In which patients is mirtazapine (Remeron) contraindicated, particularly in pediatric and adolescent populations with a history of suicidal ideation, Attention Deficit Hyperactivity Disorder (ADHD), bipolar disorder, or previous use of monoamine oxidase inhibitors (MAOIs)?

Contraindications for Mirtazapine

Mirtazapine is absolutely contraindicated in patients currently taking or who have taken monoamine oxidase inhibitors (MAOIs) within the past 14 days, and in patients with known hypersensitivity to mirtazapine or its excipients. 1

Absolute Contraindications

MAOI Use (Current or Recent)

• Concurrent use with MAOIs or use within 14 days of stopping MAOIs is strictly contraindicated due to increased risk of serotonin syndrome 1
• This includes traditional MAOIs (phenelzine, tranylcypromine, isocarboxazid, selegiline) as well as linezolid and intravenous methylene blue 1
• MAOIs play a central role in most cases of serotonin syndrome, which can progress to fever, seizures, arrhythmias, unconsciousness, and death 2
• A 14-day washout period is mandatory after discontinuing MAOIs before initiating mirtazapine 1

Hypersensitivity Reactions

• Known hypersensitivity to mirtazapine or any excipients is an absolute contraindication 1
• Severe skin reactions have been reported, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, and toxic epidermal necrolysis 1

Critical Warnings for Specific Populations

Pediatric and Adolescent Patients

• Mirtazapine is NOT FDA-approved for use in pediatric patients with major depressive disorder, as safety and effectiveness have not been established in this population 1
• Antidepressants, including mirtazapine, increase the risk of suicidal thoughts and behaviors in pediatric patients 1
• In an 8-week pediatric trial, 49% of mirtazapine-treated patients experienced weight gain of at least 7%, compared to only 5.7% of placebo-treated patients, with mean weight increase of 4 kg versus 1 kg 1

Patients with Bipolar Disorder

• While not an absolute FDA contraindication, antidepressant monotherapy (including mirtazapine) should be avoided in bipolar disorder due to risk of triggering manic episodes or rapid cycling 3
• Treatment with antidepressants should be avoided in patients with a history of bipolar depression due to risk of mania 3
• If antidepressants are used in bipolar disorder, they must always be combined with a mood stabilizer (lithium, valproate, or lamotrigine) and never used as monotherapy 4, 3
• Antidepressant-induced mood destabilization is a recognized phenomenon in bipolar disorder, and considerable research indicates that mixed states are associated with suicidality 5
• Antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion in bipolar disorder 5

Patients with History of Suicidal Ideation

• All antidepressants, including mirtazapine, carry a boxed warning for increased risk of suicidal thinking and behavior in patients under age 24 2
• The pooled absolute rates for suicidal ideation are 1% for antidepressant-treated youth versus 0.2% for placebo, with a number needed to harm of 143 2
• Close monitoring for suicidality is mandatory, especially in the first months of treatment and following dosage adjustments 2
• The link between suicidality and antidepressant use in adolescents may be due to inappropriate treatment of misdiagnosed bipolar disorder that has yet to manifest with hypomanic/manic symptoms 6

Pregnancy and Lactation

• While not an absolute contraindication, mirtazapine use during pregnancy requires careful risk-benefit assessment 1
• Women who discontinue antidepressants during pregnancy are more likely to experience relapse of major depression 1
• Mirtazapine is present in human milk at low levels (relative infant doses 0.6-2.8% of maternal weight-adjusted dose), though no adverse effects have been reported in most breastfed infants 1

Important Drug Interactions Requiring Caution

Serotonergic Drugs

• Concomitant use with other serotonergic drugs increases risk of serotonin syndrome and requires careful monitoring 1
• This includes SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St. John's Wort, tramadol, tryptophan, and buspirone 1
• Monitor for signs of serotonin syndrome (mental status changes, neuromuscular hyperactivity, autonomic hyperactivity) particularly during treatment initiation and dose increases 2, 1

CNS Depressants

• Avoid concomitant use of benzodiazepines and alcohol with mirtazapine, as they increase impairment of cognitive and motor skills 1

CYP3A Modulators

• Strong CYP3A inducers (phenytoin, carbamazepine, rifampin) decrease mirtazapine plasma concentrations and may require dose increases 1
• Strong CYP3A inhibitors (itraconazole, ritonavir, nefazodone) and cimetidine increase mirtazapine plasma concentrations and may require dose decreases 1

Special Population Considerations

Elderly Patients

• Caution is indicated in elderly patients due to decreased clearance, increased risk of confusion, over-sedation, and hyponatremia 1
• Mirtazapine is substantially excreted by the kidney (75%), and elderly patients have decreased clearance 1
• Dose selection should be conservative, starting at the low end of the dosing range 1

Renal or Hepatic Impairment

• Dosage decrease may be necessary in patients with moderate to severe renal or hepatic impairment due to reduced clearance and increased plasma levels 1

Common Pitfalls to Avoid

• Never initiate mirtazapine in patients currently taking MAOIs or within 14 days of MAOI discontinuation—this is the most critical contraindication 1
• Never use mirtazapine as monotherapy in patients with known or suspected bipolar disorder—always combine with a mood stabilizer 3
• Do not overlook the increased suicide risk in pediatric and young adult patients—implement close monitoring protocols 2, 1
• Avoid combining mirtazapine with multiple serotonergic agents without careful monitoring for serotonin syndrome 2, 1
• Do not prescribe standard adult doses in elderly patients or those with renal/hepatic impairment without dose adjustment 1