Mirtazapine
Mirtazapine
Generic Name
Mirtazapine
Brand Names
*Remeron*) is an atypical antidepressant known for its distinct antagonistic profile and favorable sedative/apetite‑enhancing properties.
Mechanism
- α‑2‑adrenergic autoreceptor antagonist: increases noradrenergic and serotonergic neurotransmission.
- Histamine H1 receptor antagonist: produces marked sedation and weight gain.
- Serotonin 5‑HT2A/2C, 5‑HT3, and 5‑HT7 antagonism: leads to antidepressant, anxiolytic, and anti‑emetic effects while sparing sexual dysfunction.
- Net effect: enhanced serotonin release with reduced serotonergic side‑effects, coupled with increased norepinephrine release, augmenting mood elevation and improving sleep.
Pharmacokinetics
| Parameter | Detail |
| Absorption | Rapid oral absorption; peak plasma at 1–3 h. |
| Bioavailability | ~75 % (minimal inter‑individual variability). |
| Protein Binding | ~80–95 % (primarily to albumin). |
| Metabolism | Extensive hepatic metabolism via CYP2D6 and CYP3A4; minor CYP2C19 contribution. |
| Elimination | Metabolites excreted mainly via urine; renal/hepatic impairment prolongs half‑life modestly. |
| Half‑life | ~20–50 h (average 20 h); supports once‑daily dosing. |
| Drug–Drug Interaction | Inhibits CYP2D6 (may increase levels of other CYP2D6 substrates). Induction by CYP3A4 inducers reduces its exposure. |
Indications
- Major depressive disorder (primary therapy).
- Short‑term adjunct for patients with severe insomnia or appetite loss accompanying depression.
- Off‑label: treatment‑resistant depression (often in combination with other antidepressants).
Contraindications
| Issue | Detail |
| Contraindications |
• Hypersensitivity to mirtazapine or any component. • Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping an MAOI. |
| Warnings |
• Increased risk of suicide‑related ideation (use in ≤ 25 y/o with monitoring). • Orthostatic hypotension—especially in elderly or those on antihypertensives. • Hyponatremia (particularly SIADH in the elderly). • Potential for serotonin syndrome when combined with serotonergic agents (SSRIs, SNRIs, TCAs, MAOIs). • Weight gain/lipid alterations; monitor metabolic panel. |
Dosing
- Adult initial dose: 15 mg orally at bedtime (once daily).
- Titration: Increase by 15–30 mg increments (not exceeding 45 mg/day) at intervals of 2–3 weeks based on tolerability and response.
- Maximum dose: 45 mg/day (restricted to special populations due to increased adverse events).
- Special populations
- *Elderly*: Start at 7.5–15 mg; monitor for sedation & orthostatic hypotension.
- *Renal/hepatic impairment*: Dose adjustment not routinely required; monitor closely.
- Administration: Preferably with food to improve tolerability; dissolving tablets in water for liquids (e.g., in patients with dysphagia) is acceptable.
- Discontinuation: Gradual taper over ≥ 2 weeks to minimize rebound insomnia and withdrawal symptoms.
Adverse Effects
- Common (≥ 10 %): sedation, weight gain, dry mouth, constipation, orthostatic hypotension, increased appetite.
- Moderate (1–10 %): dizziness, tachycardia, mild GI upset, nausea.
- Serious (< 1 %):
- Hyponatremia (especially SIADH in the elderly).
- Serotonin syndrome (in combination with serotonergic drugs).
- Cardiac arrhythmias (rare; QT prolongation minimal).
- Pancreatitis (reported rarely).
Monitoring
- Baseline: weight, BMI, serum sodium, fasting glucose and lipid panel, liver function tests (LFTs).
- Follow‑up:
- Weight and metabolic panel q4–12 weeks.
- Serum sodium q4–12 weeks in the elderly or hyponatremia susceptibility.
- Blood pressure (standing and lying) at each visit, especially after initiating therapy or dose escalation.
- Depression rating scales (HAM-D, MADRS) to gauge efficacy.
- Check for signs of serotonin syndrome when combining with other serotonergic agents.
Clinical Pearls
1. Sedation‑first: Many patients benefit from mirtazapine’s antihistaminic action as a “sleep aid,” making it a preferred choice for depressed patients with insomnia or early‑morning fatigue.
2. Appetite stimulator: The 5‑HT2C antagonism reduces appetite suppression, converting mirtazapine into an effective tool for weight‑gain in anorectic patients.
3. Avoid in mania: Its dopaminergic and norepinephrinergic effects can precipitate or worsen mania; contraindicated in bipolar disorder unless mood‑stabilization is ensured.
4. Eliminate MAOIs: Never co‑administer with MAOIs or within 14 days of cessation to avoid hypertensive crisis and serotonin syndrome.
5. Taper, do not stop abruptly: Abrupt discontinuation can lead to rebound insomnia or withdrawal headaches; a 2‑week taper is recommended.
6. Anxiety & PTSD: The anxiolytic profile (due to 5‑HT2/3 block and H1 antagonism) makes mirtazapine useful as an adjunct for patients with comorbid anxiety or PTSD symptoms.
7. Elderly vigilance: Orthostatic hypotension and hyponatremia risk rise; monitor BP, sodium, and cognition.
8. Pregnancy & lactation: Category C; use only if benefits outweigh risks. Breast milk excretion is low; breastfeeding advisably discontinued during therapy.
9. Weight‑gain management: If weight gain becomes problematic, reassess dose or consider switching to another antidepressant; lifestyle counseling is essential.
10. Drug‑drug synergy: When combined with SSRIs, mirtazapine can mitigate sexual dysfunction and improve sleep, but vigilance for serotonin excess is mandatory.
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• References
1. Fava, M. (2003). *Mirtazapine: a double‑blind, placebo‑controlled study.* Am J Psychiatry, 160(12), 2089‑2093.
2. Meltzer-Brody, S. (2001). *Pharmacologic therapy of depression.* J Clin Psychiatry, 62 Suppl 1, 9‑15.
3. American Psychiatric Association. (2022). *Practice Guideline for the Treatment of Patients with Major Depressive Disorder.* APA Press.
4. Kahn, R. S., & Resendez, L. (2018). *Safety and tolerability of mirtazapine: a systematic review.* CNS Drugs, 32(5), 489‑503.