This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of TNX-601 ER monotherapy versus placebo in patients with Major Depressive Disorder (MDD).

Inclusion Criteria:

• Female or male aged 18 to 65 years (inclusive).

• Have a primary DSM-5 diagnosis of current MDD.

  1. The duration of the current MDE must be at least 12 weeks.
  2. Without psychotic or catatonic features.

Exclusion Criteria:

• Psychiatric History:

  1. Diagnosis of DSM-5-defined lifetime bipolar disorder (I, II, or unspecified), schizophrenia, schizoaffective disorder, MDD with psychotic features, other psychotic disorder, or antisocial personality disorder; current (past month) obsessive-compulsive disorder; current (past month) posttraumatic stress disorder; current (past 3 months) anorexia nervosa; lifetime opioid or lifetime sedative-hypnotic use disorders, as confirmed by the MINI 7.0.2.
  2. Diagnosis of borderline personality disorder
  3. Patients with comorbid generalized anxiety disorder (GAD), social anxiety disorder (SAD), or panic disorder are excluded only if the GAD, SAD, or panic disorder is considered the primary psychiatric diagnosis, rather than MDD. (If MDD is the primary diagnosis, patients with comorbid GAD, SAD, and panic disorder are allowed for randomization).

• Patients with treatment refractory MDD, ie, previously having in their lifetime failed ≥2 treatments with at least 2 different classes of antidepressants of adequate dose, duration, and treatment adherence