In an adult without seizures, eating disorders, or uncontrolled hypertension, which antidepressant is appropriate for treating depression without worsening fatigue?

Bupropion is the Antidepressant of Choice for Depression Without Worsening Fatigue

For an adult without seizures, eating disorders, or uncontrolled hypertension, bupropion is the preferred antidepressant because it does not increase fatigue and may actually reduce it, unlike SSRIs which commonly cause somnolence. 1, 2, 3

Why Bupropion Specifically Addresses Fatigue

Bupropion's unique dopamine-norepinephrine reuptake inhibition mechanism distinguishes it from serotonergic antidepressants, giving it stimulant-like properties that counteract fatigue rather than worsen it. 1, 2

• Bupropion shares biological properties with psychostimulants through its primary action on dopaminergic and noradrenergic neurotransmissions, making it particularly effective for fatigue-related depressive symptoms 1
• Anecdotal reports indicate bupropion may lower fatigue in cancer patients and help reduce concentration problems 2
• Bupropion is associated with significantly less somnolence compared to tricyclic antidepressants and SSRIs 4, 3

Comparative Evidence Against SSRIs for Fatigue

SSRIs like paroxetine have been specifically studied for fatigue and show no benefit—in fact, antidepressants are not recommended to reduce fatigue according to cancer fatigue guidelines. 5

• A phase III randomized controlled trial of paroxetine in 549 cancer patients found no statistically significant alleviation of fatigue compared to placebo 5
• The NCCN guidelines explicitly state that antidepressants (specifically SSRIs like paroxetine) are not recommended to reduce fatigue 5
• While SSRIs may treat depression effectively, their use for fatigue has not shown consistent benefits in clinical trials 5

Practical Prescribing for Bupropion

Start bupropion SR at 100-150 mg once daily in the morning, then increase to 150 mg twice daily after 3-4 days, with a maximum dose of 400 mg/day in divided doses. 5

• The most common side effects are nervousness and insomnia, which can be minimized by avoiding late-afternoon or evening dosing 2, 6
• Administer the second dose no later than mid-afternoon to reduce sleep disturbance 7
• Bupropion has minimal anticholinergic effects and is generally well tolerated, with dry mouth being the most common side effect 6

Critical Safety Considerations

Bupropion is absolutely contraindicated in patients with seizure disorders, eating disorders (bulimia/anorexia), or abrupt benzodiazepine/alcohol withdrawal due to lowered seizure threshold. 6

• When dosage is maintained at 450 mg/day or less in a divided schedule, the seizure rate is comparable to other antidepressants in patients without risk factors 6
• Bupropion is 10 to 100 times less likely to induce cardiac conduction problems than tricyclic antidepressants, and orthostatic hypotension is rare 6
• Bupropion has inhibitory effects on CYP2D6, raising concern for drug interactions with medications metabolized by this pathway 2

Additional Advantages Over SSRIs

Bupropion causes significantly less sexual dysfunction than SSRIs—probably the least of any antidepressant—making it preferable when sexual side effects are a concern. 5, 2, 4, 3

• Bupropion is associated with lower rates of sexual adverse events than fluoxetine, sertraline, and especially paroxetine 5
• Bupropion causes less weight gain compared to SSRIs and tricyclic antidepressants 4, 3
• Nausea appears slightly less common with bupropion than with SSRIs 2

Efficacy Comparable to SSRIs

Bupropion demonstrates equivalent antidepressant efficacy to SSRIs and SNRIs in treating major depressive disorder, so choosing it does not compromise treatment effectiveness. 4, 3

• Bupropion was as efficacious as fluoxetine, escitalopram, and had similar efficacy to venlafaxine XR in multiple placebo-controlled trials 4, 3
• Continue treatment for 4-9 months after satisfactory response for first-episode depression 5, 8

When Bupropion Cannot Be Used

If bupropion is contraindicated due to seizure risk, eating disorders, or uncontrolled hypertension, consider these alternatives:

• Mirtazapine has a faster onset than SSRIs and may be less likely to cause fatigue due to its unique mechanism, though it causes significant weight gain 7
• Venlafaxine (SNRI) may have slightly better response rates than SSRIs for depression with anxiety, though it has higher discontinuation rates due to nausea 5
• Among SSRIs, sertraline is preferred due to superior tolerability, but it still carries risk of somnolence and fatigue 5, 7