Mirtazapine ups calorie consumption in NSCLC patients with anorexia

In advanced nonsmall cell lung cancer (NSCLC) patients with anorexia, treatment with mirtazapine leads to a substantial increase in energy intake despite having no effect on appetite, as shown in a study.

After 4 weeks of treatment, patients who received mirtazapine consumed significantly more calories than they did at baseline, averaging 379.3 Kcal per day (95 percent confidence interval [CI], 182.6–576.1; p<0.001), which corresponded to an increase of 26.1 percent in the percentage of the energy requirement achieved. This increase comprised proteins (22.4 g/d; p=0.001), carbohydrates (43.4 g/d; p=0.006), and fats (13.2 g/d; p=0.006). [JAMA Oncol  2024;doi:10.1001/jamaoncol.2023.5232]

The improvements in the mirtazapine group were maintained through the 8-week follow-up, especially fat intake, which is a crucial source of energy, according to the investigators.

When compared with placebo, mirtazapine led to a significant improvement in carbohydrate consumption (43.4 vs 5.5 g/d; p=0.01) and the percentage of energy requirement achieved (26.1 percent vs 8.8 percent; p=0.001) at week 4, as well as in fat intake (14.5 vs 0.7 g/d; p=0.02) at week 8. Notably, appetite scores did not significantly differ between the treatment groups.

Muscle loss attenuated

The beneficial effect of mirtazapine on energy intake translated to a decrease in the number of patients with sarcopenia. At week 8, fewer mirtazapine-treated vs placebo-treated patients had sarcopenia (57.1 percent vs 82.8 percent; p=0.03). Meanwhile, body weight remained stable in both groups throughout the follow-up.

“A possible explanation of this phenomenon … could be the fact that most patients had a normal weight because the inclusion criteri[on] was lack of appetite and not necessarily weight loss. However, the independent association that cachexia has with overall survival in patients with NSCLC treated with immunotherapy must be recognized, as well as in patients treated with tyrosine kinase inhibitors who have higher risk of severe gastrointestinal toxic effects,” the investigators explained.

A total of 71 patients (mean age 63.5 years, 57.7 percent women, mean body mass index 22.1 kg/m², mean body weight 56.2 kg) with advanced NSCLC who were receiving active oncologic treatment and had a median Anorexia Cachexia Scale (ACS) score of 19.5 were included in the study. These patients were randomly assigned to receive mirtazapine (n=38) or placebo (n=33) for 8 weeks. Mirtazapine was given at 15 mg for the first 2 weeks, followed by a dose escalation to 30 mg until week 8. Patients in both groups received nutritional assessment and dietary advice.

Mirtazapine was well tolerated. Patients on mirtazapine reported a higher perception of nightmares at 2 weeks based on a 10-cm VAS score (p=0.009) but a lower severity perception of fatigue at 8 weeks (p=0.03) compared with those on placebo.

Add-on intervention

A standard treatment for cancer-associated anorexia has yet to be established. Apart from mirtazapine, which has shown promising effects on appetite and weight, other treatment options are either limited by availability (eg, cannabinoids or ghrelin) or by tolerability issues (eg, corticosteroids, progestins, or androgens). [Support Care Cancer 2018;26:3029-3038; Cancer 2018;124:606-616; Lancet Oncol 2016;17:519-531; Nutr Rev 2022;80:857-873; J Clin Oncol 2020;38:2438-2453; Geriatr Nurs 2019;40:531-532]

“Based on the findings of this study, mirtazapine is a feasible and safe option to add as a nutritional intervention in patients with advanced NSCLC with anorexia given its benefit in energy intake, including high-quality macronutrients, considering that increased energy intake is the first step to stop unintentional weight loss and stability or increase of body weight,” the investigators said.

Additional data showed that mirtazapine had favourable effects on global health status at 8 weeks, Hospital Anxiety and Depression Scale (HADS) score, and functional scales, especially cognitive functioning, which the investigators deemed as a positive effect of better energy intake similar to the findings reported with olanzapine. [J Clin Oncol 2023;41:2617-2627]

“We suggest that therapeutic options to increase appetite, energy intake, and body weight need to be individualized according to catabolic state, muscle reserve, benefit and risk evaluation along with psychiatric and nutritional surveillance,” the investigators said.

“In addition, personal characteristics such as comorbidities, history of depression, concomitant medications (ie, other stimulants, cannabinoids, opioids, benzodiazepines) and a higher risk for somnolence (age, use of alcohol, kidney or liver impairment) could be considered as well, but further evidence is needed to make a definitive recommendation,” they noted. [Nutr Rev 2022;80:857-873]