Combination Treatment Study for Memory Impairment and Depression

Study Overview
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Brief Summary
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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.

Detailed Description
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In the elderly, the most common neuropsychiatric disorders are depression (DEP) and cognitive impairment (CI). Their co-occurrence (DEP-CI) may exceed chance. The lack of research in DEP-CI, the need to determine early prognostic indicators, and to develop optimal treatment strategies, was emphasized by a NIH consensus panel. Since depression in patients with CI increases the risk of conversion to dementia, treatment strategies for DEP-CI have longer-term implications beyond acute antidepressant treatment response. However, in DEP-CI, there is a lack of data on treatment response of mood symptoms to antidepressant treatment and of cognitive deficits to cognitive enhancer treatment, and the long-term prognosis in these patients remains unclear. The investigators have initial pilot data showing that donepezil was superior to placebo in improving memory performance in DEP-CI patients, and pilot data showing that patients with DEP-CI treated with combined escitalopram and memantine have a low conversion rate to dementia, primarily Alzheimer's disease (AD), over one year. This proposal is for the first study to explicitly examine cognitive change, including conversion to dementia, in a randomized, double-blind, placebo-controlled donepezil treatment trial in DEP-CI patients treated openly with antidepressants. The investigators will conduct systematic follow-up to evaluate 18-month outcome. In addition to apolipoprotein E ε4 genotype, the investigators will explore MRI hippocampal and entorhinal cortex atrophy and odor identification deficits as biomarkers that moderate response. This pilot trial will enroll about 80 DEP-CI patients who present to the departments of Psychiatry, Neurology and Internal Medicine at NYSPI/Columbia University and Duke University medical centers, ensuring broad representation for clinical relevance. In the treatment protocol, all 80 DEP-CI patients will receive open antidepressant treatment with citalopram for 8 weeks. At 8 weeks, citalopram responders will continue to be treated on citalopram, while non-responders will switch to venlafaxine treatment for an additional 8 weeks. At 16 weeks, all subjects will be randomized to add-on donepezil or placebo (N.B. Patients with a prior history of nonresponse to both citalopram and venlafaxine will be enrolled in the protocol and treated with bupropion and subsequently with doctor's choice of antidepressant). Patients will be followed for a total period of up to 18 months in the trial, with antidepressant treatment adjusted as needed based on clinical response and side effects, i.e., open antidepressant treatment is continuous for all subjects throughout the trial and is not the experimental intervention. The investigators chose to study antidepressant plus donepezil compared to placebo based on our pilot data and to increase the likelihood of obtaining a signal. Aim 1 (primary aim of the study). To assess change in cognitive status over 18 months in antidepressant-treated DEP-CI patients comparing donepezil to placebo. Hypothesis 1. Antidepressant-treated DEP-CI patients on donepezil will show a lower rate of conversion to dementia, primarily AD, compared to antidepressant-treated DEP-CI patients on placebo by the end of the 18-month trial. Hypothesis 2 (secondary). Compared to the placebo group, the donepezil group will show better cognitive outcome by the end of the 18-month trial (SRT total recall: primary measure; modified ADAS-cog: secondary measure). Hypothesis 3 (secondary). At the end of 24 weeks on add-on donepezil or placebo, the donepezil group will show better cognitive outcome than placebo (SRT total recall: primary measure; modified ADAS-cog: secondary measure). Aim 2: To evaluate moderators of treatment on cognitive change in the 18-month donepezil-placebo trial, based on the view that patients with incipient AD brain pathology will have superior cognitive outcome on donepezil. These Aim 2 hypotheses are considered exploratory. Hypothesis 1. Patients with the apolipoprotein E ε4 allele (homozygote or heterozygote), compared to patients without this allele, will have better cognitive outcome on donepezil compared to placebo. Hypothesis 2. Lower scores on the UPSIT (odor identification test) at baseline will be associated with better cognitive outcome on donepezil compared to placebo. Hypothesis 3. Smaller MRI hippocampal and entorhinal cortex volumes (atrophy) will be associated with better cognitive outcome on donepezil compared to placebo.

Official Title
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Pilot Combination Treatment Trial of Mild Cognitive Impairment With Depression

Conditions
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Depression, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Donepezil
* Drug: Placebo
* Drug: Citalopram
* Drug: Venlafaxine


Participation Criteria
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Eligibility Criteria
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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: 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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Donepezil Treatment Group<br>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<br>* 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.<br>* Other names: Aricept;|
| Other: Placebo Treatment Group<br>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<br>* 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.<br>|
| Other: Citalopram<br>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<br>* 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.<br>|
| Other: Venlafaxine<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) | 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. | Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Dysthymia, Cognitive Impairment, Cognitive Decline, Memory