Posted by Phillipa on January 10, 2011, at 19:27:26
Donepezil May be a risk factor for recurrent Depression In MCI patients. Phillipa
From Medscape Medical News > Psychiatry
Donepezil May Increase Risk for Depression Recurrence in MCI Patients
Caroline CasselsAuthors and Disclosures
January 7, 2011 â Adding the cholinesterase inhibitor (ChEI) donepezil to antidepressant therapy in patients with symptoms of major depression and mild cognitive impairment (MCI) may increase the risk for depression recurrence, new research suggests.Further, in cognitively intact older patients with depression, donepezil does not appear to slow progression to MCI or dementia or prevent depression recurrence.
In a randomized, double-blind, placebo-controlled maintenance trial, investigators at the University of Pittsburgh in Pennsylvania found the combination of donepezil and maintenance antidepressant therapy temporarily improved global cognition, although effect sizes were small.
Although combination therapy reduced conversion to dementia during 2 years in those with MCI, it was also associated with increased depression recurrence.
Further, researchers report donepezil was of no benefit to subjects who were cognitively normal at the start of maintenance treatment.
"The positive effects of donepezil â modest cognitive and functional enhancement and slowing of the dementia conversion rate â must be weighed against the risk of recurrence of major depression in those with MCI and possible appearance of manic symptoms and worsening of suicidal ideation or behavior," the investigators led by Charles F. Reynolds, MD, write.
The study is published in the January issue of Archives of General Psychiatry.
Cognitive Impairment Core Feature of Late-Life Depression
According to investigators, cognitive impairment in late-life depression is a core feature of the illness, contributing to disability and impaired quality of life. Even after remission, they point out that cognitive function does not improve to levels seen in nondepressed subjects and, further, that impairment may progress.
Furthermore, they note that depression is increasingly thought to be a "possible risk factor for, or a prodrome to, dementing illnesses."
The study authors report their primary hypotheses were that donepezil and antidepressant therapy would be superior to antidepressant therapy plus placebo in improving global cognitive performance and cognitive instrumental activities of daily living (C-IADL) during a 2-year period and would reduce recurrences of major depression in older nondemented adults with a recent major depressive episode.
The randomized, double-blind, placebo-controlled maintenance trial included 130 adults 65 years and older with recently remitted major depression.
Subjects were randomly assigned to receive maintenance antidepressant pharmacotherapy plus donepezil (n = 67) or maintenance antidepressant pharmacotherapy plus placebo (n = 63).
The study's primary outcome measures were improved global neuropsychological performance, C-IADL, and recurrent depression.
The investigators report that they chose ChEI therapy because of previous evidence that it may prevent symptomatic progression of MCI, particularly in patients with depressive symptoms, remediate cholinergic deficits and enhance cerebral blood flow, and modify amyloid precursor protein metabolism and have neuroprotective effects.
They specifically chose donepezil because of its potential efficacy in MCI, the fact that it allows for once daily dosing, and because it is safe and well tolerated.
Temporary Advantage
In terms of neuropsychological performance, the researchers found subjects in the donepezil group showed a temporary advantage at 1 year that was not sustained at 2-year follow-up. However, they point out that even at 1 year effect sizes were small and not statistically significant.
The researchers also found a marginal benefit in the donepezil group on C-IADL. However, perhaps of greater interest and concern was that among the entire cohort, subjects in the donepezil group were significantly more likely than the placebo group to experience a recurrence of major depression â 35% (95% confidence interval [CI], 24% â 46%) vs 19% (95% CI, 9% â 29%) (hazard ratio = 2.09).
Post hoc subgroup analyses revealed that 57 subjects had MCI â 30 in the donepezil group and 27 in the placebo group. Of these, 12 subjects â 3 receiving donepezil and 9 receiving placebo â converted to dementia at 2-year follow-up.
The study authors report that the MCI subgroup had recurrence rates of 44% with donepezil vs 12% with placebo. They also report that "for cognitively intact patients after remission of depression, the addition of donepezil to maintenance antidepressant pharmacotherapy appeared to have no clear benefit: it did not prevent relapse or progression to MCI or dementia over 2 years."
The study authors also point out that although their data do not show whether patients with a history of depression vs a recent episode may also be at higher risk for recurrence of major depression with donepezil, "such subjects should be watched carefully" when clinicians initiate treatment with the drug.
The study was funded by the National Institute of Mental Health. Dr. Reynolds reports he has received pharmaceutical supplies for his National Institutes of Healthâsponsored work from Forest Laboratories, Pfizer/Eisai, Bristol-Myers Squibb, Wyeth, and Eli Lilly and Co. The disclosures of the remaining investigators are published in the original study.
Arch Gen Psychiatry. 2011;68:51-60
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