GLYX-13 is a NMDA receptor glycine site partial agonist being studied in subjects with major depressive disorder (depression) who have responded inadequately to another antidepressant drug during the current episode. This trial will assess the effects of GLYX-13 on depression when added to another antidepressant drug that the patient is already taking.

To evaluate the mean difference in Hamilton Depression Rating Scale 17 (HDRS-17) score for the combined GLYX-13 mean change versus the placebo group mean change at the end of a 6 week randomized withdrawal phase (predose baseline score - score at end of randomized withdrawal period).

Inclusion Criteria:

• Male and female subjects
• Aged 18 to 65 years
• Meets DSM-IV-TR) criteria for major depressive disorder (MDD)
• Current episode has lasted ≥ 8 weeks before Screening with an inadequate response to all approved antidepressant agent(s) administered at an adequate dose and duration for the current episode
• Taking no antidepressant agent currently or taking an SSRI or SNRI
• HDRS-17 score ≥ 18 at screening and predose baseline
• Female subjects of childbearing potential with a negative serum pregnancy test prior to entry into the study and who are practicing an adequate method of birth control and who do not plan to become pregnant during the course of the study.
• Clinical laboratory values < 2 times the upper limit of normal (ULN) or deemed not clinically significant per the investigator and Naurex medical monitor
• Ability to understand the requirements of the study, provide written informed consent, abide by the study restrictions, and agree to return for the required assessments
• Based on the investigator and Naurex medical monitor's clinical judgment, subjects with eating disorders, obsessive compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), and generalized anxiety disorders secondary to major depressive episodes (MDEs) are permitted.

Exclusion Criteria:

• Axis I diagnosis of delirium, dementia, dysthymia, amnestic or other cognitive disorder, schizophrenia or other psychotic disorder, bipolar I or II disorder, eating disorder (anorexia or bulimia nervosa), obsessive-compulsive disorder, panic disorder, acute stress disorder, agoraphobia, social phobia, attention-deficit hyperactivity disorder (ADHD), or PTSD
• A clinically significant current Axis II diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder
• Experiencing hallucinations, delusions, or any psychotic symptomatology in the current episode; lifetime history of psychosis
• Huntington's, Parkinson's, Alzheimer's, Multiple Sclerosis, or a history of seizures or strokes
• Currently hospitalized or residing in an in-patient facility during the study participation
• Substance abuse within the last 12 months
• Women who are planning to become pregnant during the course of the study
• Allergy or intolerance to current antidepressant or other current medications
• Participation in any clinical trial of an investigational product or device within 30 days of enrollment in this trial with the exception of GLYX13-C-201.
• Positive screen for drugs of abuse
• Have received electroconvulsive therapy, transcranial magnetic stimulation (TMS), or vagal nerve stimulation (VNS) for the current depressive episode
• Pose current (past 6 months) suicide risk based on administration of the C SSRS and the investigator's clinical judgment
• Human immunodeficiency virus (HIV) infection (based on the HIV-1 & HIV-2 antibody screen) or other ongoing infectious disease
• Females who are currently pregnant or planning to become pregnant during the course of the study
• Dextromethorphan or tramadol since these are serotonin uptake inhibitors
• History of allergy, sensitivity, or intolerance to N-methyl-D-aspartate receptor [NMDAR] ligands