What is the initial treatment for major depressive disorder?

Initial Treatment for Major Depressive Disorder

First-Line Treatment Recommendation

Clinicians should initiate treatment with either cognitive behavioral therapy (CBT) or a second-generation antidepressant (specifically sertraline 50 mg daily or escitalopram 10 mg daily), selecting based on patient preference, cost, accessibility, and discussion of adverse effect profiles. 1, 2

Treatment Selection Algorithm

Option 1: Second-Generation Antidepressant (SGA)

• Start with sertraline 50 mg daily or escitalopram 10 mg daily as the preferred first-line SSRIs due to well-established efficacy and favorable tolerability 2
• Fluoxetine 20 mg daily is an alternative first-line option, as this dose is sufficient to obtain satisfactory response in most cases 3
• Choose bupropion instead if the patient expresses concerns about sexual dysfunction, as it has significantly lower rates of sexual adverse events compared to SSRIs 2
• Avoid paroxetine due to higher rates of sexual dysfunction compared to fluoxetine, fluvoxamine, nefazodone, and sertraline 1

Option 2: Cognitive Behavioral Therapy

• CBT demonstrates equivalent efficacy to SGAs with moderate-quality evidence showing no difference in response rates 1
• CBT has lower relapse rates than SGAs in long-term follow-up, making it particularly valuable for sustained recovery 1, 2
• CBT has fewer adverse effects than SGAs, with similar discontinuation rates overall but lower discontinuation due to adverse events 1

Dosing and Monitoring Strategy

Initial Dosing

• Fluoxetine: 20 mg daily in the morning (can increase after several weeks if insufficient improvement; maximum 80 mg/day) 3
• Sertraline: 50 mg daily 2
• Escitalopram: 10 mg daily 2

Response Assessment

• Monitor using PHQ-9 or HAM-D scores at 2-week intervals 4
• Define response as ≥50% reduction in depression severity scores 1, 4
• Define remission as HAM-D score ≤7 1, 4
• Allow 4 weeks of treatment or longer for full therapeutic effect before concluding inadequate response 3

Comparative Effectiveness Evidence

The evidence base demonstrates:

• Moderate-quality evidence shows no difference in response or remission between SGAs and CBT after 8-52 weeks of treatment 1
• Five trials comparing fluoxetine, fluvoxamine, paroxetine, or sertraline with CBT found equivalent efficacy 1
• Discontinuation rates are similar between CBT and SGAs, though discontinuation due to adverse events trends higher with SGAs 1

Critical Safety Considerations

Adverse Effect Profiles

• SGAs have lower toxicity in overdose compared to tricyclic antidepressants, a crucial safety feature in patients with elevated suicide risk 4
• Common adverse effects include constipation, diarrhea, dizziness, headache, insomnia, nausea, and somnolence 1
• Sexual dysfunction varies significantly among SGAs: bupropion has lower rates than fluoxetine and sertraline, while paroxetine has the highest rates 1

Special Populations

• Lower or less frequent dosing should be used in patients with hepatic impairment and elderly patients 3
• Dosage adjustments for renal impairment are not routinely necessary 3

Duration of Treatment

Acute Phase

• 6-12 weeks to achieve initial response 1

Continuation Phase

• Continue treatment for 4-9 months after achieving remission to prevent relapse 1, 4, 2

Maintenance Phase

• ≥1 year for patients with recurrent episodes to prevent recurrence of new depressive episodes 1, 2

Common Pitfalls to Avoid

• Premature discontinuation or switching: Wait 6-8 weeks at therapeutic dose before concluding treatment failure, not just 2-4 weeks 4
• Underdosing: Studies suggest typical starting doses may be suboptimal; higher starting doses are associated with better response rates (though also higher discontinuation due to adverse events) 5
• Ignoring patient preference: The choice between CBT and SGAs should involve shared decision-making, as both are equally effective 1
• Not discussing adverse effects proactively: Physicians and patients should discuss adverse event profiles, particularly sexual dysfunction, before selecting a medication 1