
Declaration of interest
M.E.T. is an advisor/consultant for H. Lundbeck A/S. During the past 5 years has been advisor/consultant for, and/or received research funding and/or honoraria for talks from: the Agency for Healthcare Research and Quality, Aldolor, Alkermes, AstraZeneca, BristolMyers Squibb, Cephalon, Cyberonics, Dey Pharmaceuticals, Eli Lilly, Forest Laboratories (including PGx), GlaxoSmithKline, Janssen Pharmaceutica, MedAvante, Merck (including Organon and ScheringPlough), National Institute of Mental Health, Neuronetics, Novartis, Otsuka, PamLab, Pfizer (including Wyeth), Rexahn, Sanofi Aventis, Sepracor, Shire US, Takeda and Transcept. He has equity holdings in MedAvante and has received income from royalties from American Psychiatric Publishing, Guilford Publications and Herald House. S.H.K has received grant funding and consulting honoraria from H. Lundbeck A/S. In the past 5 years he has also received grant funding or consulting honoraria from AstraZeneca, Biovail, BoehringerIngelheim, Eli Lilly, GlaxoSmithKline, JanssenOrtho, MerckFrosst, Organon, Pfizer, Servier and St Jude Medical. K.G.L. is an employee of H. Lundbeck A/S.
Abstract
Background
There is controversy about the implications of relatively small average drug–placebo differences observed in randomised controlled trials of antidepressant medications.
Aims
To investigate whether efficacy is better understood as a large effect in a subgroup of patients.
Method
The mixture model was used to identify patient subgroups (patients benefiting or not benefiting from treatment) to directly model the skewness of Montgomery–Åsberg Depression Rating Scale (MADRS) scores at week 8.
Results
The MADRS scores improved by 15.9 points (95% CI 15.2–16.6) among patients who benefited from treatment. The proportion of patients who benefited from escitalopram and not from placebo treatment was 19.5%, corresponding to a number needed to treat of 5.
Conclusions
This model gave a considerably better fit to the data than the analysis of covariance model in which all patients were assumed to benefit from treatment. The small average antidepressant–placebo difference obscures a much larger effect in a clinically meaningful subgroup of patients.
It has been proposed that a small mean difference can be magnified when continuous data are transformed to categorical data (e.g. response or remission).^{1} This apparent discrepancy between continuous and response/remission measures implies that the rating scale scores are not normally distributed, which is a violation of the assumptions underlying the analysis of covariance (ANCOVA) model. Hence, it is also an indication that not all patients benefit from the intervention. This issue has important implications with respect to understanding the clinical significance of antidepressant medications, as some have argued that the small mean differences in symptom scores (compared with placebo) observed in metaanalyses of randomised controlled trials (RCTs) of newer generation antidepressants indicate that the utility of these treatments falls below the threshold of clinical significance for all but the most severely depressed patients.^{2–4}
There are various ways in which continuous parameters, such as total scores on a depression rating scale, can change as a result of an intervention. For example, one intervention can move the whole distribution, indicating an improvement for all patients, whereas another intervention might improve scores in only some patients. These different patterns of improvement can result in the same mean change in the study population. Although data can be analysed using ANCOVA, assuming that all patients benefit from the intervention in terms of improvement on a rating scale, models that address the latter pattern of improvement have not been explored using data from RCTs of antidepressants. The analysis reported here was undertaken to determine whether it is possible to distinguish between these two patterns by pooling data from a comprehensive dataset of placebocontrolled RCTs in major depressive disorder. Specifically, we aimed to determine whether the distribution of posttreatment scores shifts laterally from baseline to the end of treatment or, conversely, whether the shape of the distribution changes. Thus, we applied the mixture model, which includes the ANCOVA as a special case, in an attempt to improve the description of the observed score distribution while preserving a relatively simple interpretation of the effect of the intervention.
Method
Data were pooled from all five of the trials of escitalopram sponsored by Forest and Lundbeck.^{5–9} These were randomised placebocontrolled trials in which it was possible to receive escitalopram at a dose of 20 mg per day (Table 1). Khan et al have shown that antidepressant–placebo differences are greater in patients with severe depression than in those with moderate depression,^{10,11} and Bech et al have demonstrated that 20 mg is a more effective daily dose of escitalopram than 10 mg for treatment of patients with severe depression,^{12} defined as those with a baseline score of 30 or above on the Montgomery–Åsberg Depression Rating Scale (MADRS).^{13} Thus, in order to have as large a signaltonoise ratio as possible, only patients with a baseline MADRS score of 30 or over were included in the initial analyses. After validating the analyses in the more severe subset, analyses were repeated for the overall study group, as well as the subset with less severe depression.
Details of the individual studies have been published elsewhere;^{5–9} no unpublished study was excluded. Analyses are based on the fullanalysis set, comprising all patients who took at least one dose of study medication, and had at least one valid postbaseline MADRS assessment. Data are from week 8, using the method of last observation carried forward (LOCF). Although we are aware of the limitations of this conservative approach to account for the data of participants who drop out of the study (see, for example, papers by Lavori and Mallinckrodt et al),^{14,15} we used LOCF because it was used in several of the metaanalyses that support the contention that antidepressants have small effects.^{2–4} Remission was defined as a MADRS score of ≤10 or ≤12 and response as a 50% or greater decrease from baseline in MADRS total score.
Statistical analysis
The mixture model, a parametric, groupbased approach,^{16} was used to identify patient subgroups and to directly model the skewness of the observed MADRS scores at week 8. By using a mixture of probability distributions that are suitably specified to describe the data, this modelling strategy explicitly recognises uncertainty in group membership and assumes no single factor as necessary and sufficient in determining group membership.^{17} It was assumed that both treatment groups (placebo or escitalopram) consisted of two subgroups (i.e. two latent classes,^{18} or mixture components): one comprising patients who benefited from treatment and the other comprising patients who did not. The MADRS score at week 8 was assumed to be normally distributed within each of the subgroups regardless of treatment group. Hence, the distribution of the scores among patients who benefit from the treatment was assumed to be the same for the two treatment groups and the same assumption was made for patients who did not benefit. So, a difference in the distribution of MADRS scores at week 8 between treatment groups would be attributed to different proportions of patients benefiting from the treatment, rather than a shift in a single distribution as in the ANCOVA model. This leads to three types of patients: those who benefit from either of the treatments (placebo benefiters), those who benefit from neither treatment (escitalopram nonbenefiters) and those who benefit from escitalopram but not placebo. It is noted that the case with no placebo benefiters, no escitalopram nonbenefiters and equal variance in the benefiter and nonbenefiter groups is identical to the standard ANCOVA. In this sense, the mixture model is a generalisation of the ANCOVA.
It is not directly known to which subgroup each specific patient belongs, and class assignment is done implicitly during the estimation of the parameters of the model, although individual probabilities of the likelihood of a patient belonging to the benefiter group can be obtained. Our focus here is on finding a model that fits the data better than the ANCOVA, while keeping an intuitive clinical interpretation of the treatment effect. To this end, the mixture model allows for a flexible shape of the distribution of the observed MADRS scores at week 8, including bimodal or just skewed distributions. Based on the above assumptions, the model for the MADRS score at week 8 (MADRS_{W8}) included the effect (β) of the baseline MADRS score (MADRS_{BL}) and an intercept (α_{STUDY}), which varied between the five studies:
All parameters including λ, σ_{0}^{2} and σ_{1}^{2} were estimated jointly by the maximum likelihood principle using a program written in R (http://www.rproject.org). Although the ANCOVA model is statistically nested within the mixture model (the ANCOVA is obtained from the mixture model by restricting the probabilities of being a benefiter to 1 in the escitalopram group and 0 in the placebo group and setting σ_{0}^{2} equal to σ_{1}^{2}), a formal test comparing these models is not possible, and Akaike’s information criterion was used instead.^{19} The primary criterion for judging the fit of the model was the fit to the observed distribution of MADRS scores observed at week 8. The predictions of the observed response and remission rates were compared between the ANCOVA and mixture model to investigate whether the mixture model is a substantial improvement.
Results
There was no significant difference between treatment groups at baseline (Table 2). For all patients (n = 1357) the mean baseline MADRS total score was 29.6 (s.d. = 4.5), the mean age was 41 (s.d. = 12) years and 61.5% of patients were women. Using a median split, patients with MADRS scores below 30 were classified as less severely depressed and those scoring 30 or higher were classified as more severely depressed. Among the subset with more severe depression, 335 patients were treated with escitalopram and 332 with placebo.
Conventional analyses
For all patients (n = 1357) the observed mean treatment difference (escitalopram v. placebo) from baseline after 8 weeks of treatment (LOCF) was 3.2 (s.d. = 9.5) MADRS points (Table 3), with observed response rates of 53.8% (escitalopram) and 36.9% (placebo), and remission rates (MADRS≤12) of 44.5% (escitalopram) and 32.2% (placebo) (Table 4). These values correspond to numberneededtotreat (NNT) values of 6 for response and 8 for remission. For more severely depressed patients (MADRS≥30, n = 667) estimated MADRS means at last visit were 16.8 (s.d. = 10.5) for escitalopram treatment and 21.5 (s.d. = 10.9) for placebo, with an estimated mean treatment difference from baseline of 4.7 (s.d. = 10.7) (see Table 3). Response rates were 54.3% (escitalopram) and 33.4% (placebo), and remission rates (MADRS≤12) were 38.5% (escitalopram) and 25.3% (placebo) (Table 4). These values correspond to an NNT of 5 (100/20.9) for response and 8 (100/13.2) for remission. Corresponding values for the less severely depressed patients are also shown in Tables 3 and 4.
Mixture model v. ANCOVA
The distributions of MADRS total scores (LOCF) after 8 weeks of treatment with escitalopram or placebo are shown in Fig. 1. Inspection of the six graphs shows that the mixture model substantially improves the fit of the histograms compared with the ANCOVA, which assumes just one bellshaped curve. Akaike’s information criterion strongly supported this in the entire population (a difference of 106.78 points in favour of the mixture model) as well as in both subgroups (differences of 74.03 points in severe depression and 48.98 points in moderate depression). Whereas the ANCOVA model explains about 6% of the variance, the mixing component of the mixture model accounts for about 60% (see Table 3). A bimodal distribution of outcomes is evident in five of the six panels, with the curve on the left capturing patients who benefited from treatment (‘responders’, characterised by low MADRS scores at week 8), whereas that on the right captures patients who did not benefit from treatment (‘nonresponders’, characterised by high MADRS scores at week 8).
Distribution of MADRS scores at week 8
All patients
The distribution of MADRS total scores after 8 weeks of treatment is shown for all patients in Fig. 1(a,b). The treatment difference for those who benefited was 15.9 (95% CI 15.2–16.6) MADRS points (Table 3). The mean MADRS scores decreased from approximately 30 at baseline to approximately 10 at week 8 for patients benefiting from treatment (whether treated with placebo or escitalopram) and to approximately 25 at week 8 for patients who did not benefit from treatment. The proportion of patients who benefited from placebo was 39.2%, whereas 41.7% of patients did not benefit from treatment with escitalopram (see Table 3). The difference in proportions of patients who benefited from escitalopram v. placebo treatment (58.3%–39.2%) was 19.1% (95% CI 13.1–25.3; P<0.001). The mean treatment difference was therefore 3.0 MADRS points (19.2% of 15.9 points) and the NNT was 5 (100/19.2). Among those who did not benefit from treatment was a small group of patients whose scores increased. Specifically, depression worsened in 6.3% (n = 43) of patients given escitalopram and 10.3% (n = 70) of patients given placebo.
Less severely depressed patients
For patients with less severe depression at baseline, the distribution of MADRS total scores after 8 weeks of treatment is shown in Fig. 1(c,d). The mean scores decreased from approximately 26 at baseline to approximately 9 at week 8 for patients benefiting from treatment (whether treated with escitalopram or placebo) and to 22 at week 8 for patients who did not benefit from treatment. The treatment difference for those who benefited was 13.9 (95% CI 12.7–15.2; P<0.001) MADRS points (see Table 3). The proportion of patients who benefited from placebo was 36.6%, whereas the proportion of patients who benefited from escitalopram was 50.2%. Thus, the absolute difference was 13.6% (95% CI 4.2–23.1), with a mean treatment difference of 1.9 MADRS points (13.6% of 13.9 points) and an NNT of 7 (100/13.6). Depression became worse in 8.8% (n = 30) of escitalopramtreated patients and in 10.3% (n = 36) of placebotreated patients.
More severely depressed patients
For patients with more severe depression at baseline, the distribution of MADRS total scores after 8 weeks of treatment is shown in Fig. 1(e,f). The mean scores decreased from approximately 33 at baseline to approximately 10 at week 8 for patients benefiting from treatment (either escitalopram or placebo) and to approximately 27 at week 8 for patients who did not benefit from treatment. The treatment difference for those who benefited was 17.8 (95% CI 16.7–18.7) MADRS points (see Table 3). A higher percentage of patients treated with escitalopram benefited compared with those receiving placebo (difference 23.2%, P<0.001).
Patients who benefited from placebo treatment (35.2%) could be regarded as patients who would benefit regardless of treatment (i.e. the easiest to treat). Patients who did not benefit from escitalopram treatment (41.6%) could likewise be regarded as those who are more difficult to treat (i.e. they would also not have responded to placebo). The difference in the proportions of patients benefiting from escitalopram (58.4%) v. placebo (35.2%) was 23.2% (95% CI 14.8–1.6). The estimated mean treatment difference was therefore 4.1 MADRS points (23.2% of 17.8 points) and the NNT was 5 (100/23.2). Depression became worse in 3.9% (n = 13) of escitalopramtreated patients and in 10.2% (n = 34) of placebotreated patients.
To test the robustness of the mixture model, it was applied to a single study in elderly depressed patients in which the treatment difference between escitalopram (n = 170) and placebo (n = 180) of 0.03 MADRS points was not statistically significant.^{20} The treatment effect of 11.9 (s.d. = 4.7) MADRS points for participants who benefited was similar to that found for moderately depressed patients in the pooled analyses (13.9, s.d. = 4.6; see Table 3). The predicted benefiter rates were 33.9% for escitalopram and 30.8% for placebo, with a nonsignificant difference of 3.1% (P = 0.85).
Prediction of response and remission
The response and remission rates predicted by the ANCOVA and mixture model are shown in Table 4 with the observed rates. The mixture model performs consistently better than the ANCOVA in terms of the predicted rates being close to the observed rates (in all of the three criteria in each of the treatment groups and severity subgroups).
Discussion
We used a mixture model to identify two groups of patients: those who benefited from treatment and those who did not. In the total population we found that approximately 39% of patients benefited and 42% failed to benefit, regardless of treatment. We found that approximately 19% of the total would benefit from treatment with escitalopram but not with placebo. Consistent with earlier studies, we found that the percentage of patients who benefited specifically from treatment with the active antidepressant was higher among the subgroup with more severe depressive symptoms (23%) than it was for the subset with less severe symptoms (14%), corresponding to an NNT of 5 and 7 respectively.
It has been argued that the large sample sizes available in metaanalyses that use individual patient data can show statistical significance even when the clinical difference between two treatment groups is small.^{21} Mayer gives as an example a difference of 6.5 points in pain perception on a visual analogue scale of 0–100.^{22} If another study had shown that patients could not discriminate a difference of less than 13 points on this scale, he argues that the difference, although statistically significant, would not be clinically important. In this case, the difference for a group of patients is compared with an individual patient, and assumes that all patients responded (i.e. a single distribution) and showed the same, relatively small, mean difference. The same argument was recently made following a metaanalysis of RCTs of antidepressants, which observed a mean difference of about 2 points v. placebo.^{23} Our analyses using the mixture model indicate that a difference from placebo of 1 MADRS point corresponds to a difference of 5 percentage points in the proportion of benefiters, calculated as (52.3–37.0) / 3.04, which is close to the value of 5.2, calculated as (53.8–36.9) / 3.23, in the proportion of observed responder rates for all patients.
The mixture model is a substantial improvement on the standard ANCOVA in fitting the empirical distribution of the MADRS score at week 8. This is supported by the test criterion (Akaike’s information criterion) and the graphical fit of the week 8 MADRS scores, as well as the prediction of response and remission rates. Scrutinising the graphs, one may argue that the mixture model – although vastly improving the ANCOVA fit – still has problems capturing the floor effect, as there tends to be a ‘piling up’ of patients with a very low score. However, we consider this as a minor misfit, and it should come as no surprise, as the mixture model comprises components of the normal distributions. With the risk of overinterpretation, the distribution of patients with less severe depression receiving placebo looks multimodal (i.e. more complex than bimodal). As this pattern is not present in any of the three other subgroups, we interpret this as artefactual. In any case the number of patients is probably too small to draw valid conclusions based on a more elaborate model, although one could argue that there might be three or more classes of outcomes. More classes would allow for a slightly better fit to the empirical distribution, but would require more data. Three classes might correspond clinically to ‘remitters’ (patients with very low final scores), ‘responders’ (patients who benefit but who have too many residual symptoms to be classified as ‘well’) and ‘nonresponders’ (patients who obtain less than 20% improvement from baseline). An obvious next step would be to use the mixture model approach on longitudinal data from major depressive disorder trials, using a strategy similar to that of Uher et al.^{24}
The ANCOVA model systematically underestimated the proportion of ‘responders’ and ‘remitters’, whereas the mixture model did not, and was closer to the observed rates in both treatment groups and in more and less severely affected patient subgroups. This might be because the mixture model is richer in terms of the number of parameters, but neither model was tailored specifically to capture the response and remission rates. Therefore, we believe that the superior prediction of the response/remission rates in the mixture model is because it better captures the distribution of MADRS scores at week 8.
The National Institute for Health and Clinical Evidence (NICE) has concluded that although there is evidence suggesting a statistically significant difference favouring selective serotonin reuptake inhibitors (SSRIs) over placebo on reducing depression symptoms as measured by the Hamilton Rating Scale for Depression (HRSD; N = 16, n = 2223; random effects standardised mean difference effect size –0.34, 95% CI –0.47 to –0.22), the size of this mean difference is unlikely to be of clinical significance.^{25} For patients with severe depression, they concluded that there is evidence to support a clinically significant difference favouring SSRIs over placebo on reducing depression symptoms as measured by the HRSD (N =4, n = 344; effect size –0.61, 95% CI –0.83 to –0.4). Thus, a standardised mean difference effect size of 0.61 is considered clinically relevant, whereas 0.34 is not. The basis for this is that 0.5 is considered to be a ‘medium’ effect size (Cohen), although it should be noted that Cohen also stated, ‘The values chosen had no more reliable a basis than my own intuition’.^{26} Metaanalyses by Kirsch et al and Fournier et al,^{2,4} using a mean drug v. placebo difference of 3 points on the HRSD as the criterion of clinical significance, likewise reached a similar conclusion, namely that antidepressants conveyed a significant advantage over inert placebos only for patients with relatively severe depressive episodes. Our findings indicate that what appears to be a modest effect in the grouped data – on the boundary of clinical significance, as suggested above – is actually a very large effect for a subset of patients who benefited more from escitalopram than from placebo treatment. This subset ranged from 14% to 23% for milder and more severe depression respectively, and in both cases the NNT values derived from these analyses were above accepted thresholds of clinical significance. Said another way, a relatively small mean difference in grouped data can obscure a large difference in benefit in a clinically meaningful proportion of patients.
Limitations of the study
Our analysis has several limitations. First, the model is based on data from patients with major depressive disorder who were recruited on the basis of strict inclusion and exclusion criteria and who provided informed consent for participation in placebocontrolled RCTs. Second, our analysis was limited to studies of a single antidepressant, escitalopram, and was further limited to studies that permitted use of the maximum approved daily dose of that medication (20 mg). As escitalopram at this dose may be particularly effective,^{27,28} it is possible that analyses of other antidepressants at other doses might have resulted in smaller estimates of drug v. placebo differences. Third, the model tested here assumed that the fourth cell in the theoretical 2 × 2 table (i.e. patients who did not respond to escitalopram but would have responded to placebo) was empty. It is likely that a small percentage of those who did not respond to escitalopram did so because they either were made worse by the medication or withdrew early because of intolerable sideeffects; such patients might have responded had they been allocated to placebo. However, as attrition due to intolerable sideeffects was relatively small in the escitalopram group (approximately 6.8% v. 2.2% in the placebo group) and the placebo response rate was 37%, it is plausible that the hypothetical proportion of benefiters in our dataset was underestimated by about 3%. Finally, it is worth remembering that ‘Essentially, all models are wrong, but some are useful’.^{29}
Implications of the study
These analyses indicate that small mean differences obscure large and clinically meaningful responses for a subgroup of people with depression. Specifically, the use of a mixture model indicates that the modest mean difference favouring the group receiving the active antidepressant is actually explained by a large and clinically relevant effect of 14–18 points on the MADRS among the subgroup of depressed patients who specifically benefited from active treatment. This subgroup, in turn, represented between 14% (less severe) and 23% (more severe) of the patients who consented to doubleblind therapy. Application of the mixture model to this pooled dataset gave a considerably better fit to the data than one in which all patients were assumed to benefit from treatment.
Funding
The original studies were sponsored by H. Lundbeck A/S or Forest Pharmaceuticals, Inc.
Acknowledgments
We thank David Simpson, PhD, for assistance in the preparation of the manuscript. Dr Simpson is an employee of H. Lundbeck A/S.
 Received February 17, 2011.
 Revision received June 23, 2011.
 Accepted July 28, 2011.
 Royal College of Psychiatrists
Royal College of Psychiatrists, This paper accords with the NIH Public Access policy and is governed by the licence available athttp://www.rcpsych.ac.uk/pdf/NIH%20licence%20agreement.pdf