To the Editor: The central cholinergic system is believed to play a role in mood disorders, with inhibition of cholinergic activity correlating with mania and facilitation with depression.¹ In contrast, six cases of mania related to treatment with donepezil, a centrally-acting acetylcholinesterase inhibitor, have been reported in the literature.^2–4 We report a woman who developed mania after starting donepezil.

“Mrs. W,” a 65-year-old woman with no personal or family history of mental illness, presented with a several day history of insomnia, hyperreligiosity, and agitation. She had a 6- to 12-month history of worsening cognitive dysfunction, personality changes, and functional impairment. Cognitive examination demonstrated recent-memory impairment and executive dysfunction.

Laboratory evaluation, including TSH, MMA, cortisol, RPR, HIV, and serum cryptococcal antigen, was unremarkable. An electroencephalogram was normal. CT and MRI of the brain showed left cerebellar encephalomalacia, white-matter microvascular disease, and lacunar disease in the basal ganglia.

The mania did not resolve with discontinuation of donepezil and treatment with low dose quetiapine, and the patient was transferred to a psychiatric hospital 6 days after admission. She was started on donepezil 5 mg daily for suspected Alzheimer’s disease 5 days before presentation.

The patient had had a cerebellar stroke 8 years earlier and had hypertension, type II diabetes, and hyperlipidemia. She was noncompliant with all medical medications except clopidogrel.

On examination, she acknowledged elevated mood and energy levels. Hypergraphia, pressured speech, and spontaneous singing were noted. Thought examination revealed over-inclusiveness, religious preoccupation, and grandiose delusions.

The six patients reported previously who developed mania with donepezil ranged in age from 50 to 78. Four were women; five carried diagnoses of dementia; and one had cognitive impairment related to a cerebral aneurysm and repair. Two patients had histories of bipolar I disorder, and two had depression. Four were on other medications that can cause mania (antidepressants, carbidopa/levodopa). Mania developed in most patients within 1 week of donepezil initiation, and resolved in most within 1 week of discontinuation. Our patient resembled previous reported cases wherein she was elderly, had vascular dementia, and developed mania within days of starting donepezil. It is unclear how donepezil may induce mania; one possibility is an increase in acetylcholine leading to changes in norepinephrine, dopamine, serotonin, or other neurotransmitters.⁵ Our case and those previously reported suggest that donepezil could precipitate mania in the context of cerebrovascular or other brain diseases, mood disorders, and/or treatment with other medications that can cause mania.