What is the first‑line selective serotonin reuptake inhibitor (SSRI) for treating major depressive disorder in adults?

First-Line SSRI for Major Depressive Disorder

No single SSRI is definitively superior to others for treatment-naïve adults with major depression—all second-generation antidepressants (including all SSRIs) demonstrate equivalent efficacy—but sertraline, citalopram, and escitalopram are preferred first-line choices based on their favorable side effect profiles, lower drug interaction potential, and specific guideline recommendations. 1, 2

Selection Algorithm for First-Line SSRI

For General Adult Population (Ages 25-64)

• Start with sertraline, citalopram, or escitalopram as these agents balance efficacy with tolerability 1, 2
• All SSRIs have a number needed to treat of 7-8 for achieving remission 1, 2
• Selection should prioritize adverse effect profile, cost, and dosing convenience over perceived efficacy differences (which do not exist between SSRIs) 3

For Older Adults (≥60 Years)

• Sertraline is the preferred first choice due to its favorable side effect profile and minimal drug interaction potential 4, 2
• Citalopram and escitalopram are acceptable alternatives, but citalopram must not exceed 40 mg daily (20 mg daily for patients >60 years) due to QT prolongation risk 4, 2
• Avoid paroxetine and fluoxetine in older adults due to higher anticholinergic effects and adverse event rates 1, 2

For Breastfeeding Mothers

• Sertraline or paroxetine are preferred as they transfer to breast milk in lower concentrations than other antidepressants 3, 1

For Patients with Suicide Risk

• Escitalopram or citalopram are acceptable, with mandatory dose limits for citalopram 2
• In adults ≥65 years, SSRIs demonstrate a protective effect against suicidal outcomes (OR=0.06,95% CI 0.01-0.58) 2
• Young adults aged 18-24 have modestly increased risk of suicidal ideation with SSRIs (OR=2.30,95% CI 1.04-5.09), requiring weekly visits for the first month 2

Why Sertraline Stands Out

While guidelines emphasize that all SSRIs are equally effective 1, 2, sertraline has specific advantages:

• Lowest drug interaction potential among SSRIs—unlike fluoxetine, fluvoxamine, and paroxetine, sertraline is not a potent inhibitor of cytochrome P450 isoenzymes 5, 6
• Meta-analysis evidence shows a trend favoring sertraline over other antidepressants in both efficacy and acceptability 7
• Superior to fluoxetine in head-to-head comparisons for efficacy 7
• Better tolerability than amitriptyline, imipramine, paroxetine, and mirtazapine in terms of discontinuation rates 7
• FDA approval for PTSD, making it advantageous when trauma symptoms coexist with depression 4

Dosing Approach

• Start low, go slow, particularly in older adults 3, 1
• Higher SSRI doses (up to 250 mg imipramine equivalents, equivalent to 50 mg fluoxetine) show slightly increased efficacy but plateau beyond this level 8
• Higher doses increase side effect-related discontinuation but decrease all-cause dropout 8

Common Adverse Effects to Anticipate

• 63% of patients on SSRIs experience at least one adverse effect 1, 2
• Nausea and vomiting are the most common reasons for discontinuation 3, 1, 2
• Sertraline specifically is associated with higher rates of diarrhea compared to other SSRIs 7
• Sexual dysfunction, sweating, tremor, and weight gain are common across all SSRIs 1

Treatment Duration

• Minimum 4-9 months after symptom resolution for a first depressive episode 2
• At least 12 months for recurrent depression 3, 2
• Begin monitoring within 1-2 weeks of initiation 1

Critical Pitfalls to Avoid

• Do not assume all SSRIs are interchangeable in terms of side effects—paroxetine has notably higher sexual dysfunction and anticholinergic effects 2
• Do not use paroxetine or fluoxetine as first-line in older adults 1, 2
• Do not exceed citalopram dose limits (40 mg daily, or 20 mg daily if >60 years) due to QT prolongation 4, 2
• Do not prescribe SSRIs for mild or subsyndromal depression—antidepressants are most effective in moderate to severe depression 2