Most of the current antidepressants for major depressive disorder (MDD) are based upon the monoamine hypothesis which cannot fully explain the etiology of depression. NMDA hypofunction has been implicated in the pathophysiology of depression. Therefore, this study will examine the efficacy and safety as well as cognitive function improvement of an NMDA enhancer (NMDAE) in the treatment of MDD in the adults.

Major depressive disorder (MDD) is a complex and multi-factorial disorder. Most of the current antidepressants are based upon the monoamine hypothesis which cannot fully explain the etiology of depression. Many patients have significant side effects after treatment with antidepressants which hamper the motivation for treatment and medication adherence. NMDA hypofunction has been implicated in the pathophysiology of depression. MDD is often associated with cognitive deficits which are not necessarily recovered by current antidepressants. The NMDA receptor regulates synaptic plasticity, memory, and cognition. In our previous studies, cognitive improvement has been observed with treatment of NMDA enhancers. Therefore, this study will examine the efficacy and safety as well as cognitive function improvement of NMDAE in the treatment of MDD in the general adults by comparing with sertraline (a selective serotonin reuptake inhibitor [SSRI]) and placebo. The investigators will enroll non-elderly adult patients with MDD for an 8-week treatment. All patients will be randomly assigned into three groups: NMDAE, sertraline, or placebo. The investigators will biweekly measure clinical performances and side effects. Cognitive functions will be assessed at baseline and at endpoint of treatment by a battery of tests. The efficacy of three groups will be compared.

Inclusion Criteria:

• Have a DSM-5 (American Psychiatric Association) diagnosis of MDD
• 17-item Hamilton Rating Scale for Depression total score ≥ 18
• Free of antidepressant drugs for at least 2 weeks
• Agree to participate in the study and provide informed consent

Exclusion Criteria:

• Current substance abuse or history of substance dependence in the past 6 months
• History of epilepsy, head trauma, stroke or other serious medical or neurological illness which may interfere with the study
• Bipolar depression, schizophrenia or other psychotic disorder
• Moderate-severe suicidal risks
• Severe cognitive impairment
• Initiating or stopping formal psychotherapy within six weeks prior to enrollment
• A history of severe adverse reaction to SSRIs
• A treatment-resistant history (that is, they have failed to respond to two or more different classes of antidepressants with adequate dosage and treatment duration
• A history of previously received electroconvulsive therapy
• Inability to follow protocol