What is the recommended approach for selecting an antidepressant for the treatment of depression?

How to Select an Antidepressant for Depression

For treatment-naive patients with moderate to severe depression, select any second-generation antidepressant (SSRI or SNRI) based on adverse effect profile, cost, and patient preference, as all are equally effective for general depressive symptoms. 1

Initial Medication Selection Framework

The choice of antidepressant should follow this algorithmic approach:

Step 1: Assess Depression Severity

• Only prescribe antidepressants for moderate to severe depression—do not use for mild depression or subsyndromal symptoms without a current moderate-to-severe episode. 2
• Antidepressants show the greatest drug-placebo difference in patients with severe depression. 1, 2

Step 2: Identify Target Symptom Profile

For cognitive symptoms (brain fog, concentration problems, indecisiveness):

• First choice: Bupropion due to its dopaminergic and noradrenergic effects with lower cognitive side effects. 2, 3
• Second choice: SNRIs (venlafaxine or duloxetine) as their noradrenergic component may improve attention better than SSRIs. 2, 3
• Avoid paroxetine and TCAs due to anticholinergic effects that worsen cognition. 2, 3

For general depressive symptoms without specific cognitive concerns:

• Any SSRI or SNRI is appropriate, as efficacy does not differ among second-generation antidepressants. 1

Step 3: Consider Adverse Effect Profiles

Sexual dysfunction considerations:

• Bupropion has the lowest rates of sexual adverse events compared to fluoxetine or sertraline. 1, 2
• Paroxetine has the highest rates of sexual dysfunction among SSRIs. 1, 2

Common adverse effects across second-generation antidepressants:

• Approximately 63% of patients experience at least one adverse effect. 1, 2
• Nausea and vomiting are the most common reasons for discontinuation. 1
• SNRIs (duloxetine and venlafaxine) have slightly higher discontinuation rates due to nausea and vomiting compared to SSRIs. 1

Suicidality monitoring:

• SSRIs are associated with increased risk for suicide attempts compared to placebo. 1
• All patients require close monitoring for suicidal thoughts and behaviors, particularly in the first 1-2 weeks after initiation. 1, 4

Step 4: Special Population Considerations

Older adults (≥65 years):

• Preferred agents: citalopram, escitalopram, sertraline, mirtazapine, venlafaxine, and bupropion. 1, 2, 4
• Avoid paroxetine and fluoxetine due to higher anticholinergic effects and less favorable profiles. 1, 2
• Use a "start low, go slow" approach with dose titration. 1, 4

Breastfeeding mothers:

• Sertraline and paroxetine transfer to breast milk in lower concentrations than other antidepressants. 1, 4

Dosing and Initiation

Starting doses for common first-line agents:

• Fluoxetine: 20 mg daily in the morning; may increase after several weeks if needed (maximum 80 mg/day). 5
• Venlafaxine: 75 mg/day in divided doses with food; may increase to 150 mg/day, then up to 225 mg/day in outpatient settings (maximum 375 mg/day for severe depression). 6
• Sertraline, citalopram, escitalopram: Follow standard SSRI dosing protocols. 1, 2

Monitoring Requirements

Timeline for assessment:

• Begin monitoring within 1-2 weeks of initiation for adverse effects and suicidality. 1, 4
• Assess therapeutic response at 4-6 weeks; full effect may be delayed until 4-5 weeks or longer. 1, 5
• Modify treatment if inadequate response by 6-8 weeks. 1, 4

What to monitor:

• Suicidal ideation and behavior (especially first 1-2 months). 1, 4
• Emergence of agitation, irritability, or unusual behavioral changes. 1
• Both mood and cognitive symptoms using standardized measures. 2, 3
• Side effects that could worsen function (sedation, anticholinergic effects). 2, 3

Treatment Duration

First episode of major depression:

• Continue treatment for at least 4-9 months after symptom resolution. 1, 2, 4
• Clinical guidelines suggest 4-12 months total for initial episodes. 1, 4

Recurrent depression:

• Consider prolonged treatment of at least one year to prevent recurrence. 1, 4
• Patients with recurrent episodes may benefit from indefinite maintenance therapy. 1

Critical Pitfalls to Avoid

• Do not prescribe antidepressants for mild depression or subsyndromal symptoms without a moderate-to-severe episode. 2
• Do not use TCAs as first-line agents due to higher adverse effect burden, overdose risk, and anticholinergic effects. 2, 3
• Do not assume all SSRIs are identical—paroxetine has notably higher anticholinergic effects and sexual dysfunction rates. 2
• Do not underdose or discontinue prematurely—response rates may be as low as 50%, and full effect requires 4-5 weeks. 1, 5
• Do not abruptly discontinue—taper gradually to avoid discontinuation symptoms. 6

Evidence Quality Note

The number needed to treat for achieving remission is 7-8 for SSRIs and 7-16 for TCAs, indicating modest superiority over placebo. 1 However, publication bias has inflated reported efficacy—FDA analysis shows only 51% of studies had positive results versus 94% in published literature. 1 Despite this limitation, second-generation antidepressants remain the evidence-based first-line treatment for moderate to severe depression. 1, 4