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.

BACKGROUND: For 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. METHODS: This 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. RESULTS: Between 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. CONCLUSIONS: In 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 REGISTRATION: ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010.

Whose depression deteriorates during acute phase antidepressant treatment?

BACKGROUND: Few studies have investigated the proportion of patients with depression who experience worsening of depression symptoms during adequate antidepressant treatment. The current study aimed to investigate the proportion and predictors of worsening depression during antidepressant treatment in a multi-center randomized trial involving patients with major depression. METHODS: We defined the deterioration of depression using depression symptom severity evaluated by total Patient Health Questionnaire (PHQ-9) score increases from week 0 to week 9 during acute phase antidepressant treatment. Patients' baseline demographic and clinical data, change in PHQ-9 scores from week 0 to week 3, and side effects at week 3 were evaluated as potential predictors of subsequent deterioration of depression. RESULTS: Of 1,647 patients, 99 (6.0%) exhibited deterioration of depression, and this proportion was smaller when reliable change index criteria were applied. Logistic regression analysis revealed that the following factors were significantly associated with deterioration of depression: younger age at onset of first episode of major depressive disorder, current older age, and greater increase in PHQ-9 scores between week 0 and week 3. LIMITATIONS: The time of the primary endpoint might not have been sufficiently long. The present study did not include a placebo arm, and potentially relevant predictors might not have been comprehensively investigated. CONCLUSIONS: A small proportion of patients may experience deterioration of depression during acute phase antidepressant treatment. Age at onset at first depressive episode, current age, and early negative response to antidepressants may be useful predictors of subsequent worsening of depression.