This study's primary objective is to compare the efficacy and tolerability of switching patients with inadequate relief on generic SSRIs to levomilnacipran versus adding a new treatment (quetiapine) to the participants' existing treatment with people diagnosed with depression (major depression disorder).

The secondary objective is to examine the response and remission rates following the switch from a generic SSRI to levomilnacipran ER and augmentation with quetiapine along with examining changes in neurocognitive and apathy measures after the switch.

1. Study Design 1) An 8-week, randomized rater blinded parallel group, 2-arm trial 2) Trial duration - 9 weeks 3) Drug doses

   • Levomilnacipran ER; Switching to a flexible dose regime of levomilnacipran ER 40-120 mg/day after initial dose of 20mg.
   • Quetiapine XR; Adjunct a flexible dose regimen of quetiapine XR 150-300 mg/day after initial dose of 50mg.

2. Objective 1) To compare the efficacy and tolerability of switching to levomilnacipran ER (40-120 mg/d) versus augmentation with quetiapine XR 150-300 mg/day to the patients' existing treatment for patients with inadequate relief on generic SSRIs in patients with MDD.

2) To examine the response following the switch from generic SSRI to levomilnacipran ER and augmentation with quetiapine XR.

3) To examine changes in neurocognitive and apathy measures after switching from SSRI to levomilnacipran ER and after augmentation with quetiapine XR in MDD

Inclusion Criteria:

• Age 18-65 years inclusive
• Current diagnosis of MDD based on DSM-IV criteria
• Able to understand study rules and procedures and willing to sign written informed consent for study participation
• Inadequate response to antidepressants: having a score of ≥14 on the 17-item Hamilton Anxiety Scale (HAMD) and not having a ≥ 50% reduction in HAMD or CGI-S scores from baseline after a retrospective confirmation of an adequate trial of a single antidepressant (defined as a minimum 6-week trial of acceptable therapeutic dose (daily dose ≥ 40 mg of fluoxetine, 40 mg of paroxetine, 20 mg of citalopram, 10 mg of escitalopram, 37.5 mg of paroxetine CR, 150 mg of sertraline, 100 mg of fluvoxamine).
• If female, nonpregnant/nonlactating status
• Duration of current MDD ≥ 4 weeks and < 24 months
• Not more than 2 treatment failures of adequate antidepressant trials for current episode of MDD

Exclusion Criteria:

• Has previously participated in a levomilnacipran ER or quetiapine XR or quetiapine clinical study in previous 12 months

Has 1 or more the following:

• Current or past history of: manic or hypomanic episode, schizophrenia or any other psychotic disorder defined in the DSM- 5

• Diagnosis of alcohol or other substance use disorder (except nicotine and caffeine) as defined in the DSM-5 that has not been in sustained full remission for at least 6 months prior to screening (participant must also have negative urine drug screen prior to baseline).

• Presence or history of a clinically significant neurological disorder (including epilepsy)

• Poorly controlled Hypertension or Diabetes

• uncontrolled narrow-angle glaucoma

• hypersensitivity to levomilnacipran, milnacipran , quetiapine or quetiapine XR

• Neurodegenerative disorder.

• Has a thyroid stimulating hormone value outside the normal range at the Screening Visit that is deemed clinically significant by the investigator.

• Has clinically significant abnormal vital signs as determined by the investigator.

• Has a clinical significant abnormal electrocardiogram.

• Has screening laboratory values greater than 2.5 times the upper or lower limits of normal range or judged to be clinically significant

• Has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy or prevent the individual from completing the study.

• Female subjects of childbearing potential not on adequate contraception methods in the opinion of the investigator

  o If the female is childbearing, she must agree to use appropriate contraceptive measures for the duration of the study and for one month afterwards. Medically acceptable contraceptives include: (1) surgical sterilization (such as tubal ligation of hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants, or injections), (3) barrier methods (such as condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive measures such as Plan B ™, sold for emergency use after unprotected sex, are not acceptable methods for routine use. If the female does become pregnant during this study she must inform the study physician immediately.

• Has a significant risk of suicide according to Columbia Suicide Severity Rating Scale (CSSRS) or in the clinical judgment of the investigator

• History of suicide attempt in the previous 12 months

• MDD with postpartum onset, psychotic features or seasonal features

• Hamilton Anxiety Scale (HAM-A) baseline score ≥ 24

• Failure of ≥ 3 adequate trials of different antidepressants for the current episode of MDD

• ≥ 3 episodes major depression in previous 12 months or ≥ 8 lifetime episodes of MDD

• Current or previous use of an atypical or typical antipsychotic agent for augmentation of major depression or treatment of psychotic depression, mania psychosis, or agitation. Previous use of antipsychotics for insomnia will be permitted.

Screening to Week 9