Combination Treatment Study for Memory Impairment and Depression
Condition: Depression; Mild Cognitive Impairment
MeSH terms: Depression; Depressive Disorder; Cognitive Dysfunction
Intervention: Donepezil; Placebo; Citalopram; Venlafaxine
Intervention description: 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.
Intervention MeSH terms: Donepezil; Venlafaxine Hydrochloride; Citalopram
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 86.0
Sex: All
Minimum age: 55 Years
Maximum age: 95 Years
Healthy volunteers: No
Keywords: Depression; Dysthymia; Cognitive Impairment; Cognitive Decline; Memory

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:

               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.