What is the most likely medication to increase appetite and intake in a patient with end-stage cancer and depression, between mirtazapine and dexamethasone?

Mirtazapine is Most Likely to Increase Appetite and Intake in End-Stage Cancer Patients with Depression

For a patient with end-stage cancer who is depressed, mirtazapine is the superior choice over dexamethasone because it addresses both the depression and anorexia simultaneously, while dexamethasone's appetite-stimulating effects are transient (lasting only 1-3 weeks) and come with significant adverse effects including muscle wasting and insulin resistance that worsen cachexia. 1

Why Mirtazapine is the Better Choice

Dual Therapeutic Benefit

• Mirtazapine functions as both an antidepressant and appetite stimulant, making it uniquely suited for patients with comorbid depression and anorexia 1, 2
• The drug blocks presynaptic alpha-2 adrenergic receptors and postsynaptic serotonin receptors, producing both antidepressant and appetite-enhancing effects 2
• Depression itself is a major contributor to poor appetite in cancer patients, and treating the underlying depression may improve nutritional intake more sustainably 1, 3

Evidence for Appetite Stimulation

• ASCO guidelines recognize mirtazapine as a clinically established appetite enhancer, with phase II studies showing improvement in appetite and weight gain in approximately one-third of cancer patients 1
• The typical starting dose is 15 mg daily at bedtime, with the most common side effects being somnolence, increased appetite, and weight gain—effects that may actually be beneficial in this population 2
• Mirtazapine has demonstrated efficacy comparable to megestrol acetate (the gold standard appetite stimulant) in treating cancer-related anorexia, suggesting it can serve as a viable alternative 4

Sustained Effect Profile

• Unlike dexamethasone, mirtazapine's effects are sustained over time rather than transient 1, 3
• An open-label study showed that depressive symptoms improved within the first month and this improvement was maintained for 24 weeks of treatment 3
• The drug is well-tolerated in cancer patients undergoing chemotherapy and radiotherapy, with most adverse effects described as mild to moderate 3

Why Dexamethasone is Less Suitable

Transient and Declining Efficacy

• Corticosteroids like dexamethasone provide only short-term appetite stimulation (1-3 weeks) before the antianorectic effect disappears 1
• ESPEN guidelines recommend restricting corticosteroid use to 1-3 weeks due to rapidly diminishing benefits 1

Harmful Metabolic Effects

• Dexamethasone causes muscle wasting (myopathy), which directly worsens cachexia—the opposite of the desired therapeutic goal 1
• Early adverse effects include insulin resistance, while long-term use leads to immunosuppression and osteopenia 1
• These catabolic effects make corticosteroids particularly inappropriate for patients with cancer cachexia who need to preserve lean body mass 1

Limited Appropriate Use

• Corticosteroids are most suitable for patients with very short life expectancy (weeks to a couple months) who have other symptoms like pain or nausea that may benefit from steroid therapy 1
• For patients with depression and longer prognosis, the adverse metabolic profile outweighs any transient appetite benefit 1

Clinical Implementation Algorithm

Step 1: Initiate mirtazapine 15 mg orally at bedtime 1, 2

• This dose addresses both depression and anorexia simultaneously
• The sedative effect at bedtime may improve sleep, which is often disrupted in depressed cancer patients 2

Step 2: Monitor response over 4 weeks 3, 4

• Assess appetite improvement using validated tools
• Monitor for adverse effects (primarily somnolence, which may be beneficial) 3, 2
• Depressive symptoms should begin improving within the first month 3

Step 3: Consider dose adjustment if needed 2

• If response is inadequate and no significant adverse effects occur, the dose can be increased
• Most studies used 15-30 mg daily 5, 4

Step 4: Reserve dexamethasone for specific scenarios only 1

• Use only if life expectancy is very limited (weeks) AND
• Patient has other symptoms (pain, nausea) that would benefit from corticosteroids AND
• Patient has not responded to or cannot tolerate mirtazapine 1
• Typical dose: 2-8 mg daily for maximum 1-3 weeks 1, 6

Important Caveats

Evidence Limitations

• While mirtazapine is recognized as an appetite enhancer, one recent double-blind RCT found no significant difference between mirtazapine and placebo in improving appetite in cancer-associated cachexia 5
• However, this study excluded patients with significant depression (depression score >3 on 0-6 scale), which is the opposite of your clinical scenario 5
• The key distinction is that your patient has depression—mirtazapine's dual mechanism makes it more appropriate than in patients with isolated anorexia 1

Addressing Underlying Contributors

• Both medications work better when reversible causes of anorexia are addressed: oropharyngeal candidiasis, uncontrolled pain, constipation, and nausea 6
• Nutrition consultation for calorie-dense, high-protein supplementation should complement pharmacologic intervention 6

Alternative if Both Fail

• If mirtazapine proves ineffective and life expectancy extends beyond weeks, consider megestrol acetate (400-800 mg/day) as the next option, though it carries thromboembolic risk (1 in 6 patients) and does not address depression 6, 7, 8
• Olanzapine (5 mg daily) is another alternative that may benefit patients with comorbid nausea or anxiety 6, 9