conclusions differ between extension and placebo substitution trials. Because second-generation drugs are now the most frequently prescribed antidepressants, our goal was to evaluate systematically data on the efficacy of second-generation antidepressants for maintaining remission and to assess this evidence in light of their tolerability during ongoing treatment.
We conducted a systematic review and meta-analysis of comparative and placebo-controlled evidence for 12 second-generation antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine). We refer to these agents collectively as antidepressants. The key questions for this review were:
Key questions designed to address efficacy, effectiveness, and tolerability of antidepressants for maintaining remission guided our work. The key questions were formulated through a public process involving the public, the US Scientific Resource Center for the Effective Health Care program of the Agency for Healthcare Research and Quality (AHRQ), and various stakeholder groups. The AHRQ provided funding for the initial review, although the current update and analysis was unfunded.
To identify articles relevant to each key question we searched MEDLINE, Embase, The Cochrane Library, PsychLit, and the International Pharmaceutical Abstracts. Our searches covered 1980 through April 2007. We manually searched reference lists of relevant review articles and letters to the editor. Additionally, we hand-searched the Center for Drug Evaluation and Research (CDER) database to identify unpublished research submitted to the US Food and Drug Administration (FDA).
Two persons independently reviewed titles and abstracts. We included head-to-head trials comparing one antidepressant to another, as well as placebo-controlled trials. Studies included adult inpatients and outpatient populations with depressive illness with demonstrated response or remission to treatment. Head-to-head trials were included if they reported relapse or recurrence rates, regardless of whether participants were randomized following successful acute or continuation-phase treatment (i.e., extension versus randomized substitution). For the purpose of our meta-analysis, inclusion criteria were more stringent for placebo-controlled evidence; only studies that randomized participants after demonstrating either an acute-phase response or lack of relapse during the continuation phase were included (i.e., randomized placebo substitution trials).
Trained reviewers abstracted data from each study; a senior reviewer read each abstracted article and evaluated completeness of data extraction. We recorded intention-to-treat results if available.
We assessed the internal validity (quality) of trials based on predefined criteria from the US Preventive Services Task Force (ratings: good-fair-poor) (6) and the National Health Service Centre for Reviews and Dissemination (7). Elements of internal validity assessment included randomization, allocation concealment, similarity of compared groups at baseline, use of intention-to-treat analysis, and overall and differential loss to followup. Discrepancies in quality assessment were resolved by discussion and, when necessary, consultation with a third-party.
We qualitatively summarized all studies. For placebo-controlled trials – the majority of the included studies – we also conducted quantitative analyses. We calculated the relative risk of loss of response for active treatment compared with placebo. The primary outcome measure was defined as loss of response or remission (i.e., continuation-phase relapse or maintenance-phase recurrence); in most trials this was defined as an increase in the Hamilton Depression rating scale (HAM-D) or Montgomery-Asberg Depression Rating Scale (MADRS) above a predefined cut-off point. We conducted relative risk meta-analysis of relapse rates for trials stratified by duration of followup: less than 1 year and 1 year or more. Risk difference meta-analyses were used to calculate numbers needed to treat (NNT) overall and for each time period.
Trials with multiple placebo comparisons were included in the analysis. For example, in trials that compared multiple dosing arms to a single placebo group, the dosing arms were combined for a single comparison as long as doses were within the range of approved doses. In trials that compared one or more drug to placebo, each drug-placebo comparison was included as an observation, but the sample size of the placebo group was reduced proportionately to the number of comparisons so as not to over-represent the placebo group. For each meta-analysis, we tested for heterogeneity of treatment effects using I2 statistics. We report the results of the more conservative random effects models (8). To estimate possible publication bias, we used funnel plots, Beggs adjusted rank correlation test, and the Egger regression approach (9, 10). However, because these tests have low statistical power when the number of trials is small (11), undetected bias may still be present.
As an additional means of comparing relapse rates for active treatment with those for placebo over time, we calculated weighted mean relapse rates for all reported time points across included trials. We plotted the weighted mean relapse rates for active treatment and placebo against time (weeks) and added a linear trend line for each group. A general linear model was used to test whether differences in relapse rates between active treatment and placebo were consistent over time.
The most common trial design was an open-label acute treatment phase of 6 to 15 weeks, followed by a randomized, double-blind, placebo-controlled continuation- and/or maintenance-phase for acute-phase responders or remitters. Because trials differed in the length of open-label treatment prior to randomization and the duration of treatment after randomization, we conducted a meta-regression to explore how heterogeneity in design impacted estimates of relative risk. Similarly, we used meta-regression to explore whether pooling antidepressants as a class was a reasonable approach. For simplicity, this analysis explored heterogeneity by comparing SSRI trials (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) to other second-generation antidepressant trials (e.g., bupropion, duloxetine, mirtazapine, nefazodone, trazodone, and venlafaxine).
To balance our assessment of benefits, we examined reported rates of adverse events and rates of loss to followup due to adverse events. We qualitatively compared the rates from included relapse/recurrence prevention studies with rates reported in acute-phase trials (1, 12). We also conducted a relative risk meta-analysis for active treatment compared with placebo for both overall loss to followup and loss to followup due to adverse events. However, because of variability in study populations and in adverse event assessment and reporting among trials, caution should be taken in interpreting this evidence.
All statistical analyses were conducted using STATA 9.1 (StataCorp, 2005).
Our search identified 2,318 titles and abstracts (Appendix 1). Of these, we reviewed 902 full text articles and retained 29 articles describing 27 unique trials that addressed relapse or recurrence prevention (Table 1 and Table 2). The most common reason for exclusion was “wrong study design”; many of the excluded studies assessed acute-phase treatment. Included studies differed in their design (e.g., timing of randomization, eligibility criteria, etc.), although most studies randomized acute-phase responders or remitters to ongoing treatment with active drug or placebo. Most trials used a predefined cut-off point on a standardized scale (e.g., HAM-D or MADRS) to determine eligibility for randomization, although the cut-off point varied among trials. Likewise, operational definitions for relapse and recurrence varied among trials. The majority of included trials were given a “fair” quality rating; they represent a broad range of methodological quality.
Four head-to-head trials (five publications) provide evidence of moderate strength that the overall efficacy of second-generation antidepressants for maintaining remission does not differ between drugs studied in these trials (Table 1)(13–17). Comparisons included duloxetine with paroxetine (17), fluoxetine with sertraline (13), fluvoxamine with sertraline (14, 15), and trazodone with venlafaxine (16). Relapse rates did not differ significantly among trials. Although these trials reported relapse or recurrence rates, no comparative trial used a substitution design to randomize participants following successful acute or continuation treatment.
Twenty-three RCTs provided placebo-controlled evidence to support the general efficacy of second-generation drugs for preventing relapse or recurrence in patients with depressive disorders (Table 2) (18–40). Twelve trials (13 placebo comparisons) were shorter than 1 year for the randomized followup (18–27, 29, 40). These trials provide consistent evidence in favor of active drug over placebo, with the majority representing the efficacy of relapse prevention. The unadjusted frequency of relapse was 22% for active treatment, compared with 42% for placebo. An additional 11 RCTs were 1 year or longer (28, 30–39). These trials also provide consistent evidence in favor of active treatment over placebo, with the majority representing recurrence prevention during maintenance-phase treatment. The unadjusted frequency of relapse was 26% for active treatment, compared with 48% for placebo.
Twelve trials were included in our relative risk meta-analysis of trials lasting less than 1 year after randomization (Figure 1): one on bupropion (18), three on citalopram (19, 27, 40), one on escitalopram (20), three on fluoxetine (21, 22, 29), and one each on mirtazapine (23), nefazodone (24), sertraline (25), and venlafaxine (26). The pooled relative risk of relapse was 0.54 (95% CI 0.46 to 0.62) and the NNT to prevent one additional relapse over a mean time of 8 months was 5 (95% CI: 4–6). Moderate heterogeneity was detected among these trials (I2 = 47%). Tests for publication bias were not statistically significant.
Eleven trials provided data points for followup of 1 year or more (Figure 2): one on citalopram (28), one on escitalopram (38), one on fluvoxamine (30), one on nefazodone (31), two on paroxetine (32, 37), four on sertraline (33–35, 39), and one on venlafaxine (36). Trials consistently favored active treatment over placebo for preventing relapse and/or recurrence, although differences were not always statistically significant. For example, during a 100-week comparison of sertraline 50-100mg/d to placebo, 45% of sertraline-treated participants and 54% of placebo-treated participants had a recurrence, but differences were not statistically significant (P=0.21) (35). The pooled relative risk of recurrence was consistent with our estimates of relapse for trials with shorter followup (RR = 0.56; 95% CI: 0.48–0.66) and the NNT to prevent one additional recurrence over a mean time of 16 months was 5 (95% CI: 4–6). As with the analysis of shorter trials, moderate heterogeneity was detected among the longer trials (I2 = 30%). Tests for publication bias were not statistically significant.
To aid in assessing the risk of relapse or recurrence over time with active drug treatment compared with placebo, we calculated the weighted mean relapse/recurrence rates and plotted them over time (Figure 3). Although this plot demonstrates some inconsistencies in relapse and recurrence rates among trials, adding a linear trend to these data points demonstrates a relatively consistent difference between active drug and placebo. Comparing the linear trends using a general linear model revealed a statistically non-significant treatment by time interaction (P=0.59), supporting the conclusion that differences in pooled relapse/recurrence rates between active treatment and placebo persist over time.
Our meta-regression explored heterogeneity in included trials with regard to the duration of open-label treatment prior to randomization of responders, the length of the post-randomization phase, and drug type (SSRI or other second-generation antidepressant). None of these variables statistically significantly influenced our estimates of effect size (P = 0.716, P = 0.480, and P = 0.507 respectively).
The most common adverse event documented in continuation- and maintenance-phase studies was headache, followed by nausea (weighted mean incidence = 15.5% and 7.4% respectively). Compared with the incidence of adverse events in acute-phase studies (1, 41), the relative incidence of these events during long-term treatment was slightly lower. Based on 22 trials that provided sufficient data, loss to followup in general and loss to followup because of adverse events represented an average of 50% and 7%, respectively, of patients randomized to active treatment and 68% and 4%, respectively, of patients randomized to placebo. Based on data pooled from 17 placebo-controlled trials, the relative risk of dropping out for any reason was statistically significantly lower for active treatment than for placebo (RR = 0.75; 95% CI 0.69 to 0.83). Data pooled from 18 placebo-controlled trials demonstrated that loss to followup because of adverse events was not statistically significantly different between active treatment and placebo (RR = 1.42; 95% CI: 0.92–2.20).
We systematically assessed the efficacy and tolerability of second-generation antidepressants for the prevention of relapse and recurrence during treatment in the continuation- and maintenance-phases of major depression. Only a small number of trials directly compared one antidepressant to another. Results of these trials did not demonstrate statistically significant differences between duloxetine and paroxetine (17), fluoxetine and sertraline (13), fluvoxamine and sertraline (14, 15), and trazodone and venlafaxine (16) for preventing relapse or recurrence. Although results are relatively consistent, we consider the strength of comparative evidence to be moderate because additional studies could change our conclusions. Pooled data for second-generation antidepressants as a class compared with placebo suggest a relatively large effect size that persists over time, reflecting high strength evidence for continued treatment beyond the acute phase. The NNT to prevent one additional relapse or recurrence is in the range of four to six patients.
The tolerability profile of continuation- and maintenance-phase treatment is fair to good. In clinical trials, 7% of patients randomized to active treatment and 5% of patients randomized to placebo discontinued continuation- or maintenance-phase treatment because of adverse events. Although loss to followup was high (i.e., 50% and 68% for active drug and placebo, respectively), the relative risk of discontinuing treatment because of adverse events did not differ significantly between active treatment and placebo. Overall loss to followup in acute-phase studies has been estimated at approximately 24% (12), which is considerably lower than our estimates from continuation- and maintenance-phase studies. Our estimates likely are high because of longer trial duration, the preventive aim of this treatment, and misclassification of clinical endpoints (i.e., relapse or recurrence) as loss to followup.
Current practice guidelines for MDD recommend continuation-phase treatment for 4 to 9 months for patients who demonstrate an adequate response to acute-phase treatment (2, 3). For patients with recurrent MDD, maintenance treatment is recommended. Our systematic review and meta-analysis provide relatively strong support for these guidelines. Based on the consistency of effect sizes over time, our review illustrates stable benefits of active treatment over placebo for up to 2 years of treatment. Although our analysis was able to demonstrate continued benefits of drug treatment over time, we were not able to draw inferences as to the most appropriate duration of antidepressant treatment. We identified only one RCT that compared relapse rates for differing lengths of antidepressant treatment (21), but the sample size of the longest treatment arm in this trial may have been insufficiently powered. Still, fluoxetine was shown to be more efficacious than placebo for up to 38 weeks (i.e., approximately 9 months) in this trial. More research is needed to determine the most appropriate length of therapy.
In a well-conducted systematic review of relapse prevention with first- and second-generation antidepressants in depressive disorders, Geddes and colleagues (2003) reported a 70% reduction in the odds of relapse for patients continuing antidepressant treatment compared with patients discontinuing treatment. The effect sizes reported in this analysis were “similar for all classes of antidepressants,” (5) but such unadjusted indirect comparisons may not be valid. To explore this further, we used data reported in the Geddes et al. review and converted their odds ratio to a relative risk -- namely, 0.45 for active drug compared with placebo (95% CI 0.41 – 0.49) and 0.41 specifically for second-generation antidepressants compared with placebo (95% CI 0.35 – 0.48). The confidence intervals for the relative risk of relapse that we calculated for only second-generation antidepressants (less than 1 year, 0.46 – 0.62; 1 year or longer, 0.48 – 0.66) overlapped this relative risk estimate from the Geddes et al. study, and our analysis included nearly twice as many trials of newer antidepressants.
Even though a small number of comparative studies found no statistically significant differences between second-generation antidepressants, we are unable to draw firm conclusions as to whether one drug may be better than another for long-term treatment. These comparative trials were extension trials and did not re-randomize patients to continuation or maintenance treatment, but rather gave patients the option to continue on with their blinded acute-phase treatment. This trial design has been shown to produce overall lower relapse rates, but larger differences between active treatment and placebo than placebo substitution trials that randomizes participants at the time of successful acute- or continuation-phase completion (42). For this reason, we limited our meta-analyses to placebo substitution trials. Although this does not answer the question of whether the extension or placebo-substitution design provides a more accurate assessment of the benefits of drug treatment, we believe our results provide strong evidence for the benefits of continuing versus discontinuing antidepressant treatment after successful acute- or continuation-phase treatment.
Although it is tempting to draw inferences about one drug compared with another by indirectly comparing effect sizes among placebo-controlled trials (e.g., figure 1–figure 2), we caution against such inferences because included trials differed in design and because unadjusted comparisons may be inaccurate. Adjusted indirect comparisons usually agree with results of head-to-head comparisons, but only when the trials being indirectly compared are similar (43). Because of differences in trial design and in operational definitions (e.g., definition of relapse or recurrence) used by investigators, we chose not to conduct adjusted indirect comparisons. More research is needed to verify whether second-generation antidepressants differ in relapse rates.
Our analysis is limited in other ways. The primary problem is the quantity and quality of available evidence addressing our question. Only a handful of comparative studies have been published, making it difficult to generalize about one drug compared with any other. Furthermore, the number of placebo-controlled trials is insufficient to make adjusted indirect comparisons. Evidence for some drugs was limited to a single study. Although we conducted a meta-regression to explore heterogeneity, data were insufficient to assess all important differences among trials. One important distinction that we could not address is whether presenting with a history of a single episode versus recurrent episodes made a difference in relapse or recurrence rates. Because this is a primary decision point for psychiatrists in deciding whether to continue with maintenance-phase treatment, more work is needed in this area.
This review confirms the benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants. Our review supports current clinical practice guidelines. Additionally, our meta-regression provides some evidence that the efficacy of different types of second-generation antidepressants does not differ in clinically significant ways, although more research is needed to confirm this conclusion. Given that ongoing treatment can prevent a relapse or recurrence for approximately one in five patients, clinicians should continue to encourage treatment beyond the acute phase and work with patients to find the most suitable drug.
No funding was provided for the current literature search and analysis. However, this review is based in part on work funded through a contract from the Agency for Healthcare Research and Quality (AHRQ) to the RTI International-University of North Carolina Evidence-based Practice Center (contract no. 290-02-0016). For their contribution to the initial AHRQ review, we would like to thank our colleagues from the University of North Carolina at Chapel Hill: Tim Carey, Laura Morgan, Janelle Shumate, and Stacey Williams. We also express our appreciation to Linda Lux and Loraine Monroe of RTI International.
* Multiple articles published for a single trial
STATEMENT OF INTEREST
No authors have competing interests in the content of this paper. Dr. Hansen is funded by the US National Institutes of Health (NIH) grant K12 RR023248. During the past 5 years, Dr. Gaynes has received financial support from AHRQ, NIMH, Robert Woods Johnson Foundation, GlaxoSmithKline, Ovation Pharmaceuticals, Pfizer, Shire Pharmaceuticals, and Wyeth Ayerst. Ms. DeVeaugh-Geiss also has received funding from GlaxoSmithKline.