Background:

Despite a growing number of prescriptions for antidepressants (over 70 million in 2018), there is uncertainty about when people with depression might benefit from antidepressant medication and concern that antidepressants are prescribed unnecessarily.

Objectives:

The main objective of the PANDA (What are the indications for Prescribing ANtiDepressAnts that will lead to a clinical benefit?) research programme was to provide more guidance about when antidepressants are likely to benefit people with depression. We aimed to estimate the minimal clinically important difference for commonly used self-administered scales for depression and anxiety, and to understand more about how patients respond to such assessments. We carried out an observational study of patients with depressive symptoms and a placebo-controlled randomised controlled trial of sertraline versus placebo to estimate the treatment effect in UK primary care. The hypothesis was that the severity and duration of symptoms were related to treatment response.

Design:

The programme consisted of three phases. The first phase relied on the secondary analysis of existing data extracted from published trials. The second phase was the PANDA cohort study of patients with depressive symptoms who presented to primary care and were followed up 2, 4 and 6 weeks after a baseline assessment. Both quantitative and qualitative methods were used in the analysis. The third phase was a multicentre randomised placebo-controlled double-blind trial of sertraline versus placebo in patients presenting to primary care with depressive symptoms.

Setting:

UK primary care in Bristol, London, Liverpool and York.

Participants:

Patients aged 18–74 years who were experiencing depressive symptoms in primary care. Eligibility for the PANDA randomised controlled trial included that there was uncertainty about the benefits about treatment with an antidepressant.

Interventions:

In the PANDA randomised controlled trial, patients were individually randomised to 100 mg daily of sertraline or an identical placebo. The PANDA cohort study was an observational study.

Main outcome measures:

Depressive symptoms measured using the Patient Health Questionnaire were the primary outcome for the randomised controlled trial. Other outcomes included anxiety symptoms using the Generalised Anxiety Disorder-7; depressive symptoms using the Beck Depression Inventory, version 2; health-related quality of life; self-reported improvement; and cost-effectiveness.

Results:

The secondary analysis of existing randomised controlled trials [GENetic and clinical Predictors Of treatment response in Depression (GenPod), TREAting Depression with physical activity (TREAD) and Clinical effectiveness and cost-effectiveness of cognitive Behavioural Therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care (CoBalT)] found evidence that the minimal clinically important difference increased as the initial severity of depressive symptoms rose. Our estimates of minimal clinically important difference were a 17% and 18% reduction in Beck Depression Inventory scores for GenPod and TREAD, respectively. In CoBalT, a 32% reduction corresponded to the minimal clinically important difference but the participants in this study had depression that had not responded to antidepressants. In the PANDA study cohort, and from our analyses in existing data, we found that the minimal clinically important difference varies considerably with the initial severity of depressive and anxiety symptoms. Expressing the minimal clinically important difference as a percentage reduction reduces this variation at higher scores, but at low scores the percentage reduction increased substantially. The results from the qualitative studies pointed out many limitations of the Patient Health Questionnaire-9 items in assessing change and recovery from depression. In the PANDA randomised controlled trial, there was no evidence that sertraline resulted in a reduction in depressive symptoms within 6 weeks of randomisation, but there was some evidence of a reduction by 12 weeks. However, sertraline led to a reduction in anxiety symptoms, an improvement of mental health-related quality of life and an increased likelihood of reporting improvement. The mean Patient Health Questionnaire-9 items score at 6 weeks was 7.98 (standard deviation 5.63) in the sertraline group and 8.76 (standard deviation 5.86) in the placebo group (5% relative reduction, 95% confidence interval –7% to 15%; p = 0.41). Of the secondary outcomes, there was strong evidence that sertraline reduced anxiety symptoms (Generalised Anxiety Disorder-7 score reduced by 17% (95% confidence interval 9% to 25%; p = 0.00005). Sertraline had a high probability (> 90%) of being cost-effective at 12 weeks. The PANDA randomised controlled trial found no evidence that treatment response or cost-effectiveness was related to severity or duration of depressive symptoms. The minimal clinically important difference estimates suggested that sertraline’s effect on anxiety, but not on depression, was likely to be clinically important.

Limitations:

The results from the randomised controlled trial and the estimates of minimal clinically important difference were not sufficiently precise to provide specific clinical guidance for individuals. We had low power in testing whether or not initial severity and duration of depressive symptoms are related to treatment response.

Conclusions:

The results of the trial support the use of sertraline and probably other selective serotonin reuptake inhibitors because of their action in reducing anxiety symptoms and the likelihood of longer-term benefit on depressive symptoms. Sertraline could be prescribed for anxiety symptoms that commonly occur with depression and many patients will experience a clinical benefit. The Patient Health Questionnaire-9 items and similar self-administered scales should not be used on their own to assess clinical outcome, but should be supplemented with further clinical assessment.

Future work:

We need to examine the longer-term effects of antidepressant treatment. We need more precise estimates of the treatment effects and minimal clinically important difference at different severities to provide more specific guidance for individuals. However, the methods we have developed provide an approach towards providing such detailed guidance.

Trial registration:

Current Controlled Trials ISRCTN84544741 and EudraCT number 2013-003440-22.

Funding:

This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 10. See the NIHR Journals Library website for further project information.

Article history

The research reported in this issue of the journal was funded by PGfAR as project number RP-PG-0610-10048. The contractual start date was in March 2012. The final report began editorial review in September 2018 and was accepted for publication in June 2019. As the funder, the PGfAR programme agreed the research questions and study designs in advance with the investigators. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The PGfAR editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Rachel Churchill reports grants from the National Institute for Health Research (NIHR) (Programme Grants for Applied Research programme) during the conduct of the study. Simon Gilbody serves as deputy chairperson of the NIHR Health Technology Commissioning Board, but was not involved in the commissioning of this programme of research. Catherine Harmer reports personal fees from P1vital (Wallingford, UK), grants from UCB Pharma (Brussels, Belgium), grants and personal fees from Johnson & Johnson (New Brunswick, NJ, USA), and personal fees from H. Lundbeck A/S (Copenhagen, Denmark), Servier Laboratories (Neuilly-sur-Seine, France) and Pfizer Inc. (New York, NY, USA) outside the submitted work. Tony Kendrick reports grants from NIHR during the conduct of the study. Marcus Munafo reports grants and personal fees from Cambridge Cognition (Cambridge, UK) and personal fees from Jericoe Ltd (Bristol, UK) outside the submitted work. Tim Peters reports grants from NIHR during the conduct of the study. Howard Thom reports personal fees from Novartis Pharma AG (Basel, Switzerland), Pfizer Inc., Roche Holding AG (Basel, Switzerland) and Eli Lilly and Company (Indianapolis, IN, USA) outside the submitted work. Nicky Welton reports grants from NIHR during the conduct of the study; and she is the principal investigator on a Medical Research Council-funded project in collaboration with Pfizer Inc. Pfizer Inc. part funded a junior researcher on the project. The project is purely methodological using historical data on pain relief, and unrelated to this work. Nicola Wiles reports grants from NIHR during the conduct of the study. Glyn Lewis reports grants from University College London during the conduct of the study and personal fees from Fortitude Law (London, UK) outside the submitted work.