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

Study Overview
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Brief Summary
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The primary aims of this study are to: 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). 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: 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. 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.

Detailed Description
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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.

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

Conditions
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Depression

Intervention / Treatment
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* Drug: venlafaxine XR plus aripiprazole
* Drug: venlafaxine plus placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 60 years. Major depressive disorder (MDD), single or recurrent, as diagnosed by the SCID-IV. MADRS ≥ 15. Exclusion Criteria: Inability to provide informed consent. Depressive symptoms not severe enough (i.e., MADRS < 15) at the baseline assessments. 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. 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. Abuse of or dependence on alcohol or other substances within the past 3 months as determined by SCID, and confirmed by study physician interview. 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. 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). Failure to respond to at least 6 weeks of venlafaxine (>225 mg/d) plus aripiprazole (>10 mg/d). 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). Non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview) 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. 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.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1: venlafaxine plus aripiprazole<br>antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo | Drug: venlafaxine XR plus aripiprazole<br>* Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.<br>* Other names: effexor XR, abilify;|
| Experimental: 2: Placebo Comparator<br>antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo | Drug: venlafaxine plus placebo<br>* Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Who Met Criteria for Remission Based on the Montgomery-Asberg Depression Rating Scale (MADRS) | The Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician rated ten item instrument assessing depression symptoms. Possible scores range from 0-60; higher scores indicate greater severity of depression. Remission defined as score of 10 or less based on the MADRS. | 12 weeks | 
| Akathisia | Percentage of participants who developed clinically significant akathisia. | 12 weeks | 
| Weight | Weight change in kilograms | Baseline through12 weeks | 
| Parkinsonism | Percentage of participants who develop signs of parkinsonism | 12weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emergent Suicidal Ideation in Those With no Ideation at the Start of Treatment | percentage of participants who reported suicidal ideation during treatment but not at baseline | 12 weeks | 
| QTc Prolongation on EKG (to Greater or Equal to 480 Msec) | percentage of participants | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Aripiprazole, Venlafaxine, Partial Remission, Augmentation strategy, Treatment resistance, Elderly, Late-life