Antidepressant Medication Plus Donepezil for Treating Late-life Depression

• Global Cognitive Performance [ Time Frame: Measured at baseline and Years 1 and 2 in maintenance ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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.

• 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

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

• Depression
• Dementia

• 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

• 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

• 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.

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