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Examining the Case for Involuntary Weight Loss After Switching Acetylcholinesterase Inhibitors
There has been published literature and anecdotal reports of weight changes following the use of acetylcholinesterase inhibitors (AChEIs); thus, this is a recognized side effect of AChEI use.1 Stewart and colleagues’ article “Involuntary Weight Loss After Switching Acetylcholinesterase Inhibitors” reports an interesting case of an 86-year-old man with vascular dementia who experienced this side effect, losing weight when switched from donepezil to galantamine and then regaining most of this weight when switched back to donepezil. The Minimum Data Set 3.0 requires nursing homes to report weight changes of 5% or more. By the time the patient was admitted to the nursing home, he had already lost 24% of his body weight. Our commentary reviews some of the factors that have been associated with switching or discontinuing AChEI therapy and examines some of the other factors that may have contributed to the cognitive benefits attributed to the case patient’s donepezil regimen and to the adverse effects he experienced after being switched to galantamine.
Factors Associated With Switching or Discontinuing AChEI Therapy
The efficacy of AChEIs, especially over the long term, is still being reviewed and varies greatly with each patient. Although the case patient in Stewart and colleagues’ report took donepezil for many years without incidence, and his daughter reported that it improved his cognitive function, his AChEI was switched due to a change in his hospital’s outpatient formulary. In the medical literature, numerous factors have been reported to lead to a change in or discontinuation of a patient’s AChEI regimen.
In 2010, Gardette and colleagues2 examined the clinical factors leading to changes in the AChEI regimens of a large population of community-dwelling persons with Alzheimer’s disease. Since there is a paucity of data concerning the optimal drug treatment duration and the reasons for discontinuation of AChEIs, particularly outside of the clinical trial setting, the authors sought to identify predictive factors for discontinuing or switching AChEIs in a real-world setting. The multicenter cohort study was conducted in France and included 686 ambulatory patients with mild to moderate Alzheimer’s disease that was diagnosed between 2000 and 2002 in any one of 16 Alzheimer’s disease centers. All patients were assessed twice annually for 2 years. The main outcome measure was AChEI discontinuation or switch, which was assessed using Cox survival analyses. After 2 years, 100 of the 611 participants (16.4%) treated with an AChEI at baseline had discontinued or switched AChEI therapy. The incidences of discontinuing and switching were 3.6 and 9.2 per 100 person-years, respectively. Predictive factors of discontinuation included hospitalization for any reason, use of an anticholinergic drug, and weight loss. Predictive factors of switching included an ineffective AChEI dose, rapid cognitive decline, hospitalization unrelated to Alzheimer’s disease, and anxiety. This study identified four types of predictors of discontinuation or switching: disease progression, reconsideration of AChEI benefits, adverse drug reactions to AChEIs, and inappropriate concurrent use of anticholinergic drugs. Based on their findings, Gardette and colleagues concluded that particular attention should be paid to concurrent use of anticholinergic agents.2
Considering Folate and the B Vitamins
In Stewart and colleagues’ case report, the patient was presumed to have vascular dementia. The use of AChEIs for vascular dementia has not been shown to be particularly beneficial,3 but the case patient was reported to have benefited from his donepezil regimen. However, it is unclear whether the patient also supplemented with folate. The authors reported the use of cyanocobalamin (ie, vitamin B12) and a statin, but if folate was not provided, this could have affected the patient’s adverse outcomes upon being switched to galantamine, and if folate had been provided, it may have contributed to the therapeutic benefits attributed to donepezil.4
The beneficial effect of vitamin B12 on hematologic, cardiovascular, and neurologic systems may be most evident when combined with folate. Deficiencies in both of these nutrients have been associated with high homocysteine levels (>10-15 µM/L), which have been reported to increase the risk of coronary artery disease, cerebrovascular disease, and peripheral vascular disease between 2- and 40-fold.5 The role of folate in combination with other B vitamins in preventing or decreasing cognitive decline following a diagnosis of dementia has been both postulated and investigated, as evidenced by more than 600 results when the phrase “folate and dementia” is entered into a PubMed/MEDLINE search of the literature.
In a 2012 study, the self-reported concomitant use of folate and vitamin B12 for more than 1 year was associated with a lower rate of dementia diagnosis.6 Serum levels of homocysteine and vitamin B12, as measured at baseline and at 5 years, were not found to have an impact on the rate of diagnosing dementia. The investigators used magnetic resonance imaging to assess participants’ brain morphology and found that persons with higher serum folate levels at baseline tended to have less atrophy of their medial temporal lobes. These persons also tended to have higher homocysteine levels at baseline. Collectively, these findings were predictive of participants
developing moderate or severe global brain atrophy by 5-year follow-up. Individuals who supplemented with vitamin B12 or folate had lower grades of periventricular hyperintensities and of deep white matter lesions as compared with persons who did not use these supplements; this finding was independent of time and pattern of supplement use.6
In addition to assessing the role of vitamin B12 and folate in preventing cognitive decline, the issue of whether folate affects the efficacy of cholinesterase inhibitors has been examined. In a pilot double-blind study by Connelly and colleagues,7 patients with Alzheimer’s disease who supplemented with folate showed an improved response to their AChEI at 6 months. The study included 57 consecutive outpatients (mean age, 76.27 years) who were treated concurrently with an AChEI and either folic acid (n=23) or a placebo (n=18); both groups were well matched for demographics and AChEI use. At 6 months, a significant change from baseline was observed between the folate and placebo arms when their combined Instrumental Activities of Daily Living and Social Behaviour scores were examined, with scores of +1.50 and -2.29, respectively (P=.03); however, no significant changes in Mini-Mental State Examination scores were observed.7
Considering Acetylcholinesterase Formulations
The relative half-lives of donepezil (≥70 hours) and of galantamine sustained-release (SA; ≤24 hours) also need to be considered with regard to the case patient’s anorexia. If his galantamine was not titrated upward from an initial 8-mg daily dose, and he was instead started at the 24-mg SA dose as the case report suggests, this could offer an explanation for the patient’s decreased appetite and reduced food intake upon being switched to galantamine. The lack of concomitant adverse gastrointestinal (GI) side effects, such as nausea, vomiting, heartburn, or diarrhea, suggests that the anorexia from the galantamine was more centrally mediated. In their discussion, Stewart and colleagues reviewed reports that address the central cholinergic mediation effect on appetite,8,9 and they also point to a prior case of weight loss attributed to use of an AChEI in a patient with Parkinson’s disease.10 The longer half-life of donepezil and no mention of dose titration upon initiating or reinitiating this treatment also suggest that appetite changes may not be a simple GI effect on food intake. Because weight loss is more common in advanced stages of any dementia, it is encouraging that reinitiation of donepezil was beneficial.
Considering Dosages
On December 15, 2009, the US Food and Drug Administration (FDA) approved the first generic versions of donepezil, but less than a year later, on July 23, 2010, it approved a 23-mg formulation of nongeneric donepezil.11,12 This approval was controversial because it was based on a single trial and went against the recommendation of both FDA medical reviewers and statistical reviewers, who noted that this dosage failed to demonstrate efficacy and posed safety risks. Subsequent reports have indicated increased nausea and vomiting with this dosage, and many clinicians advocate against its use.13 The case patient’s donepezil 10 mg daily regimen was reinitiated after galantamine was discontinued because he had good results with it. Had he instead been titrated to donepezil 23 mg daily, he may not have experienced the same benefits or have had the same tolerance. Therefore, when considering switching or discontinuing an AChEI, clinicians should also carefully consider drug dosages and previous drug regimens. Regardless of which AChEI is used, there are a number of medication adverse drug reaction sequences that need to be evaluated. In addition to their GI side effects, the cholinergic dominance of AChEIs can lead to bradycardia, incontinence, difficulty breathing, worsening chronic obstructive pulmonary disease, and falls.14
Considering Polypharmacy
Stewart and colleagues’ case patient received several co-administered medications that could have contributed to his weight loss during the 17-month period when he received galantamine and during the 3-month period when he regained most of his weight after being switched back to donepezil. However, the authors reported no significant changes to any of these coadministered medications during either period, making it unlikely that these agents contributed to his weight changes.
Another problem that is mentioned is the patient’s repeated falls, which was a major contributor to his nursing home admission. The authors do not discuss whether the falls resolved upon the patient being switched back to donepezil or after he regained his weight. Although falls are a known risk of AChEI use, he was taking several other medications that have been associated with falls, including risperidone, gabapentin, and citalopram. Therefore, a patient’s total psychoactive drug load needs to be considered when he or she experiences recurrent falls.15,16 The patient’s history of schizophrenia suggests that discontinuing risperidone was not an option. Because his gabapentin dosage was very low, his serum drug concentrations may have been too low to determine whether this agent posed any risk; however, the reason for using gabapentin and the additive effect of his psychoactive drug load on his falls need to be considered.
Stewart and colleagues also report that the patient’s depression medication was switched from citalopram to mirtazapine to improve his appetite, but this switch was not successful and he continued to lose weight. Because weight gain was not an objective in this overweight diabetic patient, no nutritional supplements or nutritional aides were added to his 2000-calorie per day diet that also enabled him to eat snacks as desired.17 The authors did not provide information on his baseline serum albumin, vitamin B12, homocysteine, and folate levels and on his total lymphocyte count, but this information might have shed additional light on his nutritional status and enabled the authors to fully account for any changes in his condition.1
Conclusion
Although it is possible that several other factors contributed to Stewart and colleagues’ case patient losing weight after being switched to galantamine, we agree with the authors that their report provides a reminder of how the risk and benefits of AChEIs need to be carefully assessed and their use individualized. We also agree that all agents in a particular medication class may not always have the same side effect profile for a given patient.
References
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2. Gardette V, Andrieu S, Lapeyre-Mestre M, et al. Predictive factors of discontinuation and switch of cholinesterase inhibitors in community-dwelling patients with Alzheimer’s disease: a 2-year prospective, multicentre, cohort study. CNS Drugs. 2010;24(5):432-442.
3. Levine DA, Langa KM. Vascular cognitive impairment: disease mechanisms and therapeutic implications. Neurotherapeutics. 2011;8(3):361-373.
4. Sharma B, Singh N. Salutary effect of NFkB inhibitor and folacin in hyperhomocysteinemia-hyperlipidemia induced vascular dementia. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(2):207-215.
5. Beers MH, Berkow R, eds. Merck Manual of Geriatrics. 3rd ed. West Point, PA: Merck & Co, Inc; 2000:591-593.
6. Blasko I, Hinterberger M, Kemmler G, et al. Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort. J Nutr Health Aging. 2012;16(8):687-694.
7. Connelly PJ, Prentice NP, Cousland G, Bonham J. A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer’s disease. Int J Geriatr Psychiatry. 2008;23(2):155-160.
8. Taylor KM, Mark GP, Hoebel BG. Conditioned taste aversion from neostigmine or methyl-naloxonium in the nucleus accumbens. Physiol Behav. 2011;104(1):82-86.
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hypothalamus limits accumbens dopamine release while increasing acetylcholine: a possible satiation mechanism. Brain Res. 2003;963(1-2):290-297.
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11. FDA approves generic Aricept to treat dementia related to Alzheimer’s disease [news release]. Silver Spring, MD: US Food and Drug Administration; December 15, 2009. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm194173.htm. Accessed February 27, 2013.
12. Alliance for Human Research Protection. www.ahrp.org/cms/content/view/813/56. Accessed February 27, 2013.
13. Schwartz L, Woloshin S. How the FDA forgot the evidence: donepezil 23 mg. BMJ. 2012;344:e1086.
14. Stewart RB, Cooper JW. Polypharmacy in the aged. Practical solutions. Drugs Aging. 1994;4(6):449-461.
15. Cooper JW, Freeman MH, Cook CL, Burfield AH. Assessment of psychotropic and psychoactive drug loads and falls in nursing facility residents. Consult Pharm. 2007;22(6):483-489.
16. Cooper JW, Freeman MH, Cook CL, Burfield AH. Psychotropic and psychoactive drugs and hospitalization rates in nursing facility residents. Pharmacy Practice. 2007;5(3):140-144.
17. McRae A, Cooper JW. Use of nonaggressive short-term nutritional supplementation in a skilled nursing facility. Consult Pharm. 1998;13:174-181.
Disclosures:
Dr. Cooper has served in the past as a researcher, advisor, and/or speaker for donepezil, galantamine, citalopram, memantine, escitalopram, mirtazapine, risperidone, and gabapentin. He has no current activities, interests, or ownership of any kind in any of these products. Dr. Burfield reports no relevant financial relationships.
Address correspondence to:
Allison H. Burfield, RN, MSN, PhD
University of North Carolina at Charlotte
College of Health and Human Services, School of Nursing
9201 University City Blvd
Charlotte, NC 28223-0001
aburfiel@uncc.edu
jcooper@rx.uga.edu
