What non-Selective Serotonin Reuptake Inhibitor (SSRI) treatments are recommended during pregnancy?

Non-SSRI Antidepressant Treatments in Pregnancy

Bupropion is the primary non-SSRI antidepressant option for treating depression during pregnancy, with atomoxetine serving as an alternative for ADHD-related depression, though both require careful risk-benefit discussion given limited but generally reassuring safety data. 1

First-Line Non-SSRI Option: Bupropion

Bupropion does not appear to be associated with major congenital malformations or significant adverse obstetrical outcomes, making it a reasonable first-line non-SSRI choice. 1

Dosing Strategy

• Start with bupropion SR 100-150 mg once daily in the morning 2
• Titrate by 37.5-75 mg every 3 days as tolerated 2
• Maintenance dose: 100-150 mg twice daily (SR formulation) 1, 2
• Maximum dose: 450 mg per day 1, 2

Safety Profile

• No consistent association with major congenital malformations in most studies 1
• Small absolute increase in two specific cardiovascular malformations reported but confounding by indication cannot be ruled out: 1
  • Left ventricular outflow tract obstruction heart defects (incidence 0.279% vs 0.07% with other antidepressants)
  • Ventricular septal defects (aOR 2.9; 95% CI 1.5-5.5)
• Possible increased risk for spontaneous abortion, though confounding remains a concern 1
• Possible increased risk for diaphragmatic hernia (aOR 2.77; 95% CI 1.34-5.71), but absolute risk remains extremely low given population prevalence of 0.012%-0.031% 1

Critical Contraindications

• Active seizure disorder or history of seizures (bupropion lowers seizure threshold) 2
• Anorexia nervosa or bulimia nervosa 2
• Abrupt discontinuation of alcohol or benzodiazepines 2
• Current MAOI use or within 14 days of MAOI discontinuation 2

Alternative Non-SSRI Option: Atomoxetine

Atomoxetine (primarily used for ADHD but has antidepressant properties) does not appear to be associated with major congenital malformations, including cardiac malformations, though data are more limited than for bupropion. 1

Dosing Strategy

• Start with 40 mg once daily 1, 2
• Titrate every 7-14 days to 60 mg, then 80 mg if needed 1, 2
• Maximum dose: lesser of 1.4 mg/kg/day or 100 mg/day 1, 2

Safety Profile

• No association with major congenital malformations or significant adverse obstetrical outcomes in available studies 1
• Possible increased risk for spontaneous abortion, though confounding by indication cannot be ruled out 1
• Recent large, well-controlled study demonstrated no increased risks for long-term neurodevelopmental outcomes, including psychiatric disorders, vision/hearing impairments, epilepsy, seizures, or growth impairment 1

Combination Therapy Considerations

When monotherapy is insufficient, combination therapy with atomoxetine and bupropion may be considered, though this requires heightened vigilance for drug interactions and cumulative side effects. 2

• Allow at least 14 days between discontinuation of MAOIs and starting bupropion 2
• Gradual dose titration is essential to minimize seizure risk with bupropion 2
• Both medications should be used with extreme caution in pregnancy, requiring thorough risk-benefit discussion 2

Comparative Context: Why Non-SSRI Over SSRI?

While SSRIs remain commonly prescribed in pregnancy, they carry specific concerns that may make non-SSRI options preferable in certain clinical scenarios:

• SSRIs are associated with poor neonatal adaptation syndrome (continuous crying, irritability, jitteriness, tremors, feeding difficulty, respiratory distress) in 13.5-23.6% of exposed infants 1
• SSRI exposure increases risk of preterm birth (aOR 1.24; 95% CI 1.09-1.41), even when compared to depressed women not on SSRIs 3
• Paroxetine specifically carries increased risk of cardiac malformations and should be avoided in pregnancy 1, 4
• SSRIs may increase risk of persistent pulmonary hypertension of the newborn (PPHN), though evidence remains conflicting 1

Clinical Decision Algorithm

1. If patient has depression without ADHD: Consider bupropion as first-line non-SSRI option
2. If patient has ADHD with comorbid depression: Consider atomoxetine as first-line option
3. If patient has seizure history or eating disorder: Atomoxetine is preferred over bupropion
4. If monotherapy fails: Consider combination therapy with heightened monitoring
5. Avoid first trimester exposure when possible to minimize risk during organogenesis, though this must be balanced against risk of untreated depression 1

Critical Monitoring Requirements

• Fetal echocardiography should be offered to all women exposed to bupropion in first trimester given small but increased risk of cardiac defects 5
• Serial ultrasound examinations for fetal growth monitoring 1
• Neonatal monitoring for withdrawal symptoms or poor adaptation in first week of life 1
• Early postpartum follow-up within first week after hospital discharge 1