The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial.

BACKGROUND: Depression is usually managed in primary care, but most antidepressant trials are of patients from secondary care mental health services, with eligibility criteria based on diagnosis and severity of depressive symptoms. Antidepressants are now used in a much wider group of people than in previous regulatory trials. We investigated the clinical effectiveness of sertraline in patients in primary care with depressive symptoms ranging from mild to severe and tested the role of severity and duration in treatment response. METHODS: The PANDA study was a pragmatic, multicentre, double-blind, placebo-controlled randomised trial of patients from 179 primary care surgeries in four UK cities (Bristol, Liverpool, London, and York). We included patients aged 18 to 74 years who had depressive symptoms of any severity or duration in the past 2 years, where there was clinical uncertainty about the benefit of an antidepressant. This strategy was designed to improve the generalisability of our sample to current use of antidepressants within primary care. Patients were randomly assigned (1:1) with a remote computer-generated code to sertraline or placebo, and were stratified by severity, duration, and site with random block length. Patients received one capsule (sertraline 50 mg or placebo orally) daily for one week then two capsules daily for up to 11 weeks, consistent with evidence on optimal dosages for efficacy and acceptability. The primary outcome was depressive symptoms 6 weeks after randomisation, measured by Patient Health Questionnaire, 9-item version (PHQ-9) scores. Secondary outcomes at 2, 6 and 12 weeks were depressive symptoms and remission (PHQ-9 and Beck Depression Inventory-II), generalised anxiety symptoms (Generalised Anxiety Disorder Assessment 7-item version), mental and physical health-related quality of life (12-item Short-Form Health Survey), and self-reported improvement. All analyses compared groups as randomised (intention-to-treat). The study is registered with EudraCT, 2013-003440-22 (protocol number 13/0413; version 6.1) and ISRCTN, ISRCTN84544741, and is closed to new participants. FINDINGS: Between Jan 1, 2015, and Aug 31, 2017, we recruited and randomly assigned 655 patients-326 (50%) to sertraline and 329 (50%) to placebo. Two patients in the sertraline group did not complete a substantial proportion of the baseline assessment and were excluded, leaving 653 patients in total. Due to attrition, primary outcome analyses were of 550 patients (266 in the sertraline group and 284 in the placebo group; 85% follow-up that did not differ by treatment allocation). We found no evidence that sertraline led to a clinically meaningful reduction in depressive symptoms at 6 weeks. The mean 6-week PHQ-9 score was 7·98 (SD 5·63) in the sertraline group and 8·76 (5·86) in the placebo group (adjusted proportional difference 0·95, 95% CI 0·85-1·07; p=0·41). However, for secondary outcomes, we found evidence that sertraline led to reduced anxiety symptoms, better mental (but not physical) health-related quality of life, and self-reported improvements in mental health. We observed weak evidence that depressive symptoms were reduced by sertraline at 12 weeks. We recorded seven adverse events-four for sertraline and three for placebo, and adverse events did not differ by treatment allocation. Three adverse events were classified as serious-two in the sertraline group and one in the placebo group. One serious adverse event in the sertraline group was classified as possibly related to study medication. INTERPRETATION: Sertraline is unlikely to reduce depressive symptoms within 6 weeks in primary care but we observed improvements in anxiety, quality of life, and self-rated mental health, which are likely to be clinically important. Our findings support the prescription of SSRI antidepressants in a wider group of participants than previously thought, including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or generalised anxiety disorder. FUNDING: National Institute for Health Research.

A randomised controlled trial assessing the severity and duration of depressive symptoms associated with a clinically significant response to sertraline versus placebo, in people presenting to primary care with depression (PANDA trial): study protocol for a randomised controlled trial.

BACKGROUND: Depressive symptoms are usually managed within primary care and antidepressant medication constitutes the first-line treatment. It remains unclear at present which people are more likely to benefit from antidepressant medication. This paper describes the protocol for a randomised controlled trial (PANDA) to investigate the severity and duration of depressive symptoms that are associated with a clinically significant response to sertraline compared to placebo, in people presenting to primary care with depression. METHODS/DESIGN: PANDA is a randomised, double blind, placebo controlled trial in which participants are individually randomised to sertraline or placebo. Eligible participants are those who are between the ages of 18 to 74; have presented to primary care with depression or low mood during the past 2 years; have not received antidepressant or anti-anxiety medication in the 8 weeks prior to enrolment in the trial and there is clinical equipoise about the benefits of selective serotonin reuptake inhibitor (SSRI) medication. Participants who consent to participate in the trial are randomised to receive either sertraline or matching placebo, starting at 50 mg daily for 1 week, increasing to 100 mg daily for up to 11 weeks (with the option of increasing to 150 mg if required). Participants, general practitioners (GPs) and the research team will be blind to treatment allocation. The primary outcome will be depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9) at 6 weeks post randomisation, measured as a continuous outcome. Secondary outcomes include depressive symptoms measured with the PHQ-9 at 2 and 12 weeks as a continuous outcome and at 2, 6 and 12 weeks as a binary outcome; follow-up scores on depressive symptoms measured with the Beck Depression Inventory-II, anxiety symptoms measured by the Generalized Anxiety Disorder-7 and quality of life measured with the Euroqol-5D-5L and Short Form-12; emotional processing task scores measured at baseline, 2 and 6 weeks; and costs associated with healthcare use, time off work and personal costs. DISCUSSION: The PANDA trial uses a simple self-administered measure to establish the severity and duration of depressive symptoms associated with a clinically significant response to sertraline. The evidence from the trial will inform primary care prescribing practice by identifying which patients are more likely to benefit from antidepressants. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN84544741 . Registered on 20 March 2014. EudraCT Number: 2013-003440-22; Protocol Number: 13/0413 (version 6.1).