What criteria should be used to select an appropriate antidepressant, such as a selective serotonin reuptake inhibitor (SSRI)?

How to Select an Antidepressant

Start with Second-Generation Antidepressants as First-Line

Second-generation antidepressants, particularly SSRIs, are first-line treatment for depression due to their superior adverse effect profile compared to older agents like tricyclic antidepressants. 1

Primary Selection Criteria (Not Efficacy)

Since all second-generation antidepressants have essentially equivalent efficacy (remission rates 42-49%), your choice should be driven by adverse effect profile, drug interaction potential, cost, and patient-specific factors—not by presumed differences in effectiveness. 1, 2, 3

Recommended First-Line Agent: Sertraline

Sertraline is the preferred first-line antidepressant for most patients based on the following advantages: 2

• Lowest transfer to breast milk (making it safer in vulnerable populations) 1, 2
• Minimal cardiac effects (extensively studied in cardiac populations, minimal impact on conduction) 2
• Lower drug interaction potential compared to fluoxetine and paroxetine 2, 4
• Mild CYP2D6 inhibition only (little effect on CYP1A2, 2C9/10, 2C19, or 3A3/4) 4
• Linear pharmacokinetics (proportional dose-concentration relationship) 4

Alternative First-Line Options by Clinical Context

For Older Adults (≥65 years):

Preferred agents: sertraline, citalopram (≤20 mg/day if >60 years), escitalopram, mirtazapine, or venlafaxine using a "start low, go slow" approach at 50% of standard adult starting doses. 1, 2, 5

Avoid in elderly:

• Paroxetine (high anticholinergic effects) 2, 5
• Fluoxetine (long half-life, drug interactions, agitation risk) 2, 5
• All tricyclic antidepressants (anticholinergic effects, cardiac toxicity) 2, 5

For Depression with Cognitive Symptoms/Brain Fog:

Bupropion is preferred due to dopaminergic/noradrenergic effects and lower cognitive side effects. 2

Alternative: SNRIs (venlafaxine, duloxetine) may be more effective than SSRIs for cognitive symptoms due to noradrenergic component. 2

For Depression with Comorbid Pain:

SNRIs provide additional benefits for comorbid pain disorders, though remission rates are only marginally superior to SSRIs (49% vs 42%). 1

For Cardiovascular Disease:

Sertraline is preferred due to minimal cardiac conduction effects. 2

Avoid citalopram >40 mg/day (>20 mg/day if >60 years) due to dose-dependent QT prolongation per 2012 FDA boxed warning. 1, 5

Antidepressants to Avoid

Never use as first-line:

• Paroxetine: Higher anticholinergic effects, greater drug interaction potential, nonlinear pharmacokinetics 1, 2, 4
• Fluoxetine: Long half-life (2-4 days; active metabolite 7-15 days), highest infant plasma concentrations via breast milk, greater drug interaction risk 1, 2, 4
• Tricyclic antidepressants: Anticholinergic effects, cardiac toxicity, dangerous in overdose 2

Critical Drug Interaction Considerations

Fluoxetine and paroxetine substantially inhibit CYP2D6, which can dramatically increase levels of co-administered drugs metabolized by this pathway (tricyclics, Type 1C antiarrhythmics like propafenone/flecainide). 4

Fluvoxamine inhibits CYP1A2, CYP2C19, and probably CYP3A3/4, creating high interaction potential. 4

Sertraline has the lowest interaction potential with only mild CYP2D6 inhibition. 4

Dosing Strategy

Start at standard adult doses for most patients, but use 50% of standard starting dose in older adults. 5

Assess response within 1-2 weeks for adverse effects and therapeutic response. 2

Modify treatment if inadequate response by 6-8 weeks. 2

Treatment Duration

Continue for 4-12 months after symptom resolution for initial episode. 1, 2

Consider longer treatment for recurrent depression (recurrence risk: 50% after first episode, 70% after second, 90% after third). 5

Common Pitfalls to Avoid

• Don't exceed citalopram 20 mg/day in patients >60 years (QT prolongation risk) 1, 5
• Monitor for hyponatremia in first month (0.5-12% incidence in older adults on SSRIs) 1, 5
• Assess GI bleeding risk when combining SSRIs with NSAIDs or antiplatelet drugs (OR 1.2-1.5) 1, 5
• Don't assume all SSRIs are interchangeable for drug interactions—they differ substantially in CYP enzyme effects 4
• Recognize that approximately 63% of patients experience at least one adverse effect, with nausea/vomiting being the most common reason for discontinuation 1, 3

Special Population: Pregnancy and Breastfeeding

For breastfeeding: sertraline or paroxetine transfer in lowest concentrations to breast milk with undetectable infant plasma levels. 1

Avoid fluoxetine and venlafaxine during breastfeeding (highest infant plasma concentrations). 1

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