What is the mechanism by which mirtazapine (Remeron) stimulates appetite?

Mechanism of Mirtazapine's Appetite Stimulation

Mirtazapine stimulates appetite primarily through its antagonism of histamine H1 receptors, which is most pronounced at lower doses (15mg), while its antagonism of serotonin 5-HT2 and 5-HT3 receptors also contributes to this effect by reducing nausea and enhancing appetite. 1, 2

Primary Pharmacological Mechanisms

• Mirtazapine acts as a potent antagonist of histamine (H1) receptors, which directly stimulates appetite and is most pronounced at lower doses (15mg) 1, 2
• It functions as an antagonist at serotonin 5-HT2 and 5-HT3 receptors, which reduces nausea and early satiety, indirectly promoting increased food intake 1, 2, 3
• Mirtazapine's blockade of presynaptic α2-adrenergic autoreceptors and heteroreceptors enhances both noradrenergic and serotonergic neurotransmission, but with selective effects on serotonin receptor subtypes 1, 4
• Unlike SSRIs, mirtazapine does not increase serotonin at all receptor subtypes, which helps avoid the appetite suppression and nausea often seen with those medications 4, 5

Receptor Activity Profile and Appetite Effects

• At lower doses (15mg), the H1 receptor antagonism predominates, leading to stronger appetite stimulation and sedation 2, 5
• At higher doses (30-45mg), the noradrenergic effects become more prominent while the antihistaminic effects remain but are relatively less dominant 2, 6
• The 5-HT2 and 5-HT3 receptor blockade prevents the appetite-suppressing and nauseating effects typically seen with increased serotonergic activity 3, 5
• Mirtazapine has minimal effect on 5-HT1A receptors, which differentiates its appetite effects from other antidepressants 1, 6

Clinical Manifestations of Appetite Stimulation

• Increased appetite is reported in approximately 11-17% of patients taking mirtazapine compared to 2% with placebo 1, 5
• Weight gain of ≥7% of body weight occurs in approximately 7.5% of adult patients taking mirtazapine 1
• In clinical settings, mirtazapine has been specifically used for patients with appetite loss and weight loss, especially when depression is also present 2, 3
• The appetite-stimulating effect is evident within the first weeks of treatment, often before the full antidepressant effect is achieved 4, 2

Therapeutic Applications of Appetite Stimulation

• Mirtazapine is particularly useful in conditions where both depression and appetite stimulation are desired therapeutic goals 2, 3
• In gastroparesis, mirtazapine has shown benefits for nausea, vomiting, and weight loss through its 5-HT3 antagonism and appetite-stimulating effects 3, 2
• For patients with functional dyspepsia, mirtazapine has demonstrated improvement in weight loss, dyspeptic symptoms, and early satiety 3, 2
• In patients with dementia and depression, mirtazapine may be preferred over other antidepressants when weight loss is a concern 3, 2

Clinical Considerations

• The appetite-stimulating effect is dose-dependent, with stronger effects at lower doses (15mg) due to predominant H1 receptor antagonism 2, 5
• Weight gain may be undesirable in some patients, particularly those with cardiovascular disease or metabolic disorders 2, 1
• In patients without depression, the systematic use of mirtazapine solely as an appetite stimulant is not generally recommended 3
• The sedative effects of mirtazapine, which are also mediated through H1 antagonism, often accompany the appetite-stimulating effects, especially at lower doses 4, 5