A Study to Evaluate TNX-102 SL Monotherapy Versus Placebo in Participants With Major Depressive Disorder (MDD)

• TNX-102 SL (Drug), also known as cyclobenzaprine, cyclobenzaprine HCl: Participants will take 5.6 mg of TNX-102 SL ( 2 x 2.8 mg TNX-102 SL tablets) daily at bedtime.
• Placebo sublingual tablet (Drug): Participants will take placebo ( 2 x placebo sublingual tablets) daily at bedtime.

Primary outcomes

• Change from Baseline (Visit 2) in the MADRS total score at Week 6. [From Day 1 to Week 6]: Change from Baseline (Visit 2) in the MADRS total score at Week 6. Scores range from 0 to 60. Lower scores indicate less depression.

Secondary outcomes

• Change from Baseline (Visit 2) in the Clinician Global Impression - Severity (CGI-S) score at Week 6 [From Day 1 to Week 6]: Change from Baseline (Visit 2) in the Clinical Global Impression of Severity Scale (CGI-S) score at Week 6. Scores range from 1 to 5. Lower scores indicate less severe illness.
• Change from Baseline (Visit 2) in the PROMIS Sleep Disturbance T-score at Week 6 [From Day 1 to Week 6]: Change from Baseline (Visit 2) in the PROMIS Sleep Disturbance T-score at Week 6. The Patient-Reported Outcome Measurement Information System (PROMIS) sleep disturbance instrument consists of 8 items in which responses are scored 1 to 5 for each item. PROMIS scores are presented as T-scores in which the raw score has been rescaled into a standardized score with a mean of 50 and a standard deviation of 10. Higher T-scores represent more of the concept being measured (in this case, sleep disturbance).
• Change from Baseline (Visit 2) in the MADRS total score at Week 4. [From Day 1 to Week 4]: Change from Baseline (Visit 2) in the MADRS total score at Week 4. Scores range from 0 to 60. Lower scores indicate less depression.
• Change from Baseline (Visit 2) in the MADRS total score at Week 2. [From Day 1 to Week 2]: Change from Baseline (Visit 2) in the MADRS total score at Week 2. Scores range from 0 to 60. Lower scores indicate less depression.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Primary DSM-5 diagnosis of current MDD.
* The duration of the current MDE must be between 6 weeks and 18 months.
* Without psychotic or catatonic features.
* Capable of reading and understanding English and able to provide written informed consent to participate.

Exclusion Criteria:

* 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,
* Diagnosis of borderline personality disorder that is known, suspected
* Participants 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.
* Participants with treatment refractory MDD, ie, previously having failed in their lifetime ≥2 treatments (due to inadequate efficacy) with at least 2 different classes of antidepressants of adequate dose, duration, and treatment adherence.
* History of substance use disorder and/or alcohol use disorder during the preceding 12 months
* Use of antidepressants (including ketamine/esketamine, St. John's Wort, S-adenosyl methionine, and/or trazodone used as an antidepressant) within 4 weeks of Baseline (Visit 2), except for fluoxetine, which must not be within 6 weeks of Baseline (Visit 2)