Atypical Antidepressants

Atypical antidepressants are agents with mechanisms that differ from reuptake inhibition: mirtazapine, bupropion, agomelatine, reboxetine, esketamine and the neurosteroids used in postnatal depression (zuranolone, brexanolone). They are used when SSRIs cause sexual dysfunction, insomnia or weight problems, or when resistance occurs.

Mechanism. Mirtazapine antagonises alpha-2, 5-HT2, 5-HT3 and histamine H1 receptors. Bupropion inhibits dopamine and noradrenaline reuptake. Agomelatine is a melatonin MT1 and MT2 agonist and a 5-HT2C antagonist. Reboxetine is a selective noradrenaline reuptake inhibitor. Esketamine blocks NMDA receptors. Zuranolone and brexanolone are GABA-A modulators.

Pharmacokinetics. Mirtazapine half-life 20 to 40 hours. Bupropion is metabolised to active compounds that strongly inhibit CYP2D6. Agomelatine undergoes extensive first-pass metabolism by CYP1A2.

Differences. Mirtazapine promotes sleep and appetite and has little sexual dysfunction. Bupropion is activating, weight neutral and has little sexual dysfunction. Agomelatine suits patients with sleep disturbance and needs liver monitoring.

• Depression with insomnia, anorexia or weight loss, or in older adults: mirtazapine at night.
• Depression with sexual dysfunction or weight gain on an SSRI: bupropion, or switch or augment.
• Smoking cessation: bupropion 150 mg daily for 3 days then 150 mg twice daily, started 1 to 2 weeks before the quit date, for 7 to 12 weeks.
• Treatment-resistant depression: esketamine with an oral antidepressant under specialist supervision, or augmentation.
• Postnatal depression: neurosteroid infusion or course in specialist centres where available.
• Agomelatine: liver enzymes at baseline and at 3, 6, 12 and 24 weeks.

Special groups. Pregnancy: mirtazapine and bupropion have limited data; weigh risks. Breastfeeding: mirtazapine low infant exposure; avoid agomelatine. Children: not routinely used. Older adults: mirtazapine at 7.5 to 15 mg. Kidney impairment: reduce mirtazapine and bupropion doses. Liver impairment: avoid agomelatine; reduce bupropion. Regional: mirtazapine is increasingly available; efavirenz, lopinavir and ritonavir reduce bupropion levels by up to 50%.

Adverse effects. Mirtazapine: sedation, weight gain, dry mouth, rare neutropenia. Bupropion: insomnia, anxiety, tremor, headache, raised blood pressure, dose-related seizure risk (about 0.1% at 300 mg), psychosis. Agomelatine: liver injury. Esketamine: dissociation, sedation and transient hypertension.

Contraindications. Bupropion: seizure disorder, eating disorders, alcohol or benzodiazepine withdrawal, brain tumour, and monoamine oxidase inhibitors. Agomelatine: liver impairment.

Interactions. Bupropion inhibits CYP2D6 and raises levels of tricyclics, antipsychotics, tamoxifen and metoprolol. Carbamazepine lowers mirtazapine levels. Fluvoxamine and ciprofloxacin raise agomelatine levels and are contraindicated.

Monitoring. Weight and blood count (mirtazapine), blood pressure (bupropion and esketamine), seizure risk, and liver enzymes (agomelatine).

Referral and escalation. Treatment resistance, psychosis, seizures, jaundice, or postnatal depression with suicidality.