What is the management of major depressive disorder (MDD)?

Management of Major Depressive Disorder

First-Line Treatment Selection

For patients with major depressive disorder, initiate treatment with either cognitive behavioral therapy (CBT) or a second-generation antidepressant (SGA), as both demonstrate equivalent effectiveness in reducing depressive symptoms and achieving remission. 1

Treatment Algorithm Based on Severity

Mild Depression:

• Start with CBT alone, specifically incorporating behavioral activation to target anhedonic symptoms 2
• SGAs may be reserved if psychotherapy is insufficient or unavailable 1

Moderate to Severe Depression:

• Initiate either CBT or second-generation antidepressants (SSRIs or SNRIs) 2
• For anhedonia-predominant depression, avoid SSRIs/SNRIs as they show limited efficacy and may worsen anhedonia; instead, use bupropion which has lower rates of sexual adverse effects 2
• Consider combination therapy (SGA plus CBT) for patients with comorbid conditions, chronicity, or treatment resistance 3, 4

Pharmacotherapy Details

Initial Dosing

• Sertraline: Start 50 mg once daily for MDD; may increase to maximum 200 mg/day based on response 5
• Fluoxetine: Start 20 mg once daily in the morning; doses above 20 mg/day may be given once daily or BID, maximum 80 mg/day 6
• Dose adjustments should not occur at intervals less than 1 week given the 24-hour elimination half-life 5

Monitoring Response

• Assess treatment response within 1-2 weeks of initiation, with full therapeutic effect potentially delayed until 4 weeks or longer 1, 6
• Response is typically defined as ≥50% reduction in measured severity using PHQ-9 or HAM-D scales 1
• Monitor closely for increased suicidal thoughts during the first 1-2 months of antidepressant treatment 7

Evidence-Based Psychotherapy Options

The following psychotherapies demonstrate equivalent effectiveness 1:

• Acceptance and commitment therapy 1
• Behavioral therapy/behavioral activation 1
• Cognitive behavioral therapy 1
• Interpersonal therapy 1
• Mindfulness-based cognitive therapy 1
• Problem-solving therapy 1
• Short-term psychodynamic psychotherapy 1

No specific psychotherapy approach shows superiority over others; selection should be based on provider training and patient past experience with treatment 1

Combination Therapy Considerations

Combined psychotherapy plus antidepressants outperforms antidepressants alone at 6 months or longer (OR=2.93,95%CI 2.15-3.99) 3

However, combined therapy shows equal effectiveness to psychotherapy alone in the acute phase, making psychotherapy an adequate alternative to combination treatment 3

Reserve combination therapy for:

• Chronic major depressive disorder (symptoms lasting ≥2 years) 4
• Treatment-resistant depression 4, 8
• Comorbid psychiatric conditions 8
• Severe or recurrent episodes 8

Treatment Duration

Acute Phase (6-12 weeks)

• Continue treatment until response or remission is achieved 1

Continuation Phase (4-9 months)

• For first episodes: Continue treatment for 4-9 months after satisfactory response to prevent relapse 1, 2
• For recurrent episodes: Continue for ≥1 year to prevent recurrence 1, 2
• Patients with 2 or more episodes may benefit from even longer duration therapy 1

Maintenance Phase (≥1 year)

• Combined maintenance psychotherapy with antidepressants results in better-sustained treatment response compared to antidepressants alone (OR=1.61,95%CI 1.14-2.27) 3
• Sertraline efficacy is maintained for up to 44 weeks following 8 weeks of acute treatment 5
• Fluoxetine efficacy is maintained for up to 38 weeks following 12 weeks of acute treatment 6

Adjunctive and Alternative Treatments

Bright Light Therapy:

• Recommend for mild to moderate MDD regardless of seasonal pattern, used alone or in combination with other treatments 1

Repetitive Transcranial Magnetic Stimulation (rTMS):

• Consider for patients with partial or no response to 2 or more adequate pharmacologic trials 1
• Number needed to treat: 3.4-9 for response, 5-7 for remission 1

Treatment-Resistant Depression

For patients failing initial treatment:

• Consider ketamine or esketamine for those who have not responded to other treatments 2
• Consider electroconvulsive therapy for multiple prior treatment failures or when rapid improvement is needed 2

Common Pitfalls to Avoid

• Do not discontinue antidepressants before 9-12 months after recovery, as this significantly increases relapse risk 7
• Sexual dysfunction is a common side effect with SSRIs and SNRIs; consider bupropion as alternative 2
• Lower doses should be used in patients with hepatic impairment, elderly patients, and those with concurrent diseases or multiple medications 6
• When switching from an MAOI, allow at least 14 days before starting an SGA; when switching to an MAOI, allow at least 5 weeks after stopping the SGA 6