Clinical significance of mirtazapine for anorexia in patients with non-small cell lung cancer

Loss of appetite is common in cancer and involves numerous mechanisms and molecules (1). In a study investigating 438 patients diagnosed with cancer in seven centers, the prevalence of anorexia ranged 40–65% (2). This results in severe weight loss in patients with cancer, which may lead to sarcopenia and cachexia. The rate of weight loss among 3,180 patients with gastrointestinal cancer (including liver and pancreatic) or lung cancer at the time of diagnosis was 34.1%; this rate was higher in those with advanced-stage disease (3). Moreover, the pooled prevalence rate of cachexia in a systematic review and meta-analysis of non-small cell lung cancer (NSCLC) data (26 studies involving 5,919 patients) was 39% (range, 19–64%) (4). In these analyses, weight loss or cachexia was linked to poorer overall survival. Thus, the management of anorexia and weight loss is of great importance.

The use of antidepressants, particularly tricyclics and mirtazapine, increases appetite and weight. Mirtazapine, which is a noradrenergic and serotonergic antidepressant, exerts antagonistic effects on a-2, 5-hydroxytryptamine (HT) 2 and H1 adrenergic receptors. Notably, it is more effective in increasing appetite and result in weight gain compared with selective serotonin reuptake inhibitors (5). Based on this evidence, mirtazapine can be considered for cancer-related anorexia and weight loss.

Weight gain is linked to elevated risk of several medical conditions. Therefore, increased appetite and weight gain are considered side effects of treatment with mirtazapine. Nevertheless, in certain situations, weight gain is desirable. Herein, we discuss the potential use of mirtazapine to increase appetite and weight in patients with cancer, in particular lung cancer.

To date, two studies have investigated weight and appetite in patients with cancer over time. In a study including 20 patients with advanced-stage cancer, the data did not reveal significant changes in appetite, despite a weight gain of ≥1 kg observed after 4 weeks of treatment (6). In another study including 17 patients of cancer-associated anorexia without depression, the results demonstrated that mirtazapine (15–30 mg/day) might be effective in treating anorexia and cachexia. Specifically, 24% of patients experienced improvements in their appetite and a weight gain of ≥1 kg following 4 weeks of treatment. These findings emphasize the need for trials with large sample sizes to further evaluate this effect and compare the effectiveness of mirtazapine with that of placebo and other orexigenic agents (7).

Arrieta et al. performed an 8-week, randomized, and controlled trial of mirtazapine (30 mg/day) in 86 patients with advanced NSCLC who had anorexia. The hypothesis was that mirtazapine could improve appetite and other nutritional parameters (8). The data did not indicate a difference in appetite scores among patients treated with mirtazapine versus placebo. However, at 4 and 8 weeks of follow-up, the mirtazapine group exhibited a significant increase in fat intake (an essential source of energy) compared with the placebo group. Hence, the administration of mirtazapine may assist in achieving energy requirements and lead to improvement in health-related quality of life, for example, emotional and cognitive functioning. According to the findings, the investigators stated that mirtazapine increased energy intake (e.g., protein, carbohydrate, and fat) and reduced sarcopenia.

At present, there are no exceptionally effective agents for the treatment or improvement of cancer-related cachexia. Nonetheless, phase II–III investigations have recorded improvements in clinical outcomes. Despite the significant morbidities and mortality caused by cancer anorexia-cachexia syndrome, there are currently no approved drugs by the US Food and Drug Administration. Nevertheless, the guideline established by the American Society of Clinical Oncology (ASCO) proposes the use of progesterone analogs and short-term administration of corticosteroids to improve appetite and increase weight gain in patients with cancer-related cachexia (9). Currently, numerous drugs (e.g., megestrol acetate, cannabinoids, and corticosteroids) are used to improve appetite in patients with cancer. In addition, repurposed drugs (e.g., anamorelin and mirtazapine) have shown potential for improving appetite, decreasing nausea, and enhancing food taste in patients with cancer (10). Table 1 shows drugs currently employed to improve appetite.

Currently, megestrol acetate (a progestogen) is the main medication for cancer-related anorexia-cachexia. Its effects are based on stimulation of appetite through direct/indirect pathways, as well as antagonism of the metabolic effects of catabolic cytokines (1). Megestrol acetate is administered to increase appetite and weight in patients with cancer-related cachexia. However, data from a systematic review and meta-analysis (eight studies involving 576 patients with advanced-stage cancer) revealed that treatment with megestrol acetate did not lead to significant weight gain, regardless of the dose (11). Furthermore, treatment with megestrol acetate did not improve quality of life. Therefore, although this agent may be beneficial in certain subgroups of patients, it is not recommended for the treatment of cancer-related anorexia-cachexia. Unfortunately, there are concerns regarding the side effects of megestrol acetate; consequently, it is crucial to carefully consider its use in patients. Megestrol acetate is among the most effective orexigenic agents for appetite improvement and fat mass gain. Nevertheless, clinicians should take into account the increased risk of mortality and thromboembolism, as well as adrenal and androgen suppression.

Medicinal cannabis, i.e., Cannabis sativa L. (Cannabaceae), might improve appetite loss in patients with cancer (12). Studies in animals and humans have shown that cannabinoids modulate appetite through action on the cannabinoid type I receptors in the hypothalamus (13). This effect enhances food taste by involving digestive signalling hormones (13). However, randomized controlled trials and meta-analyses of data from patients with cancer demonstrated that medicinal cannabis did not improve appetite and weight gain (14). Considering the absence of high-quality evidence, at present, it is not possible to recommend cannabinoids for cancer-associated cachexia.

Anamorelin, which is an oral ghrelin mimetic and selective agonist, acts on the ghrelin receptor (15). In numerous randomized controlled trials of incurable cancer, anamorelin showed a good safety profile and improved total body weight, lean body mass, quality of life, and appetite versus placebo (16,17). A meta-analysis found that anamorelin increases total body weight, lean body mass, and quality of life in patients with cancer-related anorexia-cachexia syndrome without increasing adverse events (18). In another meta-analysis (seven randomized controlled trials involving 1,944 patients with cancer-related anorexia-cachexia syndrome), anamorelin increased total body weight and lean body mass, while marginally improving quality of life (18). In contrast, the drug did not improve appetite, hand grip strength, and overall survival. Moreover, there was no increase in adverse events. Based on the available evidence, anamorelin is potentially effective in patients with cancer-related anorexia-cachexia syndrome. Nonetheless, additional research is warranted to validate these findings.

The class of corticosteroids includes numerous agents with glucocorticoid, mineralocorticoid, and anti-inflammatory activity. The most commonly used agents are prednisolone, methylprednisolone, and dexamethasone. These drugs are typically administered in patients with advanced disease (19,20). It has been suggested that glucocorticoids and progesterone analogs exert a similar beneficial effect on appetite (21). Nevertheless, glucocorticoids do not increase body weight, are associated with the occurrence of numerous adverse effects (e.g., myopathy, infections, and hyperglycemia), and are characterized by reduced efficacy following long-term use. Therefore, the use of glucocorticoids as an appetite stimulant is limited to patients with a short life expectancy (i.e., a few weeks to months) (22). Use of corticosteroids leads to short-term improvements in appetite and fatigue. However, there are no benefits on lean body mass or survival. Furthermore, extended use of these agents has been linked to complications, for example infections and proximal myopathy. Currently, the appropriate dosage and duration of treatment with corticosteroids remain unknown. Furthermore, there is limited research directly comparing the various corticosteroids.

The efficacy of olanzapine against chemotherapy-induced anorexia was evaluated in a randomized controlled trial of 124 patients with locally advanced or metastatic gastric, hepatobiliary, or pancreatic cancer, or lung cancer (23). Olanzapine (2.5 mg/day) or placebo was administered for 12 weeks in parallel with chemotherapy. Weight gain by >5% was observed in 60% and 9% of patients in the olanzapine and placebo groups, respectively. In addition, olanzapine improved appetite and reduced the rate of grade 3 or higher chemotherapy-induced toxicity (12% vs. 37%, respectively, P=0.002). Therefore, olanzapine might be useful against anorexia associated with cancer cachexia. Nonetheless, additional investigation is required to determine whether olanzapine improves the physical strength and body composition of patients with cancer-related anorexia.

Classical drugs that have been verified in large-scale randomized trials for patients with cancer-related cachexia include corticosteroids and progesterone analogs to increase appetite and body weight, as well as non-steroidal anti-inflammatory drugs, thalidomide, and omega-3 fatty acids against inflammation. According to the ASCO guidelines, administration of progesterone analogs and short-term use of corticosteroids are proposed to improve appetite and weight gain (9). Furthermore, in 2023, research into the usefulness of olanzapine for anorexia in patients with cancer-related cachexia attracted attention, and the ASCO guidelines on cancer cachexia were updated (24). In addition, only a few drugs have been established as standard treatments, although the efficacy and safety of various other drugs have been reported. Furthermore, growth differentiation factor 15 (GDF-15) is currently attracting research attention as a new target for the treatment of cachexia. GDF-15 is a cytokine that directly contributes to anorexia by binding to the glial cell line-derived neurotrophic factor receptor alpha-like (GFRAL), which is present in the feeding center of the brain stem. Ponsegromab (a humanized monoclonal antibody against GDF-15) is designed to block the effects of this axis by binding to GDF-15 and inhibiting its interaction with GFRAL. Recently, a randomized controlled study evaluated the usefulness of ponsegromab against cancer-related cachexia; the results revealed increased GDF-15 levels (25). The treatment increased weight gain and the level of overall activity, whereas it reduced the symptoms of cachexia. These results indicated the involvement of GDF-15 in cachexia. Despite the availability of guidelines and reports of new drugs, at present, drug therapy alone is characterized by limitations; therefore, a combination of non-drug therapies, such as nutritional therapy and exercise therapy, is important.

Regarding the study reported by Arrieta et al. (8), in our opinion, the conclusions drawn from the results are an optimistic interpretation and lack a rationale. The trial failed to meet its primary outcome, namely improvement in appetite ratings, as well as almost all primary and secondary outcomes. The majority of favorable observations emerged from intra-group analyses rather than inter-group analyses. Statistically significant differences may be false-positive results due to the numerous cross-sectional comparisons conducted at various timepoints. In addition, the advantage observed for sarcopenia may be attributed to differences between treatment groups at baseline; of note, intra-group changes in sarcopenia were minimal. Finally, intent-to-treat longitudinal analyses were not carried out. Overall, this investigation did not demonstrate improvements in 8-week nutritional and anthropometric outcomes following treatment with mirtazapine.

Anorexia, weight loss, and cachexia are frequently observed in patients with NSCLC. The mechanisms underlying cancer-related cachexia are multifactorial. Thus, linear strategies alone might be inadequate for the successful management of this complex syndrome. Based on the available evidence, mirtazapine does not improve outcomes in this setting. As the pathophysiology of cachexia becomes clearer, multiple drug treatments are being tested, particularly for cancer-related cachexia. However, the clinical effects of drug treatment alone may have limitations. Therefore, it is important to determine a clear goal for improvement and the positioning of drug treatment in the circle of multidisciplinary treatment.

Acknowledgments

The authors thank Ms. Kyoko Nakagawa and Ms. Miho Ishida for their administrative assistance in preparing the manuscript.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2225/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2225/coif). The authors have no conflicts of interest to declare.

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