What is the first‑line medication and initial dosing for an adult with newly diagnosed major depressive disorder?

First-Line Medication for Major Depressive Disorder

Start with a selective serotonin reuptake inhibitor (SSRI) at 50 mg daily for sertraline, 20 mg daily for fluoxetine/paroxetine/citalopram, or 10 mg daily for escitalopram—all second-generation antidepressants demonstrate equivalent efficacy, so selection should be guided by adverse-effect profile, cost, and patient-specific factors rather than presumed differences in effectiveness. 1

Standard First-Line Approach

Medication Selection

• Second-generation antidepressants (SSRIs and SNRIs) are the recommended first-line pharmacologic treatment for treatment-naïve adults with moderate to severe major depressive disorder. 1
• All SSRIs show comparable efficacy, with response rates of 42–49% and remission rates of 46–54%, and a number needed to treat of 7–8 for achieving remission. 1
• The American College of Physicians confirms that second-generation antidepressants and cognitive-behavioral therapy demonstrate equivalent efficacy, making either an appropriate first-line choice. 1, 2

Standard SSRI Dosing (FDA-Approved)

• Sertraline: Start at 50 mg once daily (may initiate at 25 mg for panic disorder, PTSD, or social anxiety disorder for one week before increasing to 50 mg). 3
• Fluoxetine, paroxetine, citalopram: Start at 20 mg once daily. 1
• Escitalopram: Start at 10 mg once daily. 1
• Dose adjustments should not occur at intervals less than one week, given the 24-hour elimination half-life. 3

Tailoring Selection to Patient Profile

For Cognitive Symptoms (Concentration, Mental Fog, Indecisiveness)

• Bupropion is the most effective first-choice agent for prominent cognitive symptoms due to its dopaminergic and noradrenergic effects and lower rate of cognitive side effects. 1
• SNRIs (venlafaxine or duloxetine) are second-choice for cognitive symptoms, as their noradrenergic component may improve attention better than SSRIs. 1

For Patients Concerned About Sexual Dysfunction

• Bupropion has the lowest overall rate of sexual adverse effects (approximately 8%) compared with fluoxetine, sertraline, and especially paroxetine. 1
• Paroxetine has the highest rates of sexual dysfunction among SSRIs and should be avoided when sexual side effects are a concern. 1

For Older Adults (≥65 Years)

• Preferred agents are citalopram, sertraline, venlafaxine, and bupropion. 1
• Citalopram and escitalopram have dose limits: maximum 40 mg/day for citalopram, or 20 mg/day for patients >60 years, due to QT-prolongation risk. 1
• Avoid paroxetine and fluoxetine in older adults due to higher anticholinergic effects and less favorable profiles. 1

For Breastfeeding Mothers

• Sertraline or paroxetine are first-line options because they achieve lower concentrations in breast milk compared with other antidepressants. 1

For Comorbid Chronic Pain

• Consider an SNRI (venlafaxine or duloxetine) when chronic pain coexists with depression, with remission rates of approximately 49% versus 42% for SSRIs. 1

Monitoring and Safety

Age-Specific Suicide Risk Monitoring

• Adults aged 18–24 years: Modestly increased risk of suicidal ideation or behavior with SSRIs (OR = 2.30). Schedule weekly clinical visits during the first month, then bi-weekly through week 8, with explicit assessment of suicidal thoughts, plans, and means at each encounter. 1
• Adults aged 25–64 years: SSRIs show neutral effect on suicide risk. 1
• Adults aged ≥65 years: SSRIs are associated with a protective effect against suicidal outcomes (OR = 0.06). 1

Response Assessment

• Use standardized measures (PHQ-9 or HAM-D) at each visit to assess treatment response. 2
• Response is defined as ≥50% reduction in measured severity; remission is HAM-D score ≤7. 2
• Allow 6–8 weeks at therapeutic dose before declaring treatment failure. 1, 4
• Approximately 38% of patients will not achieve treatment response within 6–12 weeks. 1

Common Adverse Effects

• Approximately 63% of patients on second-generation antidepressants experience at least one adverse effect. 1
• Most common: nausea and vomiting (leading cause of discontinuation), diarrhea, dizziness, dry mouth, fatigue, headache, and sexual dysfunction. 1
• Sertraline is generally associated with higher rates of diarrhea compared with other SSRIs. 5

Treatment Duration

• Continue treatment for at least 4–9 months after symptom resolution for a first episode of major depressive disorder. 1, 4
• For recurrent depression, extend treatment to at least 12 months to prevent recurrence. 1

Critical Contraindications and Pitfalls

• Do not prescribe antidepressants for mild depression or subsyndromal depressive symptoms without a current moderate-to-severe episode. 1
• Do not use tricyclic antidepressants (TCAs) as first-line agents due to higher adverse-effect burden, overdose risk, and lack of superiority over second-generation antidepressants. 1, 2
• Antidepressants are most effective in patients with severe depression, with the drug-placebo difference increasing with initial severity. 1
• Do not assume all SSRIs have identical profiles—paroxetine has notably higher anticholinergic effects and sexual dysfunction rates. 1