A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Intervention: Aripiprazole 5mg; Aripiprazole 2mg; Placebo
Intervention description: Tablet dose of aripiprazole will be 2 mg/day during the first phase (30 days) of the study, and 5 mg/day in the second phase (30 days); For patients randomly assigned to the placebo/drug sequence, the dose of aripiprazole will be 2 mg/day during the second phase of the study (30 days); for patients randomly assigned to the placebo/placebo sequence, study medication will be placebo during both phases of the study (60 days)
Intervention MeSH terms: Aripiprazole
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 225.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Depression

Summary:

      The purpose of this study is to determine whether a reduced dose of aripiprazole is effective
      in treating patients with major depressive disorder
    

Eligibility criteria:

        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.