Why are selective serotonin reuptake inhibitors (SSRIs) preferred as first‑line therapy for major depressive disorder when bupropion is well tolerated and has fewer side effects?

Why SSRIs Remain First-Line Despite Bupropion's Favorable Side-Effect Profile

SSRIs are considered first-line treatment for major depressive disorder primarily because of historical precedent, broader evidence base, and guideline consensus—not because they are inherently superior to bupropion in efficacy or tolerability. In fact, the evidence shows that all second-generation antidepressants, including bupropion and SSRIs, have equivalent efficacy for treatment-naïve patients with MDD. 1

The Evidence Shows Equivalent Efficacy

The American College of Physicians guidelines explicitly state that no clinically significant differences exist in efficacy, effectiveness, or quality of life among SSRIs, SNRIs, and other second-generation antidepressants (including bupropion) for treating acute-phase major depressive disorder. 1 When all agents work equally well—with response rates of 42–49% and remission rates around 46–54%—the choice should be driven by side-effect profile, cost, and patient preference rather than presumed efficacy differences. 1, 2

Bupropion Actually Has Superior Tolerability in Key Domains

Sexual Dysfunction

Bupropion demonstrates significantly lower rates of sexual adverse events compared to fluoxetine and sertraline (8% vs. higher rates with SSRIs). 1 Paroxetine, in particular, has the highest rates of sexual dysfunction among all second-generation antidepressants. 1 This advantage is so pronounced that bupropion is commonly added to SSRIs specifically to reverse SSRI-induced sexual dysfunction. 3

Weight and Sedation

Bupropion is associated with minimal weight gain or even weight loss, unlike many SSRIs, and has lower rates of sedation and somnolence than SSRIs like paroxetine. 1, 2, 4, 5 Mirtazapine and paroxetine result in higher weight gain than other agents. 1

Cognitive Effects

For patients with prominent cognitive symptoms (difficulty concentrating, mental fog, indecisiveness), bupropion is the most effective first-choice antidepressant due to its dopaminergic and noradrenergic effects. 2

Why SSRIs Persist as "First-Line" in Practice

Historical Momentum and Marketing

SSRIs were introduced earlier (fluoxetine in 1987) and became the default choice through decades of marketing and clinical habit. The guideline designation of SSRIs as "first-line" reflects historical precedent rather than superiority in head-to-head trials. 1

Broader Indication Profile

Fluoxetine is the only antidepressant with FDA approval for pediatric depression (ages 8 and older), which reinforces its position in treatment algorithms. 6 SSRIs also have FDA approval for multiple anxiety disorders, making them appear more versatile.

Perceived Safety Margin

Clinicians often cite SSRIs' "safety" despite evidence to the contrary. SSRIs are associated with an increased risk for nonfatal suicide attempts (odds ratio 1.57–2.25) compared to placebo, whereas bupropion does not show this signal. 1 Additionally, bupropion has a seizure risk of approximately 0.1% (1 in 1,000) at standard doses of 300 mg/day, which is often overemphasized despite being rare. 6

The Real Clinical Algorithm Should Be Symptom-Driven

Rather than defaulting to SSRIs, the optimal approach is to match the antidepressant to the patient's symptom profile:

• Cognitive symptoms (poor concentration, mental fog): Start with bupropion 150 mg SR once daily × 3 days, then 150 mg twice daily. 2
• Sexual dysfunction concerns or prior SSRI-induced sexual side effects: Choose bupropion. 1, 2
• Comorbid smoking cessation need: Bupropion addresses both depression and nicotine dependence simultaneously. 6
• Prominent anxiety or panic: SSRIs (escitalopram, sertraline) may be preferred, though bupropion does not worsen anxiety in most patients. 6
• Older adults: Bupropion, citalopram, escitalopram, or sertraline are preferred; avoid paroxetine (high anticholinergic burden) and fluoxetine (agitation risk). 2

Common Pitfalls in Antidepressant Selection

Overestimating SSRI Safety

Nausea and vomiting are the most common reasons for discontinuation in SSRI efficacy studies, and approximately 63% of patients on second-generation antidepressants experience at least one adverse effect. 1, 2 The notion that SSRIs are universally "well-tolerated" is not supported by the data.

Underutilizing Bupropion Due to Seizure Fear

The seizure risk with bupropion at 300 mg/day is 0.1% (1 in 1,000), which is comparable to or lower than the risk of serious adverse events with SSRIs (e.g., hyponatremia, serotonin syndrome, bleeding). 1, 6 Absolute contraindications include active seizure disorder, eating disorders, and abrupt alcohol/benzodiazepine withdrawal—but these are specific and identifiable. 6

Ignoring Augmentation Data

When SSRIs fail, augmenting with bupropion is more effective and better tolerated than augmenting with buspirone (discontinuation rates 12.5% vs. 20.6%, P < 0.001). 6, 2 This suggests bupropion should have been considered earlier in the treatment sequence.

The Bottom Line

There is no evidence-based reason to reflexively choose SSRIs over bupropion as first-line therapy for major depressive disorder. The American College of Physicians explicitly recommends that clinicians select between cognitive behavioral therapy or second-generation antidepressants (including bupropion) after discussing treatment effects, adverse effect profiles, cost, accessibility, and patient preferences. 1 Bupropion should be strongly considered as a first-line option, particularly for patients with cognitive symptoms, sexual dysfunction concerns, weight gain concerns, or comorbid smoking, where it offers clear advantages over SSRIs. 1, 6, 2, 4, 5