Incomplete Response in Late Life Depression: Getting to Remission (IRL GREY)

Official Title: “Incomplete Response in Late Life Depression: Getting to Remission”

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.

Incomplete response in the treatment of late-life depression (LLD) is a large public health challenge: at least 50% of older people fail to respond adequately to antidepressant pharmacotherapy, even under optimal treatment conditions. Treatment resistant late-life depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater burden on family caregivers, and increases the risk for early mortality, including suicide.

Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of controlled studies of how best to manage TRLLD.

This is a multi-site study being conducted by 3 sites: University of Pittsburgh, University of Toronto, and Washington University. We propose to enroll 500 subjects aged 60 and older with major depressive disorder at this site and treat them openly for 12 weeks with venlafaxine XR (up to 300mg/d) (phase 1). Participants meeting criteria for incomplete response will be randomly assigned to receive either aripiprazole (2-15 mg/d; target dose:

10 mg/d) or placebo augmentation (adding a pill without active medicine) of venlafaxine for 12 weeks (phase 2), with the goal of achieving remission (MADRS≤10 for two consecutive assessments). Those who remit in phase 2 will receive continuation treatment, with the same double-blinded intervention to which they were randomly assigned (phase 3), for 12 weeks to determine the stability of remission. Efficacy and tolerability data will provide a clinically informative estimate of benefits and risks of aripiprazole augmentation for TRLLD.

In addition to the primary goal of assessing these benefits and risks, we will develop evidence relevant to personalized treatment for LLD by testing the roles of clinical (comorbid anxiety, medical burden, and executive impairment) and genetic (selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while controlling for variability in drug exposure for efficacy and tolerability analyses. This approach will allow us to distinguish treatment-specific resistance factors versus general prognostic factors.

Intervention(s) in this Clinical Trial

• Drug: venlafaxine XR plus aripiprazole
  • Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.
• Drug: venlafaxine plus placebo
  • Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1: venlafaxine plus aripiprazole
  • antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo
• Experimental: 2: Placebo Comparator
  • antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo

Primary Measures

• Montgomery-Asberg Depression Rating Scale (MADRS)
  • Time Frame: 36 weeks
    Safety Issue?: No
• Neuropsychological battery (RBANS, 4 executive tasks) to assess cognitive performance
  • Time Frame: once
    Safety Issue?: No
• Penn State Worry Questionnaire, Brief Symptom Inventory-Anxiety, Anxiety Sensitivity Index
  • Time Frame: 36 weeks
    Safety Issue?: No
• Hamilton Depression Rating Scale-measure of depressive symptoms
  • Time Frame: 36 weeks
    Safety Issue?: No

Secondary Measures

• Barnes Akathisia, AIMs, Simpson Angus scales will be used to measure tolerability of medication
  • Time Frame: 36 weeks
    Safety Issue?: Yes
• Suicide Ideation Scale
  • Time Frame: 36 weeks
    Safety Issue?: Yes
• MOS 36-Item Short Form Survey Instrument (SF-36), Late Life Function and Disability Index to measure disability and health related quality of life
  • Time Frame: 36 weeks
    Safety Issue?: No
• DEXA Scan
  • Time Frame: 36 weeks
    Safety Issue?: Yes
• lipid profile, glucose level
  • Time Frame: 36 weeks
    Safety Issue?: Yes

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 60 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: University of Pittsburgh Other

Overall Clinical Trial Officials and Contacts

Charles F. Reynolds, MD Principal Investigator University of Pittsburgh  

Overall Contact: Jacqueline Stack, M.S.N. 412-246-6006 stackja@upmc.edu

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00892047

Study ID Number: MH083660-01A1

ClinicalTrials.gov Identifier: NCT00892047

Health Authority: United States: Institutional Review Board

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