What are the dosing guidelines, contraindications, drug interactions (including monoamine oxidase inhibitors (MAOIs) and cytochrome P450 3A4 (CYP3A4) inhibitors), common adverse effects, and monitoring recommendations for mirtazapine in adults, with special considerations for elderly patients and those with severe hepatic impairment?

Mirtazapine: Comprehensive Clinical Guide

Dosing Guidelines

Start mirtazapine at 15 mg once daily at bedtime, with a therapeutic range of 15-45 mg daily. 1, 2, 3

Standard Adult Dosing

• Initial dose: 15 mg at bedtime for 4 days 4
• Standard therapeutic dose: 30 mg daily after initial 4 days 4
• Maximum dose: 45 mg daily 5, 1, 6
• Dose adjustments: Allow 1-2 weeks between increases due to the 20-40 hour half-life 1, 6

Special Population Dosing

Elderly Patients:

• Start at 7.5 mg at bedtime for elderly, debilitated, or frail patients 5
• Clearance is reduced by 40% in elderly males and 10% in elderly females compared to younger patients 1
• Elderly patients face greater risk of confusion, over-sedation, and hyponatremia 1

Severe Hepatic Impairment:

• Reduce dose by approximately 30% as oral clearance decreases by this amount 1
• Start conservatively and titrate slowly with close monitoring 1

Moderate to Severe Renal Impairment:

• Reduce dose by 30-50% depending on severity (30% reduction for GFR 11-39 mL/min/1.73m², 50% reduction for GFR <10 mL/min/1.73m²) 1
• 75% of mirtazapine is renally excreted, increasing risk in renal dysfunction 1

Mechanism of Action

Mirtazapine enhances noradrenergic and serotonergic neurotransmission through alpha-2 adrenergic receptor antagonism, while blocking postsynaptic 5-HT2 and 5-HT3 receptors. 1, 7, 4, 3

• Blocks presynaptic alpha-2 autoreceptors and heteroreceptors, increasing norepinephrine and serotonin release 7, 4, 3
• Antagonizes 5-HT2 and 5-HT3 receptors while sparing 5-HT1A receptors, providing antidepressant effects without typical serotonergic side effects 7, 4
• Antagonizes histamine H1 receptors, explaining prominent sedative effects 1, 7
• Has minimal anticholinergic and muscarinic activity 7, 4

Contraindications and Precautions

Absolute Contraindications

Do not use mirtazapine within 14 days of MAOI therapy due to risk of serotonin syndrome 8

Pregnancy and Lactation

• Not recommended during pregnancy or nursing 8
• Mirtazapine is present in breast milk at relative infant doses of 0.6-2.8% of maternal weight-adjusted dose 1
• Women of reproductive potential require counseling on reliable contraception 8

Clinical Cautions

• Use caution with signs of depression, compromised respiratory function (asthma, COPD, sleep apnea), or hepatic/heart failure 8
• Monitor elderly patients closely for confusion, over-sedation, orthostatic hypotension, and hyponatremia 9, 1
• Safety and effectiveness not established in patients under 18 years 1

Drug Interactions

Major Interactions Requiring Dose Adjustment

CYP3A4 Strong Inhibitors (e.g., Ketoconazole):

• Increase mirtazapine AUC by >50% 1
• Consider dose reduction when co-administering strong CYP3A4 inhibitors 1

CYP Inducers:

• Phenytoin increases mirtazapine clearance 2-fold, decreasing plasma concentrations by 45% 1
• Carbamazepine increases clearance 2-fold, decreasing concentrations by 60% 1
• Consider dose increase when co-administering enzyme inducers 1

Weak CYP Inhibitors (e.g., Cimetidine):

• Increases mirtazapine AUC by >50% 1
• Monitor for increased sedation and other adverse effects 1

Other Significant Interactions

• Warfarin: Mirtazapine 30 mg daily increases INR by 0.2; monitor INR closely 1
• CNS Depressants and Alcohol: Additive impairment of cognitive and motor performance 8, 4
• QTc-Prolonging Drugs: May increase risk of QT prolongation and ventricular arrhythmias, though mirtazapine at 75 mg does not prolong QTc to clinically meaningful extent 1

Metabolism Details

• Mirtazapine is metabolized by CYP2D6, CYP1A2, and CYP3A4 1
• Mirtazapine is not a potent inhibitor or inducer of these enzymes, minimizing interaction potential 7

Common Adverse Effects

Most Frequent Side Effects

Somnolence/Sedation:

• Occurs in 23% of patients (vs. 14% placebo) 9
• Most common side effect, may be less frequent at higher doses 7, 3
• Therapeutically beneficial for patients with insomnia when dosed at bedtime 9, 5

Weight Gain and Increased Appetite:

• Weight gain occurs in 10% (vs. 1% placebo) 9
• Increased appetite in 11% (vs. 2% placebo) 9
• In pediatric trials, 49% had ≥7% weight gain (mean 4 kg increase) vs. 5.7% with placebo 1
• Can be therapeutically beneficial in patients with anorexia, weight loss, or elderly with dementia 9

Dry Mouth:

• Occurs in 25% (vs. 16% placebo) 9, 5

Constipation:

• Frequently reported gastrointestinal effect 9

Advantageous Side Effect Profile

• Minimal cardiovascular, anticholinergic, and gastrointestinal effects compared to tricyclics 9, 7, 3
• Essentially lacks sexual dysfunction common with SSRIs 9, 7, 3
• No significant insomnia or agitation unlike SSRIs 9, 3
• Safe in cardiovascular disease patients 9

Serious but Rare Adverse Effects

• Rare cases of agranulocytosis and neutropenia reported 4
• Transient elevations in cholesterol (3-4%) and liver function tests 4, 6
• Orthostatic hypotension, particularly in elderly 9, 1
• Hyponatremia, especially in elderly patients 9, 1

Overdose Profile

• Very low seizure potential 4, 3
• Overdoses up to 975 mg caused significant sedation but no cardiovascular, respiratory effects, or seizures 3

Monitoring Recommendations

Initial Assessment and Follow-up Timeline

Begin assessing therapeutic response and adverse effects within 1-2 weeks of treatment initiation. 5

• Week 1-2: Assess for early improvement in sleep disturbances and anxiety symptoms 3
• Week 2-4: Evaluate onset of antidepressant effect 5, 6, 3
• Week 6-8: If inadequate response, consider treatment modification 5
• Steady state: Achieved within 5 days with 50% accumulation 1

Specific Monitoring Parameters

Therapeutic Response:

• Continue treatment for 4-9 months after satisfactory response in first episode depression 5
• For patients with ≥2 episodes, consider longer duration therapy 5

Adverse Effects:

• Monitor weight and appetite at each visit 9, 1
• Assess sedation level, particularly in elderly 9, 1
• Check blood pressure for orthostatic hypotension, especially in elderly 9, 1
• Monitor for hyponatremia in elderly patients 9, 1

Laboratory Monitoring:

• Baseline and periodic cholesterol levels (mean increases 3-4%) 4, 6
• Baseline and periodic liver function tests 4, 6
• Complete blood count if signs of infection develop (rare agranulocytosis risk) 4

Drug Interactions:

• Monitor INR closely if co-administered with warfarin 1
• Assess for increased sedation with CYP3A4 inhibitors 1
• Evaluate for reduced efficacy with enzyme inducers 1

Discontinuation

• Avoid abrupt discontinuation; taper gradually to minimize withdrawal symptoms 8

Clinical Pearls

Onset of Action:

• Sleep and anxiety symptoms may improve within the first week 3
• Full antidepressant effect typically requires 2-4 weeks 5, 6, 3
• Faster onset than some SSRIs (fluoxetine, paroxetine, sertraline) 5

Optimal Patient Selection:

• Particularly suitable for depression with insomnia, anxiety, or weight loss 9, 5, 7
• Beneficial in elderly patients with dementia and depression who need weight gain 9
• Appropriate for patients who cannot tolerate SSRI sexual dysfunction or gastrointestinal effects 9, 7
• Safe option in cardiovascular disease 9

Administration:

• Administer on empty stomach to maximize effectiveness 8
• Once-daily bedtime dosing due to 20-40 hour half-life 1, 6, 3
• Females have longer elimination half-life (37 hours) than males (26 hours) 1