Emergent Complications Following Donepezil Switchover to Galantamine in Three Cases of Dementia With Lewy Bodies

DLB is a common dementia with overlapping features with AD and Parkinson’s Disease (PD). Despite the overlap, the pathophysiology appears distinct from AD.^7,8 Lack of neurofibrillary tangles as well as absence of significant tau pathology, both hallmarks of AD, characterize DLB. Neocortical cholinergic activity (assessed by choline acetyltranferase activity) also appears more severely depleted, which correlates with visual hallucinations and global cognitive impairment.⁸ In DLB, postsynaptic muscarinic receptors appear better preserved and functionally more intact than AD, in part due to absence of neocortical neurofibrillary tangles. All these findings suggest that ChEIs might offer better outcomes in DLB despite its more aggressive course.⁷ A randomized, double-blind, placebo-controlled trial demonstrated rivastigmine to have greater improvements in attention and apathy, while reducing anxiety and psychotic symptoms.³ Open-label follow up over 96-weeks also showed ongoing stabilization.⁵ It remains to be seen whether long-term treatment can affect the rate of decline when compared to the natural course of the disease. In our series, patients had a 2–3 point decline in MMSE over the 1- to 2-year follow up; in addition, significant neurobehavioral symptoms emerged despite ongoing maintenance treatment. To patients and caregivers, these symptoms are more disconcerting than MMSE performance. The behavioral changes increase caregiver burden and lead to dissatisfaction with the previously effective pharmacotherapy.

The progressive and sometimes spiraling downward course often leads clinicians to consider alternative ChEIs; yet the evidence is scant in support of alternate ChEI in DLB. Switching is presently unknown for DLB, although there appears to be some merit for this in AD.^9,10 Similar to the case for use of alternate selective serotonin reuptake inhibitors (SSRIs) in depression nonresponders, Ballard argues that each ChEI exhibits different pharmacologic activity, so as to make switching a valid option.⁹ In one open-label trial involving 382 AD subjects, over half of donepezil nonresponders (56.2%) had successful response to rivastigmine.¹⁰ While it is tempting to generalize these findings to DLB, clinicians should be wary since the DLB population is particularly medication-sensitive.

There are several mechanisms that could account for the deterioration. It is possible that overlap of two ChEIs may have led to additive toxicity, so-called “cholinergic toxicity.” Centrally, this is manifest as confusion, sedation, coma, and possibly seizures and peripherally as miosis, lacrimation, salivation, bradycardia, bronchospasm, emesis, and diarrhea. Only one case of aspiration pneumonia, coma and death has emerged following donepezil and rivastigmine titration.¹¹ None of our patients experienced symptoms suggestive of cholinergic excess.

Alternatively, donepezil discontinuation could lead to a discontinuation syndrome similar to SSRIs.^12–14 In an open trial involving PD and DLB, abrupt donepezil discontinuation led to delusions, irritability and hallucinations.¹⁴ Although formal follow up in this study was reported only one-and-half months following discontinuation, 11 of 19 subjects were unable to tolerate the discontinuation and resumed donepezil within 2 weeks of discontinuation.¹⁴ Our patients were closely followed in the first 2-week period following the switch, which enabled thorough ongoing assessments. The 2-week period appears critical since it reflects donepezil’s half-life of 70 hours, and where five half-lives (or approximately 2 weeks) are required for complete donepezil elimination.¹⁵

The cases pose the clinical dilemma of pharmacotherapy adjustment in DLB. Theoretically, there is a risk of “cholinergic toxicity” if two ChEIs are combined or overlapped.^11,15 In our series, introduction of the second ChEI did not lead to immediate sequelae. Delayed deterioration has also been noted by others¹⁴ and thus suggests a need for gradual dosage reduction and ongoing vigilance when discontinuing donepezil.

Finally, there is concern whether abrupt ChEI discontinuation and ensuing complications can lead to irreversible deterioration. This issue remains unresolved. Our patients did not appear to return fully to baseline at 3-month follow up. In the open-label series, return to baseline was reported,¹⁴ although the large dropout rates make this interpretation difficult. Therefore, given the limited data and follow up, in patients who appear to be deteriorating or developing adverse effects, dosage tapering remains the preferred method to avoid accelerated decline. Dosage reduction is also recommended for patients whose clinical improvement is unclear.¹⁴

The advent of ChEIs has helped DLB management, with patients and families obtaining much relief from the disturbing aspects of the illness. While ChEIs have shown symptomatic gains, ongoing disease progression and loss of efficacy remain ongoing concerns. Discontinuing or switching donepezil to alternate ChEI requires vigilance, particularly for the first 2 weeks, since discontinuation symptoms may emerge after a delay. Although our findings are preliminary and require placebo-controlled trials for confirmation, emerging literature supports this recommendation.

Presented in part at the International Psychogeriatrics Association Eleventh Annual Meeting, Chicago, August 17–22, 2003.

The authors thank Dr. Keith Edwards for reviewing and providing thoughtful comments and critiques of the manuscript.