What is mirtazapine and how is it used in treating major depressive disorder?

Mirtazapine Overview

Mirtazapine is a second-generation antidepressant (noradrenergic and specific serotonergic antidepressant) FDA-approved for treating major depressive disorder in adults, with a unique mechanism that blocks presynaptic α2-adrenergic receptors and postsynaptic 5-HT2 and 5-HT3 receptors, resulting in enhanced noradrenergic and serotonergic neurotransmission. 1

Mechanism of Action

Mirtazapine works through a distinct pharmacological profile compared to other antidepressants:

• Acts as an antagonist at central presynaptic α2-adrenergic inhibitory auto-receptors and heteroreceptors, which enhances both noradrenergic and serotonergic activity 1
• Blocks postsynaptic serotonin 5-HT2 and 5-HT3 receptors while having no significant affinity for 5-HT1A and 5-HT1B receptors, providing antidepressant effects without typical serotonergic side effects 1, 2
• Also antagonizes histamine H1 receptors, peripheral α1-adrenergic receptors, and muscarinic receptors, which explains its sedating effects and potential for orthostatic hypotension 1

Clinical Efficacy

Comparative Effectiveness

When treating acute-phase major depressive disorder, second-generation antidepressants including mirtazapine do not significantly differ in overall efficacy, effectiveness, or quality of life outcomes. 3

However, mirtazapine has one notable advantage:

• Mirtazapine demonstrates a statistically significantly faster onset of action compared to citalopram, fluoxetine, paroxetine, or sertraline, though after 4 weeks most response rates become similar 3
• Response rates between mirtazapine and venlafaxine do not differ 3

Treatment Response Rates

• Approximately 38% of patients do not achieve treatment response during 6-12 weeks of treatment with second-generation antidepressants 3
• About 54% do not achieve remission 3
• Second-generation antidepressants do not differ in the rate of achieving remission 3

Special Populations and Symptom Clusters

Mirtazapine is particularly useful in patients with depression accompanied by anxiety symptoms, sleep disturbance, or appetite problems due to its unique side effect profile 4, 5:

• Evidence shows no significant differences among second-generation antidepressants for treating depression with accompanying anxiety, insomnia, or pain 3
• Mirtazapine's anxiolytic and sleep-improving effects may be related to its pharmacodynamic properties 2

Pharmacokinetics

• Bioavailability is approximately 50% following oral administration with peak plasma concentrations reached within 2 hours 1
• Half-life ranges from 20-40 hours, enabling once-daily dosing 1, 6
• Steady-state plasma levels are attained within 5 days with about 50% accumulation 1
• Food has minimal effect on absorption 1
• Approximately 85% protein-bound 1
• Extensively metabolized via CYP2D6, CYP1A2, and CYP3A4 pathways 1
• Eliminated predominantly via urine (75%) with 15% in feces 1

Dosing

The recommended starting dosage is 15 mg once daily at bedtime, with an effective dosage range of 15-45 mg/day. 5, 6

• Oral clearance is reduced in elderly patients compared to younger subjects 1
• Dosage adjustments should be considered in geriatric populations 1

Adverse Effects Profile

Mirtazapine has a unique tolerability profile distinct from both tricyclic antidepressants and SSRIs:

Most Common Adverse Effects

• Somnolence (most commonly reported), increased appetite, weight gain, and dizziness are the primary adverse effects 5, 6
• Somnolence appears less frequent at higher dosages 2
• These effects are attributed to antihistaminic (H1) activity, particularly at low doses 2

Advantages Over Other Antidepressants

• Anticholinergic events, tremor, and dyspepsia are less common with mirtazapine than with tricyclic antidepressants 4
• Mirtazapine does not appear to be associated with sexual dysfunction, unlike SSRIs 2
• Lacks typical serotonergic side effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction due to 5-HT2 and 5-HT3 receptor blockade 6
• Has minimal cardiovascular and anticholinergic effects 6

Serious Adverse Events

• No significant cardiovascular adverse effects at multiples of 7-22 times the maximum recommended dose 2
• At 75 mg (1.67 times maximum recommended dosage), mirtazapine does not prolong QTc interval to a clinically meaningful extent 1
• Cases of overdose up to 975 mg caused significant sedation but no cardiovascular or respiratory effects or seizures 6

Suicidality

• Studies show no differences in suicidality risk among second-generation antidepressants 3
• However, SSRIs as a class are associated with increased risk for nonfatal suicide attempts 3

Treatment Duration and Monitoring

The American College of Physicians recommends:

• Assess patient status, therapeutic response, and adverse effects regularly beginning within 1-2 weeks of initiation 3
• Modify treatment if inadequate response within 6-8 weeks 3
• Continue treatment for 4-9 months after satisfactory response in patients with first episode of major depressive disorder 3
• For patients with 2 or more episodes, even longer duration may be beneficial 3
• Continuation of antidepressant therapy reduces risk for relapse 3

Drug Selection Considerations

When choosing pharmacologic therapy for acute major depression, select second-generation antidepressants based on adverse effect profiles, cost, and patient preferences. 3

Clinical Scenarios Favoring Mirtazapine

• Patients requiring rapid symptom improvement (faster onset of action) 3
• Depression with prominent anxiety symptoms 4, 5
• Depression with insomnia or sleep disturbance 2, 4
• Patients who cannot tolerate sexual dysfunction from SSRIs 2
• Patients who have experienced gastrointestinal side effects with SSRIs 6
• Elderly patients with depression and poor appetite/weight loss 1

Clinical Scenarios to Avoid Mirtazapine

• Patients concerned about weight gain or increased appetite 4, 5
• Patients who cannot tolerate sedation during daytime hours 2
• Situations where alertness is critical (though sedation decreases at higher doses) 2

Drug Interactions

• Mirtazapine is unlikely to affect metabolism of drugs metabolized by CYP2D6, making it suitable for patients requiring polytherapy 4
• Low potential for interaction with antipsychotics, tricyclic antidepressants, and some SSRIs 4
• Few formal drug-drug interactions have been reported 5