What is the recommended first‑line treatment plan for an adult with major depressive disorder?

First-Line Treatment for Major Depressive Disorder in Adults

For adults with major depressive disorder, initiate either cognitive behavioral therapy (CBT) or a second-generation antidepressant (SSRI or SNRI) as first-line treatment, as both options demonstrate equivalent effectiveness with moderate-quality evidence. 1, 2

Treatment Selection Algorithm

The choice between CBT and pharmacotherapy should be guided by:

• Adverse effect profiles: SSRIs/SNRIs cause sexual dysfunction in >60% of patients, weight gain, and sedation, while CBT avoids these medication-related harms 1, 2
• Cost and accessibility: Generic SSRIs are typically most affordable; CBT requires trained therapists who may not be readily available 2
• Patient preference: Discuss both options explicitly, as patient engagement predicts adherence and outcomes 1

Severity-Based Approach

Mild Depression (5-6 symptoms, minimal functional impairment)

• Start with CBT alone as the preferred first-line option, reserving pharmacotherapy for patients who prefer medication or lack access to psychotherapy 2

Moderate Depression (7-8 symptoms, moderate functional impairment)

• Either CBT or second-generation antidepressant monotherapy is appropriate, with comparable remission rates (NNT = 7-8 for antidepressants vs placebo) 2
• If choosing pharmacotherapy, select any SSRI (escitalopram, sertraline, citalopram, fluoxetine, paroxetine) or SNRI (venlafaxine, duloxetine) based on side-effect profile rather than efficacy, as no agent demonstrates superiority 2

Severe Depression (≥9 symptoms, severe functional impairment, or high-risk features*)

• Initiate combination therapy with both an antidepressant AND CBT concurrently, not sequentially—this approach nearly doubles remission rates (57.5% vs 31.0%, P < 0.001) compared to antidepressant monotherapy 2

*High-risk features include: specific suicide plan/intent, recent attempt, active psychotic symptoms, or first-degree relative with bipolar disorder 2

Specific Pharmacotherapy Recommendations

Starting Dosages (FDA-Approved)

• Escitalopram: 10 mg once daily 2
• Sertraline, fluoxetine, paroxetine, citalopram: 20 mg once daily 2
• Duloxetine: 40 mg/day (20 mg twice daily) to 60 mg/day; some patients benefit from starting at 30 mg once daily for 1 week before increasing to 60 mg 3

Agent Selection by Clinical Context

• Bupropion: Lowest sexual dysfunction rates among antidepressants; preferred when sexual side effects are a primary concern 2, 4
• Paroxetine: Highest sexual dysfunction rates; avoid as first choice unless other factors favor it 2
• SNRIs (duloxetine, venlafaxine): Achieve higher remission rates than SSRIs in patients with comorbid chronic pain (49% vs 42%) 2

Critical Early Monitoring (Weeks 1-2)

All patients require assessment within 1-2 weeks of treatment initiation to evaluate: 2

• Suicidality: Suicide risk peaks during the first 1-2 months; SSRIs increase suicide attempt risk in adults 18-24 years (OR 2.30 vs placebo) 2
• Behavioral activation syndrome: Agitation, irritability, or unusual behavioral changes 2
• Adverse effects: Sexual dysfunction, nausea, sedation, weight changes 1, 2
• Adherence: Up to 50% of patients demonstrate non-adherence, which can masquerade as treatment resistance 2

Response Assessment (Weeks 6-8)

If symptom reduction is <50% on validated scales (PHQ-9, HAM-D, MADRS): 2

• Dose escalation to maximum FDA-approved dose
• Switch to a different antidepressant class
• Augmentation with buspirone or bupropion SR (moderate-certainty evidence for comparable efficacy to switching) 2
• Add CBT if not already initiated (produces superior outcomes in treatment-resistant depression) 2

Treatment Duration

• First episode: Continue for 4-9 months after achieving remission to prevent relapse 1, 2
• Recurrent depression (≥2 prior episodes): Maintain for ≥1 year or longer 2

Common Pitfalls to Avoid

• Inadequate trial duration: Therapeutic effects typically require 4-6 weeks; premature discontinuation before this timeframe prevents accurate assessment 2
• Insufficient dosing: Ensure maximum FDA-approved doses are reached before declaring treatment failure 2
• Ignoring adherence: Check plasma levels if adherence is uncertain, as non-adherence affects up to 50% of patients 2
• Using tricyclic antidepressants first-line: These have higher adverse-effect profiles, greater overdose risk, and no superiority over second-generation agents 2
• Overlooking safety planning: Develop a written safety plan at the initial visit that limits access to lethal means, identifies a monitoring third party, and establishes emergency communication protocols 2

Alternative Evidence-Based Options

Beyond CBT and second-generation antidepressants, the following have demonstrated efficacy: 2

• Acceptance and Commitment Therapy, Behavioral Activation, Interpersonal Psychotherapy, Mindfulness-Based Cognitive Therapy, Problem-Solving Therapy, Short-Term Psychodynamic Psychotherapy: All endorsed as first-line psychotherapies
• Bright light therapy: Recommended for mild-to-moderate MDD regardless of seasonal pattern
• Supervised aerobic exercise: Achieves remission comparable to sertraline with lower discontinuation rates due to adverse events (moderate-certainty evidence)
• Acupuncture as adjunct to antidepressants: Increases remission rates (35.7% vs 26.1%; RR 1.45) in three trials with ~800 participants (moderate-certainty evidence)