Combination Treatment Study for Memory Impairment and Depression (DEP-CI)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT01658228 |
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Recruitment Status :
Completed
First Posted : August 6, 2012
Results First Posted : October 17, 2017
Last Update Posted : October 17, 2017
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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 or disease | Intervention/treatment | Phase |
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| Depression Mild Cognitive Impairment | Drug: Donepezil Drug: Placebo Drug: Citalopram Drug: Venlafaxine | Phase 4 |
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| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 86 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | Pilot Combination Treatment Trial of Mild Cognitive Impairment With Depression |
| Study Start Date : | September 2011 |
| Actual Primary Completion Date : | January 2016 |
| Actual Study Completion Date : | January 2016 |
| Arm | Intervention/treatment |
|---|---|
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Donepezil Treatment Group
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.
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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 |
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Placebo Treatment Group
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.
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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. |
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Citalopram
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.
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Drug: Citalopram
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. |
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Venlafaxine
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.
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Drug: Venlafaxine
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. |
- Selective Reminding Test (SRT) Total Recall [ Time Frame: Week 16 ]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.
- Selective Reminding Test (SRT) Delayed Recall [ Time Frame: Week 16 ]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.
- Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) [ Time Frame: Week 16 ]The modified ADAS-Cog is a cognitive battery that assesses learning, memory, language production, language comprehension, constructional praxis, ideational praxis, and orientation. Subjects' scores represent the total number of errors made throughout the various tasks. The total number of possible errors is between 0-85.
- WMS-III Visual Reproduction Subtest [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ]
- Trails A and B [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ]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 ]
- WAIS-III Digit Symbol Subtest [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ]
- WAIS-III Block Design Subtest [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ]
- COWAT [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ]
- Boston Naming [ Time Frame: Screen (Week 0), Week 16, Week 40, Week 64, Week 78 ]
- Apolipoprotein E Genotype [ Time Frame: Week 2 ]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) ]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) ]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 ]
- FC-SRT [ Time Frame: Week 0 Screening ]
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| Ages Eligible for Study: | 55 Years to 95 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
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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.
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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)
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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.)
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01658228
| United States, New York | |
| New York State Psychiatric Institute | |
| New York, New York, United States, 10032 | |
| United States, North Carolina | |
| Duke University | |
| Durham, North Carolina, United States, 27710 | |
| 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 |
| Responsible Party: | New York State Psychiatric Institute |
| ClinicalTrials.gov Identifier: | NCT01658228 |
| Other Study ID Numbers: |
#6459 R01AG040093-01 ( U.S. NIH Grant/Contract ) |
| First Posted: | August 6, 2012 Key Record Dates |
| Results First Posted: | October 17, 2017 |
| Last Update Posted: | October 17, 2017 |
| Last Verified: | October 2017 |
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Depression Dysthymia Cognitive Impairment Cognitive Decline Memory |
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Depression Depressive Disorder Cognitive Dysfunction Behavioral Symptoms Mood Disorders Mental Disorders Cognition Disorders Neurocognitive Disorders Donepezil Venlafaxine Hydrochloride Citalopram Cholinesterase Inhibitors Enzyme Inhibitors |
Molecular Mechanisms of Pharmacological Action Cholinergic Agents Neurotransmitter Agents Physiological Effects of Drugs Nootropic Agents Serotonin and Noradrenaline Reuptake Inhibitors Neurotransmitter Uptake Inhibitors Membrane Transport Modulators Antidepressive Agents, Second-Generation Antidepressive Agents Psychotropic Drugs Serotonin Uptake Inhibitors Serotonin Agents |