Phase 4
N=61
Combination Treatment Study for Memory Impairment and Depression
Depression · Mild Cognitive Impairment
Bottom Line
View on ClinicalTrials.gov: NCT01658228 ↗Enrolled (actual)
61
Serious AEs
24.6%
Results posted
Oct 2017
Primary outcome: Primary: Selective Reminding Test (SRT) Total Recall — 45.6; 46.6 Words
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 4
- Interventions
- Donepezil (Drug); Placebo (Drug); Citalopram (Drug); Venlafaxine (Drug)
- Age
- Adult, Older Adult · 55+ yrs
- Sex
- All
- Sponsor
- New York State Psychiatric Institute
- Primary completion
- Jan 2016
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Selective Reminding Test (SRT) Total Recall |
45.6; 46.6 | — |
| PRIMARY Selective Reminding Test (SRT) Delayed Recall |
7.4; 7.4 | — |
| SECONDARY Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) |
13.2; 13.9 | — |
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.
Eligibility 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:
- 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.
Data sourced from ClinicalTrials.gov (NCT01658228). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.