Acta Psychiatr Scand 2015: 131: 408–416 All rights reserved DOI: 10.1111/acps.12381
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA
Review
Drug dose as mediator of treatment effect in antidepressant drug trials: the case of fluoxetine Purgato M, Gastaldon C, Papola D, Magni L, Rossi G, Barbui C. Drug dose as mediator of treatment effect in antidepressant drug trials: the case of fluoxetine.
M. Purgato1, C. Gastaldon1,
D. Papola1, L. R. Magni2, G. Rossi2, C. Barbui1 1
Objective: This study aimed at investigating whether dose is a mediator of treatment effect in fluoxetine-randomized trials. Specifically, we investigated whether dose was higher in trials in which the aim was to demonstrate fluoxetine efficacy in comparison with older antidepressants and lower in trials in which the aim was to demonstrate a new drug’s efficacy against fluoxetine. Method: We applied the model developed by Baron and Kenny to investigate the mediational role of drug dose on treatment effect. We included all randomized controlled trials comparing fluoxetine with other antidepressants as monotherapy in the acute-phase treatment of unipolar major depression. Results: A total of 173 studies were included. In 76 comparisons (44%), fluoxetine was the experimental antidepressant. A metaregression analysis indicated that after adjusting for possible confounders, studies where fluoxetine was the experimental agent were associated with a significant advantage for fluoxetine. However, the Baron and Kenny model revealed no mediational role of drug dose in influencing treatment effect. Conclusion: The outcome of fluoxetine-randomized trials changed according to whether this drug was used as a new compound or as a reference. This finding cannot be attributed to antidepressants dose, as dose failed to emerge as mediator of treatment effect in the Baron and Kenny approach.
Section of Psychiatry, Department of Public Health and Community Medicine, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, and 2 Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Key words: fluoxetine; dose; mediator; randomized controlled trials; systematic reviews Marianna Purgato, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy. E-mail: [email protected]
Accepted for publication November 18, 2014
Summations
• In randomized controlled trials where fluoxetine was the experimental drug, fluoxetine was dosed higher compared with studies where it was the control drug.
• Trials where fluoxetine was the experimental drug were associated with a significant advantage for fluoxetine.
• This result cannot be attributed to fluoxetine or control AD dose, as dose failed to emerge as mediator in the Baron and Kenny approach.
Considerations
• Some included studies did not clearly report which compound was the experimental and which was • • 408
the control drug. When studies did not report this information, they were allocated to the two groups depending on whether reference compounds were marketed before fluoxetine (comparators), or after fluoxetine (experimental drugs). Many included studies did not report the average fluoxetine dose, and we extracted the dose range of fluoxetine planned before the study and reported in the Methods. Individual patient data meta-analysis would help to understand the role of dose and other individuallevel characteristics in influencing the results of trials.
Dose as possible mediator of fluoxetine effect Introduction
Recent network meta-analyses of antidepressant randomized controlled trials (RCTs) in adults highlighted differences between commonly prescribed individual antidepressants (AD) (1, 2). These differences may be real, reflecting different drug profiles in terms of efficacy and acceptability, or may be the consequence of some trial characteristics that are associated with treatment outcome (3). One of these characteristics is whether an AD is studied as experimental or control drug. Fluoxetine, for example, has been studied both as experimental drug, in comparison with tricyclic (TCA) and related ADs, and as control drug, in comparison with other selective serotonin reuptake inhibitors (SSRIs) and newer ADs. Meta-analyses of fluoxetine data suggested that studies where fluoxetine was the experimental agent were positively associated with treatment effect, indicating a significant advantage for fluoxetine (4, 5). This prompted investigators to suggest that dose might influence AD trials results (6,7), as dose may vary according to whether a drug is used as new or reference compound. On the same line of reasoning, Sinyor et al. (8) recently showed that sponsor drugs were dosed higher than nonsponsor drugs in AD studies. In the light of these findings, clinicians need to carefully consider the characteristics and design of randomized controlled trials. However, a formal analysis of the potential role of dose as mediator of treatment effect in AD trials has never been performed. Aims of the study
This study aimed at investigating whether drug dose is a mediator of treatment effect in randomized controlled trials comparing fluoxetine with any other conventional and non-conventional antidepressant for unipolar major depression.
Material and methods Search methods for identification of studies
Data were extracted from a Cochrane systematic review published in 2013 comparing fluoxetine versus other antidepressants for unipolar major depression (9). We refer to Magni et al. (9) for a detailed description of the search strategy. Briefly, the Cochrane Collaboration Depression, Anxiety
and Neurosis Group Trials Register (CCDANTR) was searched. This register includes relevant RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL) (all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). No language restriction was applied. Reference lists of relevant papers and previous systematic reviews were hand-searched. Moreover, the pharmaceutical company marketing fluoxetine, experts in this field and trial authors were contacted for additional unpublished data. Types of studies
We included randomized comparisons of fluoxetine versus any other AD as monotherapy in the acute-phase treatment of unipolar major depression. We excluded trials in which depressed patients had a concomitant medical illness and fluoxetine dose-finding studies. For trials that had a crossover design, only results from the first randomized period were considered. Types of participants
Participants were in- and out-patients aged 18 years or older of both sexes, with a primary diagnosis of unipolar major depression, according to the criteria described in the Diagnostic and Statistical Manual of Mental Disorders (DSM) (10) and International Classification of Disease (ICD) (11), or according to any other clinical or standardized criteria adopted by the study authors. We included participants with the following subtypes of depression: chronic, with catatonic features, with melancholic features, with atypical features, with postpartum onset and with a seasonal pattern. We included studies in which up to 20% of participants presented with depressive episodes in bipolar affective disorder. We also included participants with a concurrent secondary diagnosis of another psychiatric disorder. We excluded participants with a concurrent primary diagnosis of Axis I or II disorders and participants with a serious concomitant medical illness. Types of interventions
Intervention included fluoxetine compared to any conventional and non-conventional pharmacological treatment for unipolar major depression. Conventional agents included TCAs, heterocyclics, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) or newer ADs and other conventional 409
Purgato et al. psychotropic drugs. Non-conventional agents included hypericum and Crocus Sativus. Trials in which fluoxetine was compared with other classes of pharmacological treatment (i.e. antipsychotics, mood stabilizers, anxiolytics), or in which fluoxetine was used as an augmentation strategy, were excluded.
baseline to endpoint, at the Hamilton Depression Rating Scale (HDRS) (14), Montgomery and Asberg Rating Scale (MADRS) (15) or Clinical Global Impression (CGI) (16) were extracted, together with the standard deviation (SD) of these values, and the number of patients included in these analyses.
Data extraction
Statistical analysis
Two reviewers (CG, LM) independently extracted data from the included studies, and any disagreement was discussed with a third member of the review team (CB). The following information was collected in an electronic spreadsheet: year of publication, number of study sites, country, blindness, type of comparison, sample size, inclusion of elderly participants, setting of intervention, weeks of follow-up, diagnostic criteria, information on whether fluoxetine was the experimental or the control drug, and information on dose. As mean doses are erratically reported in fluoxetine trial, we extracted fluoxetine and control AD minimum and maximum doses in milligrams as reported in the methods of each included study. Minimum and maximum doses were converted into multiples of the defined daily dosage (DDD) for each drug by dividing the prescribed daily dosage (PDD) by the DDD (PDD/DDD). This measure is the international unit of drug use approved by the World Health Organisation for drug use studies (12, 13). Efficacy data were exacted as well. The mean scores at endpoint, or the mean change from
Characteristics of studies where fluoxetine was the experimental or control AD were initially analysed by chi-square statistics. As second step, the Baron and Kenny mediational model was applied (17, 18). According to this approach, a mediating role of a variable exists when four conditions are met: (i) the predictor variable must be significantly related to the outcome variable; (ii) the hypothesized mediator must be significantly related to the predictor variable; (iii) the mediator must be significantly related to the outcome; and (iv) the relationship between the predictor and the outcome must be attenuated when controlling for the mediator (18). When predictor remains significant with the mediator is controlled, mediation is deemed to be partial. When controlling for the mediator renders the predictor non-significant, mediation is deemed complete. A graphical representation of the model, applied to fluoxetine trials, is presented in Fig. 1. The predictor variable is whether fluoxetine was the experimental or control AD; the mediator variable is dose, which was inserted into the model employing
Fluoxetine is the experimental drug (yes = 1, no = 0)
Model 1
Efficacy of Effi fluoxetine versus control antidepressants
Fluoxetine dose or fluoxetine/control p dose antidepressant
Model 2
Fluoxetine is the experimental drug (yes = 1, no = 0)
Model 3
Model 4
Efficacy of fluoxetine versus control antidepressants
Fig. 1. Baron and Kenny mediational model showing both the direct and the mediated pathway by which fluoxetine trials (trials where fluoxetine was the experimental drug versus trials where fluoxetine was the control drug) might be associated with the overall treatment effect. The mediated pathway investigates the potential mediational role of dose (expressed in terms of fluoxetine dose and in terms of ratio between fluoxetine and control antidepressant dose) in the relationship between studies where fluoxetine was the experimental agent and the overall treatment effect.
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Dose as possible mediator of fluoxetine effect the following methodology. First, we run the Baron and Kenny model using fluoxetine minimum or maximum dose expressed in milligrams, as extracted from the study reports. Second, a measure of ‘fairness of dose comparison within each included trial’ was calculated by dividing the minimum and maximum fluoxetine dose, expressed as multiples of the DDD, by the minimum and maximum control AD dose, expressed as multiples of the DDD. A ratio of 1 indicates that fluoxetine dosage is equal to control AD dose; a ratio greater than 1 indicates that fluoxetine dose is higher than control AD dose; and a ratio lower than 1 means that fluoxetine dose is lower than control AD dose. In our model, the outcome variable is efficacy at endpoint, expressed as standardized mean difference (SMD) together with the 95% confidence interval (CI) according to standard Cochrane methodology. Negative SMDs indicate more symptom reduction in the fluoxetine group. To investigate whether the predictor variable is significantly related to the outcome variable (model 1), and whether dose is significantly related to the outcome (model 3), a metaregression analysis was carried out with the metareg command in STATA, which performs standard random-effects metaregression using aggregate-level data (19). Analyses were adjusted for the following variables: year of publication, multicentre study, country, weeks of follow-up, blindness, type of comparator
AD (TCA, SSRI or newer), placebo arm, sample size, elderly patients and setting. Model 4 was similar to model 1 with the addition of dose to the list of adjusting variables. To investigate whether the hypothesized mediator (dose) is significantly related to the predictor variable (model 2), a linear regression analysis was carried out, adjusting for the same variables listed above. A non-parametric bootstrap method of statistical accuracy was used (20). All calculations were performed with Stata13 (STATA Corp, College Station, TX, USA). Beta coefficients and P values for all covariates included in the metaregression analyses are available from the authors.
Results Characteristics of studies
The electronic search yielded 244 fluoxetine RCTs. Of these, 171 studies (173 comparisons) with a total of 24 868 participants met the inclusion criteria and were considered in this systematic review. In 76 comparisons (44%), fluoxetine was the experimental AD (Fig. 2) (references and main characteristics of included studies available on request). The distribution of trial characteristics by whether fluoxetine was the experimental or control AD is shown in Table 1. In comparison with
1357 Initial records identified
12 Unpublished studies 5 ongoing studies
1374 Records potentially relevant for this review
1130 Records excluded
244 Full-text articles assessed for eligibility
73 Full text excluded: 68 no RCTs 5 ongoing studies
171 Randomized controlled trials meeting the inclusion criteria (173 comparisons) were included in the analysis
Fig. 2.
PRISMA
flow diagram.
Fluoxetine is the control drug = 76
Fluoxetine is the experimental drug = 97
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Purgato et al. Table 1. Distribution of trial characteristics by whether fluoxetine is the experimental or control antidepressant Fluoxetine (173 comparisons) Experimental AD (76) N (%) Year of publication 1990–1994 34 (35.05) 1991–1995 22 (22.68) 1996–2000 24 (24.84) 2001–2005 14 (14.43) 2006–2012 3 (3.09) Multicentre study Yes 34 (35.05) No 63 (64.95) Country North America 27 (27.84) Other 70 (72.16) Double–blind Yes 94 (96.91) No 3 (3.09) Fluoxetine vs TCA Yes 73 (75.26) No 24 (24.74) Fluoxetine vs SSRI Yes 10 (10.31) No 87 (89.69) Fluoxetine vs newer ADs Yes 14 (14.43) No 83 (85.57) Minimum fluoxetine dose (mg/day) ≤20 79 (81.44) 20–80 18 (18.56) Maximum fluoxetine dose (mg/day) 20 34 (35.05) 40 16 (16.49) 80 47 (48.45) Fluoxetine minimum dose/Comparator AD minimum dose (PDD/DDD) ≤1 38 (40.00) >1 57 (60.00) Fluoxetine maximum dose/Comparator AD maximum dose (PDD/DDD) ≤1 43 (45.26) >1 52 (54.74) Placebo control Yes 0 No 97 (100.00) Duration of follow–up, weeks ≤6 73 (75.26) >6 24 (24.74) Number of participants ≤50 33 (34.38) 51–100 24 (25.00) 101–200 30 (31.25) > 200 9 (9.38) Setting Inpatients 26 (26.80) Outpatients or other 71 (73.20) Elderly patients included Yes 38 (39.18) No 59 (60.82)
Comparator AD (97) N (%)
1 (1.32) 16 (21.05) 30 (39.47) 18 (23.68) 11 (14.47)
v2= 35.77 P < 0.001
40 (52.63) 36 (47.37)
v2 = 5.38 P = 0.020
22 (28.95) 54 (71.05)
v2 = 0.02 P = 0.872
71 (93.42) 5 (6.58)
v2 = 1.17 P = 0.279
4 (5.26) 72 (94.74)
v2 = 84.52 P < 0.001
20 (26.32) 56 (73.68)
v2 = 7.61 P = 0.006
52 (68.42) 24 (31.58)
v2 = 52.63 P < 0.001
72 (94.74) 4 (5.26)
v2 = 6.78 P = 0.009
31 (40.79) 24 (31.58) 21 (27.63)
v2 = 9.26 P = 0.010
43 (64.18) 24 (35.82)
v2 = 9.188 P = 0.002
36 (53.73) 31 (46.27)
v2 = 1.127 P = 0.288
14 (18.42) 62 (81.58)
v2 = 19.442 P = 0.000
31 (40.79) 45 (59.21)
v2 = 21.11 P < 0.001
13 (17.11) 15 (19.74) 20 (26.32) 28 (36.84)
v2 = 20.48 P < 0.001
20 (26.32) 56 (73.68)
v2 = 0.06 P = 0.94
31 (40.79) 45 (59.21)
v2 = 0.046 P = 0.830
TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; AD, antidepressant; PDD, prescribed daily dose; DDD, defined daily dose.
studies where fluoxetine was the control AD, studies where fluoxetine was the experimental AD were older, more often single site, shorter in duration and with less participants. As expected, fluoxetine was more often compared with SSRIs and newer 412
ADs in trials where it was the control AD (Table 1). Fluoxetine was dosed higher in studies where this drug was the experimental AD as compared to studies where it was the control AD, as can be seen
Dose as possible mediator of fluoxetine effect from the distribution of fluoxetine minimum and maximum doses in milligrams. In terms of ratio between the minimum and maximum fluoxetine dose, expressed as multiples of the DDD, and the minimum and maximum control AD dose, expressed as multiples of the DDD (fairness of comparison), fluoxetine was dosed higher than control AD only when minimum doses were analysed (Table 1). Mediational analyses
Tables 2 and 3 presents the results of the Baron and Kenny approach, developed using fluoxetine dose in milligrams as mediator variable in the first mediational analysis (Table 2), and fluoxetine dose divided by control AD dose, expressed as multiples of the DDD (fairness of comparison) in the second mediational analysis (Table 3). Model 1 tested the relationship between fluoxetine treatment and efficacy. This model showed that studies where fluoxetine was the experimental agent were negatively associated with treatment effect, indicating a significant advantage for fluoxetine. Model 2 tested the relationship between fluoxetine treatment and dose. This model showed that studies where fluoxetine was the experimental agent were not associated with higher doses. This finding was consistently shown for fluoxetine minimum and maximum dose (Table 2), and for fluoxetine maximum dose divided by control AD maximum dose (Table 3). For fluoxetine maximum dose divided by control AD maximum dose, a significant association was observed (Table 3).
Model 3 tested the relationship between dose and efficacy. This model showed that dose was not associated with efficacy. This finding was consistently shown for fluoxetine minimum and maximum dose (Table 2), and for fluoxetine minimum and maximum dose divided by control AD minimum and maximum dose (Table 3). Model 4 tested the combined effect of fluoxetine treatment and dose on efficacy. When dose was added to model 1, the model was unchanged: it showed that studies where fluoxetine was the experimental agent were negatively associated with treatment effect, indicating a significant advantage for fluoxetine (Tables 2 and 3). Discussion
To our knowledge, this is the first analysis that formally investigated the potential role of dose as mediator of treatment effect in AD trials. Included randomized trials were very similar in design and conduct. The majority failed to report key methodological issues, for example information about randomization and allocation concealment. Additionally, the reporting of outcome data was often unclear or incomplete. Clearly, it is possible that the paucity of information about randomization and allocation concealment reflects a problem of reporting and not a real defect in study design; however, the average quality of trials was generally low. A detailed description of study quality and risk of bias tables are reported in the published Cochrane review (9). The output of the Cochrane risk of bias tool was not useable in our model, so that here we considered publication year as a
Table 2. Baron and Kenny mediational model showing that studies where fluoxetine was the experimental agent were significantly associated with the overall treatment effect, indicating an advantage for fluoxetine (model 1 and model 4). By contrast, studies where fluoxetine was the experimental agent were not significantly associated with fluoxetine dose (model 2), and fluoxetine dose was not significantly associated with the overall treatment effect (model 3) Independent variable
Dependent variable
Adjusted for
b coefficient (95% CI)
P value
Model 1
Fluoxetine experimental drug (yes = 1, no= 0)
0.004
Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine minimum dose
Year of publication, multicentre study, country, weeks of follow up, blindness, placebo arm, type of comparator AD (TCA, SSRI or newer), sample size, elderly patients, setting
0.313 ( 0.524 to 0.103)
Model 2
Efficacy: SMD at Endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Fluoxetine minimum dose
0.115 ( 2.597 to 2.365)
0.927
Fluoxetine maximum dose
3.643 ( 3.335 to 10.622)
0.306
Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD>0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD >0 favours control AD)
0.001 ( 0.007 to 0.008)
0.859
0.001 ( 0.004 to 0.003)
0.797
0.259 ( 0.489 to
0.003
Model
Model 3
Fluoxetine maximum dose
Model 4
Fluoxetine experimental drug (yes = 1, no= 0)
Same variables as in Model 1 plus fluoxetine minimum dose and fluoxetine maximum dose
0.102)
SMD, standardized mean difference; AD, antidepressant; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor.
413
Purgato et al. Table 3. Baron and Kenny mediational model showing that studies where fluoxetine was the experimental agent were significantly associated with the overall treatment effect, indicating an advantage for fluoxetine (model 1 and model 4). By contrast, studies where fluoxetine was the experimental agent were significantly associated with the ratio between fluoxetine and control antidepressant dose only when minimum dosages were considered (model 2), and the ratio between fluoxetine and control antidepressant dose was not significantly associated with the overall treatment effect (Model 3) Model
Independent variable
Dependent variable
Adjusted for
Model 1
Fluoxetine experimental drug (yes = 1, no= 0)
Model 2
Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine minimum dose/ Control AD minimum dose
Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Fluoxetine minimum dose/Control AD minimum dose Fluoxetine maximum dose/Control AD maximum dose Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD)
Year of publication, multicentre study, country, weeks of follow up, blindness, placebo arm, type of comparator AD (TCA, SSRI or newer), sample size, elderly patients, setting
Model 3
Fluoxetine maximum dose/ Control AD maximum dose Model 4
Fluoxetine experimental drug (yes = 1, no= 0)
Same variables as in Model 1 plus fluoxetine minimum dose/Control AD minimum dose and fluoxetine maximum dose/Control AD maximum dose
b coefficient (95% CI) 0.313 ( 0.524 to
0.103)
P value 0.004
0.537 (0.038 to 1.036)
0.035
0.211 ( 0.110 to 0.533)
0.198
0.043 ( 0.136 to 0.049)
0.357
0.052 ( 0.157 to 0.053)
0.328
0.290 ( 0.483 to
0.004
0.097)
Legend: SMD: standardized mean difference; AD: antidepressant; TCA: tricyclic antidepressant; SSRI: selective serotonin reuptake inhibitor.
proxy measure of trials’ quality. The evidence that the outcome of fluoxetine RCTs varied according to whether this drug was used as a new compound or a reference one suggests the presence of bias. This bias worked in favour of fluoxetine in trials where it was the experimental drug and in favour of comparators in trials where fluoxetine was the reference agent. This finding, observed by means of metaregression analyses that adjusted for potential confounding variables, cannot be attributed to fluoxetine or control AD dose, as dose failed to emerge as mediator in the Baron and Kenny approach. This is a new and compelling finding as several authors have suggested dose as a potential reason for this bias (8). It is true that in univariate analyses, fluoxetine dose was higher in trials in which the aim was to demonstrate its efficacy in comparison with older ADs and lower in trials in which the aim was to demonstrate a new drug’s efficacy against fluoxetine, as shown in Table 1, but we additionally showed that this difference is likely attributable to other study-level characteristics, including year of publication and choice of control AD, as can be inferred by the Baron and Kenny analytical framework. Strengths and limitations
Strengths of this study include the following. Data were extracted from a very recent Cochrane systematic review, the search was comprehensive without language restrictions, and included unpublished studies. Standard Cochrane methodology was applied to data handling and analysis. 414
Additionally, the case example of fluoxetine is particularly appropriate for this analysis, as this AD has often been used both as experimental and control agent in AD trials. Another strength is that our findings can unlikely be attributed to the confounding effect of other study characteristics as all analyses have been adjusted for a number of studylevel confounders. However, a number of limitations should be acknowledged. First, some study reports did not clearly state which compound was the experimental and which was the control drug. When studies did not report this, they were allocated to the two groups depending on the drug used in comparison with fluoxetine. Reference compounds marketed before fluoxetine were considered comparators, and new AD drugs marketed after fluoxetine were considered experimental drugs. A second limitation is that we extracted and analysed data only for efficacy on a continuous outcome, without considering efficacy on dichotomous outcomes, such as, for example, responders or remitters. This approach was followed as dichotomous outcomes are erratically reported in AD studies, and this would have led to the exclusion of a relevant proportion of studies (21). A third limitation is that many studies did not mention the average fluoxetine dose administered during the study period. To overcome this problem, which might have dramatically reduced the sample of included studies, the dose range of fluoxetine planned before the study and reported in the methods was extracted. Although this measure may be considered a proxy of the average fluoxetine dose administered during
Dose as possible mediator of fluoxetine effect the study period, we acknowledge it is far from being optimal. However, it is worth noting that the main findings of this study were consistently replicated four times, using fluoxetine minimum and maximum dose in milligrams, and using the ratio of fluoxetine dose (minimum and maximum) by control AD dose (minimum and maximum) expressed in multiples of the DDD. Study implications
If dose does not have a mediational role, alternative explanations might be hypothesized. A first possibility is publication bias. Although effort has been made to include accessible unpublished data into this review, evidence suggests that current strategies to locate unpublished studies are imperfect, and therefore, we may have missed some unpublished trials. If publication bias had systematically excluded from publication RCTs failing to show a robust effect of experimental agents in comparison with reference ones, then the evidence that the outcome of fluoxetine RCTs varied according to whether this drug was used as a new compound or a reference one would be expected as a possible consequence (22). A second possibility is that the adverse effect profile of competitive agents revealed the identity of medication to participants or investigators or outcome assessors, thus influencing them when rating the effect of new and reference drug. The same might have been occurred during data analysis, especially for old studies where the process of data handling and analysis might have not clearly reported a priori into a study protocol. It should additionally be recognized that other study-related factors might have influenced this analysis. The construct of depression itself has evolved during the past quarter of a century since the introduction of fluoxetine, and also, the use of antidepressants in clinical practice has changed considerably. This might have affected trials in terms of types of participants recruited for RCTs. The growing placebo response in antidepressant trials may be seen as an indirect evidence of this evolution (23). There is also a broader and general phenomenon in science where first and initial findings seem to be stronger and become increasingly difficult to replicate with time (24). This might apply to fluoxetine trials, with initial studies (where fluoxetine was the experimental drug) showing a stronger treatment effect in comparison with later studies (where fluoxetine was the comparator drug). Considering that the included studies have been published over a very wide period of time, a confounding effect of these study-related factors
cannot be excluded, despite statistical adjustment for year of publication should have limited this potential bias. Implications for research and practice include the following. We argue that in future, RCTs’ investigators will always report the mean dose of drugs administered during the study, as well as which drug is the experimental one. Similarly, journal editors should no longer accept for publication trial reports that do not include this information. This would allow more precise re-analyses of trial data, although we note that only systematic reviews and meta-analyses of individual patientlevel data would help understand the role of each variable, including dose and other individual-level characteristics, in influencing trial results (25, 26). Implications for practice include awareness that investigators tend to overemphasize the effect of new drugs in comparison with reference ones. This attitude has negative consequences, because it may give the impression of a benefit even when there might be no added value. Clinicians should be aware that this bias is very difficult to detect from a scrutiny of the characteristics and design of a single trial. Acknowledgements MP and CB had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Declaration of interest None.
References 1. Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373:746–758. 2. Gartlehner G, Gaynes BN, Hansen RA et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008;149:734–750. 3. Malhi GS, Hitching R, Berk M, Boyce P, Porter R, Fritz K. Pharmacological management of unipolar depression. Acta Psychiatr Scand Suppl 2013;443:6–23. 4. Barbui C, Cipriani A, Brambilla P, Hotopf M. “Wish bias” in antidepressant drug trials? J Clin Psychopharmacol 2004;24:126–130. 5. Barbui C, Hotopf M, Garattini S. Fluoxetine dose and outcome in antidepressant drug trials. Eur J Clin Pharmacol 2002;58:379–386. 6. Naudet F, Maria AS, Falissard B. Antidepressant response in major depressive disorder: a meta-regression comparison of randomized controlled trials and observational studies. PLoS ONE 2011;6:e20811. 7. Khan A, Khan SR, Walens G, Kolts R, Giller EL. Frequency of positive studies among fixed and flexible dose
415
Purgato et al.
8.
9.
10. 11.
12.
13.
14. 15.
16.
416
antidepressant clinical trials: an analysis of the food and drug administration summary basis of approval reports. Neuropsychopharmacology 2003;28:552–557. Sinyor M, Schaffer A, Smart KA, Levitt AJ, Lanctot KL, Grysman NH. Sponsorship, antidepressant dose, and outcome in major depressive disorder: meta-analysis of randomized controlled trials. J Clin Psychiatry 2012;73: e277–e287. Magni LR, Purgato M, Gastaldon C et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev 2013;7:CD004185. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 1994. World Health Organization. The Tenth Revision of the International Classification of Diseases and Related Health Problems (ICD-10). 1992. Nose M, Barbui C. A simple approach to manage dosages in drug-epidemiology research. Epidemiol Psichiatr Soc 2008;17:186–187. World Health Organization. WHO Collaborating Centre for Drug Statistics Methodology (WHOCC): DDD Definition and general considerations. 2009. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–389. GUY. Clinical Global Impressions. Assessment Manual for Psychopharmacology, revised. Rockeville, MD: Na- tional Institute of Mental Health. 1976.
17. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 1986;51:1173–1182. 18. Kraemer HC, Wilson GT, Fairburn CG, Agras WS. Mediators and moderators of treatment effects in randomized clinical trials. Arch Gen Psychiatry 2002;59:877–883. 19. Higgins JP, Thompson SG. Controlling the risk of spurious findings from meta-regression. Stat Med 2004;23: 1663–1682. 20. Befron RT. Bootstrap Methods for Standard Errors, Confidence Intervals, and Other Measures of Statistical Accuracy. Stat Sci 1986;1:54–77. 21. Furukawa TA. How can we make the results of trials and their meta-analyses using continuous outcomes clinically interpretable? Acta Psychiatr Scand 2014;130:321–323. 22. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252–260. 23. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002;287:1840–1847. 24. Burman LE, Reed WR, Alm J. A call for replication studies. Public Finance Rev 2010;38:787–793. 25. Clarke MJ. Individual patient data meta-analyses. Best Pract Res Clin Obstet Gynaecol 2005;19:47–55. 26. Clarke MJ, Stewart LA. Systematic reviews of randomized controlled trials: the need for complete data. J Eval Clin Pract 1995;1:119–126.
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Review
Drug dose as mediator of treatment effect in antidepressant drug trials: the case of fluoxetine Purgato M, Gastaldon C, Papola D, Magni L, Rossi G, Barbui C. Drug dose as mediator of treatment effect in antidepressant drug trials: the case of fluoxetine.
M. Purgato1, C. Gastaldon1,
D. Papola1, L. R. Magni2, G. Rossi2, C. Barbui1 1
Objective: This study aimed at investigating whether dose is a mediator of treatment effect in fluoxetine-randomized trials. Specifically, we investigated whether dose was higher in trials in which the aim was to demonstrate fluoxetine efficacy in comparison with older antidepressants and lower in trials in which the aim was to demonstrate a new drug’s efficacy against fluoxetine. Method: We applied the model developed by Baron and Kenny to investigate the mediational role of drug dose on treatment effect. We included all randomized controlled trials comparing fluoxetine with other antidepressants as monotherapy in the acute-phase treatment of unipolar major depression. Results: A total of 173 studies were included. In 76 comparisons (44%), fluoxetine was the experimental antidepressant. A metaregression analysis indicated that after adjusting for possible confounders, studies where fluoxetine was the experimental agent were associated with a significant advantage for fluoxetine. However, the Baron and Kenny model revealed no mediational role of drug dose in influencing treatment effect. Conclusion: The outcome of fluoxetine-randomized trials changed according to whether this drug was used as a new compound or as a reference. This finding cannot be attributed to antidepressants dose, as dose failed to emerge as mediator of treatment effect in the Baron and Kenny approach.
Section of Psychiatry, Department of Public Health and Community Medicine, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, and 2 Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Key words: fluoxetine; dose; mediator; randomized controlled trials; systematic reviews Marianna Purgato, WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy. E-mail: [email protected]
Accepted for publication November 18, 2014
Summations
• In randomized controlled trials where fluoxetine was the experimental drug, fluoxetine was dosed higher compared with studies where it was the control drug.
• Trials where fluoxetine was the experimental drug were associated with a significant advantage for fluoxetine.
• This result cannot be attributed to fluoxetine or control AD dose, as dose failed to emerge as mediator in the Baron and Kenny approach.
Considerations
• Some included studies did not clearly report which compound was the experimental and which was • • 408
the control drug. When studies did not report this information, they were allocated to the two groups depending on whether reference compounds were marketed before fluoxetine (comparators), or after fluoxetine (experimental drugs). Many included studies did not report the average fluoxetine dose, and we extracted the dose range of fluoxetine planned before the study and reported in the Methods. Individual patient data meta-analysis would help to understand the role of dose and other individuallevel characteristics in influencing the results of trials.
Dose as possible mediator of fluoxetine effect Introduction
Recent network meta-analyses of antidepressant randomized controlled trials (RCTs) in adults highlighted differences between commonly prescribed individual antidepressants (AD) (1, 2). These differences may be real, reflecting different drug profiles in terms of efficacy and acceptability, or may be the consequence of some trial characteristics that are associated with treatment outcome (3). One of these characteristics is whether an AD is studied as experimental or control drug. Fluoxetine, for example, has been studied both as experimental drug, in comparison with tricyclic (TCA) and related ADs, and as control drug, in comparison with other selective serotonin reuptake inhibitors (SSRIs) and newer ADs. Meta-analyses of fluoxetine data suggested that studies where fluoxetine was the experimental agent were positively associated with treatment effect, indicating a significant advantage for fluoxetine (4, 5). This prompted investigators to suggest that dose might influence AD trials results (6,7), as dose may vary according to whether a drug is used as new or reference compound. On the same line of reasoning, Sinyor et al. (8) recently showed that sponsor drugs were dosed higher than nonsponsor drugs in AD studies. In the light of these findings, clinicians need to carefully consider the characteristics and design of randomized controlled trials. However, a formal analysis of the potential role of dose as mediator of treatment effect in AD trials has never been performed. Aims of the study
This study aimed at investigating whether drug dose is a mediator of treatment effect in randomized controlled trials comparing fluoxetine with any other conventional and non-conventional antidepressant for unipolar major depression.
Material and methods Search methods for identification of studies
Data were extracted from a Cochrane systematic review published in 2013 comparing fluoxetine versus other antidepressants for unipolar major depression (9). We refer to Magni et al. (9) for a detailed description of the search strategy. Briefly, the Cochrane Collaboration Depression, Anxiety
and Neurosis Group Trials Register (CCDANTR) was searched. This register includes relevant RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL) (all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). No language restriction was applied. Reference lists of relevant papers and previous systematic reviews were hand-searched. Moreover, the pharmaceutical company marketing fluoxetine, experts in this field and trial authors were contacted for additional unpublished data. Types of studies
We included randomized comparisons of fluoxetine versus any other AD as monotherapy in the acute-phase treatment of unipolar major depression. We excluded trials in which depressed patients had a concomitant medical illness and fluoxetine dose-finding studies. For trials that had a crossover design, only results from the first randomized period were considered. Types of participants
Participants were in- and out-patients aged 18 years or older of both sexes, with a primary diagnosis of unipolar major depression, according to the criteria described in the Diagnostic and Statistical Manual of Mental Disorders (DSM) (10) and International Classification of Disease (ICD) (11), or according to any other clinical or standardized criteria adopted by the study authors. We included participants with the following subtypes of depression: chronic, with catatonic features, with melancholic features, with atypical features, with postpartum onset and with a seasonal pattern. We included studies in which up to 20% of participants presented with depressive episodes in bipolar affective disorder. We also included participants with a concurrent secondary diagnosis of another psychiatric disorder. We excluded participants with a concurrent primary diagnosis of Axis I or II disorders and participants with a serious concomitant medical illness. Types of interventions
Intervention included fluoxetine compared to any conventional and non-conventional pharmacological treatment for unipolar major depression. Conventional agents included TCAs, heterocyclics, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) or newer ADs and other conventional 409
Purgato et al. psychotropic drugs. Non-conventional agents included hypericum and Crocus Sativus. Trials in which fluoxetine was compared with other classes of pharmacological treatment (i.e. antipsychotics, mood stabilizers, anxiolytics), or in which fluoxetine was used as an augmentation strategy, were excluded.
baseline to endpoint, at the Hamilton Depression Rating Scale (HDRS) (14), Montgomery and Asberg Rating Scale (MADRS) (15) or Clinical Global Impression (CGI) (16) were extracted, together with the standard deviation (SD) of these values, and the number of patients included in these analyses.
Data extraction
Statistical analysis
Two reviewers (CG, LM) independently extracted data from the included studies, and any disagreement was discussed with a third member of the review team (CB). The following information was collected in an electronic spreadsheet: year of publication, number of study sites, country, blindness, type of comparison, sample size, inclusion of elderly participants, setting of intervention, weeks of follow-up, diagnostic criteria, information on whether fluoxetine was the experimental or the control drug, and information on dose. As mean doses are erratically reported in fluoxetine trial, we extracted fluoxetine and control AD minimum and maximum doses in milligrams as reported in the methods of each included study. Minimum and maximum doses were converted into multiples of the defined daily dosage (DDD) for each drug by dividing the prescribed daily dosage (PDD) by the DDD (PDD/DDD). This measure is the international unit of drug use approved by the World Health Organisation for drug use studies (12, 13). Efficacy data were exacted as well. The mean scores at endpoint, or the mean change from
Characteristics of studies where fluoxetine was the experimental or control AD were initially analysed by chi-square statistics. As second step, the Baron and Kenny mediational model was applied (17, 18). According to this approach, a mediating role of a variable exists when four conditions are met: (i) the predictor variable must be significantly related to the outcome variable; (ii) the hypothesized mediator must be significantly related to the predictor variable; (iii) the mediator must be significantly related to the outcome; and (iv) the relationship between the predictor and the outcome must be attenuated when controlling for the mediator (18). When predictor remains significant with the mediator is controlled, mediation is deemed to be partial. When controlling for the mediator renders the predictor non-significant, mediation is deemed complete. A graphical representation of the model, applied to fluoxetine trials, is presented in Fig. 1. The predictor variable is whether fluoxetine was the experimental or control AD; the mediator variable is dose, which was inserted into the model employing
Fluoxetine is the experimental drug (yes = 1, no = 0)
Model 1
Efficacy of Effi fluoxetine versus control antidepressants
Fluoxetine dose or fluoxetine/control p dose antidepressant
Model 2
Fluoxetine is the experimental drug (yes = 1, no = 0)
Model 3
Model 4
Efficacy of fluoxetine versus control antidepressants
Fig. 1. Baron and Kenny mediational model showing both the direct and the mediated pathway by which fluoxetine trials (trials where fluoxetine was the experimental drug versus trials where fluoxetine was the control drug) might be associated with the overall treatment effect. The mediated pathway investigates the potential mediational role of dose (expressed in terms of fluoxetine dose and in terms of ratio between fluoxetine and control antidepressant dose) in the relationship between studies where fluoxetine was the experimental agent and the overall treatment effect.
410
Dose as possible mediator of fluoxetine effect the following methodology. First, we run the Baron and Kenny model using fluoxetine minimum or maximum dose expressed in milligrams, as extracted from the study reports. Second, a measure of ‘fairness of dose comparison within each included trial’ was calculated by dividing the minimum and maximum fluoxetine dose, expressed as multiples of the DDD, by the minimum and maximum control AD dose, expressed as multiples of the DDD. A ratio of 1 indicates that fluoxetine dosage is equal to control AD dose; a ratio greater than 1 indicates that fluoxetine dose is higher than control AD dose; and a ratio lower than 1 means that fluoxetine dose is lower than control AD dose. In our model, the outcome variable is efficacy at endpoint, expressed as standardized mean difference (SMD) together with the 95% confidence interval (CI) according to standard Cochrane methodology. Negative SMDs indicate more symptom reduction in the fluoxetine group. To investigate whether the predictor variable is significantly related to the outcome variable (model 1), and whether dose is significantly related to the outcome (model 3), a metaregression analysis was carried out with the metareg command in STATA, which performs standard random-effects metaregression using aggregate-level data (19). Analyses were adjusted for the following variables: year of publication, multicentre study, country, weeks of follow-up, blindness, type of comparator
AD (TCA, SSRI or newer), placebo arm, sample size, elderly patients and setting. Model 4 was similar to model 1 with the addition of dose to the list of adjusting variables. To investigate whether the hypothesized mediator (dose) is significantly related to the predictor variable (model 2), a linear regression analysis was carried out, adjusting for the same variables listed above. A non-parametric bootstrap method of statistical accuracy was used (20). All calculations were performed with Stata13 (STATA Corp, College Station, TX, USA). Beta coefficients and P values for all covariates included in the metaregression analyses are available from the authors.
Results Characteristics of studies
The electronic search yielded 244 fluoxetine RCTs. Of these, 171 studies (173 comparisons) with a total of 24 868 participants met the inclusion criteria and were considered in this systematic review. In 76 comparisons (44%), fluoxetine was the experimental AD (Fig. 2) (references and main characteristics of included studies available on request). The distribution of trial characteristics by whether fluoxetine was the experimental or control AD is shown in Table 1. In comparison with
1357 Initial records identified
12 Unpublished studies 5 ongoing studies
1374 Records potentially relevant for this review
1130 Records excluded
244 Full-text articles assessed for eligibility
73 Full text excluded: 68 no RCTs 5 ongoing studies
171 Randomized controlled trials meeting the inclusion criteria (173 comparisons) were included in the analysis
Fig. 2.
PRISMA
flow diagram.
Fluoxetine is the control drug = 76
Fluoxetine is the experimental drug = 97
411
Purgato et al. Table 1. Distribution of trial characteristics by whether fluoxetine is the experimental or control antidepressant Fluoxetine (173 comparisons) Experimental AD (76) N (%) Year of publication 1990–1994 34 (35.05) 1991–1995 22 (22.68) 1996–2000 24 (24.84) 2001–2005 14 (14.43) 2006–2012 3 (3.09) Multicentre study Yes 34 (35.05) No 63 (64.95) Country North America 27 (27.84) Other 70 (72.16) Double–blind Yes 94 (96.91) No 3 (3.09) Fluoxetine vs TCA Yes 73 (75.26) No 24 (24.74) Fluoxetine vs SSRI Yes 10 (10.31) No 87 (89.69) Fluoxetine vs newer ADs Yes 14 (14.43) No 83 (85.57) Minimum fluoxetine dose (mg/day) ≤20 79 (81.44) 20–80 18 (18.56) Maximum fluoxetine dose (mg/day) 20 34 (35.05) 40 16 (16.49) 80 47 (48.45) Fluoxetine minimum dose/Comparator AD minimum dose (PDD/DDD) ≤1 38 (40.00) >1 57 (60.00) Fluoxetine maximum dose/Comparator AD maximum dose (PDD/DDD) ≤1 43 (45.26) >1 52 (54.74) Placebo control Yes 0 No 97 (100.00) Duration of follow–up, weeks ≤6 73 (75.26) >6 24 (24.74) Number of participants ≤50 33 (34.38) 51–100 24 (25.00) 101–200 30 (31.25) > 200 9 (9.38) Setting Inpatients 26 (26.80) Outpatients or other 71 (73.20) Elderly patients included Yes 38 (39.18) No 59 (60.82)
Comparator AD (97) N (%)
1 (1.32) 16 (21.05) 30 (39.47) 18 (23.68) 11 (14.47)
v2= 35.77 P < 0.001
40 (52.63) 36 (47.37)
v2 = 5.38 P = 0.020
22 (28.95) 54 (71.05)
v2 = 0.02 P = 0.872
71 (93.42) 5 (6.58)
v2 = 1.17 P = 0.279
4 (5.26) 72 (94.74)
v2 = 84.52 P < 0.001
20 (26.32) 56 (73.68)
v2 = 7.61 P = 0.006
52 (68.42) 24 (31.58)
v2 = 52.63 P < 0.001
72 (94.74) 4 (5.26)
v2 = 6.78 P = 0.009
31 (40.79) 24 (31.58) 21 (27.63)
v2 = 9.26 P = 0.010
43 (64.18) 24 (35.82)
v2 = 9.188 P = 0.002
36 (53.73) 31 (46.27)
v2 = 1.127 P = 0.288
14 (18.42) 62 (81.58)
v2 = 19.442 P = 0.000
31 (40.79) 45 (59.21)
v2 = 21.11 P < 0.001
13 (17.11) 15 (19.74) 20 (26.32) 28 (36.84)
v2 = 20.48 P < 0.001
20 (26.32) 56 (73.68)
v2 = 0.06 P = 0.94
31 (40.79) 45 (59.21)
v2 = 0.046 P = 0.830
TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; AD, antidepressant; PDD, prescribed daily dose; DDD, defined daily dose.
studies where fluoxetine was the control AD, studies where fluoxetine was the experimental AD were older, more often single site, shorter in duration and with less participants. As expected, fluoxetine was more often compared with SSRIs and newer 412
ADs in trials where it was the control AD (Table 1). Fluoxetine was dosed higher in studies where this drug was the experimental AD as compared to studies where it was the control AD, as can be seen
Dose as possible mediator of fluoxetine effect from the distribution of fluoxetine minimum and maximum doses in milligrams. In terms of ratio between the minimum and maximum fluoxetine dose, expressed as multiples of the DDD, and the minimum and maximum control AD dose, expressed as multiples of the DDD (fairness of comparison), fluoxetine was dosed higher than control AD only when minimum doses were analysed (Table 1). Mediational analyses
Tables 2 and 3 presents the results of the Baron and Kenny approach, developed using fluoxetine dose in milligrams as mediator variable in the first mediational analysis (Table 2), and fluoxetine dose divided by control AD dose, expressed as multiples of the DDD (fairness of comparison) in the second mediational analysis (Table 3). Model 1 tested the relationship between fluoxetine treatment and efficacy. This model showed that studies where fluoxetine was the experimental agent were negatively associated with treatment effect, indicating a significant advantage for fluoxetine. Model 2 tested the relationship between fluoxetine treatment and dose. This model showed that studies where fluoxetine was the experimental agent were not associated with higher doses. This finding was consistently shown for fluoxetine minimum and maximum dose (Table 2), and for fluoxetine maximum dose divided by control AD maximum dose (Table 3). For fluoxetine maximum dose divided by control AD maximum dose, a significant association was observed (Table 3).
Model 3 tested the relationship between dose and efficacy. This model showed that dose was not associated with efficacy. This finding was consistently shown for fluoxetine minimum and maximum dose (Table 2), and for fluoxetine minimum and maximum dose divided by control AD minimum and maximum dose (Table 3). Model 4 tested the combined effect of fluoxetine treatment and dose on efficacy. When dose was added to model 1, the model was unchanged: it showed that studies where fluoxetine was the experimental agent were negatively associated with treatment effect, indicating a significant advantage for fluoxetine (Tables 2 and 3). Discussion
To our knowledge, this is the first analysis that formally investigated the potential role of dose as mediator of treatment effect in AD trials. Included randomized trials were very similar in design and conduct. The majority failed to report key methodological issues, for example information about randomization and allocation concealment. Additionally, the reporting of outcome data was often unclear or incomplete. Clearly, it is possible that the paucity of information about randomization and allocation concealment reflects a problem of reporting and not a real defect in study design; however, the average quality of trials was generally low. A detailed description of study quality and risk of bias tables are reported in the published Cochrane review (9). The output of the Cochrane risk of bias tool was not useable in our model, so that here we considered publication year as a
Table 2. Baron and Kenny mediational model showing that studies where fluoxetine was the experimental agent were significantly associated with the overall treatment effect, indicating an advantage for fluoxetine (model 1 and model 4). By contrast, studies where fluoxetine was the experimental agent were not significantly associated with fluoxetine dose (model 2), and fluoxetine dose was not significantly associated with the overall treatment effect (model 3) Independent variable
Dependent variable
Adjusted for
b coefficient (95% CI)
P value
Model 1
Fluoxetine experimental drug (yes = 1, no= 0)
0.004
Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine minimum dose
Year of publication, multicentre study, country, weeks of follow up, blindness, placebo arm, type of comparator AD (TCA, SSRI or newer), sample size, elderly patients, setting
0.313 ( 0.524 to 0.103)
Model 2
Efficacy: SMD at Endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Fluoxetine minimum dose
0.115 ( 2.597 to 2.365)
0.927
Fluoxetine maximum dose
3.643 ( 3.335 to 10.622)
0.306
Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD>0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD >0 favours control AD)
0.001 ( 0.007 to 0.008)
0.859
0.001 ( 0.004 to 0.003)
0.797
0.259 ( 0.489 to
0.003
Model
Model 3
Fluoxetine maximum dose
Model 4
Fluoxetine experimental drug (yes = 1, no= 0)
Same variables as in Model 1 plus fluoxetine minimum dose and fluoxetine maximum dose
0.102)
SMD, standardized mean difference; AD, antidepressant; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor.
413
Purgato et al. Table 3. Baron and Kenny mediational model showing that studies where fluoxetine was the experimental agent were significantly associated with the overall treatment effect, indicating an advantage for fluoxetine (model 1 and model 4). By contrast, studies where fluoxetine was the experimental agent were significantly associated with the ratio between fluoxetine and control antidepressant dose only when minimum dosages were considered (model 2), and the ratio between fluoxetine and control antidepressant dose was not significantly associated with the overall treatment effect (Model 3) Model
Independent variable
Dependent variable
Adjusted for
Model 1
Fluoxetine experimental drug (yes = 1, no= 0)
Model 2
Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine experimental drug (yes = 1, no= 0) Fluoxetine minimum dose/ Control AD minimum dose
Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Fluoxetine minimum dose/Control AD minimum dose Fluoxetine maximum dose/Control AD maximum dose Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD) Efficacy: SMD at endpoint (SMD < 0 favours fluoxetine, SMD > 0 favours control AD)
Year of publication, multicentre study, country, weeks of follow up, blindness, placebo arm, type of comparator AD (TCA, SSRI or newer), sample size, elderly patients, setting
Model 3
Fluoxetine maximum dose/ Control AD maximum dose Model 4
Fluoxetine experimental drug (yes = 1, no= 0)
Same variables as in Model 1 plus fluoxetine minimum dose/Control AD minimum dose and fluoxetine maximum dose/Control AD maximum dose
b coefficient (95% CI) 0.313 ( 0.524 to
0.103)
P value 0.004
0.537 (0.038 to 1.036)
0.035
0.211 ( 0.110 to 0.533)
0.198
0.043 ( 0.136 to 0.049)
0.357
0.052 ( 0.157 to 0.053)
0.328
0.290 ( 0.483 to
0.004
0.097)
Legend: SMD: standardized mean difference; AD: antidepressant; TCA: tricyclic antidepressant; SSRI: selective serotonin reuptake inhibitor.
proxy measure of trials’ quality. The evidence that the outcome of fluoxetine RCTs varied according to whether this drug was used as a new compound or a reference one suggests the presence of bias. This bias worked in favour of fluoxetine in trials where it was the experimental drug and in favour of comparators in trials where fluoxetine was the reference agent. This finding, observed by means of metaregression analyses that adjusted for potential confounding variables, cannot be attributed to fluoxetine or control AD dose, as dose failed to emerge as mediator in the Baron and Kenny approach. This is a new and compelling finding as several authors have suggested dose as a potential reason for this bias (8). It is true that in univariate analyses, fluoxetine dose was higher in trials in which the aim was to demonstrate its efficacy in comparison with older ADs and lower in trials in which the aim was to demonstrate a new drug’s efficacy against fluoxetine, as shown in Table 1, but we additionally showed that this difference is likely attributable to other study-level characteristics, including year of publication and choice of control AD, as can be inferred by the Baron and Kenny analytical framework. Strengths and limitations
Strengths of this study include the following. Data were extracted from a very recent Cochrane systematic review, the search was comprehensive without language restrictions, and included unpublished studies. Standard Cochrane methodology was applied to data handling and analysis. 414
Additionally, the case example of fluoxetine is particularly appropriate for this analysis, as this AD has often been used both as experimental and control agent in AD trials. Another strength is that our findings can unlikely be attributed to the confounding effect of other study characteristics as all analyses have been adjusted for a number of studylevel confounders. However, a number of limitations should be acknowledged. First, some study reports did not clearly state which compound was the experimental and which was the control drug. When studies did not report this, they were allocated to the two groups depending on the drug used in comparison with fluoxetine. Reference compounds marketed before fluoxetine were considered comparators, and new AD drugs marketed after fluoxetine were considered experimental drugs. A second limitation is that we extracted and analysed data only for efficacy on a continuous outcome, without considering efficacy on dichotomous outcomes, such as, for example, responders or remitters. This approach was followed as dichotomous outcomes are erratically reported in AD studies, and this would have led to the exclusion of a relevant proportion of studies (21). A third limitation is that many studies did not mention the average fluoxetine dose administered during the study period. To overcome this problem, which might have dramatically reduced the sample of included studies, the dose range of fluoxetine planned before the study and reported in the methods was extracted. Although this measure may be considered a proxy of the average fluoxetine dose administered during
Dose as possible mediator of fluoxetine effect the study period, we acknowledge it is far from being optimal. However, it is worth noting that the main findings of this study were consistently replicated four times, using fluoxetine minimum and maximum dose in milligrams, and using the ratio of fluoxetine dose (minimum and maximum) by control AD dose (minimum and maximum) expressed in multiples of the DDD. Study implications
If dose does not have a mediational role, alternative explanations might be hypothesized. A first possibility is publication bias. Although effort has been made to include accessible unpublished data into this review, evidence suggests that current strategies to locate unpublished studies are imperfect, and therefore, we may have missed some unpublished trials. If publication bias had systematically excluded from publication RCTs failing to show a robust effect of experimental agents in comparison with reference ones, then the evidence that the outcome of fluoxetine RCTs varied according to whether this drug was used as a new compound or a reference one would be expected as a possible consequence (22). A second possibility is that the adverse effect profile of competitive agents revealed the identity of medication to participants or investigators or outcome assessors, thus influencing them when rating the effect of new and reference drug. The same might have been occurred during data analysis, especially for old studies where the process of data handling and analysis might have not clearly reported a priori into a study protocol. It should additionally be recognized that other study-related factors might have influenced this analysis. The construct of depression itself has evolved during the past quarter of a century since the introduction of fluoxetine, and also, the use of antidepressants in clinical practice has changed considerably. This might have affected trials in terms of types of participants recruited for RCTs. The growing placebo response in antidepressant trials may be seen as an indirect evidence of this evolution (23). There is also a broader and general phenomenon in science where first and initial findings seem to be stronger and become increasingly difficult to replicate with time (24). This might apply to fluoxetine trials, with initial studies (where fluoxetine was the experimental drug) showing a stronger treatment effect in comparison with later studies (where fluoxetine was the comparator drug). Considering that the included studies have been published over a very wide period of time, a confounding effect of these study-related factors
cannot be excluded, despite statistical adjustment for year of publication should have limited this potential bias. Implications for research and practice include the following. We argue that in future, RCTs’ investigators will always report the mean dose of drugs administered during the study, as well as which drug is the experimental one. Similarly, journal editors should no longer accept for publication trial reports that do not include this information. This would allow more precise re-analyses of trial data, although we note that only systematic reviews and meta-analyses of individual patientlevel data would help understand the role of each variable, including dose and other individual-level characteristics, in influencing trial results (25, 26). Implications for practice include awareness that investigators tend to overemphasize the effect of new drugs in comparison with reference ones. This attitude has negative consequences, because it may give the impression of a benefit even when there might be no added value. Clinicians should be aware that this bias is very difficult to detect from a scrutiny of the characteristics and design of a single trial. Acknowledgements MP and CB had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Declaration of interest None.
References 1. Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373:746–758. 2. Gartlehner G, Gaynes BN, Hansen RA et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008;149:734–750. 3. Malhi GS, Hitching R, Berk M, Boyce P, Porter R, Fritz K. Pharmacological management of unipolar depression. Acta Psychiatr Scand Suppl 2013;443:6–23. 4. Barbui C, Cipriani A, Brambilla P, Hotopf M. “Wish bias” in antidepressant drug trials? J Clin Psychopharmacol 2004;24:126–130. 5. Barbui C, Hotopf M, Garattini S. Fluoxetine dose and outcome in antidepressant drug trials. Eur J Clin Pharmacol 2002;58:379–386. 6. Naudet F, Maria AS, Falissard B. Antidepressant response in major depressive disorder: a meta-regression comparison of randomized controlled trials and observational studies. PLoS ONE 2011;6:e20811. 7. Khan A, Khan SR, Walens G, Kolts R, Giller EL. Frequency of positive studies among fixed and flexible dose
415
Purgato et al.
8.
9.
10. 11.
12.
13.
14. 15.
16.
416
antidepressant clinical trials: an analysis of the food and drug administration summary basis of approval reports. Neuropsychopharmacology 2003;28:552–557. Sinyor M, Schaffer A, Smart KA, Levitt AJ, Lanctot KL, Grysman NH. Sponsorship, antidepressant dose, and outcome in major depressive disorder: meta-analysis of randomized controlled trials. J Clin Psychiatry 2012;73: e277–e287. Magni LR, Purgato M, Gastaldon C et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev 2013;7:CD004185. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 1994. World Health Organization. The Tenth Revision of the International Classification of Diseases and Related Health Problems (ICD-10). 1992. Nose M, Barbui C. A simple approach to manage dosages in drug-epidemiology research. Epidemiol Psichiatr Soc 2008;17:186–187. World Health Organization. WHO Collaborating Centre for Drug Statistics Methodology (WHOCC): DDD Definition and general considerations. 2009. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–389. GUY. Clinical Global Impressions. Assessment Manual for Psychopharmacology, revised. Rockeville, MD: Na- tional Institute of Mental Health. 1976.
17. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 1986;51:1173–1182. 18. Kraemer HC, Wilson GT, Fairburn CG, Agras WS. Mediators and moderators of treatment effects in randomized clinical trials. Arch Gen Psychiatry 2002;59:877–883. 19. Higgins JP, Thompson SG. Controlling the risk of spurious findings from meta-regression. Stat Med 2004;23: 1663–1682. 20. Befron RT. Bootstrap Methods for Standard Errors, Confidence Intervals, and Other Measures of Statistical Accuracy. Stat Sci 1986;1:54–77. 21. Furukawa TA. How can we make the results of trials and their meta-analyses using continuous outcomes clinically interpretable? Acta Psychiatr Scand 2014;130:321–323. 22. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252–260. 23. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002;287:1840–1847. 24. Burman LE, Reed WR, Alm J. A call for replication studies. Public Finance Rev 2010;38:787–793. 25. Clarke MJ. Individual patient data meta-analyses. Best Pract Res Clin Obstet Gynaecol 2005;19:47–55. 26. Clarke MJ, Stewart LA. Systematic reviews of randomized controlled trials: the need for complete data. J Eval Clin Pract 1995;1:119–126.
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