Combination Treatment Study for Memory Impairment and Depression
Condition: Depression; Mild Cognitive Impairment
MeSH terms: Depression; Depressive Disorder; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      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.
    

Intervention name(s): Donepezil; Placebo; Citalopram; Venlafaxine
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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.; 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.; 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.; 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.
Other intervention name(s): Aricept
Intervention MeSH terms: Donepezil; Venlafaxine Hydrochloride; Citalopram
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depression; Dysthymia; Cognitive Impairment; Cognitive Decline; Memory