Combination Treatment Study for Memory Impairment and Depression (DEP-CI)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by New York State Psychiatric Institute
Sponsor:
Collaborator:
Information provided by (Responsible Party):
New York State Psychiatric Institute
ClinicalTrials.gov Identifier:
NCT01658228
First received: July 30, 2012
Last updated: April 16, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Depression
Mild Cognitive Impairment
Drug: Donepezil
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Combination Treatment Trial of Mild Cognitive Impairment With Depression

Resource links provided by NLM:


Further study details as provided by New York State Psychiatric Institute:

Primary Outcome Measures:
  • Selective Reminding Test (SRT) [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
    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) will be obtained.


Secondary Outcome Measures:
  • ADAS-Cog [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
    The modified ADAS-Cog is a cognitive battery that assesses learning, memory, language production, language comprehension, constructional praxis, ideational praxis, and orientation.


Other Outcome Measures:
  • MMSE [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
  • WMS-III Visual Reproduction Subtest [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
  • Trails A and B [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
    Parts A and B are composed of 25 circles. Patients are asked to scan the entire page and identify the next number or letter in a sequence.

  • Stroop [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
  • WAIS-III Digit Symbol Subtest [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
  • WAIS-III Block Design Subtest [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
  • COWAT [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
  • Boston Naming [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ] [ Designated as safety issue: No ]
  • Apolipoprotein E Genotype [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
    Using a standard protocol, DNA is amplified by the polymerase chase reaction (PCR). The genotypes are determined blind to subject status (patient or control) by the sizes of DNA fragments present.

  • University of Pennsylvania Smell Identification Test (UPSIT) [ Time Frame: Screen (Week 0) ] [ Designated as safety issue: No ]
    The subject will "scratch and sniff" 40 common odorants embedded in microcapsules on a separate page. The subject will choose the answer from a 4-item multiple choice list. Scores will range from 0-40.

  • MRI Scan [ Time Frame: Within 1 month of Screen Visit (Week 0) ] [ Designated as safety issue: Yes ]
    Images will be obtained using a GE Signa 3 Tesla whole body scanner. T1-weighted sagittal fspgr and T2 FLAIR are the pulse sequences used in order to obtain the MRI images.

  • WMS-R Logical Memory [ Time Frame: Week 0 Screening ] [ Designated as safety issue: No ]
  • FC-SRT [ Time Frame: Week 0 Screening ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: September 2011
Estimated Study Completion Date: August 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Citalopram Treatment Group
Citalopram Treatment: We will have an eight week period, using a flexible dosing schedule of citalopram, starting with 10mg/day for the first week, then increasing to 20 mg/day for the next two weeks, and then the dose can be increased to 40mg/day at the end of the fourth week (for patients under 60 only) in the absence of intolerable side effects. Dosing will be titrated up or down as necessary based on efficacy and side effects. All patients over 60 will be kept at 20 mg or maximum tolerated dose, up to the 8-week point. At the end of the eighth week, we will assess all patients for antidepressant response. At week 16, citalopram responders (those with a 50% reduction from baseline HAM-D) will be randomized to add-on donepezil or placebo. Furthermore, if a patient does not respond to either Citalopram or Venlafaxine, the study physician may choose to treat the patient with an alternative antidepressant.
Drug: Donepezil
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.
Other Name: Aricept
Drug: Placebo
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.
Venlafaxine Treatment Group
Venlafaxine Treatment: There will be an eight-week venlafaxine treatment period for those patients who did not respond to citalopram. A flexible dosing schedule will be employed, starting with 37.5mg/day for the first week, then 75mg/day for the second week, then 150mg/day for the third and fourth weeks, 225mg for the fifth and sixth weeks and -if deemed clinically necessary by the study physician- 300mg/day for the seventh and eighth weeks. For patients who cannot tolerate higher doses, 75 mg/day will be the minimum dose in continued treatment. At the end of the eighth week, we will assess patients for antidepressant response. At week 16, venlafaxine responders (those with a 50% reduction from baseline HAM-D) will be randomized to add-on donepezil or placebo. Furthermore, if a patient does not respond to either Citalopram or Venlafaxine, the study physician may choose to treat the patient with an alternative antidepressant.
Drug: Donepezil
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.
Other Name: Aricept
Drug: Placebo
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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   55 Years to 95 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • Meets Criteria for dementia (DSM-IV) or probable Alzheimer's disease (NINCDS-ADRDA criteria)
  • Meets DSM IV TR criteria for:

    1. schizophrenia, schizoaffective disorder, psychotic depression or other psychosis, or bipolar I disorder
    2. 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.)
  • An acute, severe or unstable medical condition. For cancer, acutely ill patients (including those with metastases) are excluded, but past history of successfully treated cancer does not result in exclusion.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01658228

Contacts
Contact: Kristina M D'Antonio, BS 212-543-5956 dantonk@nyspi.columbia.edu

Locations
United States, New York
New York State Psychiatric Institute Recruiting
New York, New York, United States, 10032
Contact: Kristina M D'Antonio, BS    212-543-5956    dantonk@nyspi.columbia.edu   
Principal Investigator: Davangere Devanand, MD         
United States, North Carolina
Duke University Recruiting
Durham, North Carolina, United States, 27710
Contact: Hala Husn    919-684-5929    hala.husn@duke.edu   
Principal Investigator: Murali Doraiswamy, MD         
Sponsors and Collaborators
New York State Psychiatric Institute
Investigators
Principal Investigator: Davangere Devanand, MD Columbia University
Study Director: Gregory Pelton, MD Columbia University
Study Director: Steven Roose, MD Columbia University
Study Director: Murali Doraiswamy, MD Duke University
  More Information

No publications provided by New York State Psychiatric Institute

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT01658228     History of Changes
Other Study ID Numbers: 6459, R01AG040093-01
Study First Received: July 30, 2012
Last Updated: April 16, 2013
Health Authority: United States: Data and Safety Monitoring Board

Keywords provided by New York State Psychiatric Institute:
Depression
Dysthymia
Cognitive Impairment
Cognitive Decline
Memory

Additional relevant MeSH terms:
Depression
Depressive Disorder
Cognition Disorders
Behavioral Symptoms
Mood Disorders
Mental Disorders
Delirium, Dementia, Amnestic, Cognitive Disorders
Citalopram
Venlafaxine
Donepezil
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serotonin Agents
Physiological Effects of Drugs
Cholinesterase Inhibitors
Enzyme Inhibitors
Cholinergic Agents
Nootropic Agents

ClinicalTrials.gov processed this record on July 22, 2014