Effectiveness Study of Mirtazapine Combined With Paroxetine in Major Depressive Patients Without Early Improvement
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).
Because most antidepressant treatment guidelines continue to suggest 4~6 weeks of treatment until nonresponse can be assumed, adherence is required from depressed patients. The ability to identify the early action of antidepressants allows for earlier initiation of a treatment adaptation such as alternative or adjunctive treatment. The early identification of non responders is also important because selection of an antidepressant agent is still primarily guided by trial. 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. Once a patient demonstrates an appropriate response to an antidepressant, ongoing treatment is recommended. 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. 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.
Drug: mirtazapine, paroxetine
Drug: paroxetine 20mg QD
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||A Double-blind, Active-controlled, Randomized Study Comparing Mirtazapine Combined With Paroxetine or Paroxetine Monotherapy in Patients With Major Depressive Patients Without Early Improvement in the First 2 Weeks|
- Change of 17-item Hamilton Depression Scale (HAMD-17) total score [ Time Frame: From randomization (Week 2) to endpoint(Week 8) ] [ Designated as safety issue: No ]
- The proportion of subjects at endpoint with HAMD-17≤7 [ Time Frame: From randomization (Week 2) to endpoint(Week 8) ] [ Designated as safety issue: No ]
- The incidence and nature of overall adverse events [ Time Frame: From enrollment to endpoint (Week 8) ] [ Designated as safety issue: Yes ]
- The incidence and nature of drug-related adverse events [ Time Frame: From enrollment to endpoint (Week 8) ] [ Designated as safety issue: Yes ]
- The number of subject withdrawal due to adverse events during double-blind phase [ Time Frame: From randomization (Week 2) to endpoint(Week 8) ] [ Designated as safety issue: No ]
|Study Start Date:||April 2012|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
|Active Comparator: mirtazapine,paroxetine, add-on therapy||
Drug: mirtazapine, paroxetine
mirtazapine 30mg QD, paroxetine 20mg QD
|Active Comparator: mirtazapine monotherapy||
mirtazapine 30mg QD
Other Name: Remeron
|Active Comparator: paroxetine monotherapy||
Drug: paroxetine 20mg QD
paroxetine 20mg QD
Other Name: Seroxat
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.
|Contact: Le Xiao, M.D.||firstname.lastname@example.org|
|Beijing Anding Hospital||Recruiting|
|Beijing, Beijing, China, 100088|
|Contact: Ye Zhao, Master 86-10-58303236 email@example.com|
|Sub-Investigator: Le Xiao, M.D.|
|Sub-Investigator: Yuan Feng, M.D.|
|Sub-Investigator: Ling Zhang, M.D.|
|Sub-Investigator: Wei Wang, M.D.|
|Sub-Investigator: Xue Wang, M.D.|
|Sub-Investigator: Xiaohong Li, M.D.|
|Principal Investigator:||Gang Wang, M.D., Ph.D||Beijing Anding Hospital, Capital Medical University|