Effectiveness Study of Mirtazapine Combined With Paroxetine in Major Depressive Patients Without Early Improvement

Overview

Although treatment guidelines manifest that antidepressant response usually appear with a delay of several weeks and suggest that treatment should be changed if a partial response has not occurred after 4\~6 week, these beliefs are no longer held by experts, and a new concept is raised that the first 2 weeks of treatment may be a useful strategy for improving the management of depression. New evidence indicates that early treatment response can be predicted with high sensitivity after 2 weeks of treatment in patients with major depressive disorder (MDD). Early improvement not only predicted response or remission, but also that lack of improvement was associated with little chance of response if the treatment strategy remained unchanged. The criterion of a 20% score reduction has been chosen as an early indicator of improvement because it can be reliably measured in clinical trials and translates into a clinically relevant change in the severity of depressive symptoms. Antidepressants that enhance both serotonergic and noradrenergic neurotransmission may be more effective than selective serotonin reuptake inhibitors (SSRIs) for acute-phase therapy of major depressive disorder. As a noradrenergic and specific serotonergic antidepressant, the antidepressive mechanism of mirtazapine is quite superior to SSRI and in particular has been suggested to have a faster onset of action than SSRIs in MDD patients. The aim of this study is to provide physicians with further information regarding early improvement and the effectiveness of mirtazapine combined with a SSRI antidepressant therapy in nonresponders.

Mirtazapine has significant advantages in response and remission rates compared with various SSRIs in double-blind treatment. Mirtazapine combined with SSRIs or venlafaxine was also found to be one of the more effective and successful strategy for nonresponders in MDD. The investigators hypothesized that mirtazapine as adjunctive treatment to paroxetine can boost the onset time and also can improve the antidepression action of SSRIs in patients without early improvement. The aim of this study is to provide physicians with further information regarding early improvement and mirtazapine combined with a SSRI antidepressant therapy in nonresponders, by providing a comparison of depressive symptoms outcomes associated with adjunctive mirtazapine or mono- paroxetine in MDD patients who have previously been treated with paroxetine for 2 weeks and who have not attained improvement. Paroxetine has been chosen as a comparator because it is a widely-used and relatively well-tolerated SSRI antidepressant. The study is designed as a multi-center, randomized, double-blind, active-controlled trial in subjects with MDD. Patients will be male or female, 18 to 60 years of age, inclusive, outpatient or inpatient status, with diagnosis of major depressive episode (single or recurrent) by DSM-IV. The patients should also have HAMD-17 total score ≥ 20,a HAMD-17 Item 1(depressed mood) score ≥ 2 at enrollment in open-label preliminary phase. It will consist of 2 phases. An open-label preliminary phase lasts for 2 weeks, during which paroxetine is titrated up to 20mg/day (Day 5). At Week 2, patients will be evaluated by HAMD-17. The patients who have achieved early improvement (the decrease of HAMD-17 total score ≥ 20%) will be discontinued. The patients who have not achieved early improvement (the decrease of HAMD-17 total score \< 20%), will be randomized into three treatment arms \[1.Mirtazapine (30mg/d); 2.Paroxetine (20mg/d); 3.Mirtazapine (30mg/d) +Paroxetine(20mg/d)\]. In double-blind treatment phase (consist of 6 weeks), patients will be evaluated at Week 3, 4, 6 and 8. Primary efficacy measure will be assessed based on the decrease of HAMD-17 from randomization (Week 2) to endpoint (Week 8). CGI-I and CGI-S will be used as secondary efficacy measures throughout this phase. The safety in this study will be assessed by adverse event reporting, clinical laboratory measurements and physical examinations. Up to 540 patients will enter into Open-label Phase in order to yield approximately 200 evaluable patients in Randomization Phase.