What is the best first‑line medication for an adult with major depressive disorder?

Best First-Line Medication for Major Depressive Disorder

Selective serotonin reuptake inhibitors (SSRIs)—specifically sertraline, escitalopram, or citalopram—are the recommended first-line medications for adults with major depressive disorder, with sertraline often preferred due to its optimal balance of efficacy, safety, and tolerability across diverse patient populations. 1

Primary SSRI Recommendations

All second-generation antidepressants (SSRIs and SNRIs) demonstrate equivalent efficacy for treating major depression, with no clinically meaningful differences in response or remission rates (NNT = 7-8). 1, 2 The choice among agents should therefore be guided by adverse-effect profile, drug interactions, cost, and patient-specific factors rather than presumed efficacy differences. 2

Sertraline as First Choice

• Sertraline (50-200 mg daily) is the most broadly recommended SSRI because it has minimal cytochrome P450 enzyme inhibition, resulting in the lowest risk of drug-drug interactions compared to fluoxetine, fluvoxamine, and paroxetine. 1
• Sertraline has a lower risk of QTc prolongation than citalopram or escitalopram, making it safer for patients with cardiac risk factors or unknown cardiovascular status. 1
• Start at 50 mg daily; for highly anxious or agitated patients, begin with 25 mg daily for the first week as a "test dose" to minimize initial activation symptoms. 1
• Titrate in 50 mg increments every 1-2 weeks if response is inadequate, up to a maximum of 200 mg daily. 1

Escitalopram and Citalopram as Alternatives

• Escitalopram (10-20 mg daily) and citalopram (20-40 mg daily) have the least effect on CYP450 enzymes and the lowest propensity for drug interactions after sertraline. 1
• Critical dosing limits: Citalopram must not exceed 40 mg daily in adults under 60 years and 20 mg daily in patients over 60 years due to dose-dependent QTc prolongation risk. 1, 3
• Escitalopram should not exceed 10 mg daily in patients over 60 years for the same cardiac safety reasons. 3

Agents to Avoid as First-Line

• Paroxetine should not be used as a first-line agent due to the highest anticholinergic burden among SSRIs, highest rates of sexual dysfunction, severe discontinuation syndrome, and potent CYP2D6 inhibition. 1, 3
• Fluoxetine is generally not preferred initially because of its long half-life (which delays onset and reversal of side effects), "activating" properties that can worsen agitation, and strong CYP2D6 inhibition causing multiple drug interactions. 1, 3
• Tricyclic antidepressants (TCAs) should never be used as first-line therapy due to higher adverse-effect burden, severe anticholinergic effects, cardiac toxicity, and high lethality in overdose. 2

Alternative First-Line Options for Specific Presentations

Bupropion for Cognitive Symptoms

• Bupropion (150-300 mg daily) is the most effective first-choice antidepressant when cognitive symptoms predominate—including difficulty concentrating, indecisiveness, and mental fog—due to its dopaminergic and noradrenergic effects. 2
• Bupropion has the lowest rate of sexual adverse effects among all antidepressants (approximately 8% vs. much higher rates with SSRIs). 2
• Seizure risk at standard doses (300 mg/day) is approximately 0.1% (1 in 1,000), comparable to serious adverse events with SSRIs. 2

SNRIs for Depression with Chronic Pain

• Venlafaxine or duloxetine may be considered when chronic pain coexists with depression, with remission rates of approximately 49% versus 42% for SSRIs. 2
• One trial showed venlafaxine had statistically better response rates than fluoxetine specifically for depression with prominent anxiety symptoms, though evidence is limited. 1

Treatment Timeline and Monitoring

• Allow 6-8 weeks for an adequate trial, including at least 2 weeks at the maximum tolerated dose, before concluding treatment failure. 1
• Assess treatment response formally at weeks 4 and 8 using standardized depression rating scales (e.g., PHQ-9). 1
• Approximately 38% of patients do not achieve treatment response during 6-12 weeks, and 54% do not achieve remission with initial SSRI therapy. 1

Critical Safety Monitoring

• Monitor for treatment-emergent suicidality closely during the first 1-2 weeks after initiation or dose changes, particularly in patients under age 24. 1
• All SSRIs carry FDA black box warnings for increased suicidal thinking in adolescents and young adults, with 14 additional cases per 1,000 patients treated compared to placebo. 1
• In adults aged 25-64 years, SSRIs show a neutral effect on suicide risk; in adults ≥65 years, SSRIs are protective (OR 0.06). 2

Treatment Duration

• Continue SSRI treatment for a minimum of 4-9 months after satisfactory response for first-episode major depression. 1, 2
• For patients with recurrent episodes (≥2 prior episodes), consider longer duration of at least 1 year or indefinite maintenance therapy. 1
• After three episodes, recurrence risk reaches approximately 90%, warranting consideration of lifelong maintenance. 3

When Initial Treatment Fails

• If inadequate response after 6-8 weeks at therapeutic doses, either switch to another SSRI/SNRI or augment with bupropion. 1
• Switching and augmentation strategies have comparable efficacy (approximately 25% of patients become symptom-free with either approach). 1
• Augmentation with bupropion SR 150 mg daily produces greater reduction in depression severity than augmentation with buspirone and has lower discontinuation rates. 2

Common Pitfalls to Avoid

• Do not discontinue SSRIs abruptly—taper gradually over several weeks to minimize discontinuation syndrome (dizziness, nausea, sensory disturbances). 1
• Do not combine SSRIs with MAOIs due to serotonin syndrome risk; allow at least 2 weeks washout when switching. 1
• Do not prescribe antidepressants for mild depression or subsyndromal symptoms without a current moderate-to-severe depressive episode, as the drug-placebo difference is minimal in mild depression. 2
• Do not assume treatment failure before 6-8 weeks; partial response at 4 weeks warrants continued treatment at the same dose, not premature switching. 1

Integration with Psychotherapy

• Cognitive behavioral therapy (CBT) demonstrates efficacy equivalent to SSRIs for moderate-to-severe depression and should be offered as an alternative first-line option or in combination with medication. 1, 2
• Combination treatment (CBT + SSRI) is superior to either modality alone for anxiety disorders and may produce lower relapse rates after remission. 1, 2