Cognitive relapse after discontinuation of drug therapy in Alzheimer's disease: cholinesterase inhibitors versus nootropics

Abstract

In a cross-sectional study of outpatients diagnosed with dementia of the Alzheimer type who had been treated with a broad variety of drugs supposed to improve cognition or to delay cognitive decline, we have investigated the effects of abruptly discontinuing therapy on cognition. Termination of therapy with any cholinesterase inhibitor was associated with a cognitive decline during the following 6-7 weeks which was significantly more pronounced than that experienced by patients who had received nootropic drugs or calcium channel blockers (3.41 vs. 1.17 points on the ADAS-Cog scale; -1.14 vs. -0.06 points on the MMSE scale). This effect was not modified by gender, apolipoprotein E genotype, or the extent of ventricular enlargement on CT scans. Its magnitude was comparable to the cognitive response observed in published clinical trials when cholinesterase therapy commenced, and also with the data obtained during a 6-week placebo washout phase.

Effect of Cholinergic Signaling on Neuronal Cell Bioenergetics

“…In some of these cases, sub-acute clinical decline is nevertheless judged to occur [52]. Quantitative data also show that when cholinesterase inhibitor therapy is discontinued in patients with mild and moderate AD, a six week period of accelerated cognitive decline occurs [53, 54]. Since brain mitochondria, once generated, likely function for several weeks (rat brain mitochondria reportedly have a half-life of two to five weeks, depending on how it is assessed) [55–58], it is worth considering whether a secondary mitochondrial mass destabilization contributes to this phenomenon.…”

Switching From Donepezil to Rivastigmine Is Well Tolerated

“…Although patients treated with donepezil demonstrated significant improvement on cognitive testing during active treatment, scores fell dramatically following the washout period. 20,30,31 Rainer and associates 32 also completed a small study (N = 47) that expanded the washout analysis to include a variety of drugs used to treat Alzheimer's disease. Again, the purpose was to evaluate effects on cognition following sudden medication discontinuation.…”

“…As with the donepezil trials, the investigators observed considerable cognitive decline following termination of ChE inhibitors. 32 Interestingly, a retrieved dropout analysis of the rivastigmine pivotal trials revealed that patients who discontinued rivastigmine secondary to withdrawal from the study did not experience a precipitous decline in cognition. Although still speculation, these findings suggest that rivastigmine not only alleviates the symptoms of Alzheimer's disease, but may also delay disease progression in some patients.…”