What is the recommended dosing for mirtazapine in adults, including initial dose, effective dose range, and considerations for elderly patients or those with significant medical comorbidities?

Mirtazapine Dosing

Start mirtazapine at 15 mg once daily at bedtime, with dose increases up to a maximum of 45 mg daily based on response, making dose changes no more frequently than every 1-2 weeks. 1

Initial Dosing

• Begin with 15 mg once daily, preferably in the evening prior to sleep 1
• This starting dose is supported by FDA labeling and represents the standard approach across adult populations 1, 2
• The 15 mg dose has demonstrated efficacy in clinical trials, with some patients achieving adequate response at this level 3, 4

Dose Titration

• If inadequate response occurs at 15 mg, increase the dose up to a maximum of 45 mg per day 1
• Allow 1-2 weeks between dose adjustments to permit adequate evaluation of therapeutic response 1
• The effective dosage range in clinical trials was 15-45 mg daily, with most patients responding within this range 2, 5
• Dose escalation should proceed incrementally: 15 mg → 30 mg → 45 mg as needed 6

Special Populations: Elderly Patients

For elderly patients, start at the lower end of the dosing range (7.5-15 mg) and titrate more slowly 7

• The American Family Physician guidelines for managing depression in elderly patients with comorbidities recommend:
  • Initial dose: 7.5 mg at bedtime 7
  • Maximum dose: 30 mg at bedtime 7
• Elderly patients are more susceptible to sedation and other adverse effects, necessitating cautious dosing 4
• The drug's antihistaminic effects at low doses may cause transient somnolence, which paradoxically appears less frequent at higher dosages 3, 6

Patients with Hepatic or Renal Impairment

• Careful dosage titration with regular monitoring is required in patients with hepatic or renal insufficiency 6
• Mirtazapine is extensively metabolized hepatically and excreted primarily renally (up to 85% in urine), so clearance may be reduced in organ dysfunction 4, 6

Dosing Adjustments for Drug Interactions

Strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin):

• May require increased mirtazapine dosage 1
• Conversely, decrease dose if the inducer is discontinued 1

Strong CYP3A4 inhibitors (ketoconazole, clarithromycin):

• May require decreased mirtazapine dosage 1
• Increase dose if the inhibitor is discontinued 1

Cimetidine:

• May require decreased mirtazapine dosage with concomitant use 1
• Increase dose if cimetidine is discontinued 1

Timing and Administration

• Administer as a single daily dose at bedtime 1, 5
• The elimination half-life of 20-40 hours supports once-daily dosing 2, 4
• Peak plasma concentrations occur 2.2-3.1 hours after administration 6
• Bedtime dosing capitalizes on the drug's sedative properties to improve sleep while minimizing daytime somnolence 3

Duration of Trial

• Allow 2-4 weeks for onset of antidepressant effect, though sleep disturbances and anxiety may improve within the first week 2
• Some studies demonstrated significant improvement as early as 1 week, with maintained therapeutic advantage throughout treatment 4
• An adequate trial requires at least 4-8 weeks, with at least 2 weeks at the maximum tolerated dose 7

Discontinuation

• Gradually taper the dose rather than stopping abruptly to minimize withdrawal symptoms 1
• After 9 months of treatment, consider dosage reduction to reassess the need for continued medication 7
• Discontinuing over 10-14 days limits withdrawal symptoms 7

Common Pitfalls

• Avoid premature dose escalation: The sedation commonly reported at lower doses (15 mg) often diminishes at therapeutic doses (≥30 mg), so don't mistake initial sedation for treatment failure 3, 6
• Don't underdose elderly patients indefinitely: While starting low is appropriate, many elderly patients will require and tolerate 30 mg for adequate antidepressant effect 7
• The drug's appetite-stimulating and weight-gain properties may be beneficial in patients with depression-related anorexia but problematic in others 2, 5