Major Depressive Disorder
Conditions
Brief summary
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.
Detailed description
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
Interventions
DRUGLevomilnacipran
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
DRUGQuetiapine
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.
Sponsors
Forest Laboratories
Institute for Advanced Medical Research, Alpharetta, GA
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Potential participants were identified by self-referral via the printed ad, phone script, the patients' physicians, local health providers, mental health providers, or Duke providers. Others were recommended by PI or Study Coordinator. They assessed and screened at 2 sites, an university hospital and a clinic of the research institute.
Pre-assignment details
One subject was lost to follow up after screening.
Participants by arm
| Arm | Count |
|---|---|
| Levomilnacipran Levomilnacipran ER is switched from SSRI. Levomilnacipran ER: 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. | 29 |
| Quetiapine Quetiapine XR was added in addition to current SSRI. Quetiapine XR: Quetiapine XR was 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 SSRI. | 31 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Quetiapine | Total | Levomilnacipran |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 58 Participants | 28 Participants |
| Age, Continuous | 46.13 years STANDARD_DEVIATION 11.17 | 45.75 years STANDARD_DEVIATION 12.67 | 45.34 years STANDARD_DEVIATION 14.28 |
| Baseline Dose of SSRI mg(Citalopram) | 28.00 dose of medication, mg STANDARD_DEVIATION 10.954 | 23.85 dose of medication, mg STANDARD_DEVIATION 9.608 | 21.25 dose of medication, mg STANDARD_DEVIATION 8.345 |
| Baseline Dose of SSRI mg(Escitalopram) | 16.67 dose of medication, mg STANDARD_DEVIATION 5.774 | 18.33 dose of medication, mg STANDARD_DEVIATION 3.892 | 18.89 dose of medication, mg STANDARD_DEVIATION 3.333 |
| Baseline Dose of SSRI mg(Fluoxetine) | 42.00 dose of medication, mg STANDARD_DEVIATION 6.325 | 44.62 dose of medication, mg STANDARD_DEVIATION 11.983 | 53.33 dose of medication, mg STANDARD_DEVIATION 23.094 |
| Baseline Dose of SSRI mg(Paroxetine) | 51.43 dose of medication, mg STANDARD_DEVIATION 15.736 | 48.00 dose of medication, mg STANDARD_DEVIATION 13.984 | 40.00 dose of medication, mg STANDARD_DEVIATION 0 |
| Baseline Dose of SSRI mg(Sertraline) | 150.00 dose of medication, mg STANDARD_DEVIATION 31.623 | 159.09 dose of medication, mg STANDARD_DEVIATION 30.151 | 170.00 dose of medication, mg STANDARD_DEVIATION 27.386 |
| Baseline SSRI Citalopram | 5 Participants | 13 Participants | 8 Participants |
| Baseline SSRI Escitalopram | 3 Participants | 12 Participants | 9 Participants |
| Baseline SSRI Fluoxetine | 10 Participants | 13 Participants | 3 Participants |
| Baseline SSRI Paroxetine | 7 Participants | 10 Participants | 3 Participants |
| Baseline SSRI Sertraline | 6 Participants | 11 Participants | 5 Participants |
| Baseline SSRI Unknown | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 59 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants | 45 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 13 Participants | 9 Participants |
| Region of Enrollment United States | 31 participants | 60 participants | 29 participants |
| Sex: Female, Male Female | 20 Participants | 40 Participants | 20 Participants |
| Sex: Female, Male Male | 11 Participants | 20 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 31 |
| other Total, other adverse events | 16 / 29 | 22 / 31 |
| serious Total, serious adverse events | 0 / 29 | 0 / 31 |
Outcome results
Primary
Changes of Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score
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.
Time frame: Baseline to Week 8
Population: Data not available on some participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levomilnacipran | Changes of Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -5.81 score on a scale | Standard Deviation 6.08 |
| Quetiapine | Changes of Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score | -6.97 score on a scale | Standard Deviation 7.632 |
p-value: 0.5395% CI: [-2.518, 4.836]t-test, 2 sided
Secondary
Changes in Neurocognition by Changes in Scores on Reyes Verbal Learning Test
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.
Time frame: Baseline to Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levomilnacipran | Changes in Neurocognition by Changes in Scores on Reyes Verbal Learning Test | 2.28 score on a scale | Standard Deviation 5.694 |
| Quetiapine | Changes in Neurocognition by Changes in Scores on Reyes Verbal Learning Test | 2.90 score on a scale | Standard Deviation 5.255 |
p-value: 0.66495% CI: [-3.484, 2.236]t-test, 2 sided
Secondary
Changes in Neurocognition by Changes in Scores on Scores on Digit Symbol Substitution Test (DSST)
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.
Time frame: Baseline to Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levomilnacipran | Changes in Neurocognition by Changes in Scores on Scores on Digit Symbol Substitution Test (DSST) | 3.21 score on a scale | Standard Deviation 9.321 |
| Quetiapine | Changes in Neurocognition by Changes in Scores on Scores on Digit Symbol Substitution Test (DSST) | 0.87 score on a scale | Standard Deviation 7.431 |
p-value: 0.29295% CI: [-2.07, 6.75]t-test, 2 sided
Secondary
Changes in Scores on Apathy Evaluation Scale (AES).
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.
Time frame: Baseline to Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levomilnacipran | Changes in Scores on Apathy Evaluation Scale (AES). | -2.07 score on a scale | Standard Deviation 8.689 |
| Quetiapine | Changes in Scores on Apathy Evaluation Scale (AES). | -1.83 score on a scale | Standard Deviation 7.852 |
p-value: 0.91395% CI: [-4.559, 4.088]t-test, 2 sided
Secondary
Changes in Sexual Dysfunction by Changes in Scores on Arizona Sexual Experience Scale (ASEX)
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.
Time frame: Baseline to Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levomilnacipran | Changes in Sexual Dysfunction by Changes in Scores on Arizona Sexual Experience Scale (ASEX) | -0.76 score on a scale | Standard Deviation 2.923 |
| Quetiapine | Changes in Sexual Dysfunction by Changes in Scores on Arizona Sexual Experience Scale (ASEX) | -0.30 score on a scale | Standard Deviation 4.829 |
p-value: 0.6695% CI: [-2.54, 1.623]t-test, 2 sided
Secondary
Changes of Anxiety Symptoms in Scores on Hamilton Anxiety Rating Scale (HAM-A)
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.
Time frame: Baseline to Week 8
Population: Data not available for all subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levomilnacipran | Changes of Anxiety Symptoms in Scores on Hamilton Anxiety Rating Scale (HAM-A) | -3.89 score on a scale | Standard Deviation 4.969 |
| Quetiapine | Changes of Anxiety Symptoms in Scores on Hamilton Anxiety Rating Scale (HAM-A) | -5.53 score on a scale | Standard Deviation 5.859 |
p-value: 0.25495% CI: [-1.211, 4.492]t-test, 2 sided
Secondary
Changes of Quality of Life in Scores on Sheehan Disability Scale (SDS) Total
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.
Time frame: Baseline to Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levomilnacipran | Changes of Quality of Life in Scores on Sheehan Disability Scale (SDS) Total | -3.79 score on a scale | Standard Deviation 6.477 |
| Quetiapine | Changes of Quality of Life in Scores on Sheehan Disability Scale (SDS) Total | -0.10 score on a scale | Standard Deviation 8.126 |
p-value: 0.05895% CI: [-7.52, 0.134]t-test, 2 sided
Secondary
Number of Subjects With General Improvement in Scores on Clinical Global Impression Scale- Improvement (CGI-I)
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.
Time frame: Baseline to Week 8
Population: Data not available for some participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levomilnacipran | Number of Subjects With General Improvement in Scores on Clinical Global Impression Scale- Improvement (CGI-I) | 21 Participants |
| Quetiapine | Number of Subjects With General Improvement in Scores on Clinical Global Impression Scale- Improvement (CGI-I) | 24 Participants |
p-value: 0.90595% CI: [0.245, 3.129]Mantel Haenszel
Secondary
Number of Subjects With Global Improvement in Scores on Clinical Global Impression Scale- Severity (CGI-S)
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.
Time frame: Baseline to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levomilnacipran | Number of Subjects With Global Improvement in Scores on Clinical Global Impression Scale- Severity (CGI-S) | 13 Participants |
| Quetiapine | Number of Subjects With Global Improvement in Scores on Clinical Global Impression Scale- Severity (CGI-S) | 13 Participants |
p-value: 0.88495% CI: [0.38, 2.971]Mantel Haenszel
Secondary
Remission Rate
Remission was defined as \[\>or=50% reduction in MADRS score with MADRS \<or=10\]
Time frame: Week 8
Population: Data not available on some participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levomilnacipran | Remission Rate | 2 Participants |
| Quetiapine | Remission Rate | 3 Participants |
p-value: 0.27295% CI: [0.109, 1.866]Mantel Haenszel
Secondary
Response Rate
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.
Time frame: Week 8
Population: Data not available on some participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levomilnacipran | Response Rate | 3 Participants |
| Quetiapine | Response Rate | 7 Participants |
p-value: 0.42895% CI: [0.101, 2.388]Mantel Haenszel