Optimizing Treatment for Treatment-Resistant Depression

Introduction to Optimizing Current Medications

The American Academy of Child and Adolescent Psychiatry recommends that bupropion dose can be increased to optimize current combination therapy, with a therapeutic target dose of 300mg daily for depression 1
The standard titration for bupropion is 150mg once daily initially, then increasing to 300mg once daily, which is the typical maintenance dose for depression 1
The maximum dose for bupropion XL formulation is 450mg daily, though 300mg is usually sufficient 1
Increasing bupropion to 300mg XL once daily in the morning is recommended, as this dose has been studied in combination with escitalopram and is well-tolerated 1

The combination of escitalopram and bupropion is safe, with no contraindications existing between bupropion and SSRIs like escitalopram 2
Adding Rexulti (brexpiprazole) as an augmentation agent to this combination is FDA-approved for treatment-resistant depression 3

Bupropion inhibits CYP2D6, which can increase escitalopram levels modestly, but this is not clinically significant at standard doses, and escitalopram has minimal effect on CYP enzymes and low drug interaction potential 1
Administering bupropion in the morning and ensuring any second dose is given before 3 PM can minimize insomnia 1

Never combining bupropion with MAOIs (monoamine oxidase inhibitors) or within 14 days of stopping MAOIs due to hypertensive crisis risk is recommended by the American Academy of Child and Adolescent Psychiatry 4, 1
Avoiding adding tramadol, meperidine, or other serotonergic opioids due to serotonin syndrome risk with escitalopram is recommended 4

If inadequate response persists after increasing bupropion to 300mg daily for 6-8 weeks, additional augmentation options include increasing Rexulti dose, adding lithium, adding thyroid hormone (T3), or switching to a different antidepressant class 1, 3, 2

Watching for increased agitation or activation, as bupropion is an activating medication, and monitoring blood pressure, as bupropion can elevate BP, is recommended 1
Screening for seizure risk factors, such as eating disorders, alcohol withdrawal, or head trauma history, as bupropion lowers seizure threshold, and monitoring for serotonin syndrome symptoms if any serotonergic agents are added, is recommended 1, 4

The National Comprehensive Cancer Network recommends avoiding the combination of bupropion with MAOIs or within 14 days of stopping MAOIs due to hypertensive crisis risk, and also avoiding its use in patients with seizure disorders or brain metastases, as bupropion lowers seizure threshold 5, 6
The National Comprehensive Cancer Network suggests screening for seizure risk factors, including eating disorders, alcohol withdrawal, or head trauma history, and also monitoring for neuropsychiatric effects, including depression worsening and suicidal ideation, though large studies show no increased risk compared to nicotine replacement therapy 6, 7

The National Comprehensive Cancer Network advises exercising caution when considering the use of bupropion in breastfeeding mothers, as one case report documented seizure-like symptoms in a breastfed infant exposed to this combination, suggesting infants may have higher susceptibility to bupropion's epileptogenic effects 5, 6

Bupropion lowers the seizure threshold with a documented 0.1% seizure risk in clinical trials, and patients with active seizure disorder or history of seizures, brain metastases or structural brain lesions, eating disorders, alcohol withdrawal or abrupt benzodiazepine discontinuation, and head trauma history are at higher risk 8, 9, 10
The American College of Cardiology and other guideline societies recommend monitoring for worsening depression, suicidal ideation, and increased agitation, as bupropion is an activating medication, with recent large-scale trials showing no significant increase in neuropsychiatric events with bupropion compared to nicotine patch or placebo 8, 9
Patients with uncontrolled hypertension should avoid bupropion due to its potential to cause mild elevations in blood pressure and heart rate, and regular blood pressure monitoring is required 10

In patients with hepatic impairment (moderate to severe), the maximum bupropion dose should be 150 mg daily, and in patients with renal impairment (moderate to severe), the bupropion dose should be reduced by 50% 10

The combination of bupropion and escitalopram may be particularly beneficial for patients with depression plus low energy, apathy, or who want to quit smoking, as it addresses depression through complementary mechanisms: escitalopram via serotonin and bupropion via norepinephrine/dopamine pathways 8, 9