What is the recommended initial treatment for a patient with moderate to severe depression, considering the use of antidepressants?

Recommended Initial Treatment for Moderate to Severe Depression

For treatment-naive patients with moderate to severe depression, initiate a second-generation antidepressant (SSRI or SNRI) as first-line pharmacologic treatment, with specific medication selection based on the patient's target symptom profile, age, and tolerability considerations. 1

First-Line Medication Selection

General Approach

• All second-generation antidepressants demonstrate equivalent efficacy for treatment-naive patients with general depressive symptoms, achieving remission with a number needed to treat of 7-8. 2, 1
• SSRIs are modestly superior to placebo and are the preferred initial choice due to better tolerability compared to tricyclic antidepressants (TCAs). 2
• Antidepressants demonstrate maximum effectiveness in patients with severe depression, with the drug-placebo difference increasing as a function of initial severity. 2, 1

Symptom-Specific Selection

For cognitive symptoms (difficulty concentrating, indecisiveness, mental fog):

• First choice: Bupropion due to its dopaminergic and noradrenergic effects and lower rate of cognitive side effects. 1
• Second choice: SNRIs (venlafaxine or duloxetine) as their noradrenergic component may improve attention and concentration better than SSRIs. 1

For general depressive symptoms without specific cognitive complaints:

• Any SSRI (sertraline, citalopram, escitalopram) or SNRI is appropriate. 1
• Fluoxetine 20 mg/day demonstrates significant efficacy with similar activation potential to placebo. 3

Age-Specific Considerations

For older adults (≥65 years):

• Preferred agents: citalopram, escitalopram, sertraline, mirtazapine, venlafaxine, or bupropion. 2, 1
• Avoid paroxetine and fluoxetine due to higher anticholinergic effects and less favorable adverse effect profiles in this population. 2, 1

For adolescents:

• Fluoxetine may be considered, but NOT other SSRIs or TCAs in non-specialist settings. 2
• Monitor closely for suicidal ideation and behavior when prescribing fluoxetine to adolescents. 2, 1

Critical Exclusions

Do NOT prescribe antidepressants for:

• Mild depression or subsyndromal depressive symptoms without a current moderate-to-severe episode. 2, 1
• Initial treatment of adults with depressive symptoms in the absence of current or prior moderate-to-severe depressive episode/disorder. 2

Do NOT use TCAs as first-line agents due to higher adverse effect burden (number needed to harm 4-30 vs. 20-90 for SSRIs), overdose risk, and lack of superiority over second-generation antidepressants. 2, 1

Expected Adverse Effects and Management

Approximately 63% of patients on second-generation antidepressants experience at least one adverse effect. 2, 1

Most common adverse effects:

• Nausea and vomiting (most common reason for discontinuation) 2
• Diarrhea, dizziness, dry mouth, fatigue, headache, sexual dysfunction, sweating, tremor, weight gain 2, 1

Medication-specific considerations:

• Duloxetine and venlafaxine have slightly higher discontinuation rates (67% and 40% increased risk) compared to SSRIs as a class. 2
• Bupropion has lower rates of sexual adverse events than fluoxetine and sertraline. 1
• Paroxetine has higher rates of sexual dysfunction than other SSRIs. 1

Treatment Duration and Monitoring

Minimum treatment duration:

• Continue treatment for at least 4-9 months after symptom resolution for a first episode of major depression. 2, 1
• For recurrent depression, extend treatment to at least one year or longer to prevent recurrence. 1
• Do not stop antidepressant treatment before 9-12 months after recovery. 2

Monitoring schedule:

• Assess every 1-2 weeks initially for suicidal ideation, behavioral changes, and depressive symptom severity. 1, 4
• Monitor for adverse effects including sedation, sexual dysfunction, and gastrointestinal symptoms. 1, 4
• If inadequate response after 6-8 weeks, increase dose to maximum therapeutic range rather than adding agents. 4

Dosing Strategy

Initial approach:

• Start at standard initial dose for the chosen agent
• Increase using increments of the initial dose every 5-7 days until therapeutic benefits or significant side effects appear. 2
• Allow at least 4-8 weeks for a full therapeutic trial before concluding treatment failure. 2

Example with sertraline:

• Start 50 mg daily
• Increase to 100 mg daily after 1-2 weeks if tolerated
• If inadequate response after 6-8 weeks, increase to 150-200 mg daily rather than adding additional agents. 4

Common Pitfalls to Avoid

• Do not prescribe antidepressants for mild depression or subsyndromal symptoms—the drug-placebo difference is virtually nonexistent in mild depression. 2, 1
• Do not combine multiple serotonergic agents (e.g., SSRI + trazodone + TCA) as this significantly increases serotonin syndrome risk. 4
• Do not assume all SSRIs are identical—paroxetine has notably higher anticholinergic effects and sexual dysfunction rates. 1
• Do not use two sedating antidepressants concurrently (e.g., trazodone + amitriptyline) as this causes excessive sedation without added therapeutic benefit. 4
• Do not discontinue abruptly—taper over 10-14 days to limit withdrawal symptoms. 2