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Orexigenic agents in geriatric clinical practice Vishal Viswambharan*1, Jothika N Manepalli1 & George T Grossberg1 The problem of involuntary weight loss (IWL) is more pronounced among elderly individuals with psychiatric ailments, with depression being the leading cause. The combination of precipitating factors such as multiple medical comorbidities, polypharmacy, depression and the cachexia of aging, which are unique to elderly patients, present difficulties for physicians treating these individuals. Although research has indicated that certain medications may help promote appetite and weight gain in elderly patients with IWL, as a general rule, drugs should not be considered as first-line treatment. Although the focus of this article has been limited to reviewing the evidence for current orexigenic agents that are used to treat elderly individuals who are experiencing IWL, maintaining a healthy weight is an essential element of well-being and decreased morbidity and mortality. This article will discuss the increased occurrence and risk of IWL in elderly patients and will review the various pharmacotherapeutic agents in the management of IWL.
Scope of the problem
Involuntary weight loss (IWL) is clinically defined as a loss of 5% or more of an individual’s baseline bodyweight in 1 month or a loss of 10% in a 6-month period [1] . IWL of 4–5% or more of bodyweight within 1 year, or 10% or more over 5–10 years or longer, is associated with increased mortality or morbidity or both; the rate of increased mortality ranges from 9% to as high as 38%. The loss of bodyweight and fat late in life is associated with premature death and increased risk of disability, even after excluding elderly subjects who have a pre-existing disease [2] . When examining the population admitted to either a geriatric acute care ward or a rehabilitation ward, 33% of female patients and 27% of male patients were anorexic [3] . Until recently, clinicians simply addressed the broad concept of IWL as a loss of muscle mass, sometimes combined with loss of fat; however, it is now feasible to distinguish between three categories of IWL: starvation; sarcopenia; and cachexia, each with its own root cause and prognosis [4] . Starvation is a pure deficiency in the amount of calories consumed compared with the amount of calories utilized, resulting in a loss of both fat and muscle mass. This condition can be remedied through the sole intervention of replenishing nutrients. Sarcopenia is generally characterized as an age-related loss of muscle mass, but is also seen concurrently with prolonged bed rest and physical inactivity [5,6] . Current research indicates that sarcopenia is associated with muscle atrophy, a decrease in proliferation of 10.2217/AHE.12.83 © 2013 Future Medicine Ltd
satellite cells and accumulation of intramuscular fat [7] . This condition, most commonly seen in the elderly, can result in not only poor quality of life (QoL), but, if left untreated, can lead to patient death [7,8] . Cachexia is a condition of physical wasting with loss of weight and muscle mass due to underlying illness or chronic disease. Owing to the comorbidities associated with cachexia, it is imperative for clinicians to distinguish between this condition and starvation, sarcopenia, and other possible causes of weight loss such as malabsorption, depression and hyperthyroidism [9,10] . Frailty encompasses the concepts of lethargy, sluggishness, weakness, decreased physical activity and exhaustion related to muscle loss [11] . Fried, in conjunction with other researchers, developed five criteria pertaining to a study of cardiovascular health (weight loss, hand grip strength, self-reported exhaustion, gait speed and calories expended per week) and developed a frailty phenotype that predicted future hospitalization and patient mortality [11] . Patients who were over the age of 65 years were considered frail if three or more of the above criteria were positive; whereas patients with only one or two positive criteria were ‘prefrail’, and patients who did not meet any of the criteria were deemed not frail. IWL is most commonly observed among elderly patients, affecting 13% of patients who live independently and 50–60% of nursing home residents [12,201] . Overall, the prevalence of IWL among the elderly is 15–20%, and there is little difference in prevalence between men Aging Health (2013) 9(1), 49–65
Department of Neurology & Psychiatry, Saint Louis University, 1438 S Grand Boulevard, Saint Louis, MO 63104, USA *Author for correspondence: Tel.: +1 618 534 9174 Fax: +1 314 977 4876
[email protected] 1
Keywords • cachexia • frailty • ghrelin • involuntary weight loss • megestrol acetate • orexigenic agents • sarcopenia
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ISSN 1745-509X
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Review – Viswambharan, Manepalli & Grossberg and women. This rate of occurrence can increase to as high as 27% in high-risk populations such as the independent-living frail elderly receiving community services. It is well known that in hospitals, the mortality rate in elderly patients, particularly those with low baseline bodyweight, is high. If the fluctuation from baseline weight is greater than 5% in a period of 6 months, it needs to be investigated further [1,13] . Between 2008 and 2050, the US population aged 65 years and older will more than double, and the number of people aged 85 years and older is expected to more than triple during this same time period (US Census Bureau, 2010) [202] . The first of the baby boomers turned 65 years in the year 2011, and all individuals born between 1946 and 1964 will be aged 65 years and older by the year 2030, by 2030 this will account for 20% of the overall US population [203] . The percentage of people aged over 65 years has been increasing steadily in the last several decades. According to recently available data published in 2010, there are 1.6 million people aged 65 years and older in the long-term care facilities in the USA [204] . IWL, which is considered a sentinel event in this subgroup of population, is also a major predictor for the decline in activities of daily living and increased rates of hospitalization [14,15] . Causes of IWL
IWL is a predictor for the decline in activities of daily living, higher rates of institutionalization and mortality. The most common cause of IWL is depression, followed by cancer, cardiac disorders, such as congestive cardiac failure, and benign gastrointestinal diseases, such as malabsorption [16] . Common mental health disorders, such as dementia and depression, are also associated with IWL. More than half of all cases of IWL in nursing home patients are attributable to some form of psychiatric disorder, such as depression [17] . The most common, treatable cause of anorexia is depression, and effective treatment of depression may lead to a reversal of patient weight loss [18] . The etiology of IWL is unknown in 25% of cases [1] . In patients older than 85 years, between 25 and 45% of the patient population have a diagnosis of severe dementia. Among this group of patients with severe dementia, approximately half also suffer from malnutrition [16] . Malnutrition in the elderly can also lead to complications such as anemia, immune deficiency, pressure ulcers, postoperative complications and increased 50
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mortality [19] . It has been noted that resistance to eating at meal time is a major contributor to IWL in people with dementia [20] . Simmons et al. did a crossover trial to see whether feeding assistance has a beneficial effect on overall food intakes [21] . The study found that in a total of 76 residents at risk for IWL, feeding assistance intervention at meal time had a positive impact on overall food intake and weight gain. Providing snacks between meals is an effective intervention requiring less expenditure of staff time and is more practical to implement [20,22] . When a clinical diagnosis of anorexia is made, the medical provider should begin to examine possible reversal through treatment of the underlying cause(s) of the weight loss. Clinical management of IWL in elderly patients requires a comprehensive approach involving psychological support, nutritional supplementation and often pharmacotherapy, which may include orexigenic agents. A patient’s failure to respond to nutritional supplementation should cause concern regarding possible cachexia. The primary clinical background for the study of orexigenic medications occurred during clinical observation of weight gain as a side effect of the use of these medications when treating other conditions [18] . Many clinicians prescribe orexigenic agents for the purpose of improving patient appetite and lean muscle mass [16] . According to Thomas et al., another possible use of these medications is to preclude patient morbidity and produce weight gain [18] . Many choices of pharmacotherapeutic agents are available; however, evidence underlying their use is limited, and no medications have been approved for geriatric anorexia by the US FDA. This article focuses on the efficacy of various pharmacotherapeutic agents used as appetite stimulants that are available today. Clinical conditions: patients who may benefit from orexigenics
Risk factors associated with IWL include various forms of cognitive and functional decline. Dementia, Parkinson’s disease, eating dependencies and constipation were the strongest risk factors when individual diagnoses were analyzed independently [23] . Elderly patients with dementia who are dependent on others for daily care are more likely to suffer IWL than either patients with dementia who are more independent, or patients without dementia [24] . IWL also occurs frequently in patients with Alzheimer’s disease (AD), with some indications that weight loss may occur future science group
Orexigenic agents in geriatric clinical practice –
before clinical symptoms of AD [25] . During the progression of AD, patients have been known to develop either pseudobulbar dysphagia or a loss of appetite [26] . In patients with AD, the patient’s IWL correlates with disease progression, and a weight loss of at least 5% of their baseline bodyweight is considered a significant predictor of death [27] . The prevalence of depression in nursing home residents ranges from 36 to 58% [28,29] . IWL is one of the key symptoms associated with a diagnosis of depression, and has also been noted to be present with bipolar, delusional and paranoid disorders, as well as with alcohol abuse [30] . Comprehensive psychotropic medication history is a valuable tool in analyzing patients with IWL and depression. It is well known that some selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine, have an anorexic effect [31] . Similarly, sedatives and narcotic analgesics may interfere with cognition and the ability to eat [32] . Conversely, subtherapeuctic dosage of this medication may not ameliorate depression, which itself can lead to poor oral intake [29,33] . Table 1 lists drugs which may cause anorexia/weight loss, either directly, or via troublesome side effects. Review of the evidence: levels of evidence
For this article, a comprehensive literature review via PubMed and Medline was performed. Although a simple PubMed search with the terms ‘orexigenics’ and ‘elderly’ yielded 122 articles, the articles on the use of specific orexigenic agents in the elderly population were limited. The other relevant search terms were: weight loss, nursing home, appetite stimulants, mirtazapine, dronabinol, megesterol acetate, cyproheptadine, tricylic antidepressants (TCAs), ornithine oxoglutarate, oxandrolone, growth hormone, ghrelin, testosterone and metoclopramide. Any studies or reviews dealing with the use of orexigenics/ appetite stimulants specifically in the elderly were focused on, in addition to reviews on appetite stimulants in HIV, AIDS and cancer populations. The recommendations mentioned in this paper are based on the levels of evidence published by the US Preventive Services Task Force [205] . Although several orexigenic agents are available, none of them have been validated in the treatment of IWL in the elderly population [34] . Before initiating treatment with orexigenic agents, the etiology of weight loss, as well as patients’ goals of care. Although widely prescribed in people with end-stage dementia, orexigenic agents may not be as effective compared with future science group
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other therapeutic agents used in this subgroup, owing to the lack of significant improvement in the patients’ ‘sense of well being’ [20,27] . Most of the evidence for the use of orexigenic agents involves younger patients with AIDS and cancer. Very few trials are available validating the use of these mediations in the elderly population. In this article, the authors identified all published reports on the use of orexigenic agents for the treatment of appetite/weight loss and known adverse events associated with these drugs. Atypical antipsychotics
Atypical antipsychotics are the primary type of pharmacotherapy for patients with schizophrenia, and they are also often utilized for patients with dementia accompanied by psychosis, aggression, severe agitation and behavioral disturbances [35] . Weight gain associated with taking atypical antipsychotics has been reported in younger patients, but data are scarce regarding possible weight gain in adults aged 65 years and older (Table 2) [36] . Weight gain is now recognized as a significant side effect of antipsychotic medication that may be paradoxically beneficial in elderly patients with IWL [37] . An increase in weight of 7% or more from baseline is considered to be significant [38] . Schneider et al. did a doubleblind, randomized clinical trial in 421 patients with AD looking into the effect of secondgeneration antipsychotics on agitation and psychosis [39] . During the course of this study, 6–11% of patients were noted to have a weight gain of more than 7%. Of the three secondgeneration antipsychotics evaluated, olanzapine and risperidone were associated with an average weight gain of 0.4–1 lb/month. Lipkovich et al. analyzed the weight gain effect of olanzapine in patients with varying BMIs [36] . The study found that olanzapine with a dose range of 2.5–7.4 mg/dl was associated with significant weight gain in the range of 1.22–1.29 kg (p = 0.006) in patients who are underweight (BMI
