Which Antidepressants Work Best for Major Depression?

A landmark network meta-analysis published in The Lancet analyzed 522 randomized controlled trials involving 116,477 patients to provide the first comprehensive head-to-head comparison of 21 antidepressants. This study definitively ranks antidepressants by both effectiveness and tolerability, revealing that amitriptyline is the most effective antidepressant (OR 2.13 vs placebo) while agomelatine and fluoxetine are the most tolerable, being the only antidepressants associated with fewer dropouts than placebo.

Dr. Kumar’s Take

This is the gold standard study that every psychiatrist and primary care physician should know. Finally, we have head-to-head comparisons of all major antidepressants based on rigorous methodology rather than marketing claims. The fact that there are meaningful differences in both effectiveness and tolerability means that antidepressant selection shouldn’t be random - it should be evidence-based. This study gives us the data to have informed conversations with patients about which medications are most likely to work and be tolerated.

Study Snapshot

This systematic review and network meta-analysis searched multiple databases from inception to January 2016, including Cochrane Central Register, Embase, MEDLINE, PsycINFO, and regulatory agency websites. The analysis included double-blind, randomized controlled trials of 21 antidepressants for acute treatment of adults with major depressive disorder diagnosed according to standard criteria. The study excluded trials with significant bipolar disorder, psychotic depression, or treatment-resistant depression populations.

Concrete Rankings: Most Effective Antidepressants

Top Performers for Efficacy (Head-to-Head Studies):

1. Agomelatine - Most effective overall (ORs 1.19-1.96 vs other antidepressants)
2. Amitriptyline - Highest efficacy vs placebo (OR 2.13)
3. Escitalopram - Strong efficacy with good tolerability
4. Mirtazapine - Highly effective with moderate tolerability
5. Paroxetine - Strong efficacy but higher dropout rates
6. Venlafaxine - Effective but poorly tolerated
7. Vortioxetine - Good efficacy and tolerability balance

Least Effective Antidepressants:

• Reboxetine - Lowest efficacy (OR 1.37 vs placebo) and poor tolerability
• Trazodone - Poor efficacy (ORs 0.51-0.84 vs other antidepressants)
• Fluvoxamine - Poor efficacy and high dropout rates
• Fluoxetine - Lower efficacy but excellent tolerability

Most Tolerable Antidepressants (Lowest Dropout Rates)

Best Tolerability:

1. Agomelatine - Only antidepressant better tolerated than placebo (OR 0.84)
2. Fluoxetine - Second-best tolerability (OR 0.88 vs placebo)
3. Citalopram - Well tolerated (ORs 0.43-0.77 vs other antidepressants)
4. Escitalopram - Good tolerability with strong efficacy
5. Sertraline - Well tolerated with moderate efficacy
6. Vortioxetine - Good tolerability and efficacy

Worst Tolerability (Highest Dropout Rates):

• Clomipramine - Worse than placebo (OR 1.30) with high dropouts (ORs 1.30-2.32)
• Amitriptyline - Most effective but poorly tolerated
• Duloxetine - High dropout rates despite moderate efficacy
• Venlafaxine - Effective but high discontinuation rates
• Reboxetine - Poor efficacy AND poor tolerability

Clinical Decision-Making Framework

For Patients Prioritizing Maximum Effectiveness:

• First choice: Agomelatine (best efficacy + tolerability combination) - Note: Not FDA-approved in the US
• US First choice: Escitalopram (strong efficacy, good tolerability, widely available)
• Second choice: Mirtazapine (highly effective, moderate tolerability)
• Consider: Amitriptyline (most effective but requires tolerability monitoring)

For Patients Prioritizing Tolerability:

• First choice: Agomelatine (only antidepressant better than placebo for tolerability) - Not FDA-approved in US
• US First choice: Fluoxetine (excellent tolerability, moderate efficacy)
• Second choice: Citalopram or Escitalopram (good tolerability, solid efficacy)
• Third choice: Sertraline (well-tolerated, moderate efficacy)

Antidepressants to Generally Avoid:

• Reboxetine: Poor efficacy AND poor tolerability
• Fluvoxamine: Poor efficacy with high dropout rates
• Trazodone: Consistently poor performance across measures

Special Considerations:

• Elderly patients: Prefer agomelatine, escitalopram, or sertraline for better tolerability
• First episode depression: Consider agomelatine or escitalopram for optimal benefit-risk ratio
• Previous treatment failures: Mirtazapine or venlafaxine may be worth trying despite tolerability concerns

Safety, Limits, and Caveats

While this meta-analysis provides valuable comparative data, several limitations exist. The study focused on acute treatment outcomes and may not reflect long-term effectiveness or tolerability. Individual patient responses can vary significantly from population-level findings, and the analysis couldn’t account for all patient-specific factors that influence treatment response.

The exclusion of treatment-resistant depression populations means the findings may not apply to patients who have failed multiple previous treatments. Additionally, the study’s focus on group-level data may not capture important individual variations in response.

Practical Takeaways

• Ask specifically for escitalopram as first-line treatment in the US (agomelatine, while optimal, is not FDA-approved)
• Avoid reboxetine, fluvoxamine, and trazodone unless specific circumstances warrant their use - they consistently underperformed
• If you prioritize effectiveness over tolerability, discuss amitriptyline, mirtazapine, or venlafaxine with close monitoring
• If you’re sensitive to side effects, request fluoxetine, citalopram, or sertraline as safer starting options
• Understand the trade-offs: The most effective antidepressants (amitriptyline, venlafaxine) often have higher dropout rates due to side effects
• Use this data in shared decision-making - show your doctor these specific rankings rather than accepting “they’re all the same”
• Know that individual responses vary - these are population averages, but they provide the best starting point for evidence-based selection

Key Study Insights That Change Clinical Practice

The “All Antidepressants Are Equal” Myth is Debunked:

• Efficacy differences range from OR 1.37 (reboxetine) to OR 2.13 (amitriptyline) vs placebo
• Head-to-head comparisons show even larger differences (ORs ranging 0.51-1.96)
• Only 2 of 21 antidepressants (agomelatine, fluoxetine) were better tolerated than placebo

Specific Numbers That Matter:

• 522 trials, 116,477 patients - the largest antidepressant comparison ever
• Moderate effect sizes overall - all antidepressants work, but differences are clinically meaningful
• 73% of trials had moderate risk of bias - results are robust but not perfect
• 8-week primary endpoint - focused on acute treatment response

Clinical Implications:

• End “trial-and-error” prescribing - use evidence-based rankings as starting points
• Agomelatine emerges as optimal first choice - best efficacy-tolerability balance
• Tricyclics (amitriptyline) remain highly effective - don’t dismiss older drugs
• Some newer drugs (reboxetine, trazodone) perform poorly - avoid unless specific indications

Related Studies and Research

• STAR*D Treatment Steps and Declining Success Rates
• Citalopram Real-World Effectiveness in STAR*D
• Sequential Combination of Pharmacotherapy and Psychotherapy
• Measurement-Based Care Strategy for Behavioral Health

FAQs

What is the single best antidepressant according to this study?

Agomelatine ranks as the optimal first choice globally, being among the most effective antidepressants while having the best tolerability profile (the only antidepressant better tolerated than placebo). However, agomelatine is not FDA-approved in the United States. For US patients, escitalopram is the best evidence-based first choice with strong efficacy and good tolerability.

Which antidepressants should be avoided?

Reboxetine performed worst overall (lowest efficacy OR 1.37, poor tolerability). Fluvoxamine and trazodone also consistently underperformed. These should generally be avoided unless specific clinical circumstances warrant their use.

How should I use these rankings with my doctor?

Show your doctor these specific numbers and ask: “Based on the Lancet meta-analysis of 116,477 patients, can we start with escitalopram since it has the best efficacy-tolerability profile among FDA-approved options?” (Note: While agomelatine ranked highest overall, it’s not available in the US). This moves the conversation from opinion to evidence.

Do these results apply if I’ve failed previous antidepressants?

The study excluded treatment-resistant depression, so these rankings apply best to first-line treatment. However, if you’ve failed an antidepressant that ranks poorly (like reboxetine or fluvoxamine), trying a top-ranked FDA-approved option (escitalopram, mirtazapine) is still evidence-based.

Why isn’t my doctor using these rankings?

Many doctors may not be aware of this 2018 study or may rely on older prescribing habits. Bringing this evidence to your appointment can help inform shared decision-making and move away from “trial-and-error” approaches.

Bottom Line

This landmark analysis of 522 trials and 116,477 patients definitively ranks antidepressants by effectiveness and tolerability. Agomelatine ranks highest globally but is not FDA-approved in the US. For US patients, escitalopram emerges as the optimal first-line choice, combining strong efficacy with good tolerability. Reboxetine, fluvoxamine, and trazodone should generally be avoided due to poor performance. The study provides concrete evidence to end “trial-and-error” prescribing and support informed, evidence-based antidepressant selection.

Read the complete Lancet study: Comparative efficacy and acceptability of 21 antidepressant drugs