What medications can be added to escitalopram (Lexapro) and bupropion (Wellbutrin) to enhance motivation and reduce symptoms of major depressive disorder?

Augmentation Options for Escitalopram and Bupropion in Major Depressive Disorder

For patients already on escitalopram (Lexapro) and bupropion (Wellbutrin) who need additional medication to boost motivation and decrease depression, aripiprazole is the most evidence-supported option to add as a third agent.

First-Line Augmentation Options

Atypical Antipsychotics

• Aripiprazole (Abilify):
  • Starting dose: 2-5 mg daily
  • Target dose: 5-15 mg daily
  • Strongest evidence for augmentation when two antidepressants have not achieved remission 1
  • Mechanism: Partial dopamine agonist that can help with motivation and energy

Other Augmentation Options

Stimulants

• Methylphenidate (Ritalin, Concerta):
  • Starting dose: 5-10 mg daily
  • Target dose: 10-60 mg daily (divided doses)
  • Particularly helpful for motivation, energy, and concentration issues
  • Use with caution due to potential for increased anxiety with bupropion

Thyroid Hormone

• Liothyronine (T3, Cytomel):
  • Starting dose: 25 mcg daily
  • Target dose: 25-50 mcg daily
  • May help with fatigue and motivation
  • Requires baseline thyroid function tests

Decision Algorithm for Choosing an Augmentation Agent

1. If motivation is the primary concern with minimal anxiety:

   • Try aripiprazole first (strongest evidence)
   • Consider methylphenidate if aripiprazole is ineffective or not tolerated

2. If fatigue is prominent:

   • Consider T3 augmentation
   • Modafinil may be considered (100-200 mg daily) but has less evidence

3. If anxiety is also present:

   • Aripiprazole is preferred over stimulants
   • Avoid stimulants which may worsen anxiety, especially with bupropion

Monitoring and Follow-up

• Assess response after 4-6 weeks of augmentation therapy 1
• Monitor for side effects:
  • Aripiprazole: weight gain, akathisia, metabolic changes
  • Stimulants: increased blood pressure, insomnia, anxiety
  • T3: cardiac effects, tremor, heat intolerance

Important Considerations

• The combination of escitalopram and bupropion already provides dual-mechanism coverage (serotonergic + dopaminergic/noradrenergic) 2
• Adding a third agent increases risk of drug interactions and side effects
• Bupropion should not be taken late in the day to minimize insomnia 1
• Bupropion may lower seizure threshold; use caution with other medications that affect seizure threshold 1

Cautions and Contraindications

• Avoid adding another SSRI or SNRI to the current regimen due to increased risk of serotonin syndrome
• Use caution when combining bupropion with medications that inhibit CYP2D6 3
• Consider non-pharmacological approaches (cognitive behavioral therapy, exercise) alongside medication augmentation

Alternative Approaches

If augmentation is unsuccessful after adequate trials:

1. Consider switching from escitalopram to another antidepressant class
2. Evaluate for treatment-resistant depression and consider consultation with a psychiatrist
3. Assess for comorbid conditions that may be limiting response (substance use, thyroid dysfunction, sleep disorders)

Remember that medication changes should be made one at a time with adequate monitoring to assess both therapeutic effects and potential adverse reactions.