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 elderly 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 in the elderly 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 elderly by comparing with sertraline (a selective serotonin reuptake inhibitor [SSRI]) and placebo.

The investigator will enroll elderly patients with MDD for an 8-week treatment. All patients will be randomly assigned into three groups: NMDAE, sertraline, or placebo. The investigator will biweekly measure clinical performances. Cognitive functions will be assessed at baseline and at endpoint of treatment by a battery of tests. The investigator hypothesize that NMDAE can safely yield better efficacy than placebo and sertraline for elderly patients with MDD.

Inclusion Criteria:

• Have a DSM-IV (American Psychiatric Association 1994) diagnosis of MDD
• 17-item Hamilton Rating Scale for Depression total score ≥ 18
• Free of psychotropic drugs for at least 2 weeks
• Have a Mini-Mental State Examination (Folstein, Folstein et al. 1975) score ≥ 20

Exclusion Criteria:

• Current substance abuse or history of substance dependence in the past 6 months
• Use of depot antipsychotics in the past 6 months
• History of epilepsy, head trauma, stroke or other serious medical or neurological illness
• 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 poor response to SSRIs or other antidepressants
• A history of previously received electroconvulsive therapy
• A history of severe adverse reaction to SSRIs or other antidepressants
• Inability to follow protocol