Incomplete Response in Late Life Depression: Getting to Remission (IRL GREY)
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Intervention: venlafaxine XR plus aripiprazole; venlafaxine plus placebo
Intervention description: Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.; Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.
Intervention MeSH terms: Aripiprazole; Venlafaxine Hydrochloride
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 468.0
Sex: All
Minimum age: 60 Years
Healthy volunteers: No
Keywords: Depression; Aripiprazole; Venlafaxine; Partial Remission; Augmentation strategy; Treatment resistance; Elderly; Late-life

Summary:

      The primary aims of this study are to:

        1. Assess the efficacy of aripiprazole augmentation for the acute and continuation
           treatment of TRLLD.

           Hypothesis 1: Patients with TRLLD (defined as those who do not remit after 12 weeks of
           acute treatment with venlafaxine XR) will have a higher rate of remission with
           aripiprazole than with placebo augmentation (primary outcome) and greater improvement in
           depressive symptoms and stability of remission (secondary outcomes).

        2. Assess the tolerability of aripiprazole in TRLLD with a focus on adiposity and
           akathisia/restlessness.

      Hypothesis 2: Aripiprazole will be associated with a higher rate of clinically significant
      akathisia and increased adiposity than placebo.

      The Secondary/exploratory aims of this study are to:

        1. Examine anxiety, medical burden, and executive impairment as moderators of aripiprazole
           augmentation efficacy in TRLLD.

           Hypothesis 3: Pre-levels of anxiety symptoms, medical burden, and executive impairment
           will be treatment-specific factors: they will moderate the efficacy of aripiprazole
           augmentation. The aripiprazole-placebo difference will be greater in individuals with
           these variables, compared to those without these variables because these three factors
           will be associated with a decreased likelihood that "staying the course" with
           venlafaxine monotherapy will achieve remission.

        2. Examine genetic predictors (phase 1) and moderators (phase 2-3) of treatment outcomes,
           while controlling for drug exposure.

      Hypothesis 4: Selected polymorphisms will reduce remission rate with venlafaxine and will
      reduce efficacy and tolerability with aripiprazole.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age > 60 years.

          2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the SCID-IV.

          3. MADRS ≥ 15.

        Exclusion Criteria:

          1. Inability to provide informed consent.

          2. Depressive symptoms not severe enough (i.e., MADRS < 15) at the baseline assessments.

          3. Dementia based upon DSM-IV criteria as well as a Folstein MMSE score of less than 24.
             Patients screened out due to dementia will be referred to a memory clinic or to the
             UPMC Alzheimer's Disease Research Center for evaluation to clarify the presence or
             absence of a dementia.

          4. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective
             disorder, schizophreniform disorder, delusional disorder, or current psychotic
             symptoms, as diagnosed by the SCID. A recommendation for psychiatric referral will be
             made in these cases.

          5. Abuse of or dependence on alcohol or other substances within the past 3 months as
             determined by SCID, and confirmed by study physician interview.

          6. High risk for suicide (e.g., active SI and/or current/recent intent or plan) AND
             unable to be managed safely in the clinical trial (e.g., unwilling to be
             hospitalized). Urgent psychiatric referral will be made in these cases.

          7. Contraindication to venlafaxine XR or aripiprazole as determined by study physician
             including history of intolerance of either venlafaxine XR or aripiprazole in the study
             target dosage range (venlafaxine XR at up to 225 mg/day; aripiprazole at up to
             15mg/day).

          8. Failure to respond to at least 6 weeks of venlafaxine (>225 mg/d) plus aripiprazole
             (>10 mg/d).

          9. Inability to communicate in English (i.e., interview cannot be conducted without an
             interpreter; subject largely unable to understand questions and cannot respond in
             English).

         10. Non-correctable clinically significant sensory impairment (i.e., cannot hear well
             enough to cooperate with interview)

         11. Unstable medical illness, including delirium, uncontrolled diabetes mellitus,
             hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that
             are not under medical management. This will be determined based on information from
             the patient's personal physician's and study physician clinical judgment. Referral to
             the patient's personal physician or to a general practitioner will be made in these
             cases.

         12. Subjects taking psychotropic medications that cannot be safely tapered or discontinued
             prior to study initiation: this would include patients on Monoamine Oxidase Inhibitors
             (MAOI) who would need to be off the MAOI for 14 days to be eligible for the study to
             avoid adverse drug interactions. Patients will not be allowed to take antidepressant
             or atypical antipsychotic medication other than the study medication, unless it is a
             low dose antidepressant prescribed for chronic pain that would not be medically
             advisable to stop (e.g., amitryptyline 50mg). If a patient's depression is adequately
             treated on his/her psychotropic medication, he/she would not be eligible for the
             study. If a patient failed a trial of venlafaxine (12 weeks of treatment with
             venlafaxine including at least 6 weeks on 300mg/day), he/she would not be eligible.
             The following are allowed: benzodiazepines up to 2mg/d lorazepam equivalent; other
             sedative-hypnotics (e.g., zolpidem, zaleplon, eszopiclone); gabapentin if prescribed
             for non-psychiatric indication (e.g., neuropathy). Except for MAOIs, there is really
             no clinical rationale to exclude patients on specific concomitant medications unless
             they are medically unstable (in which case they are excluded from participation). As
             noted, patients on an MAOI would need to be off the MAOI for 14 days to protect from
             adverse drug interactions.