Research aims
The aim of the RCT was to investigate the severity and duration of depressive symptoms that are associated with a clinically important response to sertraline and cost-effectiveness (compared with placebo) in people with depression who present to primary care. The main hypothesis was that response to antidepressants would increase with both severity and duration of depressive symptoms. Our primary analysis was a comparison between sertraline and placebo at 6 weeks.
Methods for data collection
We used broad and pragmatic inclusion criteria, recruiting people who had sought treatment for depressive symptoms of any severity or duration in primary care. The key entry criterion was that GPs and/or patients were uncertain about the potential benefits of an antidepressant and we did not set any severity or duration thresholds as exclusions. Patients were recruited from primary care surgeries in four UK sites (i.e. Bristol, London, Liverpool and York) and identified by GPs, who either invited patients during a consultation or conducted a database search and then sent an invitation in the post. Participants were randomised to 100 mg of sertraline or an identical placebo and followed up at 2, 6 and 12 weeks.
is a flow diagram of the progress through the trial.
The Consolidated Standards of Reporting Trials (CONSORT) flow diagram: PANDA RCT.
Analysis
The primary outcome was the PHQ-9 at the 6-week follow-up. Interactions terms of a realistic size, that are smaller than the main effect, require very large sample sizes for adequate power. As a result, we modelled the treatment effect on log-transformed PHQ-9 scores (continuous outcome) using an intention-to-treat analysis. The exponentiated regression coefficient is the proportional (or percentage) change in PHQ-9 scores between randomised groups. Evidence of a treatment effect using a proportional model implies that the treatment effect expressed as a mean difference would increase with severity. In sensitivity analyses we fitted an additive model using absolute depression scores (non-logged PHQ-9) and calculated an interaction between treatment allocation and baseline CIS-R depression severity score. However, we expected the power of this analysis to be low.
Secondary outcomes at 2, 6 and 12 weeks were depressive symptoms and remission assessed using the PHQ-9 and the BDI-II, generalised anxiety disorder symptoms, mental and physical health-related quality of life and self-reported global improvement. We used linear multilevel models for repeated measures of continuous secondary outcomes at 2, 6 and 12 weeks (PHQ-9, BDI-II, GAD-7 and Short Form questionnaire-12 items physical and mental health-related quality of life). Logistic multilevel models were calculated for repeated measures of binary secondary outcomes at 2, 6, and 12 weeks (remission on the PHQ-9, the BDI-II and feeling better on the GRC scale).
We undertook a cost-effectiveness analysis from the perspective of the NHS and Personal and Social Services alongside the PANDA RCT. Quality-of-life data were collected at baseline and 2, 6 and 12 weeks post randomisation using EQ-5D-5L, from which we calculated QALYs. Costs were collected using patient records and from resource use questionnaires administered at each follow-up interval. Differences in mean costs and mean QALYs and net monetary benefits were estimated. Our primary analysis used net monetary benefit regressions to identify any interaction between the cost-effectiveness of sertraline and subgroups defined by baseline symptom severity (0 to 11; 12 to 19; ≥ 20 on the CIS-R) and, separately, duration of symptoms (greater or less than 2 years’ duration). A secondary analysis estimated the cost-effectiveness of sertraline versus placebo. In sensitivity analyses, we (1) performed a complete-case analysis to check the robustness of our findings to missing data, (2) examined the impact of excluding costs that were not judged to be directly related to the treatment of depression and (3) excluded all secondary care costs from total NHS and Personal and Social Services costs to assess whether or not our findings were robust to infrequent but expensive hospitalisations.
Key findings
We found no evidence that the antidepressant sertraline reduced depressive symptoms at 6 weeks. In the sertraline group, PHQ-9 scores were 5% (95% CI –7% to 15%; p = 0.41) lower than those in the placebo group. In the sensitivity analyses using additive models, there was no evidence of an interaction with severity or duration of depressive symptoms with treatment effect, but these analyses would have lacked statistical power.
Of the secondary outcomes, there was strong evidence that sertraline reduced anxiety symptoms (GAD-7 score reduced by 17%, 95% CI 9% to 25%; p < 0.000046) and improved mental but not physical health-related quality of life as well as self-reported global improvement. There was weak evidence that depressive symptoms were reduced by sertraline at 12 weeks for both the PHQ-9 and the BDI-II. Given our findings, we also investigated whether or not the treatment effect for anxiety symptoms was influenced by baseline severity. We found no evidence that the effect of sertraline on anxiety symptoms varied according to the severity of anxiety or depressive symptoms. The number needed to treat in order to feel better according to our self-reported global improvement question was 8.5 (95% CI 5.2 to 22.1) people at 6 weeks and 6.4 (95% CI 4.6 to 10.3) people at 12 weeks.
There was no evidence of an association between the baseline severity of depressive symptoms and the cost-effectiveness of sertraline. Compared with patients with low symptom severity, the expected net benefits in patients with moderate symptoms were £64 (95% CI –£312 to £441) and the expected net benefits in patients with high symptom severity were –£51 (95% CI –£389 to £287). Patients who had a longer history of depressive symptoms at baseline had lower expected net benefits from sertraline than those with a shorter history; however, the difference was uncertain (–£132, 95% CI –£431 to £167). In the secondary analysis, patients treated with sertraline had higher expected net benefits (£118.37, 95% CI –£23.39 to £260.14) than those in the placebo group. Sertraline had a high probability (> 90%) of being cost-effective if the health system was willing to pay at least £20,000 per QALY gained.
Limitations
We had broad inclusion criteria and some participants had very few symptoms. This may have reduced the treatment effect, but our methods of analysis using a proportional approach should have helped to take account of this. There was attrition of nearly 20% by 12 weeks, although this did not differ by study arm, and when we investigated the impact of missing data, this did not appear to explain the findings. We had limited statistical power to explore interactions between treatment response and symptom severity or duration. It is possible that subgroups in which sertraline was more cost-effective might have become more evident with a larger sample size or longer follow-up.
Inter-relation with other parts of the programme
The RCT did not find evidence of an early antidepressant effect of sertraline on depressive symptoms in the population studied. There was, however, evidence that sertraline reduced anxiety symptoms and was more likely to lead to a clinically important benefit. The results of the trial and those from the MCID can be used to provide some initial guidance about the likely cost-effectiveness of sertraline and other SSRI antidepressants in primary care.
Conclusion
We chose the PHQ-9 as our primary outcome in the PANDA trial. The PHQ-9 is widely used in primary care and there is evidence that it is better at detecting changes in depressive symptoms after treatment than other measures.37,55 It also avoids the observer bias that affects clinician-rated HAMD and MADRS scores. However, our qualitative research identified a number of reasons for disagreement between the PHQ-9 and the self-reported GRC, as well as indicating that up to 50% of patients might show disagreement between self-reported change and the results of questionnaires. Our findings indicate that the processes and motivations behind completing the PHQ-9 are complex and influenced by ongoing physical, social and emotional issues. Our findings suggest that PHQ-9 and, by implication, other self-administered questionnaires should not be used alone to assess improvement or deterioration. Their use should be supplemented with further clinical assessment and the use of more open-ended questions.
The MCID is the smallest change in symptoms that is considered clinically worthwhile by the patient. Our MCID research in phases 1 and 2 has enabled us to develop appropriate analytical methods for estimating the MCID and to provide values for the MCID in a primary care population for the first time. We can apply our MCID estimates to the results of the PANDA trial, but we acknowledge that our estimates of MCID are still uncertain.
When we initially formulated our research questions we assumed that the treatment effect varied according to depression severity but that the MCID was a fixed value, irrespective of depression severity. Our results, if anything, now point in the opposite direction, at least when we estimate treatment effects and MCID using a proportional approach. Our results suggest that sertraline has a similar (proportional) effect size over the whole range of depression (and anxiety) severity and it is the MCID that changes and gets larger, proportionally, at lower levels of severity. We have found that, at higher levels of severity, the proportional approach works better for the MCID. The proportional approach also has attractions when analysing clinical trial data. It avoids the assumption that the same absolute treatment effect is observed regardless of whether a person scores 5 or 25 on a scale. This seems unlikely and a proportional reduction approach appears more plausible as well as providing a better statistical fit to the data.
Contrary to our initial hypothesis in the PANDA trial, we found no evidence of a clinically important effect of sertraline on depressive symptoms. We found a 5% reduction in the sertraline group at 6 weeks, and this is considerably smaller than the MCID estimates for the PHQ-9 we have obtained. We cannot exclude the possibility that sertraline led to a clinically important improvement at 12 weeks, as we found a 13% (95% CI 3% to 21%) reduction in PHQ-9, but this is still well below our MCID. In contrast we found strong evidence that sertraline reduced anxiety symptoms on the GAD-7, with a reduction of 21% (95% CI 11% to 30%) at 6 weeks. This is consistent with some of our estimates of the MCID for GAD-7 (see Appendix 4) and suggests that this change is clinically important. We found insufficient evidence of an interaction between the cost-effectiveness of sertraline and severity or symptom duration that GPs could use to efficiently target prescribing. There was no evidence of a substantial treatment effect of sertraline on quality of life, as measured by the EQ-5D-5L. However, sertraline is an inexpensive intervention that has a high probability of being cost-effective compared with placebo across primary care patients with depression or low mood.
Our MCID estimates are based on an average within-person change related to improvement; however, a RCT compares groups. Application of our results has therefore required a counterfactual argument in which researchers compare the same individual(s) who receive placebo but who might have received the active treatment. The MCID estimated from a within-person calculation can then be applied to the between-group differences in a clinical trial.
Our estimates of MCID could be used to guide decisions about whether or not a treatment will benefit an individual. For this, one needs to be able to predict the likely score for that person on the proposed outcome measure were they not to receive that treatment. In other words, we need to know the likely value of an individual’s PHQ-9 or GAD-7 score at follow-up, 6 or 12 weeks later, if they were to receive a placebo. The expected value of the placebo at follow-up can then be used to determine the appropriate initial value for the MCID and thus decide if the proportional reduction expected from a treatment would be larger than the MCID for such a person. For this to be feasible, we would need more precise estimates of MCID and also the ability to predict future scores of patients on the basis of their clinical and other characteristics.
Finally, we can make some very approximate estimate of what proportion of participants in the PANDA cohort would probably have benefited from treatment. From our results in Appendix 4, it is clear that those with a GAD-7 score of 3 at 6 weeks have a MCID of about 50%. It is highly unlikely that those individuals would have experienced any benefit from sertraline. In the PANDA RCT, about 30% of participants scored ≤ 3 at 6 weeks. However, we cannot conclude this with any confidence at this stage. We do not know the distribution of symptoms in those receiving antidepressants in the UK and our estimates of MCID are approximate. Our overall results are reassuring in indicating that, on average, patients in the PANDA RCT are benefiting from sertraline. However, it is probable that a substantial proportion or patients receiving antidepressants are not experiencing any individual benefit. For clinicians to be confident about recommending treatment to patients, we need accurate information on individualised treatment effects and the outcome without treatment as well as MCID. Of course, any recommendations for treatment will also have to take account of any risks and adverse effects that result from the treatment as well as patient preference.
Recommendations for future research
Our finding that sertraline seems to be effective for anxiety but not depressive symptoms has a potential implication for understanding the mechanisms of antidepressant treatment as well as the clinical benefit that patient’s will experience.
Research recommendation 1
Future research into the mechanism of action of antidepressants should examine the biology of anxiety symptoms.
The result of the RCT also questions the reliance of current clinical guidelines on existing placebo-controlled studies that have been conducted largely for regulatory purposes. Cipriani et al.’s review28 highlights the poor quality of the existing research. Antidepressants are commonly used medications and it is concerning that we still have a number of outstanding questions about their efficacy and clinical indication many years after they were introduced. The use of behavioural tasks such as face recognition and memory for words might be a useful way to investigate these mechanistic aspects.
Research recommendation 2
Future studies should investigate the clinical effectiveness of antidepressants for anxiety disorders in UK primary care population.
We would recommend that future investigation of antidepressant efficacy should have longer follow-ups to see if there are longer-term benefits for depressive symptoms as well as anxiety symptoms. We would encourage use of more detailed outcome measures, using self-reported information, to ensure that the whole range of symptoms that are common in depression and anxiety are studied. The use of self-reported improvement (GRC) seems a valuable outcome measure in clinical trials.
Research recommendation 3
Further investigation of minimal clinically important differences.
Further research is needed to investigate the size of the MCID and the factors that might influence whether or not patients report improvement. We need more precise estimates to guide decision-making. We have provided evidence that patients’ reporting of feeling better can be affected by various other factors, such as anxiety and physical changes. Further investigation of this will also help inform how MCIDs could be used clinically to provide treatment recommendations.
Implications for practice and any lessons learned
The PHQ-9 and similar self-administered questionnaires should not be used alone in assessing improvement or deterioration. It is important to supplement such standardised measures with a clinical assessment.
Sertraline is effective and cost-effective in reducing anxiety symptoms such as worry and restlessness in the first 6 weeks of treatment in people who present with depressive symptoms. Any effect on depressive symptoms takes longer to emerge; although an improvement in anxious symptoms in someone presenting with depressive symptoms could lead to a clinical benefit. Patients who present to primary care with depressive symptoms have a wide range of severity of symptoms. Overall, this population is likely to benefit from SSRI antidepressants. Our findings support the prescription of SSRI antidepressants in a wider group of participants than previously thought, including those who do not meet diagnostic criteria for depression or generalised anxiety disorder, especially when anxiety symptoms such as worry and restlessness are present.
Patient and public involvement
Paul Lanham, a service user and a co-applicant, was also a member of the independent steering committee during phase 3 of the programme and was involved in PANDA for over 6 years. Paul Lanham and Derek Riozzie have also contributed to PANDA annual meetings where all co-applicants and researchers discuss progress, review the protocols and discuss any findings. They made important contributions to the discussion and influenced the interpretation of the results and decisions about study design. All study documentations have been revised and commented on by Paul, Derek and the user group co-ordinated by Derek at Liverpool University. In addition, we enlisted the support of the North London Service Users Research Forum (SURF). The SURF was co-founded in 2007 by service users and clinical academic psychiatrists at University College London to provide meaningful consultation on research. It has 12 members with mental health problems. Since 2007, it has consulted on > 50 projects and SURF members have been invited to join steering/management groups on many of these. As a result, the group is very experienced and confident about the advice and input they provide; their comments on the trial paperwork have been invaluable. The letter templates, patient information sheets and the questionnaire were amended to reflect the patient and public involvement (PPI) feedback. We also consulted on the protocol concerning self-harm or risk of self-harm, which we used if patients reported this in the course of the cohort and RCT. Having close involvement of the PPI for the duration of the programme (i.e. over 6 years) has been invaluable for its success. It has also enabled us to build on it and we have recruited a PANDA RCT participant to represent PPI on a different depression trial: ANTidepressants to prevent reLapse in dEpRession (ANTLER).64 We plan to carry on using the services users’ comments in the design, documentation and analysis of any future studies.
