Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy (ADT) Among Outpatients With Major Depressive Disorder Who Have Responded Inadequately to Prior ADT
Brief Summary: The purpose of this study is to determine whether a reduced dose of aripiprazole is effective in treating patients with major depressive disorder


Options:
A: Inclusion Criteria:

1. Age 18-65 years inclusive
2. DSM-IV Diagnosis of major depressive disorder
3. If female, nonpregnant/nonlactating
4. If a sexually active female of reproductive potential, must be using adequate contraception (i.e., oral contraceptives, barrier protection, or prior tubal ligation)
5. Inadequate response to antidepressants: having a score of ≥14 on the 17-item HAMD or a CGI-S score of ≥ 3 after a retrospective confirmation of an adequate trial of a single antidepressant (defined as an 6-week trial of acceptable therapeutic dose \[40 mg of fluoxetine, paroxetine 30 mg of citalopram, 20 mg of escitalopram, 37.5 mg of paroxetine CR, 150 mg of sertraline, 100 mg of fluvoxamine, 225 mg of venlafaxine XR)
6. Lack of tolerability of antidepressants: Patient reports of side effects that are judged to be clinically meaningful by the investigator
7. HAMD item 2 score ≥ 2 at screening
8. Duration of current MDD ≥ 4 weeks and \< 24 months

Exclusion Criteria:

1. Any Axis I disorder within previous six months of screening except Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder and Simple Phobias
2. MDD with postpartum onset, psychotic features or seasonal features
3. DSM-IV substance abuse or dependence in the previous 6 months
4. Medically unstable as judged by study investigators on clinical and/or laboratory findings
5. Lack of capacity to provide informed, written, consent to investigators
6. Previous intolerance to vilazodone or current use of vilazodone at screening or within 3 months of study entry
7. Significant suicide risk as judged by the investigator based on information collected on the Columbia Suicide Severity Rating Scale (CSSRS)
8. History of augmentation with atypical antipsychotics, lithium, T3 or another antidepressant within 3 months of screening
9. Failure of ≥ 3 adequate trials of different antidepressants for the current episode of MDD
10. Concomitant medications: All medications for pre existing medical conditions will be permitted to continue unchanged provided subjects are on a stable dose of at least 12 weeks. Subjects on concomitant mood stabilizers or atypical antipsychotics will require a 2-week washout prior to screening visit. Subjects on a minimum of 3 month of stable dose of hypnotics (e.g. zolpidem 10 mg per day or benzodiazepine dose of ≤ 2 mg per day of lorazepam or trazodone ≤ 100 mg per day or quetiapine ≤ 100 mg per day) will be allowed to continue their hypnotic medication at the same dose. Quetiapine at doses ≤ 100 mg per day is appropriate only for hypnotic effects. Over the counter medications will be permitted if in the opinion of the investigator, they are not considered to have any significant impact on the study. Any medication that has the potential to cause a clinical significant drug interaction with vilazodone in the judgment of the investigator will require a washout.
B: Inclusion Criteria

1. Male or female participants of at least 18 years of age who meet criteria for Major Depressive Disorder (MDD), single or recurrent episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV®-TR) disease diagnostic criteria.
2. Participants (receiving or not antidepressant treatment) who, based on investigator criteria, initiate treatment with escitalopram or change their current Alzheimer's Disease (AD) treatment to escitalopram for this current MDD episode, at the initial visit.
3. Must have a baseline score of ≥ 19 on the 17-item Hamilton Depression Rating Scale (HAMD-17) at the initial visit.
4. Must have a baseline score of ≥ 4 in the Clinical Global Impression-Severity Scale (CGI-S) at the initial visit.
5. Have a level of understanding sufficient to provide Informed Consent Document (ICD), and to communicate with the investigators and site personnel.
6. Are judged to be reliable and agree to keep all appointments for clinic visits and procedures required by the protocol.

   Exclusion Criteria:
7. Have any current primary Axis I disorder other than MDD, including but not limited to dysthymia.
8. Have a diagnosis of dementia, Alzheimer's disease (AD), or organic brain syndrome; or who are cognitively impaired or who have language problems that prevent them from understanding and/or providing valid answers to the rating scale contents.
9. Concomitant participation in other studies with investigational or marketed products.
10. Are not expected to be able to be monitored throughout the entire study period for reasons unrelated to their illness (for instance, change of residence or healthcare center of reference).
11. Are demonstrating a response or demonstrated a response to the AD treatment for the current depression episode previous to baseline visit.
12. Are investigator site personnel directly affiliated with this study and/or their immediate families. "Immediate family" is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
13. Are employed by Lilly or Boehringer Ingelheim (BI) (that is, employees, temporary contract workers, or designees responsible for the conduct of the study). Immediate family of Lilly or BI employees may participate in Lilly or BI-sponsored clinical trials, but are not permitted to participate at a Lilly or BI facility. "Immediate family" is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
14. Women of childbearing potential who are not using a medically accepted means of contraception (for example, intrauterine device, oral contraceptive, contraceptive patch, implant, Depo-Provera \[medroxyprogesterone acetate injectable suspension, Pharmacia \& Upjohn\], or barrier devices) when engaging in sexual intercourse. Women who are pregnant or breast-feeding may not participate in the study.
15. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
16. Are judged to be at serious suicidal risk in the opinion of the investigator, and/or if the participant's baseline (Visit 1) HAMD-17 scores on item 3 suicide are 3.
17. Have been treated with a monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 1 or potential need to use an MAOI during the study or within 5 days after discontinuation of study drug.
18. Require initiation or discontinuation of psychotherapy within 6 weeks prior to enrollment (Visit 1) or at any time during the study.
19. Have any contraindication for the use of duloxetine based on Duloxetine Summary of Product Characteristics (SPC) or any contraindication for the use of escitalopram based on Escitalopram SPC.
20. Have a history of lack of response to duloxetine or escitalopram at a clinically appropriate dose for a minimum of 4 weeks, or have previously completed or withdrawn from this study or any other study investigating duloxetine or escitalopram.
21. Have any previous diagnosis of bipolar disorder, schizophrenia, or other psychotic disorders.
22. Have DSM-IV-defined history of substance abuse or dependence within the past year, excluding nicotine and caffeine.
23. Have serious or unstable cardiovascular, hepatic, renal, respiratory or hematological illness; symptomatic peripheral vascular disease; or other medical (including unstable hypertension and not clinically euthyroid) or psychological conditions that, in the opinion of the investigator, would compromise participation or be likely to require hospitalization during the course of the study.
24. Have had Electroconvulsive Therapy (ECT) or Transcranial Magnetic Stimulation within the past year.
C: Inclusion Criteria:

1. Patients able to give informed consent, and/or consent obtained from a legally acceptable representative (as required by IRB/IEC), prior to the initiation of any protocol required procedures.
2. Patients must be able to understand the nature of the study, agree to comply with the prescribed dosage regimens, report for regularly scheduled office visits, and communicate to study personnel about adverse events and concomitant medication use.
3. Patients with a diagnosis of major depressive episode as defined by DSM-IV-TR criteria, based on the SCID-I/P; their major depressive episode must be deemed "valid" using the SAFER criteria interview administered by remote, independent raters.
4. Patients who have reported a history for the current depressive episode of an inadequate response to at least one and no more than three adequate antidepressant treatments. An inadequate response is defined as less than a 50% reduction in depressive symptom severity, as assessed by the MGH ATRQ administered by remote, independent raters. An adequate trial is defined as an antidepressant treatment for at least 6 weeks duration at least at a minimum dose as specified in the MGH ATRQ.
5. Patients must have a HAM-D17 ≥ 18 at the end of the screening phase to qualify for inclusion. The HAM-D17 will be administered by the study clinicians at the screening and baseline visits, and by remote, independent raters during the screening phase at the time of the SAFER interview.
6. Patients must be able to be reliably rated on the psychiatric scales required by the protocol.
7. Men and women, ages 18 to 65 Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.

   WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ³ 12 consecutive months; or women on hormone replacement therapy \[HRT\] with documented serum follicle stimulating hormone \[FSH\] level \> 35 mIU/mL). Even women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.

   WOCBP must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
8. Meet DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for MDD, current;
9. Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR) (22) score of at least 16 at both screen and baseline visits;
10. Treated with an SSRI at adequate doses (defined as 20mg/day or more of fluoxetine, citalopram; paroxetine 30mg/day or more or 37.5 mg/day or more of paroxetine CR; 10 mg/day or more of escitalopram, 50mg/day or more of sertraline, and 150 mg/day or more of venlafaxine) during the current episode for at least 8 weeks, with the same, adequate dose over the last 4 weeks;
11. Between the screen and baseline visit, patients must be documented prospectively to have received a stable dose of their SSRI or venlafaxine for at least 2 weeks.

Additional criteria for defining response and non-response for patients in Phase 2 eligible for the pooling of the data with all the patients in Phase 1. Among patients pre-randomized to receive placebo in both phases or to receive placebo in Phase 1 and aripiprazole in phase 2, only those meeting non-response criteria will be added to the primary efficacy sample:

* Placebo non-responders are defined as those patients who failed to achieve a 50% decrease in their MADRS score at visit 3,
* Have a MADRS score of \> 16 at visit 3

Exclusion Criteria:

1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period \[and for up to 4 weeks after the last dose of investigational product\].
2. WOCBP using a prohibited contraceptive method.
3. Women who are pregnant or breastfeeding.
4. Women with a positive pregnancy test on enrollment or prior to investigational product administration.
5. Sexually active fertile men not using effective birth control if their partners are WOCBP.
6. Patients who report an inadequate response (less than 50% decrease in depressive symptom severity) to more than two adequate trials of antidepressant treatments during the current depressive episode (including monotherapy treatment and distinct combination regimens) at a therapeutic dose (as defined by the ATRQ) and for an adequate duration (minimum six weeks for any monotherapy).
7. Patients who report treatment with adjunctive antipsychotic medication with an antidepressant for a minimum of two weeks during the current depressive episode.
8. Patients with a current need for involuntary commitment or who have been hospitalized within four weeks of the Screening Visit for the current major depressive episode.
9. Patients who have received ECT during the current episode.
10. Patients who have a current Axis I diagnosis of:

    1. Delirium, dementia, amnestic, or other cognitive disorder;
    2. Schizophrenia or other psychotic disorder, based on the SCID-I/P;
    3. Bipolar I or II disorder, based on the SCID-I/P;
11. Patients with a clinically significant Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder.
12. Patients experiencing hallucinations, delusions, or any psychotic symptomatology in the current depressive episode.
13. Patients who have met DSM-IV-TR criteria for any significant substance use disorder within the past six months, based on the SCID-I/P.
14. Patients receiving new onset psychotherapy within 6 weeks of screening, or at any time during participation in the trial.
15. Patients who have been previously randomized in an aripiprazole clinical trial (lifetime).
16. Patients who have participated in any clinical trial with an investigational drug or device within the past month.
17. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease;
18. Patients who, in the investigator's judgment represent a significant risk of committing suicide during the course of the trial based on history or evaluation of current mental status
19. Patients who have a history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial
20. Patients with thyroid pathology (unless condition has been stabilized with medications for at least the past three months)
21. Patients with a lifetime history of neuroleptic malignant syndrome or serotonin syndrome
22. Patients with a significant history of a seizure disorder
23. Patients with detectable levels of cocaine, heroin or opioids in the urine drug screen
24. Diastolic blood pressure \> 105 mmHg
25. Any signs or symptoms that in the investigator's judgment are medically significant, in that it would impact the patients safety.

    1. Patients who are known to be allergic or hypersensitive to aripiprazole or other dihydrocarbostyrils (e.g. carteolol, vesnarinone, and cilostazol)
    2. Patients previously treated with and not responding to aripiprazole
    3. Monoamine oxidase inhibitors (e.g., Nardil, phenelzine, Parnate, tranylcypromine, Marplan, isocarboxazid) treatment within the two weeks prior to enrollment
    4. Patients who would likely require prohibited concomitant medication during the trial
    5. Prisoners or subjects who are involuntarily incarcerated
    6. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    7. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit;
    8. Patients who demonstrate a greater than 25% decrease in depressive symptoms as reflected by the QIDS-SR or HAM-D17 total score from screen visit to baseline visit;
    9. Patients with a history of antidepressant-induced hypomania.
D: Inclusion Criteria:

* Documented clinical diagnosis as confirmed by the M.I.N.I. meeting criteria from the Diagnostic and Statistical Manual of Mental disorders, 4th Edition (DSM-IV) for any of the following:296.2x MDD, Single Episode296.3x MDD, Recurrent Episode
* Current episode of depression present, at least 42 days prior to enrolment but not more than 18 months
* MADRS-Score ≥ 25 at enrolment and randomisation

Exclusion Criteria:

* Patients with a DSM-IV Axis I disorder other than MDD within 6 months of randomisation
* Patients with a diagnosis of DSM-IV Axis II disorder which has a major impact on the patient's current psychiatric status
* Patients who, in the investigator's judgment pose a current serious suicidal or homicidal risk, or have made a suicide attempt within the past 6 months

Answer: C