How should I initially treat an adult with major depressive disorder?

Initial Treatment of Major Depressive Disorder in Adults

For an adult with major depressive disorder, initiate either cognitive-behavioral therapy (CBT) or a second-generation antidepressant (SSRI or SNRI) as first-line treatment; both options have equivalent efficacy based on moderate-quality evidence. 1, 2

Treatment Selection Algorithm

Step 1: Confirm Diagnosis and Assess Severity

• Confirm at least 5 symptoms present for ≥2 weeks, including depressed mood or anhedonia, plus additional symptoms (sleep disturbance, psychomotor changes, fatigue, worthlessness, concentration difficulties, or suicidal thoughts). 1, 2
• Use validated tools (PHQ-9, HAM-D, or MADRS) to quantify severity and establish baseline for monitoring. 1, 2
• Screen immediately for suicidal ideation, specific plans, intent, recent attempts, psychotic features, and family history of bipolar disorder—these constitute high-risk features requiring immediate escalation. 1

Step 2: Severity-Based Treatment Decision

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

• Offer CBT as sole first-line intervention; moderate-quality evidence shows CBT equals antidepressant efficacy while avoiding medication adverse effects. 1

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

• Choose either CBT or a second-generation antidepressant as monotherapy; both achieve comparable remission rates (NNT 7-8). 1, 3
• If pharmacotherapy is selected, initiate an SSRI (sertraline, escitalopram, citalopram, fluoxetine) or SNRI (venlafaxine, duloxetine) at FDA-approved starting doses. 1, 2

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

• Initiate combination therapy with both an antidepressant AND CBT concurrently—this approach nearly doubles remission rates (57.5% vs 31.0%) compared to medication alone. 1
• High-risk features that mandate classification as severe regardless of symptom count: specific suicide plan/intent, recent attempt, active psychosis, or first-degree relative with bipolar disorder. 1

Step 3: Specific Antidepressant Selection

When pharmacotherapy is chosen, select based on these evidence-based considerations:

First-line SSRI options (all equally effective):

• Sertraline 50 mg once daily – preferred for general adult population; start at 25 mg in panic disorder or elderly patients, then increase to 50 mg after one week. 4
• Escitalopram 10 mg once daily or citalopram 20 mg once daily – favorable tolerability; maximum 40 mg/day (20 mg/day if age >60 years due to QT prolongation risk). 1
• Fluoxetine 20 mg once daily – longest half-life may ease discontinuation but increases drug interaction potential. 1

Avoid paroxetine – highest rates of sexual dysfunction and anticholinergic effects among SSRIs, particularly problematic in older adults. 1, 3

Consider bupropion 150-300 mg/day when:

• Prominent cognitive symptoms (concentration difficulties, mental fog) are present—most effective for this symptom cluster. 3
• Sexual dysfunction is a major concern—lowest sexual adverse event rate (≈8%) among all antidepressants. 3
• Weight gain is unacceptable—typically causes minimal weight change or modest loss. 3

Consider SNRI (venlafaxine or duloxetine) when:

• Comorbid chronic pain exists—remission rate ≈49% vs 42% for SSRIs. 1
• Cognitive symptoms are prominent—second-choice after bupropion due to noradrenergic effects. 3

Step 4: Mandatory Early Monitoring (Weeks 1-2)

• Assess ALL patients within 1-2 weeks of treatment initiation for suicidal thoughts, plans, means, agitation, irritability, or behavioral changes—suicide risk peaks during the first 1-2 months. 1
• Adults aged 18-24 have modestly increased suicide attempt risk on SSRIs (OR 2.30); ages 25-64 show neutral effect; ages ≥65 show protective effect (OR 0.06). 1
• Evaluate early adverse effects (nausea, headache, insomnia, sexual dysfunction) and adherence—approximately 63% experience at least one adverse effect. 3

Step 5: Response Assessment (Weeks 6-8)

• If symptom reduction is <50% on validated scales by 6-8 weeks, modify treatment through dose escalation (up to 200 mg/day for sertraline), switching to different antidepressant class, or augmentation with bupropion/buspirone. 1, 4
• Augmenting with bupropion produces greater symptom reduction and lower discontinuation rates than buspirone augmentation. 5
• Switching between second-generation antidepressants shows equivalent efficacy—no single switch strategy is superior. 5, 3

Step 6: Treatment Duration

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

Critical Pitfalls to Avoid

• Never use tricyclic antidepressants as first-line agents—higher adverse effects, lethal overdose risk, and no superiority over second-generation antidepressants. 1, 3
• Do not prescribe antidepressants for subsyndromal depressive symptoms without a current moderate-to-severe episode. 3
• Do not wait for therapeutic effect before monitoring suicidality—risk peaks early, not after symptom improvement. 1
• Do not assume treatment failure before 6-8 weeks at adequate dose—premature switching undermines efficacy assessment. 1
• Do not overlook non-adherence—up to 50% of patients demonstrate non-adherence, which masquerades as treatment resistance. 1