What are the indications, recommended starting dose, titration schedule, contraindications, and common adverse effects of mirtazapine for treating major depressive disorder in adults, particularly when insomnia, loss of appetite, or weight loss are present?

Mirtazapine for Major Depressive Disorder

Mirtazapine is FDA-approved for treating major depressive disorder in adults, with a recommended starting dose of 15 mg once daily at bedtime, and is particularly advantageous when depression presents with insomnia, loss of appetite, or weight loss. 1

Indications

• Major depressive disorder (MDD) in adults is the FDA-approved indication 1
• Particularly beneficial when depression is accompanied by:
  • Insomnia or sleep disturbance 2, 3, 4
  • Loss of appetite 2, 5
  • Weight loss 2, 5
  • Anxiety symptoms 4, 6

Dosing Algorithm

Starting Dose

• Begin with 15 mg once daily, administered orally in the evening prior to sleep 1
• This starting dose should be maintained for at least 1-2 weeks before considering dose adjustments 1

Titration Schedule

• If inadequate response after 1-2 weeks, increase dose up to a maximum of 45 mg per day 1
• Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response 1
• The typical titration sequence is: 15 mg → 30 mg → 45 mg (maximum dose) 1, 5
• Allow 6-8 weeks before concluding inadequate response 2

Special Dosing Considerations

• Reduce dose when co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) or cimetidine 1
• Increase dose may be needed with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin) 1
• In elderly or debilitated patients, start with lower doses and monitor for daytime sedation 7

Contraindications

• Concomitant use with MAOIs or within 14 days of discontinuing an MAOI 1
• At least 14 days must elapse after stopping mirtazapine before starting an MAOI 1

Common Adverse Effects

Most Frequent (Significantly Higher Than Placebo)

• Drowsiness/somnolence (23% vs 14% placebo) 8
• Excessive sedation (19% vs 5% placebo) 8
• Dry mouth (25% vs 16% placebo) 8
• Increased appetite (11% vs 2% placebo) 8
• Weight gain (10% vs 1% placebo) 8

Advantageous Side Effect Profile

• Minimal anticholinergic effects compared to tricyclic antidepressants 8, 9
• Lower incidence of typical SSRI side effects (nausea, vomiting, diarrhea, insomnia) compared to placebo 8
• Lower rates of sexual dysfunction compared to SSRIs 4, 6
• No significant cardiovascular adverse effects on blood pressure or heart rate 8, 9

Serious but Rare Adverse Events

• Agranulocytosis and neutropenia (rare cases reported) 9
• Seizures (very low potential; only one case in patient with prior seizure history) 8

Clinical Advantages

Onset of Action

• Mirtazapine demonstrates faster onset of action than SSRIs (fluoxetine, paroxetine, sertraline) 10, 6
• More effective than fluoxetine at weeks 3-4, and more effective than paroxetine and citalopram at weeks 1-2 6

Unique Pharmacological Profile

• Blocks presynaptic α2-adrenergic receptors and postsynaptic 5-HT2 and 5-HT3 receptors, enhancing noradrenergic and serotonergic neurotransmission 5, 4, 9
• This mechanism provides antidepressant effects without typical serotonin-related side effects 4

Comparative Efficacy

• Equivalent efficacy to tricyclic antidepressants (amitriptyline, clomipramine, doxepin) but with improved tolerability 10, 4, 6
• No clinically significant differences in efficacy compared to other second-generation antidepressants for acute-phase MDD 10

Important Clinical Considerations

Pre-Treatment Screening

• Screen patients for personal or family history of bipolar disorder, mania, or hypomania before initiating treatment 1

Monitoring Requirements

• Monitor for excessive sedation, especially in the first 1-2 weeks 2
• Counsel patients upfront about expected weight gain and increased appetite 2
• Follow up within 1-2 weeks after starting to assess tolerability and early response 2

Treatment Duration

• Continue successful treatment for 4-9 months after achieving remission in first-episode depression 2
• If inadequate response by 6-8 weeks, consider switching strategies rather than continuing ineffective treatment 2

Discontinuation

• Gradually reduce dosage rather than stopping abruptly to minimize withdrawal symptoms 1

Common Pitfalls to Avoid

• Don't assume treatment failure before 6-8 weeks of adequate dosing 2
• Don't neglect to warn patients about weight gain, as this is a common reason for discontinuation 2
• Don't increase doses more frequently than every 1-2 weeks, as this doesn't allow adequate time to assess response 1
• Paradoxically, sedation may be less frequent at higher dosages (above 15 mg), so don't automatically reduce dose if sedation occurs 4

Safety in Overdose

• Mirtazapine demonstrates excellent safety in overdose, with only transient somnolence reported in patients taking up to 315 mg 8, 9
• Very low seizure-inducing potential combined with lack of cardiotoxic properties 8

Drug Interactions

• Low potential for drug-drug interactions as mirtazapine is not a potent inhibitor or inducer of CYP450 enzymes 4
• This makes it particularly useful in patients requiring polytherapy 6
• Concomitant use with diazepam or alcohol may impair cognitive/motor performance 9