Introduction
In the elderly population, the most common cases of dementia are caused by Alzheimer's disease (AD), vascular dementia, or both. Clinicians often prescribe medicines to alleviate symptoms and postpone disease progression. Cholinesterase inhibitors (ChEIs) are widely approved for the symptomatic treatment of mild to moderate AD. We present the case history of a patient with Alzheimer-type dementia and without pre-existing psychiatric problems displaying his first manic episode after administration of rivastigmine.
Case summary
A 79-year-old Taiwanese man without previous personal and family history of mood or mental disorders presented with gradual memory loss five months before visiting our geriatric psychiatric outpatient department (OPD). His physical and neurologic examinations were normal. The laboratory work-up, which included complete blood counts, kidney function tests, liver function tests, blood sugar and electrolyte level measurements, thyroid function tests, a rapid plasma reagin (RPR) test, and measurements of folic acid and serum vitamin B12 levels, was normal. His brain computed tomography (CT) revealed mild cortical atrophy. His Mini-Mental State Examination (MMSE) revealed a score of 17/30. According to the text revision of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV-TR), he was diagnosed with Alzheimer-type dementia after three months of OPD follow-up and excluding the possibility of mere delirium and depression. He was treated with rivastigmine 1.5 mg twice daily for cognitive enhancement without taking any other prescription or over-the-counter medications. No health problems were reported except his history of essential hypertension. He had no known drug allergies.
Three days later he developed a manic episode. His symptoms consisted of elated mood, psychomotor agitation, talkativeness and pressure speech (insisting on repeated phoning, or repeatedly asking the same questions), irritability, aggressive and reckless behavior, and high levels of energy coupled with a decreased need for sleep. Rivastigmine was discontinued when the manic symptoms had persisted for three days. These symptoms resolved without any neuroleptic treatment two days after cessation of rivastigmine. No disturbance of consciousness or fluctuation during the course of his manic state was reported.
One week after rivastigmine was discontinued, his family expressed concern about his worsening cognition and we prescribed donepezil 2.5 mg once daily for a re-challenge in response. No additional manic symptoms were reported after one month of donepezil use.
Discussion
Manic episodes in the geriatric population are not common. The incidence of patients with mania who were older than 75 years has been reported to be approximately only 2 per 100,000 persons (Kennedy et al., Reference Kennedy2005). Therefore, the first manic episode in elderly patients should be considered secondary to drugs, infection, neoplasm, epilepsy, or metabolic disturbances (Krauthammer and Klerman, Reference Krauthammer and Klerman1978). In our patient, there were no causes of secondary mania, with the exception of drugs. He presented with his first manic episode three days after taking rivastigmine. To our knowledge, reports of mania induced by ChEIs are rare. Available evidence indicates that ChEIs can improve mania based on the cholinergic–adrenergic hypothesis, which revealed an imbalance in the cholinergic–adrenergic system related to mood disorders, and mania might be caused by a decreased ratio of cholinergic to adrenergic activity (Janowsky et al., Reference Janowsky, el-Yousef, Davis and Sekerke1972). Rivastigmine is a slowly reversible inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), unlike donepezil, which selectively inhibits AChE.
To date, only one case of mania following administration of rivastigmine in a patient with a history of bipolar I disorder has been reported (Ehrt et al., Reference Ehrt, Fritze and Aarsland2011). In five other cases of selective ChEI-related mania, four of which were precipitated by donepezil and one by galantamine (Benazzi, Reference Benazzi1998; Reference Benazzi1999; Benazzi and Rossi, Reference Benazzi and Rossi1999; Ehrt et al., Reference Ehrt, Fritze and Aarsland2011), all included a prior history of mood disorder. Compared with the previously reported case of mania caused by rivastigmine, our case was unique in that the patient did not have a pre-existing psychiatric disorder. Both onset and improvement of the manic episode were closely related to administration and discontinuation of rivastigmine, which suggested a strong relationship between the manic episode and ChEIs.
After re-challenging with a low dose of donepezil (2.5 mg once daily and titrating to 2.5 mg twice daily), which differs from rivastigmine by virtue of specific AChE inhibition and the absence of BuChE inhibition, no additional manic episodes were reported in our case.
The activity of BuChE increases while AD progresses (Arendt et al., Reference Arendt, Bruckner, Lange and Bigl1992), especially in the temporal cortex, hippocampus, and amygdala (Greig et al., Reference Greig2001). In addition, BuChE-positive neurons project specifically to the frontal cortex and may have roles in attention, executive function, emotional memory, and behavior (Lane et al., Reference Lane, Potkin and Enz2006). However, the mechanism of different behavioral responses of rivastigmine and donepezil requires further study. In our patient, the absence of relapse of mania after re-challenging with donepezil may not only have been attributable to the difference in cholinesterase inhibition selectivity, but may also have been effected by the lower and divided dose of donepezil.
In conclusion, this may be the first case report of a manic episode in an elderly patient without a previous psychiatric history treated with ChEIs with successful re-challenge using another ChEI. Clinicians may wish to consider the potential for this rare but crucial side effect, and may also wish to consider cautiously re-challenging with a different ChEI in order to enhance cognitive function in patients with Alzheimer-type dementia.
Conflict of interest
None.
Description of authors' roles
W. S. Tseng wrote the paper. N. S. Tzeng assisted with revision of the paper, and supervised W. S. Tseng in following up this case in the outpatient clinic.
