DepressionPhase 4IRL GREYNCT00892047
Incomplete Response in Late Life Depression: Getting to Remission (IRL GREY)
A Phase 4 study testing venlafaxine XR plus aripiprazole in people with Depression, run by University of Pittsburgh at 3 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 60 years and older
- Conditions the study is for
- Depression
- What is being tested?
- venlafaxine XR plus aripiprazole
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 468 participants
- Where
- 3 sitesin 2 countries
- Study dates
- Aug 2009to Sep 2014
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age > 60 years.
- Major depressive disorder (MDD), single or recurrent, as diagnosed by the SCID-IV.
- MADRS ≥ 15.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
United States2 sites
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
Washington University School of Medicine, St. Louis
St Louis, Missouri, 63110
About this study
Official title: Incomplete Response in Late Life Depression: Getting to Remission
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.
Read more
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.
Read the detailed description
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.
- Conditions
- Depression
- Being tested
- venlafaxine XR plus aripiprazole, venlafaxine plus placebo
- Keywords
- Depression, Aripiprazole, Venlafaxine, Partial Remission, Augmentation strategy, Treatment resistance, Elderly, Late-life
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
venlafaxine XR plus aripiprazoleDrug
Also called effexor XR, abilify
Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.
venlafaxine plus placeboDrug
Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.
| Study group | Role | What they receive |
|---|---|---|
| 1: venlafaxine plus aripiprazole | Experimental | antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo Receives: Drug: venlafaxine XR plus aripiprazole |
| 2: Placebo Comparator | Experimental | antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo Receives: Drug: venlafaxine plus placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 weeks
Akathisia
Percentage of participants who developed clinically significant akathisia.
Measured: 12 weeks
Weight
Weight change in kilograms
Measured: Baseline through12 weeks
Parkinsonism
Percentage of participants who develop signs of parkinsonism
Measured: 12weeks
Secondary outcomes (2)
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
Measured: 12 weeks
QTc Prolongation on EKG (to Greater or Equal to 480 Msec)
percentage of participants
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 May 2009 (estimated)
- Study startAug 2009
- Primary completionSep 2014
- Study completionSep 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by University of PittsburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 468 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Charles Reynolds, University of Pittsburgh
- Investigators
- Charles F. Reynolds, MD, Principal investigator, University of PittsburghEric Lenze, MD, Principal investigator, Washington University School of Medicine, St. LouisBenoit Mulsant, MD, Principal investigator, University of Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00892047
- Sponsor's protocol ID
- MH083660-01A1
- Acronym
- IRL GREY
- Status last verified
- Dec 2015
- First submitted
- 29 Apr 2009
- Last updated
- 17 Dec 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Lenze EJ, Mulsant BH, Blumberger DM, Karp JF, Newcomer JW, Anderson SJ, Dew MA, Butters MA, Stack JA, Begley AE, Reynolds CF 3rd. Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Dec 12;386(10011):2404-12. doi: 10.1016/S0140-6736(15)00308-6. Epub 2015 Sep 27.
PubMed 26423182Olgiati P, Ferri R, Luca A, Luca M, Serretti A. Anxiety sensitivity in late-life depression. Links to cognitive impairment, insomnia, and health-related quality of life. J Psychiatr Res. 2026 Feb;193:414-423. doi: 10.1016/j.jpsychires.2025.12.012. Epub 2025 Dec 5.
PubMed 41380347Olgiati P, Fanelli G, Serretti A. Age or age of onset: which is the best criterion to classify late-life depression? Int Clin Psychopharmacol. 2023 Jul 1;38(4):223-230. doi: 10.1097/YIC.0000000000000472. Epub 2023 Mar 21.
PubMed 36961017Ainsworth NJ, Brender R, Gotlieb N, Zhao H, Blumberger DM, Karp JF, Lenze EJ, Nicol GE, Reynolds CF, Wang W, Mulsant BH. Association between lean muscle mass and treatment-resistant late-life depression in the IRL-GRey randomized controlled trial. Int Psychogeriatr. 2023 Dec;35(12):707-716. doi: 10.1017/S1041610222000862. Epub 2023 Jan 3.
PubMed 36594430Diniz BS, Mulsant BH, Reynolds CF 3rd, Blumberger DM, Karp JF, Butters MA, Mendes-Silva AP, Vieira EL, Tseng G, Lenze EJ. Association of Molecular Senescence Markers in Late-Life Depression With Clinical Characteristics and Treatment Outcome. JAMA Netw Open. 2022 Jun 1;5(6):e2219678. doi: 10.1001/jamanetworkopen.2022.19678.
PubMed 35771573Altmann H, Stahl ST, Gebara MA, Lenze EJ, Mulsant BH, Blumberger DM, Reynolds CF 3rd, Karp JF. Coprescribed Benzodiazepines in Older Adults Receiving Antidepressants for Anxiety and Depressive Disorders: Association With Treatment Outcomes. J Clin Psychiatry. 2020 Sep 29;81(6):20m13283. doi: 10.4088/JCP.20m13283.
PubMed 32991792Buchalter ELF, Oughli HA, Lenze EJ, Dixon D, Miller JP, Blumberger DM, Karp JF, Reynolds CF 3rd, Mulsant BH. Predicting Remission in Late-Life Major Depression: A Clinical Algorithm Based Upon Past Treatment History. J Clin Psychiatry. 2019 Dec 10;80(6):18m12483. doi: 10.4088/JCP.18m12483.
PubMed 31846575Wei W, Karim HT, Lin C, Mizuno A, Andreescu C, Karp JF, Reynolds CF 3rd, Aizenstein HJ. Trajectories in Cerebral Blood Flow Following Antidepressant Treatment in Late-Life Depression: Support for the Vascular Depression Hypothesis. J Clin Psychiatry. 2018 Oct 23;79(6):18m12106. doi: 10.4088/JCP.18m12106.
PubMed 30358242Hsu JH, Mulsant BH, Lenze EJ, Sanches M, Karp JF, Reynolds CF, Blumberger DM. Clinical Predictors of Extrapyramidal Symptoms Associated With Aripiprazole Augmentation for the Treatment of Late-Life Depression in a Randomized Controlled Trial. J Clin Psychiatry. 2018 Jun 19;79(4):17m11764. doi: 10.4088/JCP.17m11764.
PubMed 29924506Cristancho P, Lenze EJ, Dixon D, Miller JP, Mulsant BH, Reynolds CF 3rd, Butters MA. Executive Function Predicts Antidepressant Treatment Noncompletion in Late-Life Depression. J Clin Psychiatry. 2018 May/Jun;79(3):16m11371. doi: 10.4088/JCP.16m11371.
PubMed 29659205Marshe VS, Maciukiewicz M, Rej S, Tiwari AK, Sibille E, Blumberger DM, Karp JF, Lenze EJ, Reynolds CF 3rd, Kennedy JL, Mulsant BH, Muller DJ. Norepinephrine Transporter Gene Variants and Remission From Depression With Venlafaxine Treatment in Older Adults. Am J Psychiatry. 2017 May 1;174(5):468-475. doi: 10.1176/appi.ajp.2016.16050617. Epub 2017 Jan 10.
PubMed 28068779Smagula SF, Karim HT, Lenze EJ, Butters MA, Wu GF, Mulsant BH, Reynolds CF, Aizenstein HJ. Gray matter regions statistically mediating the cross-sectional association of eotaxin and set-shifting among older adults with major depressive disorder. Int J Geriatr Psychiatry. 2017 Dec;32(12):1226-1232. doi: 10.1002/gps.4585. Epub 2016 Sep 19.
PubMed 27645461Smagula SF, Lotrich FE, Aizenstein HJ, Diniz BS, Krystek J, Wu GF, Mulsant BH, Butters MA, Reynolds CF 3rd, Lenze EJ. Immunological biomarkers associated with brain structure and executive function in late-life depression: exploratory pilot study. Int J Geriatr Psychiatry. 2017 Jun;32(6):692-699. doi: 10.1002/gps.4512. Epub 2016 Jun 10.
PubMed 27282141Kaneriya SH, Robbins-Welty GA, Smagula SF, Karp JF, Butters MA, Lenze EJ, Mulsant BH, Blumberger D, Anderson SJ, Dew MA, Lotrich F, Aizenstein HJ, Diniz BS, Reynolds CF 3rd. Predictors and Moderators of Remission With Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression: An Analysis of the IRL-GRey Randomized Clinical Trial. JAMA Psychiatry. 2016 Apr;73(4):329-36. doi: 10.1001/jamapsychiatry.2015.3447.
PubMed 26963689Kasckow J, Youk A, Anderson SJ, Dew MA, Butters MA, Marron MM, Begley AE, Szanto K, Dombrovski AY, Mulsant BH, Lenze EJ, Reynolds CF 3rd. Trajectories of suicidal ideation in depressed older adults undergoing antidepressant treatment. J Psychiatr Res. 2016 Feb;73:96-101. doi: 10.1016/j.jpsychires.2015.11.004. Epub 2015 Nov 19.
PubMed 26708830
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Incomplete Response in Late Life Depression: Getting to Remission
- ClinicalTrials.gov ID
- NCT00892047
- Acronym / sponsor ID
- IRL GREY / MH083660-01A1
- Conditions
- Depression
- Keywords
- Depression, Aripiprazole, Venlafaxine, Partial Remission, Augmentation strategy, Treatment resistance, Elderly, Late-life
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 468 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Study start
- Aug 2009
- Primary completion
- Sep 2014 (actual)
- Study completion
- Sep 2014 (actual)
- First posted
- 4 May 2009 (estimated)
- Results
- Posted 17 Dec 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1: venlafaxine plus aripiprazole | Experimental | Drug: venlafaxine XR plus aripiprazoleantidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo |
| 2: Placebo Comparator | Experimental | Drug: venlafaxine plus placeboantidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Age > 60 years.
- Major depressive disorder (MDD), single or recurrent, as diagnosed by the SCID-IV.
- MADRS ≥ 15.
Key exclusion criteria (12 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| venlafaxine XR plus aripiprazoleAlso: effexor XR, abilifyDosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks. | Drug | 1: venlafaxine plus aripiprazole |
| venlafaxine plus placeboDosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks. | Drug | 2: Placebo Comparator |
Primary outcome
Percentage of Subjects Who Met Criteria for Remission Based on the Montgomery-Asberg Depression Rating Scale (MADRS)
Time frame: 12 weeks
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.
Akathisia
Time frame: 12 weeks
Percentage of participants who developed clinically significant akathisia.
Weight
Time frame: Baseline through12 weeks
Weight change in kilograms
Parkinsonism
Time frame: 12weeks
Percentage of participants who develop signs of parkinsonism
2 secondary outcomes
Emergent Suicidal Ideation in Those With no Ideation at the Start of Treatment
Time frame: 12 weeks
QTc Prolongation on EKG (to Greater or Equal to 480 Msec)
Time frame: 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 26423182Lenze EJ, Mulsant BH, Blumberger DM, Karp JF, Newcomer JW, Anderson SJ, Dew MA, Butters MA, Stack JA, Begley AE, Reynolds CF 3rd. Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Dec 12;386(10011):2404-12. doi: 10.1016/S0140-6736(15)00308-6. Epub 2015 Sep 27.
- Derived from this study: PubMed 41380347Olgiati P, Ferri R, Luca A, Luca M, Serretti A. Anxiety sensitivity in late-life depression. Links to cognitive impairment, insomnia, and health-related quality of life. J Psychiatr Res. 2026 Feb;193:414-423. doi: 10.1016/j.jpsychires.2025.12.012. Epub 2025 Dec 5.
- Derived from this study: PubMed 36961017Olgiati P, Fanelli G, Serretti A. Age or age of onset: which is the best criterion to classify late-life depression? Int Clin Psychopharmacol. 2023 Jul 1;38(4):223-230. doi: 10.1097/YIC.0000000000000472. Epub 2023 Mar 21.
- Derived from this study: PubMed 36594430Ainsworth NJ, Brender R, Gotlieb N, Zhao H, Blumberger DM, Karp JF, Lenze EJ, Nicol GE, Reynolds CF, Wang W, Mulsant BH. Association between lean muscle mass and treatment-resistant late-life depression in the IRL-GRey randomized controlled trial. Int Psychogeriatr. 2023 Dec;35(12):707-716. doi: 10.1017/S1041610222000862. Epub 2023 Jan 3.
- Derived from this study: PubMed 35771573Diniz BS, Mulsant BH, Reynolds CF 3rd, Blumberger DM, Karp JF, Butters MA, Mendes-Silva AP, Vieira EL, Tseng G, Lenze EJ. Association of Molecular Senescence Markers in Late-Life Depression With Clinical Characteristics and Treatment Outcome. JAMA Netw Open. 2022 Jun 1;5(6):e2219678. doi: 10.1001/jamanetworkopen.2022.19678.
- Derived from this study: PubMed 32991792Altmann H, Stahl ST, Gebara MA, Lenze EJ, Mulsant BH, Blumberger DM, Reynolds CF 3rd, Karp JF. Coprescribed Benzodiazepines in Older Adults Receiving Antidepressants for Anxiety and Depressive Disorders: Association With Treatment Outcomes. J Clin Psychiatry. 2020 Sep 29;81(6):20m13283. doi: 10.4088/JCP.20m13283.
- Derived from this study: PubMed 31846575Buchalter ELF, Oughli HA, Lenze EJ, Dixon D, Miller JP, Blumberger DM, Karp JF, Reynolds CF 3rd, Mulsant BH. Predicting Remission in Late-Life Major Depression: A Clinical Algorithm Based Upon Past Treatment History. J Clin Psychiatry. 2019 Dec 10;80(6):18m12483. doi: 10.4088/JCP.18m12483.
- Derived from this study: PubMed 30358242Wei W, Karim HT, Lin C, Mizuno A, Andreescu C, Karp JF, Reynolds CF 3rd, Aizenstein HJ. Trajectories in Cerebral Blood Flow Following Antidepressant Treatment in Late-Life Depression: Support for the Vascular Depression Hypothesis. J Clin Psychiatry. 2018 Oct 23;79(6):18m12106. doi: 10.4088/JCP.18m12106.
- Derived from this study: PubMed 29924506Hsu JH, Mulsant BH, Lenze EJ, Sanches M, Karp JF, Reynolds CF, Blumberger DM. Clinical Predictors of Extrapyramidal Symptoms Associated With Aripiprazole Augmentation for the Treatment of Late-Life Depression in a Randomized Controlled Trial. J Clin Psychiatry. 2018 Jun 19;79(4):17m11764. doi: 10.4088/JCP.17m11764.
- Derived from this study: PubMed 29659205Cristancho P, Lenze EJ, Dixon D, Miller JP, Mulsant BH, Reynolds CF 3rd, Butters MA. Executive Function Predicts Antidepressant Treatment Noncompletion in Late-Life Depression. J Clin Psychiatry. 2018 May/Jun;79(3):16m11371. doi: 10.4088/JCP.16m11371.
- Derived from this study: PubMed 28068779Marshe VS, Maciukiewicz M, Rej S, Tiwari AK, Sibille E, Blumberger DM, Karp JF, Lenze EJ, Reynolds CF 3rd, Kennedy JL, Mulsant BH, Muller DJ. Norepinephrine Transporter Gene Variants and Remission From Depression With Venlafaxine Treatment in Older Adults. Am J Psychiatry. 2017 May 1;174(5):468-475. doi: 10.1176/appi.ajp.2016.16050617. Epub 2017 Jan 10.
- Derived from this study: PubMed 27645461Smagula SF, Karim HT, Lenze EJ, Butters MA, Wu GF, Mulsant BH, Reynolds CF, Aizenstein HJ. Gray matter regions statistically mediating the cross-sectional association of eotaxin and set-shifting among older adults with major depressive disorder. Int J Geriatr Psychiatry. 2017 Dec;32(12):1226-1232. doi: 10.1002/gps.4585. Epub 2016 Sep 19.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Charles F. Reynolds, MD principal investigator
University of Pittsburgh
Eric Lenze, MD principal investigator
Washington University School of Medicine, St. Louis
Benoit Mulsant, MD principal investigator
University of Toronto
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing venlafaxine XR plus aripiprazole in people with Depression, run by University of Pittsburgh at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Dec 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Dec 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Subjects Who Met Criteria for Remission Based on the Montgomery-Asberg Depression Rating Scale (MADRS) (time frame: 12 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00892047, which also lists 18 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2015.