What is a recommended initial antidepressant medication?

Initial Antidepressant Treatment

For most adult patients with major depressive disorder, start with sertraline 50 mg once daily, which represents the optimal balance of efficacy and tolerability and serves as both the starting and usually effective therapeutic dose. 1, 2

Primary Recommendation: Sertraline

• Sertraline 50 mg daily is the preferred first-line agent due to its favorable adverse effect profile and lower risk of drug interactions compared to other SSRIs, which is particularly important in patients on multiple medications 1, 2

• Start at 50 mg once daily (25 mg in elderly patients), taken at any time of day with or without food 1, 2

• The 50 mg dose is both the starting dose and the usually effective therapeutic dose for most patients—there is no need for routine dose escalation 2, 3

• If inadequate response after 2-4 weeks at 50 mg, may increase by 50 mg increments at weekly intervals to a maximum of 200 mg daily 2

• However, research demonstrates that continued treatment at 50 mg yields comparable response rates to dose escalation in most patients 3

Alternative First-Line Options

Escitalopram or Citalopram

• Escitalopram has similar efficacy to sertraline and represents another preferred option 1

• Citalopram is well-tolerated, starting at 10 mg daily with maximum of 40 mg daily (20 mg maximum in patients over 60 years due to QT prolongation risk) 1

Mirtazapine

• Consider mirtazapine 7.5 mg at bedtime when sleep disturbance, appetite loss, or weight loss are prominent features 4, 1

• Titrate to maximum 30 mg at bedtime as needed 4, 1

• Promotes sleep, appetite, and weight gain, which can be advantageous or disadvantageous depending on clinical presentation 4

Agents to Avoid as Initial Treatment

Fluoxetine

• Avoid fluoxetine as initial therapy due to its very long half-life (2-7 days for fluoxetine, 4-15 days for active metabolite norfluoxetine) 1, 5

• The extended half-life complicates dose adjustments and switching medications, requiring long washout periods 6

• Higher risk of agitation and overstimulation, particularly problematic in older adults 1

• May be less effective than tricyclics for severe melancholic depression in inpatients 5

• Some evidence suggests standard 20 mg daily dosing may exceed the therapeutic window in certain patients, with symptoms of serotonergic overstimulation resembling treatment failure 7

Paroxetine

• Avoid paroxetine in elderly patients due to higher anticholinergic effects compared to other SSRIs 1

• More anticholinergic activity increases risk of confusion, constipation, urinary retention, and falls in older adults 4

Tricyclic Antidepressants

• Reserve tricyclics (desipramine, nortriptyline) for second-line use due to higher risk of cardiotoxicity, hypotension, and anticholinergic effects 4, 1

• If used, nortriptyline 10 mg at bedtime (maximum 40 mg daily) is preferred over other tricyclics due to better tolerability profile 4

Treatment Duration and Monitoring

• Allow 4-8 weeks for full therapeutic effect before determining treatment failure 4, 1

• Increase dosage using increments of the initial dose every 5-7 days only if inadequate response and no significant side effects 4

• Continue treatment for 4-12 months after remission of a first depressive episode; longer duration for recurrent depression 1

• After 9 months, consider dose reduction to reassess need for continued medication 4

• When discontinuing, taper over 10-14 days to minimize withdrawal symptoms 4

Special Populations

Elderly Patients

• Start at approximately 50% of standard adult doses due to increased risk of adverse drug reactions 1

• Sertraline requires no altered dose recommendations in elderly compared to other SSRIs 2

• Maximum citalopram dose is 20 mg daily in patients over 60 years 1

Patients with Comorbid Conditions

• Bupropion 37.5 mg every morning (titrate to 150 mg twice daily) is activating and may rapidly improve energy levels, but avoid in patients with seizure disorders or significant agitation 4, 8

• Nefazodone 50 mg twice daily (maximum 150-300 mg twice daily) is effective when anxiety is prominent, but requires hepatotoxicity monitoring 4

Common Pitfalls to Avoid

• Do not prematurely escalate doses before 4-8 weeks—most patients respond to initial sertraline 50 mg dose without need for titration 2, 3

• Do not interpret lack of response at 3 weeks as treatment failure—continue initial dose for full 4-8 week trial 4, 1

• Do not abruptly discontinue—always taper over 10-14 days 4

• Do not combine with MAOIs—allow at least 14 days washout when switching between these medication classes 8

• Monitor for serotonin syndrome when combining with other serotonergic agents 9, 8