What are the first-line medications for treating depression?

First-Line Medications for Depression

Second-generation antidepressants, specifically SSRIs (selective serotonin reuptake inhibitors), are the first-line pharmacologic treatment for depression, with medication selection based on adverse effect profiles, cost, and patient preferences rather than efficacy differences. 1, 2

Medication Selection Strategy

All second-generation antidepressants demonstrate equal efficacy for treatment-naive patients, with no single agent superior to another based on effectiveness alone. 1, 2 The number needed to treat for SSRIs is 7-8 for achieving remission. 1, 2

Preferred First-Line Agents

For general adult patients:

• Sertraline, citalopram, or escitalopram are preferred SSRIs based on favorable adverse effect profiles and tolerability. 3, 2
• Bupropion is the optimal choice when cognitive symptoms (difficulty concentrating, indecisiveness, mental fog) predominate, due to its dopaminergic and noradrenergic effects and lower rate of sexual side effects. 1, 2
• SNRIs (venlafaxine or duloxetine) are second-choice options for cognitive symptoms, though they carry higher rates of nausea and vomiting compared to SSRIs. 1, 2

For elderly patients (≥65 years):

• Sertraline, escitalopram, or citalopram should be initiated at low doses with gradual titration. 3, 2
• Avoid paroxetine and fluoxetine in elderly patients—paroxetine has high anticholinergic effects and sexual dysfunction rates, while fluoxetine's long half-life increases drug accumulation risk. 1, 3, 2
• Mirtazapine, venlafaxine, and bupropion are also acceptable alternatives for older adults. 1, 3, 2

Critical Adverse Effect Considerations

Approximately 63% of patients on second-generation antidepressants experience at least one adverse effect. 1, 2 Common adverse effects include nausea, vomiting, diarrhea, dizziness, headache, insomnia, and sexual dysfunction. 1, 2

Key adverse effect differences:

• Bupropion has significantly lower rates of sexual adverse events than fluoxetine or sertraline. 1, 2
• Paroxetine has the highest rates of sexual dysfunction among SSRIs, exceeding fluoxetine, fluvoxamine, nefazodone, and sertraline. 1, 2
• SSRIs carry an increased risk of suicide attempts compared to placebo, requiring close monitoring. 1
• Duloxetine and venlafaxine have higher discontinuation rates due to adverse effects compared to SSRIs as a class. 1

Mandatory Monitoring Requirements

Begin monitoring within 1-2 weeks of treatment initiation for suicidal thoughts and behaviors, particularly during the first 1-2 months when suicide attempt risk is highest. 1, 3 Monitor for emergence of agitation, irritability, or unusual behavioral changes indicating worsening depression. 1

In elderly patients, additionally monitor for falls risk, hyponatremia, drug interactions, and gastrointestinal symptoms. 3

Treatment Response Assessment

Modify treatment if inadequate response occurs within 6-8 weeks of initiation at therapeutic doses. 1 The response rate to initial drug therapy may be as low as 50%, and no reliable patient factors predict individual drug response. 1

Treatment Duration

Continue treatment for 4-9 months after achieving remission for a first episode of major depression. 1, 2 For patients with two or more prior episodes, consider prolonged treatment of at least one year to prevent recurrence. 1, 3, 2

Severity-Based Approach

Antidepressants are most effective in patients with severe depression, with the drug-placebo difference increasing with initial severity. 1, 2 Do not use antidepressants for initial treatment of mild depression or subsyndromal depressive symptoms without a current moderate-to-severe episode. 2

Critical Drug Interactions

Avoid combining SSRIs with:

• MAOIs (contraindicated due to serotonin syndrome risk). 4
• Pimozide (contraindicated with fluoxetine due to QTc prolongation). 4
• TCAs require dose reduction and plasma level monitoring when combined with SSRIs, as SSRIs inhibit TCA metabolism. 2, 4, 5
• Warfarin requires careful monitoring, as SSRIs increase bleeding risk. 4, 5

Exercise caution with triptans, lithium, tramadol, and other serotonergic drugs due to serotonin syndrome risk. 4, 5

Common Pitfalls to Avoid

• Do not prescribe antidepressants for mild depression without a moderate-to-severe episode. 2
• Do not use tricyclic antidepressants as first-line agents due to higher adverse effect burden and overdose toxicity. 2
• Do not assume all SSRIs have identical profiles—paroxetine and fluoxetine have notably worse tolerability in specific populations. 1, 3, 2
• Do not delay treatment modification beyond 6-8 weeks if response is inadequate. 1