Antidepressant Medication Plus Donepezil for Treating Late-life Depression

Tracking Information
First Submitted Date ICMJE	September 13, 2005
First Posted Date ICMJE	September 15, 2005
Results First Submitted Date	February 18, 2011
Results First Posted Date	June 8, 2011
Last Update Posted Date	February 6, 2013
Study Start Date ICMJE	December 2003
Actual Primary Completion Date	September 2009 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: May 6, 2011)	Global Cognitive Performance [ Time Frame: Measured at baseline and Years 1 and 2 in maintenance ]Cognitive performance was assessed with 17 well established and validated individual tests measuring multiple domains. We transformed raw scores for individual tests into Z-scores using the baseline distribution of a non-depressed, cognitively normal, older adult comparison group (N=36)of similar age, education, and medical health recruited concurrently with the depressed participants. These Z-scores were averaged within each neuropsychological area to produce domain scores and then averaged over all 17 tests to calculate a global cognition performance score.; Cognitive Instrumental Activities of Daily Living (IADL) [ Time Frame: baseline, year 1 and year 2 ]The PASS (a performance-based assessment of instrumental activities of daily living)generates a composite measure of 13 cognitive IADL items capturing performance on activities such as shopping, bill paying, medication management, and home safety. We report the percentage of subjects at each assessment point adjudged to have independent functioning. This was determined by a clinician rater observing subjects perform each task and rating them according to predetermined criteria on a 4 point scale, ranging from 0 (unable) to 3 (independent).; Number of Participants With Recurrence of Major Depression [ Time Frame: 2 years ]Recurrence of major depressive episodes as determined by SCID/DSM IV: two weeks of low mood and/or anhedonia, together with at least five of the following symptoms: suicidal ideation, low energy, sleep disturbance, appetite disturbance, psychic anxiety or somatic anxiety. In addition, a diagnosis of major depression requires evidence of distress or impairment.
Original Primary Outcome Measures ICMJE; (submitted: September 13, 2005)	Combined treatment of antidepressant pharmacotherapy plus donepezil will lead to the maintenance and improvement of cognitive and functional competence in late-life depression.
Change History	Complete list of historical versions of study NCT00177671 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE	Not Provided
Original Secondary Outcome Measures ICMJE; (submitted: September 13, 2005)	clinical measures: HRSD, Suicide Ideation Scale, UKU; cognitive and functional performance measures: MATTIS Dementia Rating Scale, Folstein Mini-Mental, CDR, Apathy, EXIT; Chronic medical illness burden: CIRS-G, Quality of Well-being scale, GAS, SF-36, McGill Pain Questionnaire; Social Support:Interpersonal Support Evaluation List; Functional status: PASS, Keitel Function Test; Late-Life Function and Disability Instrument; MRI; SCID; ATHF
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Antidepressant Medication Plus Donepezil for Treating Late-life Depression
Official Title ICMJE	Maintenance Therapies in Late-Life Depression: MTLD III
Brief Summary	This study will determine the effectiveness of combining escitalopram, venlafaxine, or duloxetine with donepezil, a medication used in Alzheimer's disease, in improving memory, concentration, attention, and problem solving abilities, and reducing the risk of depressive relapse in older individuals with depression.
Detailed Description	The purpose of this research study is to learn if combining an antidepressant medication (escitalopram, venlafaxine, or duloxetine) with a medication used in Alzheimer's Disease (donepezil), in elderly patients age 65 and older with major depression, will help to 1) improve and/or maintain memory, concentration, attention, and problem solving abilities such as ability to balance a checkbook, pay bills, use the telephone, and 2) reduce the risk of depressive symptoms from returning. Study participation will last up to two years. We aim to investigate pharmacologic strategies for improving and stabilizing cognitive functioning in late-life depression and minimizing progression of cognitive and associated functional impairment. Cognitive impairment in late-life depression has not been adequately addressed in previous intervention research, is a core feature of the illness, contributes markedly to disability and impaired quality of life, and is an overlooked but potentially critical target of intervention. Data from the MTLD II study suggest that treating depression does not normalize cognitive functions and may not prevent their progression. We will test a pharmacologic strategy involving the cholinesterase inhibitor donepezil, in combination with maintenance antidepressant pharmacotherapy (escitalopram, venlafaxine, or duloxetine), to improve and to maintain cognitive functioning and functional competence in elderly patients with major depression. We hypothesize that maintenance antidepressant pharmacotherapy combined with donepezil will be superior to maintenance antidepressant pharmacotherapy combined with placebo/clinical management in (1) improving cognitive performance; and (2) slowing progression of cognitive impairment and decline in functional competence. We plan to recruit 200 patients aged 65 and above in current episodes of major depression. Those who respond to antidepressant pharmacotherapy with citalopram, venlafaxine, or duloxetine will then be randomly assigned on a double-blind basis to one of two 24-month treatments: 1)antidepressant pharmacotherapy plus donepezil/clinical management; or 2)antidepressant pharmacotherapy plus placebo/clinical management. For information on related studies, please follow these links: http://clinicaltrials.gov/show/NCT00000377 http://clinicaltrials.gov/show/NCT00178100
Study Type ICMJE	Interventional
Study Phase	Phase 4
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Depression; Dementia
Intervention ICMJE	Drug: Escitalopram Escitalopram, 10mg to 20mg daily. Other Name: Lexapro; Drug: Donepezil Donepezil, 5mg to 10mg daily. Other Name: aricept; Drug: Venlafaxine Venlafaxine, 150mg to 300mg daily. Other Name: effexor XR; Drug: Placebo; Drug: Duloxetine Other Name: cymbalta
Study Arms	Experimental: 1 escitalopram plus donepezil (DNP)in the experimental maintenance phase of the study. For subjects failing to respond to escitalopram during the initial open phase of acute treatment we allowed the use of duloxetine or venlafaxine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation donepezil. Participants remained on the same antidepressant medication and dosage throughout the 2 year maintenance phase of the study. In the event of a recurrence of major depression during maintenance treatment, dosages of antidepressant medication were raised, or the antidepressant was switched to venlafaxine or duloxetine. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of duloxetine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. Interventions: Drug: Escitalopram Drug: Donepezil Drug: Venlafaxine Drug: Duloxetine; Placebo Comparator: 2 escitalopram plus placebo (PBO) in the experimental maintenance phase of the study. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of duloxetine or venlafaxine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. Participants remained on the same antidepressant medication and dosage throughout the 2 year maintenance phase of the study. In the event of a recurrence of major depression during maintenance treatment, dosages of antidepressant medication were raised, or the antidepressant was switched to venlafaxine or duloxetine. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of venlafaxine or duloxetine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. Interventions: Drug: Escitalopram Drug: Venlafaxine Drug: Placebo Drug: Duloxetine
Publications *	Reynolds CF 3rd, Butters MA, Lopez O, Pollock BG, Dew MA, Mulsant BH, Lenze EJ, Holm M, Rogers JC, Mazumdar S, Houck PR, Begley A, Anderson S, Karp JF, Miller MD, Whyte EM, Stack J, Gildengers A, Szanto K, Bensasi S, Kaufer DI, Kamboh MI, DeKosky ST. Maintenance treatment of depression in old age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry. 2011 Jan;68(1):51-60. doi: 10.1001/archgenpsychiatry.2010.184.; Diniz BS, Reynolds CF 3rd, Begley A, Dew MA, Anderson SJ, Lotrich F, Erickson KI, Lopez O, Aizenstein H, Sibille EL, Butters MA. Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: a longitudinal study. J Psychiatr Res. 2014 Feb;49:96-101. doi: 10.1016/j.jpsychires.2013.11.004. Epub 2013 Nov 20.; Andreescu C, Tudorascu DL, Butters MA, Tamburo E, Patel M, Price J, Karp JF, Reynolds CF 3rd, Aizenstein H. Resting state functional connectivity and treatment response in late-life depression. Psychiatry Res. 2013 Dec 30;214(3):313-21. doi: 10.1016/j.pscychresns.2013.08.007. Epub 2013 Oct 18.; Sheffrin M, Driscoll HC, Lenze EJ, Mulsant BH, Pollock BG, Miller MD, Butters MA, Dew MA, Reynolds CF 3rd. Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission. J Clin Psychiatry. 2009 Feb;70(2):208-13. Epub 2009 Feb 10.; Karp JF, Whyte EM, Lenze EJ, Dew MA, Begley A, Miller MD, Reynolds CF 3rd. Rescue pharmacotherapy with duloxetine for selective serotonin reuptake inhibitor nonresponders in late-life depression: outcome and tolerability. J Clin Psychiatry. 2008 Mar;69(3):457-63.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: May 6, 2011)	220
Original Enrollment ICMJE; (submitted: September 13, 2005)	250
Actual Study Completion Date	September 2009
Actual Primary Completion Date	September 2009 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Current episode of major depression; HRS-D 17-item score of 15 or higher; Must be able to speak English; Willing to discontinue other psychotropics; Availability of family member/caregiver; Hearing capacity adequate to respond to raised conversational voice; Must have no formal diagnosis of dementia Exclusion Criteria: Meets DSM-IV criteria for bipolar disorder, schizophrenia, schizoaffective disorder, or a psychotic disorders; Alcohol/drug abuse within 12 months of study entry; History of treatment non-adherence in other clinic protocols; History of non-response to citalopram in other clinic protocols; History of non-tolerance to SSRI therapy
Sex/Gender	Sexes Eligible for Study: All
Ages	65 Years and older (Adult, Senior)
Accepts Healthy Volunteers	Yes
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00177671
Other Study ID Numbers ICMJE	R01MH043832-03( U.S. NIH Grant/Contract ); R01MH043832 ( U.S. NIH Grant/Contract ); 0312018; DATR A4-GPS
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	University of Pittsburgh
Study Sponsor ICMJE	University of Pittsburgh
Collaborators ICMJE	National Institute of Mental Health (NIMH)
Investigators ICMJE	Principal Investigator: Bruce G. Pollock, MD, PhD University of Pittsburgh Professor of Psychiatry, Pharmacology, and Nursing
PRS Account	University of Pittsburgh
Verification Date	January 2013
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP