Clinical trial NCT00892047: Incomplete Response in Late Life Depression: Getting to Remission (IRL GREY)
Official title: Incomplete Response in Late Life Depression: Getting to Remission
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Depression
Keywords: Depression
Aripiprazole
Venlafaxine
Partial Remission
Augmentation strategy
Treatment resistance
Elderly
Late-life
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2009-05-04
Enrollment: 468
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

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.

Primary outcomes:
measure: Percentage of Subjects Who Met Criteria for Remission Based on the Montgomery-Asberg Depression Rating Scale (MADRS)
timeFrame: 12 weeks
measure: Akathisia
timeFrame: 12 weeks
measure: Weight
timeFrame: Baseline through12 weeks
measure: Parkinsonism
timeFrame: 12weeks
Secondary outcomes:
measure: Emergent Suicidal Ideation in Those With no Ideation at the Start of Treatment
timeFrame: 12 weeks
measure: QTc Prolongation on EKG (to Greater or Equal to 480 Msec)
timeFrame: 12 weeks
Other outcomes:
Locations:
city: St. Louis
country: United States
facility: Washington University School of Medicine, St. Louis
state: Missouri
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
Study officials:
affiliation: University of Pittsburgh
name: Charles F. Reynolds, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine, St. Louis
name: Eric Lenze, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Toronto
name: Benoit Mulsant, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.