Involuntary Weight Loss After Switching Acetylcholinesterase Inhibitors: Page 2 of 2

March 15, 2013




Although our patient’s rapid weight gain after being switched back to donepezil may have been attributed to his concurrent admission to the nursing home, there was no evidence that there were any contributory problems at his daughter’s home. Even if there had been, that could not explain the almost immediate onset of weight loss that occurred when galantamine was substituted for
donepezil. This double switch in medications makes a compelling case for his weight loss being causally related to the galantamine; his other medications were unlikely to have any significant anorectic or orexigenic effects and were not changed.


It is disconcerting that our patient’s weight loss was not addressed sooner, but this is not particularly unusual based on our experience. His weight loss may have gone unaddressed for so long because it was overshadowed by his chronically suboptimal glycemic control and because he was never underweight. Nevertheless, involuntary weight loss in persons with dementia should always be addressed promptly, as it is associated with functional impairment, decreased quality of life, and increased mortality.3-6 


For patients receiving an AChEI, the overall incidence of weight loss is reported to be between 17% and 20%.1-3,7 To some extent this weight loss may be dose-dependent. Gallini and colleagues8 reported the case of a patient with dementia and Parkinson’s disease who lost weight when treated with galantamine and regained weight when the dosage was reduced. Also, as occurred with our patient, weight loss may result without any associated nausea, vomiting, or diarrhea. Stewart and Gorelik3 reported eight cases of significant weight loss in patients with dementia who were treated with AChEIs, five of who had no nausea or other gastrointestinal adverse effects. In contrast, a retrospective study published by Gillette-Guyonette and colleagues9 found a similar incidence of weight loss between patients with Alzheimer’s disease treated with AChEIs and those who were untreated; however, these patients were treated in an academic geriatric clinic, which likely resulted in greater attention being paid to weight loss. Also, two prospective but nonrandomized studies by Guerin and colleagues6,10 found an inverse relationship between weight loss and the use of AChEIs, suggesting a possible protective effect. The mechanism of weight loss associated with AChEIs is not entirely clear, but it may be related to subclinical nausea3 or to increased cholinergic activity in the nucleus accumbens, which has been associated with taste aversion11 and satiety.12


We could only locate one other report in the medical literature examining the incidence of weight loss between the various AChEIs.1 In contrast to our case report, this multifacility, retrospective analysis reviewed Minimum Data Set information for nursing homes throughout the United States and found a lower incidence of weight loss among residents treated with galantamine than with donepezil or rivastigmine. It is not clear why our patient lost weight with galantamine but not donepezil. Although both agents inhibit acetylcholinesterase, only galantamine also acts as a nicotinic receptor modulator, potentiating nicotinic cholinergic neurotransmission.13 It is unclear whether this activity provides additional cognitive benefits, but nicotinic agonists have been shown to decrease food intake in mice and in humans.14 




Weight loss in patients with dementia is generally an ominous sign, predicting poor quality of life and an increased risk of mortality, and the weight is rarely regained. A variety of factors can cause involuntary weight loss in these patients, including use of AChEIs; thus, patients on these agents must be closely monitored for accelerated weight loss. Clinicians should also keep in mind that nausea or other gastrointestinal adverse effects may not necessarily accompany weight loss in these patients. 


It is still not known whether AChEI-related weight loss is more often a class effect or whether it is more commonly associated with one specific agent in this drug class. Regardless, our case report demonstrates that switching agents may be a viable strategy for some patients who lose weight while on an AChEI. In addition, before prescribing or switching any AChEI, clinicians should conduct a diligent risk-benefit analysis, as the potential benefits of these agents are modest, even subtle, and the risk of significant weight loss can be devastating. If the liabilities of a drug are determined to exceed its benefits, or if there has been no demonstrable benefit, the drug must be discontinued, as would occur under any geriatric prescribing situation.


1. Hughes A, Musher J, Thomas SK, Beusterien KM, Strunk B, Arcona S. Gastrointestinal adverse events in a general population sample of nursing home residents taking cholinesterase inhibitors. Consult Pharm. 2004;19(8):713-720.

2. Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry. 2003;11(2):131-145.

3. Stewart JT, Gorelik AR. Involuntary weight loss associated with cholinesterase inhibitors in dementia. J Am Geriatr Soc. 2006;54(6):1013-1014.

4. Crogan NL, Pasvogel A. The influence of protein-calorie malnutrition on quality of life in nursing homes. J Gerontol A Biol Sci Med Sci. 2003;58(2):159-164.

5. Sullivan DH, Morley JE, Johnson LE, et al. The GAIN (Geriatric Anorexia Nutrition) registry: the impact of appetite and weight on mortality in a long-term care population. J Nutr Health Aging. 2002;6(4):275-281.

6. Guerin O, Andrieu S, Schneider SM, et al. Characteristics of Alzheimer’s disease patients with a rapid weight loss during six-year follow-up. Clin Nutr. 2009;28(2):141-146.

7. Imbimbo BP. Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer’s disease. CNS Drugs. 2001;15(5):375-390.

8. Gallini A, Sommet A, Salandini AM, Veyssiere P, Montastruc JL, Montastruc JL. Weight loss associated with anti-dementia drugs in a patient with Parkinson’s disease. Mov Disord. 2007;22(13):1980-1981.

9. Gillette-Guyonnet S, Cortes F, Cantet C, Vellas B. Long-term cholinergic treatment is not associated with greater risk of weight loss during Alzheimer’s disease: data from the French REAL.FL cohort. J Clin Nutr Health Aging. 2005;9(2):69-73.

10. Guerin O, Andrieu S, Schneider SM, et al. Different modes of weight loss in Alzheimer’s disease: a prospective study of 395 patients. Am J Clin Nutr. 2005;82(2):435-441.

11. Taylor KM, Mark GP, Hoebel BG. Conditioned taste aversion from neostigmine or methylnaloxonium in the nucleus accumbens. Physiol Behav. 2011;104(1):82-86.

12. Helm KA, Rada P, Hoebel BG. Cholecystokinin combined with serotonin in the hypothalamus limits accumbens dopamine release while increasing acetylcholine: a possible satiation mechanism. Brain Res. 2003;963(1-2):290-297.

13. Olin J, Schneider L. Galantamine for Alzheimer’s disease. Cochrane Database Syst Rev. 2002;(3):CD001747.

14. Chen H, Vlahos R, Bozinovski S, Jones J, Anderson GP, Morris MJ. Effect of short-term cigarette smoke exposure on body weight, appetite and brain neuropeptide Y in mice. Neuropsychopharmacology. 2005;30(4):713-719. 


The authors report no relevant financial relationships.  


Address correspondence to:

Jonathan T. Stewart, MD, DFAPA, AGSF

Mental Health and Behavioral Sciences Service (116A)

James A. Haley VA Hospital

13000 Bruce B. Downs Blvd

Tampa, FL 33612