Donepezil for Psychotropic-Induced Memory Loss
Abstract & commentary
Source: Jacobsen FM, et al. Donepezil for psychotropic-induced memory loss. J Clin Psychiatry 1999;60:698-704.
Patients who are treated with psychotropic medications for mood disorders often experience anticholinergic side effects, such as memory loss, dry mouth, and constipation. Although most patients develop tolerance to these effects after the first several weeks of treatment, some patients experience persistent anticholinergic side effects. Jacobsen and colleagues investigated the utility and tolerability of donepezil (Aricept), a acetylcholinesterase inhibitor marketed for Alzheimer’s disease, in nongeriatric, nondemented mood disordered patients for treatment of anticholinergic side effects.
Patients (n = 22; 11 men and 11 women; mean age, 45.7 years) with a DSM-IV diagnosis of either bipolar disorder or major depression who had been stabilized for at least two months on psychotropic medication were openly treated with 5 mg/d of donepezil for three weeks, then 10 mg/d for three more weeks. Patients completed self-rating scales of target symptoms before and 3-4 weeks after starting each dose. Patients who opted to continue donepezil therapy (n = 15) returned for clinical monitoring every 4-8 weeks.
Among the 21 patients with memory loss, 19 reported either complete or partial improvement while taking 5 mg/d of donepezil (P < 0.001); subsequently, six reported further improvement with 10 mg/d (P = 0.057). Patients receiving 5 mg/d also reported improvements in dry mouth (n = 16; P < 0.001) and constipation (n = 11; P < 0.05). Side effects were reported in 11 patients (46%) including insomnia, nausea, vomiting, and diarrhea. The insomnia was somewhat ameliorated by switching the administration of donepezil to morning. Two patients who had a diagnosis of bipolar disorder became manic within hours of starting donepezil. Sixteen patients (72%) continued donepezil for an average of seven months and maintained the therapeutic benefit of donepezil.
Comment by Michael F. Barber, pharmD
While limited in size and scope, the current study provides meaningful, useful data while creating questions that warrant further research. First, a subset of patients who are being treated for mood disorders and are experiencing troublesome anticholinergic side effects that are persistent and unresponsive to cholinergic agonists are likely to benefit significantly from donepezil. Clearly, the study is limited in size and is subject to bias due to its open-label design; however, the effect of donepezil was seemingly dose-dependent, sustained, and was in contrast to previous trials of cholinergic medications, thereby limiting the amount of noise from placebo response. Furthermore, the memory dysfunction usually relapsed within approximately one week after patients discontinued donepezil.
The anticholinergic side effects experienced by this cohort were predictable in patients who were receiving tricyclic antidepressants (TCAs); however, some patients receiving bupropion as well as selective serotonin reuptake inhibitors experienced unexpected anticholinergic effects. In fact, most patients who required the higher dose for a satisfactory response were patients who were receiving TCAs or bupropion. Although bupropion is not classically thought of as having strong anticholinergic effects, dry mouth and constipation are noted to occur at an incidence greater than 10%.
There were a few interesting findings in this report that warrant further investigation. First, nearly half of the cohort reporting memory dysfunction had family histories of Alzheimer’s disease. Since dementia had been ruled out and no patient was older than 64 years of age, it is suggestive that there may be an inherited vulnerability to anticholinergic-induced memory dysfunction that is reversible by inhibition of acetylcholinesterase. Although this finding is preliminary and with limited sample size, it can potentially serve as a clinical marker for early detection of patients who will develop Alzheimer’s disease, thereby allowing earlier intervention.
The other interesting finding was the fact that two patients developed manic symptoms within hours of taking the first dose of donepezil. In such a limited sample size, this finding may suggest a high and immediate risk of precipitating mania in patients with bipolar disorder. This was an unexpected finding, since cholinergic predominance has been more closely correlated with depression rather than mania. Donepezil should be used with caution in patients with a history of mania.
In summary, the current study supports the use of donepezil in a subset of mood disordered patients who have persistent anticholinergic side effects from psychotropic medications. However, since donepezil is expensive and is unlikely to be covered by managed care plans, it should be reserved for those patients who do not respond to other medications such as bethanechol or the ergot alkaloids.
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