This is the first confirmatory RCT of ChEI augmentation in older non-demented
adults with a recent major depressive episode. Our primary analyses indicated a temporary positive effects of donepezil on global cognitive function (as well as on domain-specific measures of executive function and memory), marginal effects on a composite measure of cognitive instrumental activities of daily living, and, in a post-hoc subgroup analysis of those with MCI, a lower rate of conversion to dementia over two years (33% on placebo versus 10% on donepezil). However, co-administration of donepezil also led to higher rates of recurrent depressive episodes (35% versus 19% in the entire group of participants; and 45% versus 12% in the MCI subgroup), despite the use of maintenance antidepressant pharmacotherapy. The clinical significance of increased affective episodes is not only the suffering and morbidity associated with each depressive episode, but also the risk for chronicity, with each recurrent episode becoming more difficult to treat to full remission 38
Post-hoc analyses suggested 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 nor progression to MCI/dementia over two years. In those with MCI after remission of depression, the addition of donepezil to maintenance antidepressant pharmacotherapy appeared to prevent progression to dementia over two years but also to increase recurrence of depression. We caution, however, that these observations are based upon post-hoc subgroup analyses. The study may have been underpowered to detect a potential benefit in cognitively normal subjects. These observations are, therefore, preliminary and in need of confirmation by other studies that are designed and powered to confirm them.
There are two published, short-term
pilot studies of ChEI augmentation of antidepressant treatment of non-demented older patients with major depression and cognitive impairment 39, 40
. In a 12-week, randomized, double-blind, placebo-controlled study of 23 adults older than age 50, Pelton et al 39
, reported that donepezil was associated with greater improvement in memory (immediate recall) than those on placebo. In a 24-week double-blind, placebo-controlled pilot study of 38 non-demented depressed adults older than 50, Holtzheimer et al. 40
observed no significant differences in measures of mood or cognition over the study 24 weeks, but did report high dropout among galantamine-randomized subjects.
While some treatment studies with ChEIs in non-demented
persons with MCI have shown benefit in cognitive performance and rates of conversion to dementia 6, 7
, others have not, for example.41, 42
The Cochrane review of donepezil in MCI concluded that the benefits of ChEIs are minor, short-lived, and associated with significant side effects 13
. Of interest, and consistent with our findings of a lower, slower conversion rate to dementia associated with donepezil use in MCI patients, Lu et al. study (2009)7
of 726 subjects with amnestic MCI randomized to donepezil, vitamin E, or placebo also found that depressive symptoms were predictive of progression from MCI to Alzheimer’s Disease over three years but that donepezil slowed progression to Alzheimer’s Disease relative to placebo and vitamin E. Lu et al. found that donepezil was not
associated with improvement in depressive symptoms. In contrast to our study, the authors excluded subjects with episodes of major depression occurring in the previous two years, whereas we required subjects to have a current episode. Our data appear to be consistent with those of Lu et al in suggesting a lower dementia conversion rate on donepezil in MCI subjects with a history of depression. Although our data to not allow us to say whether subjects with a history of depression (as distinct from a recent episode) are at higher risk for recurrence on donepezil, such subjects should be watched carefully if placed on donepezil.
The current study differs in several respects from previously reported cholinesterase inhibitor (ChEI) trials conducted in patients with MCI: 41-44
(1) we examined older adults with major depression, a population excluded from ChEI trials, but one which is relevant to psychiatric practice with complicated older patients; (2) our study thus expands the evidence base available to treat patients that have been excluded from trials sponsored by industry and by the Alzheimer Disease Cooperative Study (ADCS) group; and (3) our study examined a more heterogeneous group of MCI subjects, including those with non-amnestic and multiple cognitive domain forms as well as the amnestic forms included in industry-sponsored and ADCS trials. Until now there has been no evidence to guide psychiatric treatment of these complicated older adults with major depression and the full spectrum of MCI.
Furthermore, in contrast to ChEI trials in dementia, where improvements in neuropsychiatric symptoms have been noted 15, 16
, we detected a clinically significant increase in recurrent episodes of major depression. This observation may be consistent with the cholinergic hypothesis of mood disorders 19, 20
, which holds that persons with depression show cholinergic hypersensitivity to depressogenic effects of cholinoceptive agents. The observation is also consistent with a recent report of scopolamine’s antidepressant efficacy in major depressive disorder.21
Such episodes may further amplify cognitive impairment and associated disability, thus offsetting the temporary gains in cognition observed earlier on. The positive effects of donepezil--modest cognitive and functional enhancement and slowing of dementia conversion rate-- must be weighed against the risk of recurrence of major depression in those with mild cognitive impairment and possible appearance of manic symptoms and worsening of suicidal ideation or behavior.
Unstructured Abstract (requested by Editor)
Cognitive impairment in late-life depression is a core feature of the illness. We tested whether the combination of donepezil and antidepressant pharmacotherapy (n=67) is superior to placebo + antidepressant pharmacotherapy (n=63) in improving cognition and in reducing recurrences of major depression over two years of maintenance treatment. We observed that combination donepezil + antidepressant modestly improved global cognition (including executive function, language, memory) and cognitive IADL. However, donepezil-treated patients were also more likely to experience recurrent episodes of major depression: 35% versus 19% (log rank chi squared = 3.97, p=.05).
In post-hoc analyses, we observed that of 57 participants with Mild Cognitive Impairment, three of 30 on donepezil (10%; 95% CI: 0, 21) and nine of 27 (33%; 95% CI: 16, 51) on placebo converted to dementia (primarily Alzheimer’s) over two years (Fishers exact p = 0.05). However, the MCI subgroup also had a 44% recurrence rate on donepezil versus 12% on placebo (LR = 4.91, p = .03).
The cognitively normal subgroup (n = 73) showed no cognitive benefit or change in depression recurrence on donepezil.
The use of donepezil as augmentation treatment of late-life depression depends upon a careful weighing of risks and benefits in those with MCI, while no apparent benefit accrues in those with normal cognition.