Orexigenic Agents in Geriatric Clinical Practice

Vishal Viswambharan; Jothika N Manepalli; George T Grossberg

Aging Health. 2013;9(1):49-65.

Abstract and Introduction

Abstract

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.

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Next Section

Abstract and Introduction
Scope of the Problem
Causes of IWL
Clinical Conditions: Patients Who May Benefit From Orexigenics
Review of the Evidence: Levels of Evidence
Atypical Antipsychotics
Conclusion
Future Perspective
References
Sidebar

Table 1. Therapeutic agents and their adverse effects that may contribute to weight loss.
Therapeutic agents	Adverse effects
Alcohol	Dysguesia or dysosmia or both, dry mouth
Amphetamines	Dysguesia or dysosmia or both, anorexia
Antihistamines	Dysguesia or dysosmia or both, dry mouth
Antibiotics (e.g., ciprofloxacin, clarithromycin, ethambutol, griseofulvin, ofloxacin, pentamidine, rifabutin and tetracycline)	Dysguesia or dysosmia or both, nausea or vomiting or both
Antibiotic (atovaquone)	Dysguesia or dysosmia or both, anorexia
Antibiotic (doxycycline)	Dysguesia or dysosmia or both, dysphagia
Anticholinergics	Dysguesia or dysosmia or both, dysphagia
Anticonvulsants (carbamazepine and phenytoin)	Dysguesia or dysosmia or both
Antihypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, nitroglycerin, propranolol and hydralazine)	Dysguesia or dysosmia or both
Antiparkinsonian (amantadine)	Nausea or vomiting or both, anorexia
Bisphosphonates (etidronate and alendronate)	Dysguesia or dysosmia or both, nausea or vomiting or both, dysphagia
Chemotherapeutic agents	Dysguesia or dysosmia or both, dysphagia
Cocaine	Dysguesia or dysosmia or both
Corticosteroids, NSAIDs and quinidine	Dysphagia
Clonidine and loop diuretics	Dry mouth
Diuretics (acetazolamide, hydrocholorothiazide and spironolactone)	Dysguesia or dysosmia or both
Dopaminergic (levodopa)	Dysguesia or dysosmia or both, nausea or vomiting or both, dysphagia, anorexia
Digoxin, hormone replacement therapy and phenytoin	Nausea or vomiting or both
Gold	Dysguesia or dysosmia or both, dysphagia, anorexia
Iron supplements	Dysguesia or dysosmia or both, nausea or vomiting or both, dysphagia
Metformin	Dysguesia or dysosmia or both, nausea or vomiting or both, anorexia
Metronidazole	Dysguesia or dysosmia or both, nausea or vomiting or both
Methylphenidate	Dysguesia or dysosmia or both, anorexia
Mood stabilizer (lithium)	Dysguesia or dysosmia or both
Neuroleptics	Withdrawal can cause nausea, anorexia
Opiates	Dysguesia or dysosmia or both, nausea or vomiting or both, anorexia
Potassium supplement	Nausea or vomiting or both, dysphagia
Serotonergics	Nausea or vomiting or both, anorexia
Statins	Dysguesia or dysosmia or both, nausea or vomiting or both
Theophylline	Dysphagia, anorexia
Tricyclics	Dysguesia or dysosmia or both, nausea or vomiting or both
Allopurinol, chloral hydrate, methimazole, nasal vasoconstrictors, pencillamine, pergolide, selegiline, sodium cromoglycate, terbinafine, tobacco products and triazolam	Dysguesia or dysosmia or both
Anticonvulsants (e.g., benzodiazepines and topiramate), decongestants, digitalis, nicotine	Anorexia

Table 2. Levels of evidence for the use of orexigenic agents in the elderly.
Study (year)	Type of study	Level of evidence	Outcomes	Ref.
*Atypical antipsychotics*
Allison et al. (1999)	A meta-analytic study of 81 treatment trials (18 had placebo comparisons)	I	Clozapine posed the highest risk of patient weight gain, followed by olanzapine and quetiapine	[43]
Schneider et al. (2006)	Randomized double-blinded clinical trial	I	6–11% of patients (0.4–1 lb per month) were noted to have a cumulative weight gain of more than 7%	[39]
Lipkovich et al. (2007)	Post hoc analysis of 1267 patients	II-3 or III if the result is very significant	Gaining more than 7% of initial bodyweight was significantly greater in patients treated with olanzapine, vs 296 patients who received another comparator drug (risperidone or a conventional antipsychotic drug)	[36]
Sitburana et al. (2008)	Case–controlled study involving 28 Alzheimer's disease patients	II-2	BMI for 28 Alzheimer's disease patients on atypical antipsychotics increased 0.01 kg/m²/month	[45]
Mathys et al. (2009)	A retrospective chart review at a Veterans Affairs Medical Center	III	Weight gain (≥7% of baseline weight) occurred in 8.92% of the 56 eligible elderly patients	[44]
Albert et al. (2009)	A retrospective chart review	III	The study found that 20 subjects (13%) gained more than 5% of bodyweight, whereas 49 (32%) lost more than 5% of bodyweight	[35]
*Dronabinol*
Volicer et al. (1997)	A randomized, double-blind, placebo-controlled crossover design study	I	Patients' bodyweight increased more during the dronabinol treatment than during the placebo periods	[57]
Wilson et al (2007)	A 2007 retrospective observational study	III	15 subjects (53.5%) on dronabinol gained weight, of which 10 (67%) gained more than 5 lbs and 6 (40%) gained more than 10 lbs	[58]
*Megestrol acetate*
Karcic et al. (2002)	Retrospective chart review	III	With megestrol acetate treatment, all of the nutritional parameters improved (p < 0.05)	[106]
Yeh et al. (2000)	A randomized, double-blind, placebo-controlled trial	I	3 months after treatment concluded, weight gain was significantly increased in patients treated with megestrol acetate	[59]
Sullivan et al. (2002)	Prospective observational study	II-2	Nursing home residents who received appetite stimulants (12% of the sample) were 70% more likely than their counterparts to gain weight	[60]
Simmons et al. (2004)	Nonrandomized clinical trial	II-2	Megestrol acetate had a significant positive effect on patient food and fluid intake when the patient also received optimal meal time feeding assistance	[63]
Reuben et al. (2005)	A randomized, placebo-controlled clinical trial	I	After 20 days, the 800-mg treatment group's appetite was better than at baseline (p = 0.04) and at the 42-day point, the 400-mg treatment group's appetite at the start of the last meal was better than at baseline (p = 0.02)	[64]
Sullivan et al. (2007)	A randomized, double-blind/single-blind, placebo-controlled study	I	These results suggest that weight gain with megestrol acetate is correlative to an increase in body fat	[65]
Bodenner et al. (2007)	Retrospective case–controlled cohort study	II-2	Megestrol acetate treatment of elderly nursing home residents with significant weight loss was associated with a significant increase in all-cause mortality without a significant increase in weight	[107]
*Mirtazapine*
Goldberg (2002)	Retrospective chart review	III	The study concluded that elderly depressed patients, including those with dementia, are equally likely to gain weight with mirtazapine or sertraline when treated over a 4-month period	[75]
Schatzberg et al. (2002)	A randomized, double-blind study	I	Mirtazapine produced modest increases from baseline in mean bodyweight, whereas paroxetine was associated with slight decreases from baseline in mean bodyweight	[76]
Mihara et al. (2005)	Retrospective cohort study	II-2	The impact of using mirtazapine on weight was not statistically different from other nontricyclic antidepressants	[72]
Cakir and Kulaksizoglu (2008)	A 12-week open-label, prospective study	II-3	A more regular patient appetite was reported by caregivers but the study showed no difference in patient weight	[108]
*Tricyclic antidepressants*
Rigler et al. (2001)	Retrospective cohort study	III	Tricyclic antidepressants do not facilitate weight gain more than other antidepressant groups	[82]
*Ghrelin*
Cappola (2009)	Small randomized, double-blind, pilot study	II-1	The women who received the ghrelin infusion consumed 51% more calories than the placebo group, due to increased carbohydrate (p = 0.005)	[87]
*Growth hormone*
Blackman et al. (2002)	Randomized, double-blind placebo-controlled parallel group trial	I	The results showed that growth hormone increased the patient's lean body mass and decreased fat mass, whether it was administered with the sex steroids or alone	[91]
Chu et al. (2001)	8-week randomized trial of recombinant human growth factors	I	Increased their lean body mass, albumin and hemoglobin levels	[92]
*Ornthine oxigluatarate*
Brocker et al. (1994)	Randomized double-blind trial	I	Two months after the end of treatment, the values were: nutritional status (1.7 ± 0.5 vs 1.2 ± 0.7; p < 0.001), appetite (62 ± 19 vs 47 ± 23; p < 0.001), appetite for meat (p < 0.001), and weight gain (2172 ± 1912 vs 925 ± 1652 g; p < 0.01)	[97]
*Testosterone*
Bhasin et al. (2005)	Randomized, double-blind, placebo-controlled study	I	Increase in free fat mass and leg press muscle strength from baseline	[102]
Chapman et al. (2009)	Small single-center, randomized, placebo-controlled clinical trial	II-1	When compared with the no-treatment group, the combined-treatment group not only had significantly fewer subjects admitted to hospital (0 compared with 5; p = 0.03), but also fewer days in hospital (0 compared with 74; p = 0.041), and a longer time to hospital admission (p = 0.017)	[103]
Hyde et al. (2010)	Prospective cohort study	II-2	Researchers concluded that lower free testosterone levels (odds ratio: 1.22; 95% CI: 1.05–01.42) predicted frailty	[109]
O'Connell et al. (2011)	Single center, randomized, double-blind, placebo-controlled trial study	I	The study concluded that the effects of 6 months of testosterone treatment on muscle strength, lean mass and quality of life in frail men are not maintained at 6 months post-treatment	[105]

Table 3. Recommended doses and common side effects of orexigenic agents in the elderly.
Drug name	Dose range	Side effects	Comments
Cyproheptadine	Total daily dose for adults should not exceed 0.5 mg/kg/day (0.23 mg/lb/day) The therapeutic range is 4–20 mg a day, with the majority of patients requiring 12–16 mg a day	Sedation, dizziness, urinary retention, confusion and constipation	No randomized trials of cyproheptadine have studied the medicine's effects in geriatric patients
Dronabinol	2.5 mg initially in the evening Increase to 5 mg per day after 2–4 weeks	Sedation, fatigue and hallucinations
Oxandrolone	2.5 mg two- to four-times/day	Masculinization in women, fluid retention, hepatic toxicity, prostatic hypertrophy and psychiatric disturbances	No long-term care studies available
Megestrol acetate	400–800 mg per day	Edema, hypertension, deep vein thrombosis and adrenal suppression
Mirtazapine	The usual starting dose for mirtazapine is 15 mg once daily, usually at bedtime. Doses may be increased every 1–2 weeks up to a maximum dose of 45 mg daily. It may be taken with or without food	Dose-dependent drowsiness, dry mouth, increased appetite, weight gain and dizziness. Most serious side effect is agranulocytosis
Testosterone	125 mg/week deep intramuscular	Increase in hematocrit, leg edema with shortness of breath, urinary retention and prostate cancer	Doses of 300 and 600 mg/week produces a high incidence of adverse effects
Growth hormone	Usually based on bodyweight: 0.006 mg/kg (0.0027 mg per lb)	Carpal tunnel syndrome, arthralgias and increased death	Risk of severe side effects

Sidebar

Executive Summary

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 loss of 10% in a 6-month period.
Sarcopenia is age-related loss of muscle mass; if left untreated, it can lead to patient death.
IWL is observed in 50–60% of the nursing home residents and 13% of the elderly living independently.

Causes of IWL

The most common cause of IWL is depression, followed by cancer.
Clinical management of IWL in elderly patients requires a comprehensive approach involving psychological support, nutritional supplementation and often pharmacotherapy, which may include orexigenic agents.
An increase of 7% or more from baseline bodyweight is considered to be significant.

Clinical conditions: patients who may benefit from orexigenics

Weight gain is not recognized as a significant side effect of antipsychotic medication.
Of all the antipsychotics, clozapine is associated with the highest weight gain and ziprasidone with the least.
Other drugs associated with weight gain are olanzapine, risperidone and quetiapine.

Cyproheptadine

Evidences for its use as an orexigenic agent is mostly in pediatric population.
Cyproheptadines potent anticholinergic and antiserotonergic effects preclude its use in both elderly patients and patients treating with selective serotonin reuptake inhibitors (SSRIs), respectively.

Dronabinol

Dronabinol has been found to be beneficial in increasing weight in patients with Alzheimer's disease, although no randomized, double-blinded, placebo-controlled trials in the elderly population have been completed exclusively for weight loss.
The usual starting dose is 2.5 mg before bed time and then the dose can be titrated up to 5 mg/day.

Megestrol acetate

Megestrol acetate tends to increase patients' fat mass, necessitating the implementation of an exercise program.
Megestrol acetate should be avoided in bed-bound patients, owing to the risk of venous thromboembolism.
Testosterone supplementation should be considered in men treated with megestrol acetate due to the risk of impotence.
Doses of 400 mg/day can be associated with a significant risk for secondary adrenal insufficiency.

Mirtazapine

The weight gain effect of mirtazapine is due to increased norepinephrine effect, and has a ceiling effect at doses of 15 mg/day.
Mirtazapine should be considered as an option when there is a significant element of depression along with weight loss.

Tricyclic antidepressants

Tricyclic antidepressants, unlike SSRIs, are associated with a weight gain of approximately 10% of the initial bodyweight.
Propensity of weight gain is more with amitriptyline and imipramine.

Ghrelin

Ghrelin, a circulating hormone, has been used to facilitate appetite, but its effect is short-lived.
It is not US FDA approved, nor commercially available.

Metoclopramide

Metoclopramide can worsen Parkinson's disease and produce delirium.

Growth hormone

Recombinant human growth hormone has been associated with an increase in lean body mass and reduction in adiposity.
A significant drawback is the high cost and side effects such as carpal tunnel syndrome and gynecomastia.

Ornithine oxoglutarate

Ornithine oxoglutarate, a medication used to treat hyperammonemia, has been noted to improve nutritional status and has been associated with weight gain in one two-center randomized double-blind trial.

Oxandrolone

Oxandrolone, a testosterone analog, has not been studied in the elderly for IWL.
Prostate cancer can be stimulated by this medication.

Testosterone

Testosterone replacement therapy has been found to increase muscle mass strength.
Elderly men who are losing weight should be considered for supplementation if their testosterone level is low.