What is the appropriate dosage and treatment approach for an adult patient with depression, anxiety, and insomnia who is being considered for treatment with mirtazapine?

Mirtazapine for Depression, Anxiety, and Insomnia

Recommended Dosage and Administration

Start mirtazapine at 15 mg once daily at bedtime, as this is the FDA-approved initial dose that provides optimal therapeutic benefit while minimizing sedation. 1

• The 15 mg starting dose is superior to lower doses (7.5 mg) because paradoxically, sedation is more pronounced at subtherapeutic doses and decreases as the dose increases to therapeutic levels 2
• If inadequate response after 1-2 weeks, increase to 30 mg at bedtime, with a maximum dose of 45 mg per day 1
• Do not make dose changes more frequently than every 1-2 weeks to allow sufficient time for evaluation of therapeutic response 1

Why Mirtazapine is Ideal for This Patient

Mirtazapine simultaneously addresses all three presenting symptoms—depression, anxiety, and insomnia—through its unique receptor profile, making it superior to SSRIs that often worsen insomnia. 3, 4

• The American Academy of Family Physicians identifies mirtazapine as one of the few antidepressants that promotes sleep rather than causing insomnia, unlike SSRIs (fluoxetine, paroxetine, sertraline) which commonly cause sleep disturbances 3
• Sedating antidepressants like mirtazapine are recommended as first-line treatment when insomnia occurs with comorbid depression/anxiety 4
• Anxiolytic effects appear as early as the first week of treatment due to 5-HT2 receptor antagonism, while full antidepressant effects develop over 2-4 weeks 5, 6

Mechanism Supporting Triple Benefit

• Mirtazapine blocks presynaptic alpha-2 adrenergic receptors, increasing noradrenergic and serotonergic neurotransmission for antidepressant effect 7
• Antagonism of postsynaptic 5-HT2 and 5-HT3 receptors provides anxiolytic effects and eliminates SSRI-related side effects like insomnia, gastrointestinal symptoms, and sexual dysfunction 7, 5
• The 20-40 hour half-life enables once-daily bedtime dosing with sustained therapeutic levels 7, 2

Critical Pre-Treatment Screening

Screen for personal or family history of bipolar disorder, mania, or hypomania before initiating mirtazapine, as antidepressants can precipitate manic episodes. 1

• If bipolar disorder is present, ensure mood stabilizer is in place before starting mirtazapine 3
• Monitor for decreased need for sleep, increased energy, racing thoughts, or irritability during the first 4-8 weeks 3

Expected Adverse Effects

• Increased appetite and weight gain occur more commonly than with placebo but may be beneficial in patients with depression-related weight loss 7, 8
• Somnolence is dose-dependent and typically decreases when using therapeutic doses (≥15 mg) rather than subtherapeutic doses 2, 8
• Minimal cardiovascular, anticholinergic, gastrointestinal, and sexual side effects compared to tricyclics and SSRIs 7, 2

Drug Interactions Requiring Dose Adjustment

• Decrease mirtazapine dose with strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or cimetidine 1
• Increase mirtazapine dose with strong CYP3A inducers (carbamazepine, phenytoin, rifampin) 1
• Allow 14 days between discontinuing MAOIs and starting mirtazapine, and vice versa 1

Discontinuation Protocol

Gradually taper mirtazapine rather than stopping abruptly to prevent withdrawal symptoms. 1

• Taper over 10-14 days minimum to limit discontinuation symptoms 3
• Adverse reactions may occur with abrupt discontinuation or rapid dose reduction 1

Combination with Behavioral Therapy

Combine mirtazapine with Cognitive Behavioral Therapy for Insomnia (CBT-I) whenever possible, as pharmacotherapy should supplement—not replace—behavioral interventions. 4

• CBT-I includes stimulus control therapy, sleep restriction therapy, and cognitive restructuring 4
• Sleep hygiene alone is insufficient but should be included as part of comprehensive treatment 4

Cardiovascular Safety

• Mirtazapine demonstrates cardiovascular safety even in patients with end-stage cardiovascular disease, making it appropriate for patients with cardiac comorbidities 4
• Minimal cardiovascular effects compared to tricyclic antidepressants 7

Common Pitfalls to Avoid

• Do not start at 7.5 mg thinking lower doses cause less sedation—paradoxically, sedation is worse at subtherapeutic doses 2
• Do not combine with SSRIs initially, as mirtazapine alone addresses depression, anxiety, and insomnia simultaneously 5
• Do not use PRN (as needed)—mirtazapine requires nightly scheduled dosing to maintain therapeutic blood levels 9
• Do not continue long-term without periodic reassessment of ongoing need 4