Remeron (Mirtazapine)
mirtazapine tablets and orally disintegrating tablets (SolTab)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major Depressive Disorder (MDD) | Adults | Monotherapy | FDA Approved |
Mirtazapine is an atypical tetracyclic antidepressant and the first noradrenergic and specific serotonergic antidepressant (NaSSA) to reach market. FDA-approved in 1996, its efficacy for MDD was established in four 6-week controlled trials of adult outpatients dosed between 5 and 60 mg/day, and a longer-term relapse prevention study of up to 40 weeks. Mirtazapine is not approved for pediatric use. Its unique receptor pharmacology produces a distinctive clinical profile: potent sedation, appetite stimulation, antiemetic effects, and anxiolysis, with minimal sexual dysfunction. Clinicians frequently select mirtazapine for patients with depression complicated by insomnia, poor appetite, low body weight, or prominent anxiety, as well as those who have not tolerated SSRIs or SNRIs.
Insomnia: Widely used at low doses (7.5–15 mg) for its potent H1-mediated sedation. Sedation is paradoxically greater at lower doses. Evidence quality: Moderate.
Appetite stimulation (cancer, HIV, elderly): Used to counteract cachexia and anorexia; 5-HT2C and H1 antagonism drive weight gain and appetite. Evidence quality: Moderate.
Nausea/vomiting (antiemetic): 5-HT3 antagonism provides ondansetron-like antiemetic properties; used in palliative care and chemotherapy-associated nausea. Evidence quality: Low-Moderate.
PTSD, generalized anxiety, social anxiety: Anxiolytic properties from 5-HT2A and H1 antagonism; some guideline recommendations. Evidence quality: Low.
Pruritus: H1 antagonism may relieve itch in cholestatic and uremic conditions. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD — standard adult | 15 mg once daily at bedtime | 15–45 mg once daily | 45 mg/day | Dose changes at intervals ≥1–2 weeks (long half-life) Administer in the evening before sleep due to sedative effects |
| MDD — insomnia-predominant | 7.5–15 mg at bedtime | 15–30 mg at bedtime | 45 mg/day | Lower doses are paradoxically more sedating due to dominant H1 effects Increasing dose may actually reduce sedation as NE activation counterbalances H1 |
| MDD — anorexia / weight loss-predominant | 15 mg at bedtime | 30–45 mg at bedtime | 45 mg/day | Appetite stimulation and weight gain are dose-related; 7.5% had ≥7% body weight gain vs 0% placebo |
| MDD — elderly (≥65 years) | 7.5–15 mg at bedtime | 15–45 mg at bedtime | 45 mg/day | Reduced clearance (40% lower in elderly males, 10% lower in elderly females) Increased hyponatremia and over-sedation risk; start low |
| MDD — renal impairment (moderate: CrCl 11–39) | 15 mg at bedtime | Dose decrease may be needed | Clearance reduced ~30%; monitor for adverse effects Severe impairment (CrCl <10): clearance reduced ~50% | |
| MDD — hepatic impairment | 15 mg at bedtime | Dose decrease may be needed | Clearance reduced ~30% in hepatic impairment; ALT elevations ≥3× ULN occurred in 2% vs 0.3% placebo | |
| MDD — with strong CYP3A4 inhibitor | Dose decrease may be needed | Ketoconazole increases Cmax ~40% and AUC ~50%; also applies to clarithromycin, HIV protease inhibitors | ||
| MDD — with strong CYP3A inducer | Dose increase may be needed | Carbamazepine decreases mirtazapine levels by ~60%; also phenytoin, rifampin | ||
| MDD — with cimetidine | Dose decrease may be needed | Cimetidine increases mirtazapine levels by ~50% | ||
| MDD — discontinuation / tapering | Gradual dose reduction recommended | Discontinuation syndrome reported: dizziness, paresthesia, anxiety, nausea, sweating, abnormal dreams | ||
Mirtazapine’s sedative effect is paradoxically greater at lower doses (7.5–15 mg) than at higher doses (30–45 mg). This occurs because at low doses, the potent H1 histamine receptor antagonism dominates, producing marked drowsiness. At higher doses, increased noradrenergic and serotonergic neurotransmission through α2-adrenergic blockade provides an activating effect that partially counterbalances the H1-mediated sedation. Clinicians can leverage this by using lower doses for insomnia-predominant depression and titrating upward if excessive daytime sedation limits function. Patients should be counselled that increasing the dose may paradoxically improve daytime alertness.
Pharmacology
Mechanism of Action
Mirtazapine is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA). Unlike SSRIs and SNRIs, it does not inhibit the reuptake of serotonin or norepinephrine. Instead, mirtazapine enhances central noradrenergic and serotonergic neurotransmission through antagonism of central presynaptic α2-adrenergic autoreceptors and heteroreceptors, which removes the inhibitory brake on NE and 5-HT release. It selectively blocks postsynaptic 5-HT2A, 5-HT2C, and 5-HT3 receptors, channelling enhanced serotonergic activity specifically through 5-HT1A receptors, which mediate antidepressant and anxiolytic effects. Its potent H1 histamine receptor antagonism accounts for its pronounced sedative and appetite-stimulating properties. Mirtazapine has negligible affinity for muscarinic cholinergic receptors, which distinguishes it from tricyclic antidepressants.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed; Tmax ~2 h; bioavailability ~50% (first-pass metabolism); food has minor effect on rate but not extent | Can be given with or without food; administer at bedtime for optimal sleep benefit; steady state in 4–6 days |
| Distribution | Protein binding 85% (non-specific, reversible); widely distributed into tissues | Crosses blood-brain barrier; moderate protein binding unlikely to produce displacement interactions |
| Metabolism | Hepatic via CYP2D6 and CYP3A4 (both major pathways), with CYP1A2 contributing; N-demethylation (to active desmethylmirtazapine, ~3–10% of activity), hydroxylation, and conjugation | Susceptible to CYP3A inducers (carbamazepine reduces levels ~60%) and inhibitors (ketoconazole increases AUC ~50%); CYP2D6 inhibitors cause only modest increases (~17–32%); does not significantly inhibit CYP enzymes itself |
| Elimination | t½: 20–40 h (gender-dependent; females longer); 75% urine, 15% feces; ~100% excreted within 4 days | Long half-life supports once-daily dosing; dose changes ≥1–2 weeks apart; reduced clearance in elderly (especially males: 40% lower), renal impairment (~30–50%), and hepatic impairment (~30%) |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Somnolence | 54% (placebo 18%) | Most common adverse effect; dose-dependent paradox: more sedating at lower doses; resulted in 10.4% discontinuation rate (vs 2.2% placebo) |
| Dry mouth | 25% (placebo 15%) | Encourage hydration, sugar-free gum, and good oral hygiene |
| Increased appetite | 17% (placebo 2%) | Mediated by 5-HT2C and H1 antagonism; clinically useful in anorexic or cachectic patients |
| Constipation | 13% (placebo 7%) | Increase fibre and fluid intake; osmotic laxative if persistent |
| Weight gain | 12% (placebo 2%) | 7.5% had ≥7% body weight gain vs 0% placebo; 8% of premarketing patients discontinued for weight gain |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Asthenia / fatigue | 8% (placebo 5%) | Related to H1 antagonism; may improve with dose adjustment |
| Dizziness | 7% (placebo 3%) | Likely related to orthostatic effects and sedation; rise slowly from sitting/lying position |
| Flu-like syndrome | 5% (placebo 3%) | Monitor for actual infection signs, especially given agranulocytosis risk |
| Abnormal dreams | 4% (placebo 1%) | Vivid or disturbing dreams; 5-HT2A antagonism alters sleep architecture |
| Thinking abnormal | 3% (placebo 1%) | Usually mild cognitive effects related to sedation |
| Tremor | 2% (placebo 1%) | Less common than with SSRIs or SNRIs |
| Confusion | 2% (placebo 0%) | More common in elderly; monitor and consider dose reduction |
| Peripheral edema | 2% (placebo 1%) | Monitor fluid status |
| Urinary frequency | 2% (placebo 1%) | Usually mild and self-limiting |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Agranulocytosis / severe neutropenia | Rare (~0.1%; 3/2796 in premarketing trials) | Days 9–61 of treatment | Discontinue immediately if sore throat, fever, stomatitis, or infection signs develop with low WBC; closely monitor patient; all 3 cases recovered after discontinuation |
| Serotonin syndrome | Rare | Hours to days after initiation or dose increase | Discontinue mirtazapine and all serotonergic agents; supportive care; can occur alone or with concomitant serotonergic drugs |
| QTc prolongation / Torsades de Pointes | Rare (mostly in overdose or with QT-prolonging drugs) | Variable | Caution in patients with cardiovascular disease, family history of QT prolongation, or concurrent QTc-prolonging drugs; ECG if indicated |
| Suicidal ideation (age <25) | Uncommon | First weeks or dose changes | Close monitoring; FDA Black Box Warning; not approved for pediatric use |
| Hyponatremia / SIADH | Rare | Weeks to months | Monitor serum sodium if symptoms develop (confusion, weakness, falls); discontinue if symptomatic; elderly and diuretic users at higher risk |
| Severe skin reactions (SJS, TEN) | Very rare | Variable | Discontinue immediately; emergency care; permanent contraindication to rechallenge |
| Elevated cholesterol / triglycerides | 15% cholesterol ≥20% above ULN; 6% triglycerides ≥500 | Weeks to months | Monitor lipid panel; weigh cardiovascular risk; consider lipid-lowering therapy or alternative antidepressant |
| Transaminase elevations (≥3× ULN) | 2.0% (vs 0.3% placebo) | Variable | Monitor LFTs if symptoms develop; some cases resolved despite continued treatment; use with caution in hepatic impairment |
| Mania / hypomania activation | 0.2% | First weeks | Screen for bipolar before initiation; discontinue; initiate mood stabilizer |
Weight gain is the most clinically limiting metabolic side effect of mirtazapine. In controlled trials, 7.5% of patients gained ≥7% of body weight compared to 0% on placebo. In pediatric trials (not an approved population), the figure was 49%. Counsel patients about dietary management from the outset. Consider baseline weight and metabolic parameters (lipids, glucose) before starting treatment. If clinically significant weight gain develops that is not desirable, reassess the risk-benefit of continued treatment and consider alternative antidepressants.
Drug Interactions
Mirtazapine is metabolized by CYP2D6, CYP3A4, and CYP1A2 but does not significantly inhibit any CYP enzymes itself, giving it a relatively clean outbound interaction profile. The main interactions are inbound: drugs that inhibit or induce CYP3A4 significantly alter mirtazapine exposure. Additionally, its serotonergic properties create a risk of serotonin syndrome with other serotonergic agents, and its sedative properties are additive with CNS depressants.
Monitoring
- Complete Blood CountIf infection signs develop
Trigger-basedAgranulocytosis (ANC <500/mm³) occurred in 2/2796 premarketing patients (+ 1 severe neutropenia). If sore throat, fever, stomatitis, mucous membrane ulceration, or flu-like symptoms develop, obtain CBC with differential immediately. Discontinue if WBC is low. - Weight & BMIBaseline, then each visit
Routine7.5% of patients gained ≥7% body weight (vs 0% placebo). Monitor appetite and weight at every follow-up. Counsel on dietary measures from initiation. - Lipid PanelBaseline, then periodically
RoutineNonfasting cholesterol ≥20% above ULN in 15% (vs 7% placebo); triglycerides ≥500 mg/dL in 6% (vs 3% placebo). Check fasting lipids at baseline and at 3–6 months. - Suicidality AssessmentWeekly for first 4 weeks, then at each visit
RoutineEspecially important in patients under 25. Monitor for clinical worsening, agitation, irritability, and suicidal ideation. - Hepatic FunctionBaseline; as indicated
Trigger-basedALT ≥3× ULN occurred in 2.0% vs 0.3% placebo. Monitor LFTs if symptoms of hepatotoxicity develop. Use with caution in hepatic impairment (clearance reduced ~30%). - Serum SodiumAs indicated
Trigger-basedHyponatremia (SIADH) reported; check if confusion, weakness, unsteadiness, or falls develop. Elderly and diuretic users at highest risk. - Sedation LevelEach visit, especially early
Routine54% experience somnolence. Assess impact on driving and daily function. Consider dose adjustment (paradoxically, increasing dose may reduce sedation). - Renal FunctionBaseline
Routine75% renally excreted. Clearance reduced ~30% (moderate) to ~50% (severe impairment). Dose reduction may be needed.
Contraindications & Cautions
Absolute Contraindications
- Concurrent MAOI use or use within 14 days of MAOI discontinuation in either direction (serotonin syndrome risk)
- Concurrent linezolid or IV methylene blue (reversible MAO inhibition)
- Known hypersensitivity to mirtazapine or any excipient (SJS, bullous dermatitis, erythema multiforme, TEN reported)
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment: Clearance significantly reduced; dose decrease needed; ALT elevations occur more frequently
- Severe renal impairment (CrCl <10): Clearance reduced ~50%; dose decrease needed
- Known cardiovascular disease or QT prolongation risk: Post-marketing TdP reports; exercise caution and consider ECG monitoring
- Phenylketonuria (SolTab only): Contains phenylalanine (2.6 mg per 15 mg tablet, 5.2 mg per 30 mg, 7.8 mg per 45 mg)
Use with Caution
- Bipolar disorder: Screen before initiation; mania/hypomania activation reported in 0.2%
- Seizure disorders: 1 seizure in 2796 premarketing patients; prescribe with caution
- Elderly patients: Reduced clearance, increased sedation risk, increased hyponatremia risk, increased fall risk
- Patients receiving concomitant serotonergic drugs: Serotonin syndrome risk
- Cardiovascular disease or hypotension risk: Orthostatic hypotension observed in early volunteer trials
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Mirtazapine is not approved for use in pediatric patients. In an 8-week pediatric trial, 49% of mirtazapine-treated patients gained ≥7% body weight (vs 5.7% placebo), highlighting the unfavorable benefit-risk profile in this population.
Patient Counselling
Purpose of Therapy
Mirtazapine is prescribed to treat depression. Unlike many other antidepressants, it works by increasing the release of both serotonin and norepinephrine in the brain through a unique mechanism. It also helps with sleep and appetite, which are often disrupted in depression. Improvement in sleep may begin within the first few days, while improvement in mood typically takes 2 to 4 weeks. Continue taking the medication as prescribed even after you feel better.
How to Take
Take mirtazapine once daily, preferably in the evening before bedtime, as it causes drowsiness. Tablets can be taken with or without food. If using the orally disintegrating tablet (SolTab), open the blister pack with dry hands, place the tablet on your tongue, and let it dissolve in your saliva without chewing or crushing. It does not need water. Do not stop this medication suddenly; talk to your prescriber about tapering gradually.
Sources
- REMERON (mirtazapine) Tablets / REMERONSolTab (mirtazapine) Orally Disintegrating Tablets. Full Prescribing Information. Merck Sharp & Dohme Corp. Revised March 2020. accessdata.fda.govPrimary source for all dosing, adverse reaction Table 3 and 4 data, contraindications, warnings, pharmacokinetic parameters, and drug interactions cited in this monograph.
- REMERON (mirtazapine) Tablets. Full Prescribing Information. Revised 2021. accessdata.fda.govUpdated label with QTc prolongation data from thorough QT study, post-marketing TdP and sudden death reports.
- Wheatley DP, van Moffaert M, Timmerman L, Slooff CJ. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. J Clin Psychiatry. 1998;59(6):306-312. doi:10.4088/JCP.v59n0606Randomized controlled trial demonstrating comparable efficacy of mirtazapine versus fluoxetine in moderate-severe MDD with faster onset of effect on anxiety and sleep symptoms.
- Fawcett J, Barkin RL. A meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety. J Clin Psychiatry. 1998;59(3):123-127. doi:10.4088/JCP.v59n0306Meta-analysis confirming mirtazapine efficacy with particular benefit in depression with anxiety symptoms.
- Thase ME, Nierenberg AA, Keller MB, Panagides J; Relapse Prevention Study Group. Efficacy of mirtazapine for prevention of depressive relapse: a placebo-controlled double-blind trial of recently remitted high-risk patients. J Clin Psychiatry. 2001;62(10):782-788. doi:10.4088/JCP.v62n1006Relapse prevention trial establishing long-term maintenance efficacy at 15–45 mg/day for up to 40 weeks.
- Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Can J Psychiatry. 2024;69(9):641-687. doi:10.1177/07067437241245384Current Canadian guideline listing mirtazapine as a first-line antidepressant, particularly suitable for depression with insomnia, anxiety, or appetite loss.
- Qaseem A, Owens DK, Etxeandia-Ikobaltzeta I, et al. Nonpharmacologic and pharmacologic treatments of adults in the acute phase of major depressive disorder: a living clinical guideline from the American College of Physicians. Ann Intern Med. 2023;176(2):239-252. doi:10.7326/M22-1693ACP guideline including mirtazapine among recommended second-generation antidepressants for acute MDD treatment.
- de Boer T. The pharmacologic profile of mirtazapine. J Clin Psychiatry. 1996;57 Suppl 4:19-25.Foundational paper describing the NaSSA mechanism: α2-adrenergic antagonism, 5-HT2/5-HT3 antagonism, and H1 antagonism.
- Anttila SAK, Leinonen EVJ. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7(3):249-264. doi:10.1111/j.1527-3458.2001.tb00198.xComprehensive review of mirtazapine receptor pharmacology, clinical efficacy data, and the paradoxical dose-dependent sedation profile.
- Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet. 2000;38(6):461-474. doi:10.2165/00003088-200038060-00001Definitive PK review: bioavailability ~50%, t½ 20–40 h, gender/age effects, CYP enzyme contributions, and renal/hepatic impairment data.
- Mirtazapine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. ncbi.nlm.nih.govCurrent comprehensive review of mechanism, dosing, clinical applications, adverse effects, and toxicity across all clinical scenarios.
- Hassanein EHM, Althagafy HS, Baraka MA, Abd-alhameed EK, Ibrahim IM. Pharmacological update of mirtazapine: a narrative literature review. Naunyn Schmiedebergs Arch Pharmacol. 2024;397:4097-4116. doi:10.1007/s00210-023-02880-wRecent narrative review covering updated pharmacological understanding, off-label uses, and special population considerations.