What is the best first-line antidepressant for an adult with major depressive disorder and prominent agitation?

Best Antidepressant for Agitated Depression

For agitated depression, mirtazapine is the optimal first-line choice because it specifically addresses both depressive symptoms and agitation through its unique sedating and anxiolytic properties, without the risk of worsening agitation that SSRIs carry. 1, 2

Primary Recommendation: Mirtazapine

• Mirtazapine (15-45 mg daily) is specifically indicated as first-line therapy in patients with major depression and symptoms of anxiety/agitation, making it uniquely suited for this presentation 1

• The medication works through dual noradrenergic and serotonergic enhancement while blocking 5-HT2 and 5-HT3 receptors, which provides antidepressant effects without serotonin-related agitation 1, 2

• Mirtazapine demonstrates important anxiolytic effects and rapid onset of action (within 1-2 weeks), which is particularly valuable when agitation is prominent 1, 2, 3

• The sedating properties at lower doses (due to H1 antagonism) can be therapeutic for agitated patients, though this effect paradoxically decreases at higher doses 1, 3

Medications to Avoid in Agitated Depression

• Fluoxetine should be explicitly avoided in agitated depression due to its greater risk of causing agitation and overstimulation 4

• Bupropion carries risk of worsening agitation and should not be used when agitation is a prominent feature 3

• Paroxetine should be avoided, particularly in older adults, due to higher anticholinergic effects 4, 5

Alternative Second-Line Options

• If mirtazapine is not tolerated or contraindicated, consider sertraline or citalopram, which have more favorable side effect profiles than other SSRIs and are less likely to worsen agitation 4, 5

• Venlafaxine (SNRI) may be considered as an alternative, though it lacks the specific anxiolytic properties of mirtazapine 4

Special Considerations for Older Adults

• In older patients with agitated depression, mirtazapine remains appropriate, but citalopram and sertraline are also preferred alternatives with dose limits (citalopram maximum 40 mg/day, or 20 mg/day if >60 years) 4, 5

• Avoid fluoxetine and paroxetine in older adults due to less favorable profiles and higher risk of adverse effects 4, 5

Dosing Strategy

• Start mirtazapine at 15 mg at bedtime, with dose adjustments no more frequently than every 1-2 weeks due to its long half-life 1, 3

• Therapeutic range is 15-45 mg daily, with the sedating effect being more prominent at lower doses 1, 3

Monitoring Requirements

• Assess response within 1-2 weeks of initiation, as mirtazapine has a more rapid onset than SSRIs 5, 2

• Monitor for common side effects including transient somnolence, increased appetite, and weight gain 1, 3

• If inadequate response occurs within 6-8 weeks, consider treatment modification 5, 6

Treatment Duration

• Continue treatment for at least 4-9 months after achieving remission for a first depressive episode 4, 5, 6

• For recurrent depression, extend treatment to at least one year to prevent recurrence 4, 5

Critical Pitfall to Avoid

• Do not assume all antidepressants are equivalent for agitated depression—the evidence clearly shows that activating antidepressants like fluoxetine and bupropion can worsen agitation, while mirtazapine specifically addresses this symptom cluster 4, 1, 3