Mirtazapine

H1 histamine blockade is the primary driver. Near-maximal at low doses. Patients often report morning grogginess, difficulty waking, and daytime drowsiness. Bedtime dosing is standard. Sedation may paradoxically improve with dose increases as noradrenergic activation offsets the antihistamine effect. This is the most important counseling point for new prescriptions.

Driven by both H1 antagonism (appetite stimulation, metabolic effects) and 5-HT2C antagonism (appetite stimulation). Weight gain with mirtazapine is among the highest of any antidepressant. Studies report average gains of roughly 1.5–2 kg in the first 6–8 weeks, but individual variation is substantial and some patients gain considerably more over time. The early weight gain is often rapid, noticeable within the first few weeks, and is a common reason patients request a switch. In underweight or cachectic patients, this same effect is therapeutic.

Patients often report carbohydrate cravings and increased food intake. This begins early (often within the first week) and persists. For the right patient population (geriatric weight loss, cancer cachexia, anorexia in medically ill patients), this is the reason you are prescribing the medication.

Mirtazapine can raise lipid levels. Less commonly discussed than weight gain but clinically relevant for long-term use. Monitor lipids in patients on chronic mirtazapine, particularly those with pre-existing metabolic risk factors.

Likely a combination of antihistaminic and mild anticholinergic effects (mirtazapine's anticholinergic activity is low but not zero).

Rates of sexual dysfunction are substantially lower than SSRIs and SNRIs. This traces directly to the mechanism: no serotonin reuptake inhibition, plus active antagonism of 5-HT2A and 5-HT3 receptors that mediate SSRI sexual side effects. For patients intolerant of SSRI-induced sexual dysfunction who cannot take bupropion, mirtazapine is the primary alternative.

Unlike SSRIs and SNRIs, which commonly cause nausea during initiation, mirtazapine typically reduces nausea. This is clinically useful in nauseated patients and as augmentation for patients experiencing SSRI-induced GI symptoms.

Case reports exist, but the incidence is very low and routine CBC monitoring is not required. Patients should be advised to report unexplained signs of infection (fever, sore throat, mouth sores) that could suggest neutropenia. This risk is worth knowing but should not drive prescribing decisions.