The current study will evaluate the antidepressant effect of CERC-301 during 28 days of treatment in subjects with MDD who are currently experiencing a severe depressive episode despite stable ongoing treatment with selective serotonin- or serotonin-norepinephrine reuptake inhibitors (SSRI or SNRI). The study population will be enriched for subjects that would benefit most from rapid onset, those with recent active suicidal ideation, but not a risk to themselves or others and are deemed appropriate for an out-patient study with careful safety surveillance. This will allow the study to focus on the antidepressant effects of CERC-301 but also explore effects on suicidal ideation. To explore rapid onset, the primary endpoint will be at 7 days, but effects over the 28 days of treatment will be examined as a secondary endpoint.

Inclusion Criteria:

1. Male or female 18 to 70 years of age inclusive.

2. Females must be either:

   1. Post-menopausal (amenorrhea for at least 12 consecutive months), surgically sterile -or-
   2. Women of childbearing potential (WOCBP) meeting the criteria below:

   i. Uses an acceptable double-barrier method of contraception as determined by the Investigator -and- ii. Is not lactating, has a negative serum beta human chorionic gonadotropin pregnancy test at screening and a negative urine pregnancy test prior to randomization on Day 0.

3. Male subjects must agree to use a condom if partner is of childbearing potential.

4. Diagnosis of MDD recurrent without psychotic features according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria with diagnosis confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders Clinical Trials Version (SCID-CT).

5. Currently adhering to antidepressant drug regimen that consists of stable SSRI or SNRI therapy

6. Inadequate antidepressant response to current antidepressant therapy despite adequate dose and duration

7. HDRS-17 score ≥ 21 on the HDRS-17 performed by the site at screening

8. Recent active suicidal ideation defined as a score of 2 on the intensity of ideation section on the Columbia-Suicide Severity Rating Scale (C-SSRS) during the four weeks prior to screening using the "Baseline/Screening" version of the C-SSRS.

9. In otherwise good general health without any unstable medical conditions (as determined by medical history, physical examination, 12-lead ECG, clinical laboratory testing, etc.).

Exclusion Criteria:

1. History of substance abuse or dependence within the 3 months prior to screening.

2. Positive urine drug test at screening and prior to randomization on Day 0 unless due to a permitted medication that is documented in the subject's medication history.

3. Positive ethanol breath test at screening and/or prior to randomization on Day 0.

4. Elevated semi-recumbent blood pressure at screening and prior to randomization on Day 0, defined as systolic blood pressure > 140 mm Hg and diastolic blood pressure

5. Active, comorbid disease that might limit the ability of the subject to participate in the study as determined by the Investigator (i.e. poorly controlled diabetes mellitus, unstable angina, coronary artery disease, congestive heart failure, etc.).

6. Subjects with clinical laboratory test abnormality deemed clinically significant by the Investigator at screening.

7. Axis I diagnosis of obsessive compulsive disorder, posttraumatic stress disorder, bipolar I or II mood disorders, eating disorders (e.g., anorexia nervosa, bulimia nervosa), psychotic disorders (e.g., schizoaffective disorder, schizophrenia), significant cognitive disorders (e.g., delirium, dementia, amnesia), or dissociative disorders.

8. Subjects with Axis II diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder.

9. Subjects with a neurologic disorder that could cause or contribute to depression (e.g., Alzheimer's disease, Parkinson's disease).

10. Female subjects currently experiencing postpartum depression.

11. Subjects who, in the opinion of the Investigator, are not appropriate for a 35-day placebo-controlled study due to risk of significant threat to self or others during screening or study conduct.

12. Use of other NMDA-receptor modulators (e.g., dextromethorphan, ketamine, amantadine, memantine) within 30 days of screening and throughout the study.

13. The following concomitant medication use is excluded within six weeks prior to screening:

    • Bupropion or tricyclic antidepressants
    • Intermittent, symptomatic use of benzodiazepines (e.g. symptomatic treatment of anxiety or panic attacks)
    • Antipsychotics
    • Lithium
    • Any medications known to directly interact with central or peripheral serotonergic receptors, other than the permitted antidepressants.
    • Any medications known to directly interact with central noradrenergic receptors, other than the permitted antidepressants.

14. Electroconvulsive therapy, transcranial magnetic stimulation, or vagal nerve stimulation during the current depressive episode.

15. Participation in an investigational drug or device study within the 6 months prior to screening.

16. Subjects with suicidal behavior within 6 months prior to screening as measured by the C-SSRS "Baseline/Screening" version.

17. Subjects with a C-SSRS score > 2 on the intensity of ideation section at randomization (Visit 2a), using the "Since Last Visit" version of the C-SSRS.