Optimising first- and second-line treatment strategies for untreated major depressive disorder — the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial

Abstract

BackgroundFor patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished.MethodsThis multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates.ResultsBetween December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), − 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups.In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects.ConclusionsIn patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine.Trial registrationClinicalTrials.gov, NCT01109693. Registered on 23 April 2010.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1096-5) contains supplementary material, which is available to authorized users.

Trajectory of criterion symptoms of major depression under newly started antidepressant treatment: sleep disturbances and anergia linger on while suicidal ideas and psychomotor symptoms disappear early

“…This study is a secondary analysis of a 25‐week pragmatic, multi‐centre, assessor‐blinded randomised controlled trial examining the first‐ and second‐line treatments of adult patients with hitherto untreated major depressive episodes. The trial protocol and its primary results have been published elsewhere.…”

FORWARD Study: Evaluating the Comparative Effectiveness of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine

“…In 1967, Schwartz and Lellouch first used the term "pragmatic" to describe trials that assess an intervention in clinical practice to determine which of 2 treatments should be preferred. [22][23][24][25][26][27][28][29][30] The primary goal of the FORWARD study was to compare the effectiveness of onabotulinumtoxinA and topiramate in preventive treatment of CM via a pragmatic design and to explore the clinical utility of onabot-ulinumtoxinA in those who discontinued topiramate. 20 The National Institutes of Health and the Patient-Centered Outcomes Research Initiative support and promote pragmatic clinical trial methodology to obtain information directly relevant for the needs of healthcare providers.…”

Predictors of hypomanic and/or manic switch among patients initially diagnosed with unipolar major depression during acute‐phase antidepressants treatment

“…We preliminarily explored predictors of hypomanic and/or manic switch during acute‐phase antidepressants treatment by using the data of the SUN☺D trial, which is a multicenter randomized controlled clinical trial. A total of 2011 patients participated and the main findings are published elsewhere . Institutional review boards at each participating site approved the study.…”