Levomilnacipran ER vs. Adjunctive Quetiapine for Adults With Inadequate Relief With SSRIs in MDD

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

• Levomilnacipran (Drug), also known as Fetzima: treating major depression. A flexible dose regime of levomilnacipran ER 20-120 mg/d mg per day starting at 20 mg/d on Days 1-2, increasing to 40 mg/d on Days 3-7 in week 1, then flexibly dosed between 40 mg/d -120 mg/d during weeks 2 through 8
• Quetiapine (Drug), also known as Seroquel: Quetiapine will be started at 50 mg/d on Day 1-2, increasing to 150 mg/d on Days 3-7 in Week 1 and then flexibly dosed between 150-300 mg/d during Weeks 1 through 8 along with their current antidepressant.

Primary outcomes

• Changes of Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score [Baseline to Week 8]: A ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Total scores will range from 0 to 60. Higher scores indicate greater severity of depressive episodes.

Secondary outcomes

• Response Rate [Week 8]: Remission was defined as \[>or=50% reduction in MADRS score with MADRS <or=10\] and response was defined as \[>or=50% reduction in MADRS with MADRS >10\]. Response rate included remission and response.
• Remission Rate [Week 8]: Remission was defined as \[>or=50% reduction in MADRS score with MADRS <or=10\]
• Changes in Neurocognition by Changes in Scores on Reyes Verbal Learning Test [Baseline to Week 8]: Number of words correctly recalled by the respondent is recorded. 1 point for each word correctly recalled. Total score range of 0-40. Higher scores mean better cognitive function.
• Changes in Neurocognition by Changes in Scores on Scores on Digit Symbol Substitution Test (DSST) [Baseline to Week 8]: DSST measures working memory and visuospatial processing. 1 point for each object correctly substituted from number to each matched symbol. Total score range of 0-89. Higher scores mean better cognitive function.
• Number of Subjects With Global Improvement in Scores on Clinical Global Impression Scale- Severity (CGI-S) [Baseline to Week 8]: CGI-S is a 7 point scale that assess the severity of illness and requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. It is used to assess the clinician's view of the patient's global functioning. Total score range of 0-7.
• Number of Subjects With General Improvement in Scores on Clinical Global Impression Scale- Improvement (CGI-I) [Baseline to Week 8]: CGI-I a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. It is used to assess the clinician's view of the patient's global functioning. Total score range of 0-7.
• Changes of Anxiety Symptoms in Scores on Hamilton Anxiety Rating Scale (HAM-A) [Baseline to Week 8]: A questionnaire used by clinicians to rate the severity of a patient's anxiety. Total score range of 0-48. A higher score indicates greater anxiety.
• Changes of Quality of Life in Scores on Sheehan Disability Scale (SDS) Total [Baseline to Week 8]: A self-reported brief scale to assess impairment of work/school, social life and family and home. Total score range of 0-30. A higher score indicates greater impairment.
• Changes in Scores on Apathy Evaluation Scale (AES). [Baseline to Week 8]: Self-Administered assessment measuring lack of motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress. Total scores range from 0-54. Higher scores indicate greater apathy.
• Changes in Sexual Dysfunction by Changes in Scores on Arizona Sexual Experience Scale (ASEX) [Baseline to Week 8]: ASEX is scale for sexual dysfunction to assess safety and tolerability of medication. Total scores range from 5-30. Higher scores indicate greater sexual dysfunction.

Sex: All, ages: 18 Years to 65 Years

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.

Participant flow

Outcome results

• Changes of Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score (Primary), Mean, score on a scale: Levomilnacipran -5.81 +/- 6.080; Quetiapine -6.97 +/- 7.632 (p 0.53)
• Response Rate (Secondary), Count of participants, Participants: Levomilnacipran 3; Quetiapine 7 (p 0.428)
• Remission Rate (Secondary), Count of participants, Participants: Levomilnacipran 2; Quetiapine 3 (p 0.272)
• Changes in Neurocognition by Changes in Scores on Reyes Verbal Learning Test (Secondary), Mean, score on a scale: Levomilnacipran 2.28 +/- 5.694; Quetiapine 2.90 +/- 5.255 (p 0.664)
• Changes in Neurocognition by Changes in Scores on Scores on Digit Symbol Substitution Test (DSST) (Secondary), Mean, score on a scale: Levomilnacipran 3.21 +/- 9.321; Quetiapine 0.87 +/- 7.431 (p 0.292)
• Number of Subjects With Global Improvement in Scores on Clinical Global Impression Scale- Severity (CGI-S) (Secondary), Count of participants, Participants: Levomilnacipran 13; Quetiapine 13 (p 0.884)
• Number of Subjects With General Improvement in Scores on Clinical Global Impression Scale- Improvement (CGI-I) (Secondary), Count of participants, Participants: Levomilnacipran 21; Quetiapine 24 (p 0.905)
• Changes of Anxiety Symptoms in Scores on Hamilton Anxiety Rating Scale (HAM-A) (Secondary), Mean, score on a scale: Levomilnacipran -3.89 +/- 4.969; Quetiapine -5.53 +/- 5.859 (p 0.254)
• Changes of Quality of Life in Scores on Sheehan Disability Scale (SDS) Total (Secondary), Mean, score on a scale: Levomilnacipran -3.79 +/- 6.477; Quetiapine -0.10 +/- 8.126 (p 0.058)
• Changes in Scores on Apathy Evaluation Scale (AES). (Secondary), Mean, score on a scale: Levomilnacipran -2.07 +/- 8.689; Quetiapine -1.83 +/- 7.852 (p 0.913)
• Changes in Sexual Dysfunction by Changes in Scores on Arizona Sexual Experience Scale (ASEX) (Secondary), Mean, score on a scale: Levomilnacipran -0.76 +/- 2.923; Quetiapine -0.30 +/- 4.829 (p 0.660)

Adverse events

Time frame: Screening to Week 9

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2017-07-18)

• Ashwin A Patkar, MD, Principal investigator, Duke Universtiy Medical Center