What is the recommended treatment for Major Depressive Disorder (MDD)?

Treatment of Major Depressive Disorder

For initial treatment of MDD, clinicians should offer either cognitive behavioral therapy (CBT) or a second-generation antidepressant (SGA), selected based on adverse effect profiles, accessibility, and patient preference, with both approaches demonstrating equivalent efficacy. 1

First-Line Treatment Selection

The 2023 American College of Physicians systematic review demonstrates similar benefits between most nonpharmacologic treatments and antidepressants for initial treatment, though the certainty of evidence remains low for most comparisons. 1 The critical distinction lies in the adverse event profile: SGAs carry significantly higher rates of discontinuation due to adverse events compared to CBT, with more than 60% of patients experiencing at least one adverse effect. 1

When to Choose Cognitive Behavioral Therapy

• CBT demonstrates lower relapse rates compared to SGAs and should be strongly considered where accessible. 1
• CBT shows equivalent response and remission rates to SGAs after 8-52 weeks of treatment 1
• Moderate-quality evidence supports no difference in functional capacity between CBT and SGAs 1

When to Choose Pharmacotherapy

For pharmacologic treatment, select from second-generation antidepressants based on the following hierarchy:

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Start sertraline at 50 mg once daily (morning or evening), with dose increases up to 200 mg/day if no response after 6-8 weeks 2
• Start fluoxetine at 20 mg daily or bupropion at 150 mg daily, increasing to 300 mg after 4 days 3
• Bupropion demonstrates lower rates of sexual adverse events compared to fluoxetine and sertraline 1
• Paroxetine carries higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, and sertraline 1

Critical Adverse Event Considerations

Specific SGAs differ substantially in their adverse effect profiles: 1

• Sexual dysfunction: highest with paroxetine, lowest with bupropion
• Gastrointestinal effects: common across all SSRIs
• Suicidality risk: requires close monitoring, particularly in patients under age 25 3

Treatment Monitoring and Adjustment

Assess patient status, therapeutic response, and adverse effects within 1-2 weeks of initiation, then regularly throughout treatment. 1

Response Assessment Timeline

• If inadequate response after 6-8 weeks at therapeutic doses, modify treatment strategy 1
• Response is defined as ≥50% reduction in symptom severity measured by PHQ-9 or HAM-D 1
• Up to 70% of patients fail to achieve remission during initial treatment, necessitating second-step interventions 1

Dose Optimization

For SSRIs, higher starting doses (above typical recommendations) demonstrate superior response rates (54.8% vs 50.8%) but increase discontinuation due to adverse events (16.5% vs 9.8%). 4 Given this trade-off, start at standard doses and increase systematically based on tolerability and response.

Treatment Duration

Continue treatment for 4-9 months after achieving satisfactory response in first-episode MDD. 1

The three treatment phases are: 1

• Acute phase: 6-12 weeks to achieve response
• Continuation phase: 4-9 months to prevent relapse
• Maintenance phase: ≥1 year for patients with ≥2 prior episodes

For patients with two or more depressive episodes, extend treatment duration beyond 9 months, as recurrence risk increases substantially. 1

Second-Step Strategies for Non-Responders

When initial treatment fails after adequate trial (6-8 weeks at therapeutic dose), evidence shows similar benefits among different switching and augmentation strategies, though certainty remains low. 1 Options include:

• Switching to a different SGA class
• Augmenting with a second medication
• Adding psychotherapy to ongoing pharmacotherapy
• Combination therapy (SGA plus CBT) shows no consistent superiority over monotherapy for initial treatment 1

Complementary Approaches

The Canadian Network for Mood and Anxiety Treatments recommends CAM interventions as additional options for mild-to-moderate MDD: 1

• Exercise (various aerobic activities) 5
• Omega-3 fatty acids 5
• S-adenosyl-L-methionine (SAMe) 5
• St. John's wort carries significant drug interaction risks, particularly inducing CYP3A4, contraindicated with oral contraceptives, immunosuppressants, MAOIs, and SSRIs 1

Critical Pitfalls to Avoid

• Never combine St. John's wort with SSRIs or MAOIs due to serotonin syndrome risk 1
• Do not change SGA doses at intervals less than 1 week given the 24-hour elimination half-life 2
• When switching from fluoxetine to TCAs or MAOIs, allow adequate washout periods (2-7 days for fluoxetine, 4-15 days for norfluoxetine) to prevent drug interactions 6
• Monitor closely for emerging suicidal ideation, particularly in the first 1-2 weeks and in patients under age 25 3