Combination Treatment Study for Memory Impairment and Depression

NCT01658228 | Completed Phase 4 Results DMC

• 2 other identifiers: #6459R01AG040093-01
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 2

Brief Summary

Patients presenting with depression (DEP) and cognitive impairment (CI), represent a unique, understudied population that is difficult to diagnose, treat and estimate prognosis. Our pilot data, supported by the literature, suggest that many DEP-CI patients show cognitive decline and often convert to dementia, primarily Alzheimer's disease (AD). In DEP-CI, there is a lack of data on treatment response of mood symptoms to antidepressant treatment and particularly of cognitive deficits to cognitive enhancer treatment. Our initial pilot data in a double-blind study showed that donepezil was superior to placebo in improving memory in antidepressant-treated DEP-CI patients. In a second pilot study, open label es-citalopram plus memantine treatment led to a low rate of conversion to dementia. In this proposed pilot clinical trial, the investigators will evaluate, treat and follow a broad sample of 80 DEP-CI patients at NYSPI/Columbia University Medical Center (N = 40) and Duke University Medical Center (N = 40). Recruitment will be from clinics and/or advertisements. In the treatment protocol, all 80 DEP-CI patients will receive baseline mood and memory assessments and open antidepressant treatment with citalopram for 8 weeks. At 8 weeks, repeat assessment will occur and patients whose depression has responded to citalopram will be randomized to add-on donepezil or placebo. Non-responders to citalopram will receive open treatment with venlafaxine and will be randomized 8 weeks later (16 weeks of open antidepressant treatment) to add-on donepezil or placebo. Patients will be followed for a total period of 18 months with continuous open antidepressant treatment during the trial. Donepezil is being studied in order to increase the likelihood of obtaining a signal. If the results are positive, the investigators can begin clarifying the mechanism(s) in subsequent trials. Baseline apolipoprotein E e4 genotype, odor identification deficits, and MRI hippocampal and entorhinal cortex atrophy will be explored as predictors of donepezil response in the 18-month trial. Improving cognition and delaying conversion to a clinical diagnosis of dementia in this high risk group will enhance quality of life, reduce family burden, and markedly diminish overall health care costs.

Conditions

Depression; Mild Cognitive Impairment

Keywords

Depression; Dysthymia; Cognitive Impairment; Cognitive Decline; Memory

Outcome Measures

Primary Outcomes (2)

• Selective Reminding Test (SRT) Total Recall

  The 12-item, 6-trial SRT is a memory measure used to assess verbal list learning and memory. The total number of words learned over six trials (total immediate recall) was obtained.

  Week 16

• Selective Reminding Test (SRT) Delayed Recall

  The 12-item, 6-trial SRT is a memory measure used to assess verbal list learning and memory. The total number of words learned over six trials (total immediate recall) and delayed recall (after a 15-minute delay) was obtained.

  Week 16

Secondary Outcomes (1)

• Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)

  Week 16

Other Outcomes (12)

• WMS-III Visual Reproduction Subtest

  Screen (Week 0), Week 16, Week 40, Week 64, Week 78

• Trails A and B

  Screen (Week 0), Week 16, Week 40, Week 64, Week 78

• Stroop

  Screen (Week 0), Week 16, Week 40, Week 64, Week 78

Study Arms (4)

Donepezil Treatment Group

OTHER

For the initial 16 weeks of open-label antidepressant treatment, citalopram up to 20 mg daily or venlafaxine up to 225 mg daily was prescribed. At 16 weeks, all patients were randomized, double-blind, to add-on donepezil or placebo for 62 weeks. Donepezil was started at 5 mg and increased to 10 mg daily or maximum tolerated dose while continuing antidepressants.

Drug: Donepezil

Placebo Treatment Group

OTHER

For the initial 16 weeks of open-label antidepressant treatment, citalopram up to 20 mg daily or venlafaxine up to 225 mg daily was prescribed. At 16 weeks, all patients were randomized, double-blind, to add-on donepezil or placebo for 62 weeks. Placebo dose was increased during the study to match Donepezil dose increases while continuing antidepressants.

Drug: Placebo

Citalopram

OTHER

An open treatment 8 week flexible dosing schedule starting with citalopram 10mg/day for the first week, then increasing to 20 mg/day thereafter to treat the depression. At the week 8 visit, citalopram responders will continue citalopram treatment and will be randomized to add-on donepezil or placebo at the week 16 visit.

Drug: Citalopram

Venlafaxine

OTHER

For patients who did not respond to citalopram, open treatment 8 week flexible dosing schedule starting with venlafaxine 37.5mg/day for the first week, then 75mg/day for the second week, then 150mg/day for the third and fourth week, then 225mg/day for the fifth through eighth weeks. At the end of the eighth week, we will assess patients for antidepressant response. At this time-point, venlafaxine responders will be randomized to add-on donepezil or placebo.

Drug: Venlafaxine

Interventions

Donepezil DRUG

Donepezil 5mg will be given for 6 weeks and if tolerated, the dose will be increased to 10 mg per day. The dose range of 5 to 10 mg per day is the recommended dose for donepezil in the treatment of mild to moderate Alzheimer's disease.

Also known as: Aricept

Donepezil Treatment Group

Placebo DRUG

A placebo capsule will be given to randomized subjects for the starting at week 16 and continuing for the remainder of the study. This group will not receive donepezil as treatment.

Placebo Treatment Group

Citalopram DRUG

Citalopram tablet will be given to subjects during an 8 week flexible dosing open treatment. If subjects respond to citalopram treatment they will be randomized to add-on donepezil/placebo.

Citalopram

Venlafaxine DRUG

Venlafaxine tablet will be given to subjects during an 8 week flexible dosing open treatment if they did not respond to citalopram. If subjects respond to venlafaxine treatment they will be randomized to add-on donepezil/placebo.

Venlafaxine

Eligibility Criteria

• Age: 55 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Of either sex, age 55-95 years old with minimum 8 years of education who meet criteria for both depression and cognitive impairment as described below.
• Study Criteria for "depression":
• i. Patients who meet DSM-IV symptom criteria for Major Depression or Dysthymia for a minimum of 6 months (2 year duration DSM-IV TR criterion not required for dysthymic disorder in this study). ii. 24-item HAM-D ≥14.
• Study Criteria for "cognitive impairment":
• i. Subjective memory or other cognitive complaints. ii. Score ≤ 11 on the Logical Memory II (Delayed Paragraph Recall, Paragraph A) test from the Wechsler Memory Scale - Revised OR a score that is ≥ 1.5 standard deviations below the norms on the FC SRT
• Folstein Mini Mental State (MMSE) score ≥ 21 out of 30.
• Clinical Dementia Rating (CDR) of 0.5 on the memory item and global rating of 0.5 indicating questionable dementia
• Willing and capable of giving informed consent
• A family member or close friend who consents to serve as informant during the study; this can be a telephone informant in the case of patients who do not have a live-in informant or close significant other.

You may not qualify if:

• Meets Criteria for dementia (DSM-IV) or probable Alzheimer's disease (NINCDS-ADRDA criteria)
• Meets DSM IV TR criteria for:
• schizophrenia, schizoaffective disorder, psychotic depression or other psychosis, or bipolar I disorder
• alcohol or substance dependence or abuse (current or within past 6 months)
• Active suicidal ideation or suicidal attempt in last 6 months.
• Clinical stroke with residual neurological deficits.
• Use of medications known to have a negative impact on cognition: benzodiazepines in lorazepam equivalents ≥ 2 mg daily, narcotics, or anticholinergics. (N.B. Medications that may be associated with cognitive impairment but are rarely considered the likely etiology, e.g, theophylline, nifedipine, Beta blockers, will not be excluded.)
• Presence of any of the following disorders: a) CNS infection, with CSF evidence of meningitis, encephalitis, or other infectious process; b) Post-traumatic dementia, defined as dementia with a clear temporal relationship to a severe head injury where consciousness was lost; c) Huntington's disease; d) Multiple sclerosis; e) Parkinson's disease; f) Other neurologic disorders with focal signs, e.g., amyotrophic lateral sclerosis; g) Mental retardation.
• Contra-indication to MRI scan: pacemaker, metal implants following surgery, any other contraindication to MRI (e.g., ferromagnetic aneurysm clips, heart valves). For patients with possible claustrophobia, they can do the MRI with adjunct lorazepam 0.5 mg to reduce anxiety. Patients who cannot do the MRI scan will still be eligible for the clinical trial, i.e., MRI is optional.

Sponsors & Collaborators

• New York State Psychiatric Institute: lead
• National Institute on Aging (NIA): collaborator

Study Sites (2)

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Related Publications (2)

• Devanand DP, Pelton GH, D'Antonio K, Ciarleglio A, Scodes J, Andrews H, Lunsford J, Beyer JL, Petrella JR, Sneed J, Ciovacco M, Doraiswamy PM. Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial. Am J Geriatr Psychiatry. 2018 Oct;26(10):1050-1060. doi: 10.1016/j.jagp.2018.05.008. Epub 2018 Jun 28.

  PMID: 30037778 DERIVED

• Pelton GH, Andrews H, Roose SP, Marcus SM, D'Antonio K, Husn H, Petrella JR, Zannas AS, Doraiswamy PM, Devanand DP. Donepezil treatment of older adults with cognitive impairment and depression (DOTCODE study): clinical rationale and design. Contemp Clin Trials. 2014 Mar;37(2):200-8. doi: 10.1016/j.cct.2013.11.015. Epub 2013 Dec 5.

  PMID: 24315979 DERIVED

MeSH Terms

Conditions

Depression; Cognitive Dysfunction; Dysthymic Disorder

Interventions

Donepezil; Citalopram; Venlafaxine Hydrochloride

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Depressive Disorder; Mood Disorders

Intervention Hierarchy (Ancestors)

Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds; Propylamines; Amines; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Phenethylamines; Ethylamines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Lipids

Results Point of Contact

• Title: Dr. Davangere Devanand
• Organization: New York State Psychiatric Institute

dpd3@cumc.columbia.edu

646-774-8658

Study Officials

• Davangere Devanand, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

• Gregory Pelton, MD

  Columbia University

  STUDY DIRECTOR

• Steven Roose, MD

  Columbia University

  STUDY DIRECTOR

• Murali Doraiswamy, MD

  Duke University

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2012
• First Posted: August 6, 2012
• Study Start: September 1, 2011
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: October 17, 2017
• Results First Posted: October 17, 2017

Record last verified: 2017-10

Locations

US (2)