Other antidepressants (NaSSA)
ATC code: N06AX11 (Mirtazapine)
Brand names
Remeron
Noradrenergic and specific serotonergic antidepressant (NaSSA). Antagonist at presynaptic α2-adrenoreceptors — increases noradrenaline and serotonin release. Antagonist at postsynaptic 5-HT2 and 5-HT3 receptors — reducing anxiety, sexual dysfunction-free, antiemetic. Strong H1 antagonist at low doses (15 mg or less) — sedation and appetite stimulation. At higher doses, the H1 effect is relatively offset by the noradrenergic component.
First line
First-line for major depression per 2023 and NG222. Per the Cipriani 2018 Lancet meta-analysis, mirtazapine is among the most effective antidepressants. Especially useful in depression with anxiety, insomnia, anorexia, or weight loss. Start 15 mg at bedtime; target 30–45 mg.
Second line
Off-label mirtazapine 7.5–15 mg at bedtime for insomnia in patients with comorbid depression and anxiety is justifiable per 2017. In non-depressed patients, no advantage over dedicated hypnotics. Sedation is maximal at low doses — escalation to 30–45 mg paradoxically reduces sedation (noradrenergic activation).
Individual decision
Off-label mirtazapine 15–30 mg at bedtime in oncology patients with nausea, anorexia, insomnia, and depression is a common palliative practice per NCCN. 5-HT3 antagonism (like ondansetron) and H1 antagonism explain antiemetic and appetite-stimulating effects. Not first-line CINV therapy.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Mirtazapine is a tetracyclic antidepressant. It is prescribed for major depression, especially with anxiety, sleep disturbance, or reduced appetite ( 2022 and NG222 guidelines). At low doses (7.5-15 mg at bedtime), mirtazapine is often prescribed for sleep outside a depression indication, purely because of its pronounced antihistamine effect at those doses. International insomnia guidelines ( 2021, ESRS 2017, NICE NG219) do not support this use: for primary insomnia the first line is cognitive-behavioral therapy for insomnia (CBT-I), and medication is matched to the diagnosis. As a sleep aid, mirtazapine carries specific risks: weight gain (5-10 kg over six months), increased appetite, morning sedation, and restless legs syndrome. If mirtazapine was prescribed only for sleep, outside depression, consider seeking a second opinion.
18 pairs found. Sorted from critical to minor.
Mechanism
Mirtazapine increases serotonin release by blocking presynaptic α2-adrenergic autoreceptors. Linezolid reversibly inhibits MAO. Combined action multiplies serotonergic activity.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.
Management
The combination is not prescribed. Stop mirtazapine at least 2 weeks before linezolid. As bridging therapy during antibiotic course, low-dose trazodone may be used cautiously for sleep. Alternative antibiotics: vancomycin, daptomycin.
Sources
Mechanism
IV methylene blue inhibits MAO-A. Mirtazapine raises synaptic serotonin via presynaptic α2-adrenergic blockade. Combined action sharply amplifies serotonergic transmission.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.
Management
Avoid the combination. Methylene blue is reserved for emergencies with mirtazapine withdrawn 5 days in advance. If unavoidable, monitor in ICU with cyproheptadine available.
Mechanism
Mirtazapine prolongs QT dose-dependently. Combined with amiodarone, torsades de pointes risk rises, especially in older patients and with hypokalaemia.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
The combination is acceptable at low mirtazapine doses (≤30 mg/day) and normal potassium. ECG before start and at 2 weeks. Alternative antidepressant with minimal QT effect: agomelatine.
Mechanism
Mirtazapine lowers the seizure threshold less than bupropion, but the effect is additive. Both drugs may also cause insomnia and anxiety in combination.
Symptoms
Seizures (generalised tonic-clonic or focal), agitation, tremor, insomnia. Patients with prior epilepsy or eating disorders are at particular risk.
Management
The combination is possible for augmentation. Keep doses low: bupropion 300 mg, mirtazapine 30 mg/day. Avoid with prior epilepsy.
Mechanism
Mirtazapine increases serotonergic transmission via α2-adrenergic blockade and blocks 5-HT2A/2C. Serotonin syndrome is rare with citalopram but possible at high doses. Citalopram itself prolongs QT.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
The combination is used for antidepressant augmentation. Cap citalopram at 20 mg and mirtazapine at 30 mg/day. Monitor blood pressure, pulse, and mental status in the early weeks.
Mechanism
Mirtazapine prolongs QT dose-dependently (especially above 30 mg/day). Combined with dronedarone, torsades de pointes risk rises.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.
Management
The combination is acceptable at low mirtazapine doses (≤30 mg/day) and normal potassium. ECG before start and at 2 weeks. Alternative antidepressants with minimal QT effect: agomelatine or sertraline (up to 100 mg).
Mechanism
Mirtazapine + SNRI – augmentation in resistant depression ('California rocket fuel'). Serotonin syndrome is rare but possible at high doses.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
The combination is possible for augmentation. Keep doses low: mirtazapine 15–30 mg, duloxetine 30–60 mg/day. Monitor blood pressure, pulse, and mental status in the early weeks.
Mechanism
Additive serotonergic effect. Mirtazapine blocks 5-HT2A/2C/3 but activates 5-HT1A. Combined with escitalopram (SSRI), serotonin syndrome has been reported, especially at high doses.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
The combination may be used for augmentation ('California rocket fuel') but requires caution. Escitalopram up to 10 mg, mirtazapine 15–30 mg. Monitor blood pressure, pulse, and mental status in the early weeks.
Mechanism
Additive serotonergic effect. Mirtazapine blocks 5-HT2/3 but activates 5-HT1A. Combined with a potent SSRI, serotonin syndrome has been reported, especially at high doses.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
The combination is used for augmentation in resistant depression ('California rocket fuel'). Keep doses low: fluoxetine 20 mg, mirtazapine 30 mg/day. Monitor mental status in the early weeks.
Mechanism
Serotonergic load from combining two drugs with different mechanisms. Fluvoxamine also blocks CYP1A2 (a minor mirtazapine metabolic route); mirtazapine levels may rise.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
The combination is used for augmentation in resistant depression ('California rocket fuel'). Keep doses low: mirtazapine 15–30 mg, fluvoxamine 100 mg/day. Monitor mental status in the early weeks.
Sources
Mechanism
Mirtazapine prolongs QT dose-dependently, additively with haloperidol (especially parenteral). Plus combined sedation.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.
Management
Avoid the combination with mirtazapine above 30 mg and parenteral haloperidol. At low doses and normal potassium, the combination is acceptable with ECG monitoring at 2 weeks. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole.
Mechanism
SSRI augmentation with mirtazapine in resistant depression is possible ('California rocket fuel'). Additive serotonergic effect is rare, but serotonin syndrome has been reported at high doses of both.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
The combination is used for antidepressant augmentation. Keep doses low: sertraline 100 mg, mirtazapine 30 mg/day. Monitor blood pressure and mental status in the early weeks.
Mechanism
Tramadol is a serotonergic opioid; mirtazapine raises serotonergic transmission via α2-blockade. Additive serotonin syndrome risk.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
Avoid the combination. For analgesia on mirtazapine, use paracetamol, an NSAID, or morphine/oxycodone. For neuropathic pain, gabapentin or pregabalin.
Mechanism
'California rocket fuel' augmentation – mirtazapine (5-HT2/3 blocker) + venlafaxine (SNRI). Used in resistant depression. Serotonin syndrome is rare but possible at high doses.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
The combination is used for augmentation in resistant depression. Keep doses low: mirtazapine 30 mg, venlafaxine 75–150 mg/day. Monitor blood pressure, pulse, and mental status in the early weeks.
Mechanism
Additive sedation and fall risk in older patients. No direct pharmacokinetic interaction.
Symptoms
Deep sedation, drowsiness, ataxia. Older patients: fall and fracture risk. Symptoms appear in the first 1–2 weeks.
Management
Widely used in anxious-depressive disorders. Alprazolam is given for a short course (4–6 weeks) with gradual taper after mirtazapine's effect stabilises. In older patients: minimum alprazolam dose; monitor cognition.
Mechanism
Additive sedation, anticholinergic effect, and weight gain. Mirtazapine's serotonergic effect (via α2-blockade) is not pronounced on a TCA.
Symptoms
Deep sedation, drowsiness, dry mouth, constipation, weight gain. Older patients: delirium and fall risk.
Management
Avoid the combination, especially in older patients. For resistant depression augmentation: mirtazapine + SSRI (sertraline, escitalopram) instead of a TCA. For neuropathic pain: gabapentin or pregabalin.
Mechanism
Additive QT prolongation (mirtazapine weakly prolongs QT, especially above 30 mg).
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
For short azithromycin courses (3–5 days) with mirtazapine ≤30 mg, the combination is acceptable. In older patients and cardiovascular disease: ECG before start or alternative antibiotics (doxycycline, a cephalosporin).
Mechanism
Additive hypotension and sedation. Mirtazapine blocks α2-adrenergic and 5-HT2 receptors, causing orthostatic effects.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.
Management
The combination is acceptable at low mirtazapine doses (15–30 mg). Warn the patient about drowsiness and orthostatic dizziness, especially in the first 1–2 weeks. Check blood pressure standing and sitting.
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Boxed warning
FDA boxed warning: antidepressants increase suicidal ideation risk in children, adolescents, and adults under 25.
FDA categories were retired in 2015 (historically C). Large cohort data show no increased teratogenic risk. In pregnant patients with severe depression, continuation is individualized.
Transfers into milk in small amounts. Per LactMed, use is acceptable with monitoring.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Mirtazapine is evaluated for the following indications with varying evidence strength: Major depressive disorder (evidence tier A), Insomnia in older adults (evidence tier B), Chemotherapy-induced nausea and vomiting prophylaxis (evidence tier C). See the full indication matrix with dosing and citations above on this page.
Common side effects of Mirtazapine (≥ 1 in 100): Sedation (at 15 mg or less), Weight gain (5–10 kg over 6 months in some patients), Dry mouth, Increased appetite, Constipation, Dizziness. See the Safety section for uncommon and serious reactions.
FDA category C. FDA categories were retired in 2015 (historically C). Large cohort data show no increased teratogenic risk. In pregnant patients with severe depression, continuation is individualized.
Transfers into milk in small amounts. Per LactMed, use is acceptable with monitoring.
Mirtazapine is contraindicated in: Concurrent or recent (14 days) MAOI; Hypersensitivity; Severe hepatic impairment. Full list in the Safety section.
FDA boxed warning: antidepressants increase suicidal ideation risk in children, adolescents, and adults under 25.