Weight loss, particularly unintentional weight loss, is a significant concern in specific patient populations, notably those with dementia. This article explores the complex relationship between memantine, a medication commonly used to treat Alzheimer's disease and other dementias, and its potential impact on weight.
Weight Loss in Dementia: An Overview
Unintentional body weight loss is common in patients with dementia and is linked to cognitive impairment and poorer disease outcomes. Weight loss is common among patients with dementia and may decrease their quality of life and increase their risk of mortality; thus, prompt attention to weight loss is warranted. Data indicate that 30-40% of patients with dementia may experience clinically significant weight loss.
Reduced nutritional status, partially explained by a reduced food intake, often characterizes body weight loss in dementia. It has been shown that 14-45% of community-dwelling patients with mild-to-moderate AD, and up to 68% of patients with severe AD, are at risk of malnutrition. Unintentional BW loss is detrimental for the frail elderly because it is associated with higher rates of mortality, institutionalization, adverse health outcomes, decline in functional status, and overall poorer quality of life. In elderly with dementia, unintentional BW loss is associated with syndrome severity, higher rates of institutionalization, a higher incidence of behavioral problems, and ultimately mortality. In contrast, a BMI equal to or higher than overweight (≥25.0 kg/m2) has been associated with reduced mortality in dementia.
Several factors can contribute to involuntary weight loss in dementia patients. These include:
- Reduced energy intake: Due to decreased mental status, patients may forget or refuse to eat, potentially resulting from impairments in episodic memory and attention associated with medial temporal lobe atrophy.
- Behavioral changes: Repetitive actions and other behavioral disorders can increase energy expenditure while reducing energy intake.
- Sensory changes: Deterioration of the olfactory bulb and/or diminished gustatory perception can contribute to weight loss due to cholinergic deficits.
- Dysphagia: Difficulties swallowing may reduce energy intake.
- Hypermetabolism: An elevated basal metabolic rate may cause BW loss, although studies on this in AD patients are conflicting.
- Neuroendocrine dysregulation: Disruptions in hormones like leptin, secreted by adipose tissue, can affect energy metabolism and brain function.
Medications for Dementia and Weight Loss
While available pharmacologic interventions for dementia do not address the underlying etiology, but instead are symptomatic and designed to slow cognitive decline and improve the deteriorating functional status that characterizes dementia. While these treatments can be effective, some may have considerable side effects such as body weight (BW) or body mass index (BMI) loss. The US Food and Drug Administration (FDA) has currently approved four unique formulations for the treatment of dementia: donepezil, rivastigmine, galantamine, and memantine.
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Acetylcholinesterase Inhibitors (AChEIs)
Donepezil, rivastigmine, and galantamine are acetylcholinesterase inhibitors (AChEIs) and vary only slightly in pharmacological properties. Acetylcholinesterase inhibitors are at the forefront of symptomatic treatment for AD and LBD, diseases that are most often characterized by a loss of cholinergic neurons in the brain, reducing the amount of acetylcholine available for neurotransmission, leading to a deficient cholinergic system. Acetylcholinesterase inhibitors bind to brain cholinesterase enzymes in a reversible manner and inhibit them from breaking down acetylcholine at the synapse level. Thus, AChEIs increase the level and duration of neurotransmitter action in forebrain regions, in an attempt to compensate for the loss of functioning cholinergic neurons.
Weight loss has been reported to occur in up to 20% of patients receiving an AChEI. In a meta-analysis of AChEI treatment in AD, it was shown that there was an almost three-fold higher odds of the adverse event, BW loss, among patient groups taking AChEIs compared with placebo treatment groups. Furthermore, this BW loss was associated with adverse gastrointestinal side effects. Notably, AChEIs induce dose-dependent nausea, vomiting, anorexia, and diarrhea caused by cholinergic hyperstimulation of the internal muscarinic receptor in the gastrointestinal tract.
Memantine: An NMDAR Antagonist
Memantine, the fourth compound currently approved by the FDA for the management of dementia, is a partial N-Methyl D-Aspartate receptor (NMDAR) antagonist. In dementia, an excitotoxic mechanism, partially owing to excess glutamate causing over-activation of NMDARs, triggers various neurotoxic events that lead to necrosis or apoptosis. Memantine works through uncompetitive blocking of the glutamatergic NMDARs when they are excessively open, blocking the imminent excitotoxic cascade.
Studies that pooled trial data of adverse events have reported no significant difference between memantine and placebo groups in drop-out rates or the incidence of adverse events, and no significant effects were found on BW loss and other adverse events that are associated with AChEIs. There is the caveat with memantine as with all dementia medications, however, that the BW of those prescribed may have already dropped to such low levels that no further influence of the medication is observed on BW.
The Role of Memantine in Weight Management
While memantine is primarily used to treat cognitive symptoms of dementia, research suggests it may also influence weight regulation.
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Animal Studies
Studies have shown that memantine can significantly correct the binge-like eating behavior in human and animal models. One study aimed to investigate the effects of memantine on weight loss. Male C57BL/6J mice were fed with high fat food (HF group) and standard control food (Ctrl group) for 5 months. At the end of the 5 months, the weight of mice in both groups was recorded. Then obese mice were divided into three groups, which were given saline, 5 and 20 mg/kg memantine, respectively. Long-term NMDAR antagonist treatment by memantine decreased the weight of obese mice.
Compared to the saline group mice, the percentage of body weight in mice fed with HF food diet and administered with 20 mg/kg memantine showed a significant decrease during the memantine injection days. In order to investigate whether memantine decreased the weight of obese mice by decreasing food intake, mice that fasted for 24 h were intraperitoneally injected with saline and memantine (5 and 20 mg/kg). The 5 mg/kg memantine group showed similar Ctrl food intake to the saline group. However, the 20 mg/kg memantine group significantly reduced the Ctrl food intake compared to the saline group.
Human Studies
Schaefer et al. found that memantine discontinuation and re-exposition were followed by a significant weight increase and a substantial weight loss. In a therapeutic trial in five obese women, Hermanussen et al. found that memantine could significantly suppress the appetite and binge-eating disorder and finally decrease the body weight within a few days.
Potential Mechanisms
Several studies have reported NMDAR signaling in the regulation of appetite. NMDAR signaling regulates food intake at several appetite-suppressing nodes, including the solitary tract nucleus, the parabrachial nucleus, the ventromedial nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus, and the lateral habenula. In another study, the central amygdala (CeA) region was shown to play an important role in appetite regulation.
Memantine and Binge Eating
Excessive consumption of highly palatable food has been linked to the development of eating disorders and obesity, and can be modeled in non-food-deprived rats by offering them a limited (2-h daily) access to an optional dietary fat. In three separate experiments, the consumption of a standard laboratory chow and lard were measured during 12 days of medication treatment and for 6 days afterwards. The NMDA receptor antagonist memantine (5 mg/kg, IP) significantly decreased lard consumption and increased chow consumption, comparable to effects of sibutramine; however, memantine’s effects persisted after treatment discontinuation.
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Safety and Tolerability
Memantine increased locomotor activity without severe side effect. Memantine wasn't found to induce anxiety because mice injected with memantine spent more time in the center of the open field than the control group mice. Besides, in the elevated plus maze test, mice injected with memantine spent similar time in the open arms compared to control group mice.
Other Considerations
Medical Foods
Medical foods may also provide a way to combat BW loss. For AD, three medical foods are being developed that claim to offer symptomatic relief: Axona®, CerefolinNAC®, and Souvenaid®.
Atypical Antipsychotics
Weight gain is a frequently observed adverse event in the treatment with atypical antipsychotics that significantly affects the patients' physical health and treatment compliance. During this treatment we observed a marked decrease of clozapine-induced weight gain. The causal relationship to memantine could be demonstrated using an on-off-on design with a significant increase of weight after discontinuation and again a substantial weight loss after reexposition with memantine. Beside weight, also negative symptoms improved.