Orexigenic Agents in Geriatric Clinical Practice

Vishal Viswambharan; Jothika N Manepalli; George T Grossberg

Disclosures

Aging Health. 2013;9(1):49-65. 

In This Article

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 double-blind, randomized clinical trial in 421 patients with AD looking into the effect of second-generation 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 second-generation 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 <18.5 kg/m2) and normal weight (BMI 18.5–24.9 kg/m2), compared with those who are overweight and obese whose weight gain was in the range of 0.53–0.56 kg.[36]

The weight gain associated with olanzapine in younger patients was analyzed in a double-blind, placebo-controlled trial in patients with anorexia nervosa. Similar to elderly patients treated with olanzapine, the patients were able to achieve more rapid weight gain and improvement in their obsessive symptoms.[40] The weight gain associated with antipsychotic medications can happen within a few months of the initiation of treatment and can take up to a year to stabilize. The average weight gain ranges anywhere from 1 to 11 lbs. The precise physiological cause remains undetermined.[41]

During a year-long, randomized, double-blind study by McEvoy et al. comparing the weight gain of commonly used second-generation antipsychotic medications, 80% of the patients in the olanzapine, 50% in the quetiapine and 58% in the risperidal group had significant weight gain.[42]

Similarly Allison et al. did a meta-analysis looking at medication-induced weight gain of various antipsychotic medications at 52 weeks.[43] In this study, clozapine has the maximum weight gain of 3.99 kg (8.80 lbs) followed by olanzapine (3.51 kg [7.74 lbs]), while ziprasidone (0.04 kg [0.09 lbs]), and molindone (-0.41 kg [-0.89 lbs]) were not associated with any significant weight gain. In another study, the effect of weight gain with atypical antipsychotic medications was retrospectively analyzed in veterans aged 65 years or older with a primary diagnosis of dementia. A total of 8.92% of the elderly patients were found to have a significant weight gain in this study.[44]

In a case–controlled study involving 28 Alzheimer's patients, researchers measured the BMI of patients before and after taking atypical antipsychotics such as quetiapine and clozapine. They found an increase of BMI of 0.01 kg/m2/month in this subgroup of population.[45] This type of weight gain may not always be contraindicated, particularly for elderly patients suffering from dementia and/or AD, who may otherwise require pharmacological enhancement of their appetite or nutritional supplements.[35] Factors responsible for weight gain due to antipsychotic medications may be due to antagonism of histamine and serotonin receptors inducing peripheral insulin resistance and increased prolactin levels.[46] Other nonpharmaceutical factors such as age, associated illness and overall positive response to the antipsychotic medication may also contribute to the weight gain.[16]

The effect of antipsychotic medications on serum ghrelin, an orexigenic hormone secreted by the stomach, may partially explain the weight gain associated with this medication. Paradoxically, a decrease in serum ghrelin level has been noted during the initial period of treatment with antipsychotic medications.[47] Quetiapine is the only medication which is not associated with elevated ghrelin levels.[48] Unpredictable orexigenic action of atypical antipsychotics, especially clozapine and olanzapine, may lead to metabolic syndrome and diabetes, thus precluding its use in people with a higher BMI.[49,50] Another rare but significant side effect that the physician needs to be cognizant of is the occurrence of neuroleptic malignant syndrome; a life-threatening illness.[51]

The use of antipsychotics to promote weight gain in the elderly is 'off-label', and the potential benefits of weight gain have to be weighed against the risks of side effects. Specifically, the 'black-box' warning relative to increased mortality in older patients with dementia. The 'warning' applies to all antipsychotic drugs, old and new.

Cyproheptadine

Cyproheptadine is an antihistaminic, anticholinergic and antiserotoninergic medication that is known to cause a mild increase in appetite.[1] Much of the data regarding its benefit as an orexigenic medication occurred during studies involving pediatric patients.[1] No randomized trials of cyproheptadine have studied the medicine's effects in geriatric or Alzheimer's patients with IWL.[1] The medication's side effects of drowsiness, dizziness and confusion may make its use particularly problematic in elderly patients.[52] Because of its potent anticholinergic side effects, the use of cyproheptadine in the elderly is not recommended. The use of cyproheptadine as an orexigenic agent in cancer patients has been shown to increase appetite, but has failed to demonstrate any net weight gain.[18,53] Furthermore, because of its antiserotonergic action, concomitant use with SSRIs may decrease the efficacy of SSRIs.[54]

Dronabinol

Anecdotal evidence shows that dronabinol, a cannabinoid derivative, leads to weight gain and appetite stimulation among patients.[55] A study of the subjective effects of cannabis demonstrated several effects correlative to appetite stimulation and weight gain, including an increased desire for food, improved taste and smell, as well as an overall improvement in patient mood and decrease in pain.[56] This drug has been found to be beneficial in gaining weight in patients with AD[57] and for the treatment of anorexia for HIV patients with AIDS.[55] There are no randomized trials of dronabinol in elderly people with weight loss; however, dronabinol has been studied in one trial involving patients with AD who were refusing food.[57]

A randomized double-blind placebo-controlled crossover design study by Volicer et al. analyzed the efficacy of dronabinol in patients with AD.[57] A total of 15 patients were analyzed for a period of 6 weeks. Of these, 11 completed the study period. Compared with the placebo group, treatment with dronabinol resulted in an increase in basal bodyweight.[57] The most common adverse reactions associated with these medications are somnolence, tiredness and euphoria, which are usually resolved in 2–3 days. Higher dosages may be associated with ataxia, hallucinations and amnesia.[16]

Another retrospective observational study by Wilson et al., involving 28 residents of five different long-term care facilities with a mean age of 79.5 ± 19.8 years who were treated with dronabinol for a period of 12 weeks, showed a mean weight gain of 3.0 ± 8.01 lbs (Table 2).[58] Those patients who failed to respond to dronabinol had an increased risk of death.[58] In view of the side-effect profile of this medication, it is advisable to start dronabinol at 2.5 mg before bed time and titrate the dose up to 5 mg/day within 2–4 weeks depending upon the clinical response.[56]

Megestrol Acetate

Megestrol acetate is a commonly used orexigenic agent that increases a patient's appetite due to the alteration of the neurotransmitters that regulate food intake.[56] Various studies have noted an elevated cytokine concentration in patients who have weight gain with megestrol acetate.[59] Unlike other orexigenic agents, megestrol acetate tends to increase the patient's fat mass, necessitating implementation of an intense exercise program so that nonfat mass may also increase. Evidence regarding the treatment of megestrol acetate in the elderly is limited (Table 2).[1] Owing to the lack of clinical research on this issue, the optimal duration in geriatric patients is unknown.[13]

Sullivan et al. studied the effect of orexigenic agents and weight loss and their effect on mortality in 1000 nursing home patients for a period of 6 months.[60] Weight loss during the study period was associated with doubling the risk of death. The residents who received appetite stimulants were 70% more likely than their counterparts to gain weight, with the effect more pronounced in the younger age group.

Another retrospective study suggested that megestrol acetate at dosages ranging from 80 to 400 mg effectively reversed IWL in nursing home patients after 3 months of use.[61] In a randomized, double-blind, placebo-controlled trial, Yeh et al. studied the efficacy of megestrol acetate at a dose of 800 mg/day on 69 nursing-home residents with a mean age of 76 ± 1.3 years for a 12-week treatment period and 13-week follow-up.[59] At the end of the study period, the treatment group showed significant improvement in appetite, with no significant difference in weight gain. However, at the end of the follow-up period, 60% of the treated patients had a significant weight gain compared with 21% in the placebo group. The full effect of the megestrol acetate may not be seen until the completion of at least 5–6 months of treatment.[59] In a randomized, double-blind placebo-controlled study conducted at a long-term care facility, 800 mg of megestrol acetate was associated with a significant increase in weight, with the effect being more pronounced in women than in men.[62]

Simmons et al. conducted a nonrandomized clinical trial on the effect of megestrol acetate on food and fluid intake in nursing home residents with an average age of 91.9 ± 5.8 years.[63] The participants received 400 mg of megestrol acetate daily for a period of 63 days. It was found that megestrol acetate in the setting of concurrent optimal feeding assistance had a positive impact on overall food and fluid intake.[63] The study is limited by the lack of a control group and the small overall sample size of only 17 participants.

Reuben et al. conducted a randomized, placebo-controlled clinical trial on 49 skilled nursing home patients with an average age of 83.6 years and a recent history of hospitalization for acute illness of injury in the preceding 3 weeks.[64] The patients were randomized to receive megestrol acetate at either 200, 400 or 800 mg or to the placebo group. At the end of the study period the treatment group who received 400 mg showed a significant increase in pre-albumin compared with the placebo group. However, as the dose of megestol acetate increased, it was found to have a profound effect on the cortisol level, particularly at doses above 400 mg, and the effect may be persistent. They also found no additional benefit for nutritional or clinical outcome with higher doses.[64]

Sullivan et al. through his randomized, double-blind/single-blind, placebo-controlled study demonstrated that the weight gain effect with megestrol acetate corresponds with body fat, rather than an increase in lean body mass.[65] It should be questioned whether this type of weight gain has any beneficial effect on morbidity and mortality in elderly patients. Megestrol acetate should not be considered as an isolated intervention to promote weight gain and improve other markers of nutritional status in geriatric patients, as the results obtained are, at best, inconsistent. Because of its risk of venous thromboembolism, megestrol acetate should be avoided in patients who are bed bound. As already mentioned, megestrol acetate causes secondary adrenal insufficiency at doses above 400 mg.[18] Testosterone supplementation should be considered in men treated with megestrol acetate due to its risk for impotence.[18,56] Other rare side effects include vaginal spotting and bilateral pitting edema.[56]

Mirtazapine

Mirtazapine is an antidepressant with multireceptor α-2 noradrenergic presynaptic antagonist/serotonergic agonist properties.[66] Mirtazapine has antagonizing action at the presynaptic receptor which, in turn, increases noradrenergic transmission. While mirtazapine has agonist properties on the 5-HT1 receptor, it has antagonistic properties on the 5-HT2 receptor.[67] According to Morley, it is this combination of effects on the noradrenergic and serotonergic receptors that is suggestive of the specific appetite-enhancing effects of mirtazapine.[56] Patients suffering from depression are generally recommended to receive treatment with orexigenic medications without dietary restrictions.[13] Patients taking mirtazapine often report to having a voracious appetite and craving carbohydrates, specifically.[68] Treatment of depression may, in and of itself, cause weight gain.[17] Clinical studies reviewing the use of mirtazapine have shown that this medication increases patient appetite and promotes weight gain while simultaneously treating underlying depression.[69] For example, one case report discusses a patient with major depressive disorder who gained 6.5 kg in 1 week after administration of 30 mg of mirtazapine.[70]

Weight gain is the most common reported side effect of mirtazapine, and clinicians frequently prescribe it for the purpose of fostering patient weight gain.[18] Mirtazapine seems to cause substantial weight gain early in therapy.[69] For instance, in a study that compared 4 weeks of therapy of mirtazapine and venlafaxine, patients treated with mirtazapine experienced a mean weight gain of 2.4 kg after just the first week of therapy, whereas the patients treated with venlafaxine showed a decrease of 0.4 kg during the 4 weeks of treatment.[71]

Some researchers have suggested that mirtazapine is the antidepressant of choice for older patients experiencing depression and weight loss.[56] One study compared treatment of geriatric depression with trazodone and with mirtazapine, and researchers found that the patients treated with mirtazapine were significantly more likely to experience increased appetite and weight gain (mean weight gain 1.3 kg).[16]

Mihara et al. did a retrospective cohort looking at the effect of mirtazapine and other antidepressants in inducing significant weight change.[72] They found no statistically significant difference in weight change in patients who are on mirtazapine compared with nontricyclic antidepressants. The study concluded that mirtazapine had no statistically significant difference in weight gain compared with other nontricyclic antidepressants.[72]

In an 8-week open-label study of 103 outpatients with Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV (American Psychiatric Association 1994) major depressive disorder complicated by failure to respond to (or intolerance of) treatment with fluoxetine, paroxetine or sertraline, the patients were instead treated with mirtazapine. Increased appetite was exhibited in 29.7% of subjects and weight gain occurred in 22.8%. Clinicians have utilized these 'adverse' effects of mirtazapine in AIDS and cancer patients for anorexia and cachexia.[73] Studies conducted relative to the effects of mirtazapine in cancer-related cachexia/anorexia which are not limited to elderly patients have also yielded promising results.[74]

Goldberg et al. conducted a retrospective chart review on the effect of mirtazapine at a dose of 7.5–45.0 mg/day and sertraline at a dose of 25–100 mg/day on weight changes involving 50 nursing home residents with an age range of 59–98 years and with a history of depression.[75] Unlike the previously mentioned study, it was found that the chance of weight changes with mirtazapine was not significantly different from sertraline for the same duration.[75]

Another randomized, double-blind study by Schatzberg et al. compared the efficacy of mirtazapine and paroxetine in elderly patients with major depression for a period of 24 weeks.[76] It was found that more patients on mirtazpine had a positive impact in weight gain compared with patients with paroxetine (14.3 vs 3.6%). Similarly, mirtazapine was found to have a beneficial effect on the mean bodyweight when compared with the other commonly used agents citalopram, fluoxetine and paroxetine.[76]

Weight gain of mirtazapine is primarily due to its additive effect on noradrenergic transmission. Efficacy of mirtazapine in increasing appetite and weight has a ceiling effect at doses of 15 mg/day.[67] The most serious, but rare, side effect of mirtazapine is agranulocytosis, which is reversible.[77] Other common side effects are dose-dependent drowsiness, dizziness and dry mouth.[78] Since it is well tolerated in the elderly, it is now a common practice to use this medication to treat geriatric patients with unintended weight loss. This approach may work well for patients with underlying depression; however, mirtazapine may not be particularly advantageous compared with other antidepressants when weight loss is a predominant symptom (Table 2).

Tricyclic Antidepressants

The weight gain effect of TCAs in the elderly is unpredictable to younger patients who consider this an unpleasant side effect.[20] Exposure to TCAs in the elderly is associated with weight gain, unlike SSRIs which are associated with a decrease in weight.[16] A total of 15% of those patients treated with TCAs gain 10% of their initial bodyweight over the course of treatment.[79] Sussman et al. retrospectively analyzed data from clinical trials that showed propensity for weight gain to be more in patients taking imipramine, a commonly prescribed TCA, when compared with the antidepressant nefazodone, as well as with the commonly prescribed SSRIs fluoxetine, sertraline and paroxetine.[80] Among all TCAs of its class, amitriptyline and imipramine are associated with more significant weight gain.[81]

The effect of TCAs on weight gain in the elderly has been disputed in a retrospective cohort study carried out by Rigler et al. in nursing home residents (Table 2).[82] This study showed that SSRIs have a modest association with weight gain, unlike TCAs which did not show any association. This study challenged the widely-prevalent belief among the medical community that TCAs may be a better choice as an antidepressant in frail elderly patients.[82]

Miscellaneous Agents

Ghrelin. Ghrelin is a circulating orexigenic agent primarily produced by the stomach and duodenum that facilitates appetite and oral intake, the effect of which is short lived.[83] It has also shown that, in anticipation for food intake, it has a stimulatory effect on acid secretion and food intake.[84] Serum ghrelin levels increase with fasting where as food intake has an opposite effect.[83] Various studies have shown that the beneficial effect of ghrelin on weight gain is created by decreasing the latency period between food, resulting in more frequent food intake.[85] Ghrelin has also shown to induce hunger and food intake among healthy and obese humans.[86] Data show that circulating ghrelin concentration levels increase when obese humans lose weight, and decrease when anorexic patients gain weight.[86] Exogenous ghrelin has demonstrably stimulated patients eating when administered during episodes of limited or minimal food intake.[83]

In a small randomized, double-blind, pilot study by Cappola et al., five women aged 70 years or older were studied and received weekly infusions of ghrelin (2.5, 5 or 10 pmol/kg/min for 60 mins each) or placebo, with the order of ghrelin and placebo infusions randomized.[87] All of the women studied had demonstrated an IWL of >5% in the last year and two of the four standard criteria for frailty (i.e., exhaustion, weakness, slow walking speed and low physical activity), compared with a control group which included five healthy women. The women who received the ghrelin infusion consumed 51% more calories than the placebo group, due to increased carbohydrate (p = 0.005) and protein (p = 0.04) intake, rather than fat (p = 0.38) (Table 2).

A limitation of this compound is that it is not FDA-approved or commercially available.

Metoclopramide. Delayed gastric emptying is known to be associated with decreased hunger in elderly patients.[88] Most pharmaceuticals that enhance gastric emptying are antidopaminergic agents such as metoclopramide, a prokinetic agent. Metoclopramide has been shown to decrease anorexia, bloating and nausea among patients with advanced cancer.[89] However, metoclopramide is known to cross the blood–brain barrier; consequently this medication can worsen Parkinson's disease and produce delirium.[56] Overall, studies indicate that gastroprokinetic agents such as metoclopramide are limited in efficacy regarding increase in food intake among older patients, unless the patients have severe delays in gastric emptying.

Anabolic Agents

Growth Hormone. Recombinant human growth hormone has been shown to produce weight gain, particularly an increase in lean body mass, and reduction in adiposity in residents of long-term care facility (Table 2).[18,90] The effect of growth hormone on weight gain was studied by Blackman et al. among healthy community-dwelling older adults (aged 65–88 years) in a 26-week randomized, double-blind, placebo-controlled parallel group trial of 131 patients.[91] The study examined if the effect of growth hormone in combination with sex steroids had a beneficial effect. The patients were administered an initial dose of 30 µg/kg followed by 20 µg/kg of growth hormone subcutaneously three-times per week. It was found that growth hormone had a beneficial effect on the lean body mass independent of sex steroids, while decreasing the fat mass.[91,92]

A similar double-blind, placebo-controlled study of ten frail elderly men aged 60 years and over demonstrated that growth hormone increased the bodyweight as well as the mid-arm circumference.[93] Though clinically beneficial, the significant drawback is the high cost and possible debilitating side effects, such as carpal tunnel syndrome, and cosmetic side effects, such as gynecomastia.[94] Owing to the increased risk of mortality in nonclinical settings and lack of evidence for safety, its use is not recommended in elderly patients with IWL.[95]

Ornithine Oxoglutarate. Anabolic steroids and pharmaceuticals with anabolic properties (e.g., oxandrolone and ornithine) have been used with some success to treat wasting syndrome in patients with AIDS and cachexia in patients with cancer.[96] Ornithine oxoglutarate, a glutamine precursor,is a medication used to treat hyperammonemia in encephalopathy and was noted to improve patient's nutrition status.[97] Ornithine oxoglutarate led to weight gain among a geriatric population with IWL in one randomized trial but has not been studied further.[1] Its efficacy on weight gain in the geriatric population was compared by Brocker et al. in a two-center randomized, double-blind trial.[97] Although a total of 194 elderly patients with a mean age of 74 ± 8 years who were recovering from acute illness participated in the study, nine patients withdrew from the study. A total of 185 patients received either ornithine oxoglutarate at a daily dose of 10 mg after lunch or placebo for a 2-month period with a follow-up period of 4 months. At the end of the 2-month treatment period, the treatment group had a significant improvement in appetite with a weight gain of 2172 ± 1912 g versus 925 ± 1652 g (Table 2). The positive effect on appetite and weight gain persisted 2 months after treatment. There was also a significant improvement in the QoL index in the treatment group. Ornithine oxoglutarate should be considered as a cost-effective nutritional supplement for elderly convalescent patients.[97]

Oxandrolone. Oxandrolone, a testosterone analog approved by the FDA, has not been studied in the elderly for IWL.[13] The most commonly prescribed dose of 10 mg twice-daily has demonstrated results of weight gain, particularly in patients with chronic obstructive pulmonary disease.[98] Typically, owing to the side-effect profile, it is reserved for patients with profound cachexia.[56] Hepatotoxicity, fluid retention, worsening of prostatic hypertrophy leading to urinary retention, hypogonadism and testicular atrophy are the side effects that may arise in elderly patients exposed to this medication.[55] Prostate cancer, a common ailment in the elderly, could potentially be stimulated by this medication.[55]

Testosterone. Testosterone replacement therapy in men with testosterone deficiency has shown to increase muscle mass, strength and overall functionality (Table 2).[18] An average treatment in hypogonadal men resulted in 1.7 kg in fat free mass and increased lean body mass and grip strength for men older than 45 years of age.[99] As expected, the weight gain effect can be amplified by inclusion of weight training.[100] A double-blind, placebo-controlled study of 108 men over the age of 65 years showed that testosterone administration improved the perception of physical function compared with placebo (p < 0.01).[101]

A randomized double-blind, placebo-controlled study compared the effects of testosterone across varying ages who had normal level of testosterone.[102] They were given medications to suppress endogenous testosterone followed by exogenous administration of graded doses of testosterone enanthate for 20 weeks. The study found that there was an increase in fat free mass and leg press muscle strength from baseline across all age groups, directly proportional to the amount of testosterone supplementation.[102] Compared with the younger age group, the older age group had an increased risk of adverse effects with treatment. Urinary retention, prostate cancer and elevated hematocrit were the effects which were clinically significant in the elderly patients.[102]

A smaller single-center, randomized, placebo-controlled study by Chapman et al. found that testosterone supplementation along with nutritional supplementation resulted in reduced hospital admissions compared with nontreatment groups.[103] Similarly, administration of testosterone was shown to improve rehabilitation outcomes in older ill patients. Some researchers have indicated that the administration of testosterone improved the overall functioning of male patients during rehabilitation following hospitalization.[104]

A recent, single-center, randomized, double-blind, placebo-controlled trial study by O'Connell et al. assessed the durability of androgen effects in frail men aged 65 years and older.[105] The study investigated the effects of 6 months of either transdermal testosterone therapy (50 mg per day) or an identically appearing placebo gel on patient muscle strength, body composition, physical function and QoL. All of these men were also confirmed to have 'borderline-low' levels of testosterone in their blood. Participants were assessed at the end of treatment (6 months) as well as 6 months after treatment cessation (12 months). The study showed that the mean testosterone increased from 11.1 (3.1) nmol/l at baseline to 18.4 (3.5) nmol/l at 6 months, then declined to 10.5 (3.7) nmol/l at 12 months, in the medically treated group. Isometric knee extension peak torque increased in the group receiving the testosterone gel compared with the placebo group. Lean muscle mass increased in the testosterone treatment group as well: a difference between the groups of 1.2 kg (0.8–1.7) at 6 months. Somatic and sexual symptoms improved during treatment. However, 6 months after the cessation of treatment, none of these differences remained. The study concluded that the effects of 6 months of testosterone treatment on muscle strength, lean mass and QoL in frail men are not maintained at 6 months post-treatment. The conclusion of the study was that the beneficial effects of testosterone supplementation are unlikely to be maintained post-treatment, particularly beyond 6 months.[105]

Elderly men who are losing weight should have their testosterone level measured and should be considered for supplementation if the level is low. Similar beneficial effect was also noted in female patients with continuing weight loss.[56]

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