A Double-blind, Placebo-controlled Study of Antidepressant Augmentation With Agomelatine

• Age between 18 and 60 years.
• Meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria for a current major depressive episode.
• Demonstrating an inadequate response to antidepressant treatment lasting at least 2 weeks, at the minimum effective dose for antidepressants. Inadequate response is defined as a < 20% change in the Hamilton Depression Rating Scale-17 (HAMD-17) score or as per patients' self-report in the antidepressant treatment questionnaire. Minimum effective doses for some commonly used classes of antidepressants include:

• Sertraline: >50mg
• Fluoxetine: >20 mg
• Citalopram: >20 mg
• Escitalopram: >10mg
• Venlafaxine: >75 mg
• Duloxetine: >50 mg
• HAMD-17≥17; Clinical Global Impression-Severity (CGI-S) score ≥4.
• Education level of at least 6 years, with the ability to independently complete all scales and assessments.
• Agreement from primary healthcare providers and patients to maintain current antidepressant treatment while adding agomelatine.

**Exclusion Criteria:**

• Meeting criteria for other psychiatric disorders according to DSM-IV (except generalized anxiety disorder), such as schizophrenia, bipolar disorder, or mental disorders related to alcohol and drug dependence.
• Current or previous history of brain organic diseases or loss of consciousness for more than 5 minutes.
• Current or previous history of major physical diseases (including rheumatic immune system diseases, endocrine and metabolic diseases, nervous system diseases, etc.).
• Current serious suicidal ideation or suicide attempt.
• Pregnancy or lactation in women.
• Color blindness (which would hinder neurocognitive testing).
• Use of anticoagulants (e.g., heparin, warfarin), glucocorticoids, or treatment for thyroid diseases in the past 3 months.
• Having received any neurocognitive assessment similar to this study in the past 12 months.
• Positive urine drug screening results or abnormal thyroid function test.
• Liver function tests showing transaminase (ALT and AST) levels 2 times above the upper limit of the normal range.
• Electrocardiogram examination revealing a QTc ≥ 430 ms in males or QTc ≥ 450 ms in females.