What is the recommended treatment for major depressive disorder?

Treatment of Major Depressive Disorder

First-Line Treatment Selection

For moderate to severe major depressive disorder, initiate either cognitive behavioral therapy (CBT) or a second-generation antidepressant (SSRI or SNRI), selected based on adverse effect profile, cost, and patient preference—both approaches demonstrate equivalent efficacy with moderate-quality evidence. 1, 2

Severity-Based Algorithm

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

• Start with CBT alone as monotherapy 2
• Reserve 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 1, 2
• All SSRIs and SNRIs show equivalent efficacy (number needed to treat = 7-8 for remission) 3
• Select specific agent based on side-effect profile rather than presumed efficacy differences 1, 3

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

• Combination therapy with both antidepressant AND CBT initiated concurrently 2
• This approach nearly doubles remission rates (57% vs 31%) compared to antidepressant alone 2
• High-risk features requiring immediate severe classification: specific suicide plan, active psychotic symptoms, or first-degree relative with bipolar disorder 2

Specific Antidepressant Selection

Preferred SSRIs by Clinical Context

General adult population (ages 25-64):

• Sertraline 50 mg daily or escitalopram 10 mg daily as first-line 2, 4
• Citalopram 20 mg daily or fluoxetine 20 mg daily are alternatives 2, 5

Older adults (≥65 years):

• Citalopram, sertraline, or escitalopram preferred 3
• Avoid paroxetine and fluoxetine due to higher anticholinergic effects and drug interactions 3
• Maximum citalopram dose: 40 mg/day (20 mg/day if >60 years) due to QT prolongation risk 3

Breastfeeding mothers:

• Sertraline or paroxetine achieve lowest breast milk concentrations 3

Patients with prominent cognitive symptoms (concentration difficulties, mental fog):

• Bupropion is most effective due to dopaminergic/noradrenergic effects 3
• SNRIs (venlafaxine or duloxetine) are second-choice 3

Patients with comorbid chronic pain:

• SNRIs (duloxetine or venlafaxine) show superior remission rates (49% vs 42% for SSRIs) 3

Sexual Dysfunction Considerations

• Bupropion has lowest rates of sexual adverse events compared to SSRIs 1, 3
• Paroxetine has highest sexual dysfunction rates among SSRIs 1, 3

Critical Monitoring Protocol

Weeks 1-2 (Mandatory Early Assessment)

Assess all patients within 1-2 weeks of starting treatment for: 1, 2

• Emergence of suicidal thoughts, plans, or behaviors (risk peaks in first 1-2 months) 1, 2
• Agitation, irritability, or unusual behavioral changes 1
• Early adverse effects and medication adherence 2
• SSRIs increase suicide attempt risk vs placebo, especially in adults 18-24 years (OR 2.30) 3

Weeks 6-8 (Response Assessment)

If inadequate response (<50% symptom reduction on PHQ-9 or HAM-D), modify treatment: 1, 2

• Increase dose to therapeutic range (up to 200 mg/day for sertraline) 4
• Switch to different antidepressant class 2
• Add augmentation strategy (buspirone or bupropion SR) 2
• Add CBT if not already included 2

Treatment Duration

First depressive episode:

• Continue for 4-9 months after achieving remission 1, 2, 3

Recurrent depression (≥2 prior episodes):

• Maintain for ≥1 year or longer 1, 2, 3

Additional Evidence-Based Options

Psychotherapy Modalities (All First-Line)

The 2022 VA/DoD guideline expanded psychotherapy options beyond CBT to include: 1

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

Bright Light Therapy

• Recommended for mild to moderate MDD regardless of seasonal pattern 1
• Can be used as monotherapy or combined with other treatments 1

Treatment-Resistant Depression

For patients failing ≥2 adequate antidepressant trials: 1, 2

• Add CBT to ongoing pharmacotherapy (produces superior outcomes vs medication alone) 2
• Consider ketamine or esketamine 1
• Consider rTMS or theta-burst stimulation 1
• Electroconvulsive therapy for multiple treatment failures or need for rapid improvement 1

Common Pitfalls to Avoid

• Do not use antidepressants for mild depression or subsyndromal symptoms without current moderate-to-severe episode 3
• Do not use tricyclic antidepressants as first-line agents due to higher adverse effects, overdose risk, and lack of superiority over second-generation agents 1, 3
• Do not change doses more frequently than weekly intervals given 24-hour elimination half-life 4
• Do not assume all SSRIs are identical—paroxetine has notably higher anticholinergic and sexual dysfunction rates 3
• Do not stop treatment prematurely—approximately 63% of patients experience at least one adverse effect, but most are transient 3
• Do not overlook adherence issues—up to 50% of patients demonstrate non-adherence, which can masquerade as treatment resistance 2