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

NCT00892047 | Completed Phase 4 Results

• 1 other identifier: MH083660-01A1
• Study Type: interventional
• Target: 468
• Locations: 2 countries
• Sites: 3

Brief Summary

The primary aims of this study are to:

1. 1.Assess the efficacy of aripiprazole augmentation for the acute and continuation treatment of TRLLD.
2. 2.Assess the tolerability of aripiprazole in TRLLD with a focus on adiposity and akathisia/restlessness.
3. 3.Examine anxiety, medical burden, and executive impairment as moderators of aripiprazole augmentation efficacy in TRLLD.
4. 4.Examine genetic predictors (phase 1) and moderators (phase 2-3) of treatment outcomes, while controlling for drug exposure.

Conditions

Depression

Keywords

Depression; Aripiprazole; Venlafaxine; Partial Remission; Augmentation strategy; Treatment resistance; Elderly; Late-life

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (2)

• Emergent Suicidal Ideation in Those With no Ideation at the Start of Treatment

  12 weeks

• QTc Prolongation on EKG (to Greater or Equal to 480 Msec)

  12 weeks

Study Arms (2)

1: venlafaxine plus aripiprazole

EXPERIMENTAL

antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo

Drug: venlafaxine XR plus aripiprazole

2: Placebo Comparator

EXPERIMENTAL

antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo

Drug: venlafaxine plus placebo

Interventions

venlafaxine XR plus aripiprazole DRUG

Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.

Also known as: effexor XR, abilify

1: venlafaxine plus aripiprazole

venlafaxine plus placebo DRUG

Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.

2: Placebo Comparator

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 60 years.
• Major depressive disorder (MDD), single or recurrent, as diagnosed by the SCID-IV.
• MADRS ≥ 15.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Pittsburgh: lead

Study Sites (3)

Washington University School of Medicine, St. Louis

St Louis, Missouri, 63110, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Location

University of Toronto

Toronto, Ontario, M6J1H4, Canada

Location

Related Publications (17)

• 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.

  PMID: 26423182 RESULT

• Olgiati 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.

  PMID: 36961017 DERIVED

• Ainsworth 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.

  PMID: 36594430 DERIVED

• Diniz 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.

  PMID: 35771573 DERIVED

• Altmann 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.

  PMID: 32991792 DERIVED

• Buchalter 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.

  PMID: 31846575 DERIVED

• Wei 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.

  PMID: 30358242 DERIVED

• Hsu 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.

  PMID: 29924506 DERIVED

• Cristancho 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.

  PMID: 29659205 DERIVED

• Marshe 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.

  PMID: 28068779 DERIVED

• Smagula 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.

  PMID: 27645461 DERIVED

• Smagula 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.

  PMID: 27282141 DERIVED

• Kaneriya 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.

  PMID: 26963689 DERIVED

• Kasckow 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.

  PMID: 26708830 DERIVED

• Smagula SF, Butters MA, Anderson SJ, Lenze EJ, Dew MA, Mulsant BH, Lotrich FE, Aizenstein H, Reynolds CF 3rd. Antidepressant Response Trajectories and Associated Clinical Prognostic Factors Among Older Adults. JAMA Psychiatry. 2015 Oct;72(10):1021-8. doi: 10.1001/jamapsychiatry.2015.1324.

  PMID: 26288246 DERIVED

• Hall CA, Simon KM, Lenze EJ, Dew MA, Begley A, Butters MA, Blumberger DM, Stack JA, Mulsant B, Reynolds CF 3rd. Depression Remission Rates Among Older Black and White Adults: Analyses From the IRL-GREY Trial. Psychiatr Serv. 2015 Dec 1;66(12):1303-11. doi: 10.1176/appi.ps.201400480. Epub 2015 Aug 17.

  PMID: 26278231 DERIVED

• Joel I, Begley AE, Mulsant BH, Lenze EJ, Mazumdar S, Dew MA, Blumberger D, Butters M, Reynolds CF 3rd; IRL GREY Investigative Team. Dynamic prediction of treatment response in late-life depression. Am J Geriatr Psychiatry. 2014 Feb;22(2):167-76. doi: 10.1016/j.jagp.2012.07.002. Epub 2013 Feb 6.

  PMID: 23567441 DERIVED

MeSH Terms

Conditions

Depression

Interventions

Aripiprazole; Venlafaxine Hydrochloride

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Organic Chemicals; Phenethylamines; Ethylamines; Amines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Lipids

Limitations and Caveats

limited number of participants older than 75, or members of racial/ethnic minority groups; limited follow-up period

Results Point of Contact

• Title: Charles F. Reynolds III, MD
• Organization: University of Pittsburgh

reynoldscf@upmc.edu

412-246-6414

Study Officials

• Charles F. Reynolds, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

• Eric Lenze, MD

  Washington University School of Medicine, St. Louis

  PRINCIPAL INVESTIGATOR

• Benoit Mulsant, MD

  University of Toronto

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director NIMH Center of Excellence in the Prevention and Treatment of Depression in Older Adults; UPMC Endowed Professor in Geriatric Psychiatry

Study Record Dates

• First Submitted: April 29, 2009
• First Posted: May 4, 2009
• Study Start: August 1, 2009
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: December 17, 2015
• Results First Posted: December 17, 2015

Record last verified: 2015-12

Locations

US (2); CA (1)