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

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.

Inclusion criteria

• Has given written informed consent.
• Male or female outpatients aged at least 18 years and not more than 60 years.
• Has a diagnosis of major depressive disorder by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.
• HAMD-17 ≥ 20 and HAMD-17 Item 1(depressed mood) score ≥2 at enrolment in open-label preliminary phase.

Exclusion criteria

• Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug.
• Current Axis I primary psychiatric diagnosis other than major depressive disorder.
• Organic mental disease, including mental retardation.
• History of clinically significant disease, including any cardiovascular, hepatic, renal, respiratory, hematologic, endocrinologic, or neurologic disease, or clinically significant laboratory abnormality that is not stabilized or is anticipated to require treatment during the study.
• Subjects receiving an investigational agent (including different formulation and generic agents of investigational drug) in the previous 3 months prior to screening.
• Women in pregnancy or lactation, or female of child bearing potential without appropriate birth control measures.
• Use of antipsychotics or mood stabilizers within 5 days prior to screening.
• Has received depot antipsychotic medication within one cycle prior to screening.
• Known allergy or lack of response to mirtazapine.
• Has received ECT or MECT within 3 months prior to screening.
• Significant risk of suicidal and/or self-harm behaviors.