What are the pros and cons of adding low-dose bupropion to a regimen of sertraline (Selective Serotonin Reuptake Inhibitor), viloxazine (Norepinephrine Reuptake Inhibitor), and guanfacine (Alpha-2 Adrenergic Agonist) Extended Release (ER) in a patient with Obsessive-Compulsive Disorder (OCD), Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), and social anxiety disorder, who previously experienced increased irritability and muscle aches on bupropion, has a genetic predisposition to adverse effects from bupropion as indicated by a GeneSight report, and is seeking relief from emotional blunting and sexual side effects attributed to sertraline without exacerbating anxiety?

Adding Low-Dose Bupropion to This Complex Regimen: Risk Likely Outweighs Benefit

Given this patient's prior adverse reaction to bupropion (irritability, muscle aches), unfavorable genetic profile (GeneSight "red" category), and primary diagnosis of OCD—where bupropion may actually worsen symptoms—I would not recommend adding bupropion to this regimen, even at low doses.

Key Concerns That Override Potential Benefits

Bupropion May Exacerbate OCD Symptoms

• An open-label study specifically examining bupropion in OCD patients found that 8 of 12 patients (67%) experienced worsening of OCD symptoms, with a mean increase of 21% on the Yale-Brown Obsessive Compulsive Scale 1
• Only 2 of 12 patients met responder criteria, demonstrating poor efficacy and a bimodal response pattern suggesting dopamine's complex role in OCD pathophysiology 1
• This is particularly concerning given that OCD appears to be a primary diagnosis in this patient

Prior Adverse Reaction Is a Red Flag

• The patient previously experienced increased irritability and muscle aches on bupropion, which only began improving after 2 weeks [@question context]
• While some side effects may diminish over time, the initial tolerability issues combined with genetic predisposition suggest heightened vulnerability to adverse effects
• The American Academy of Family Physicians notes that bupropion is an "activating" antidepressant that can increase anxiety in susceptible patients [@4@]

Genetic Testing Indicates Poor Metabolism

• The GeneSight "red" category typically indicates genetic variants associated with altered drug metabolism or increased risk of adverse effects
• This pharmacogenetic information, combined with prior clinical experience, strongly suggests this patient is at higher risk for side effects

Limited Evidence for the Intended Benefits

Sexual Dysfunction and Emotional Blunting

• While bupropion augmentation of SSRIs has been studied for treatment-resistant depression, the evidence comes from low-quality trials showing bupropion augmentation of citalopram decreased depression severity more than buspirone, but with no difference in response or remission rates 2
• A small case series (n=4) reported successful combination of bupropion and sertraline in treatment-refractory depression, but these were highly selected cases with chronic depression and multiple failed treatments [@5@]
• No high-quality evidence specifically addresses bupropion's efficacy for SSRI-induced sexual dysfunction or emotional blunting in patients with OCD, ASD, and ADHD

Risk of Increased Anxiety

• The patient has social anxiety disorder, and bupropion's activating properties through dopamine and norepinephrine reuptake inhibition can worsen anxiety symptoms [@4@]
• Bupropion should be avoided in patients with conditions predisposing to seizures and requires blood pressure monitoring, especially at treatment initiation [@4@]

The Complex Polypharmacy Context

Current Medication Burden

• The patient is already on three psychotropic medications (sertraline, viloxazine, guanfacine ER) targeting multiple neurotransmitter systems
• Adding a fourth agent increases complexity, drug-drug interaction risk, and makes it difficult to attribute benefits or side effects to specific medications
• Viloxazine (norepinephrine reuptake inhibitor) already provides noradrenergic activity, potentially overlapping with bupropion's mechanism

Drug Interaction Considerations

• Bupropion is metabolized by CYP2B6 and inhibits CYP2D6, which could affect sertraline metabolism
• The combination increases the overall burden on hepatic metabolism and may require dose adjustments

Alternative Strategies to Consider

For Sexual Dysfunction

• Dose reduction of sertraline (if OCD symptoms are well-controlled) [@6@]
• Adding sildenafil or other phosphodiesterase-5 inhibitors for erectile dysfunction
• Switching to a different SSRI with potentially lower sexual side effect burden
• Drug holidays (though not ideal for OCD maintenance)

For Emotional Blunting

• Evaluate whether current sertraline dose is higher than necessary for OCD control [@7@, 3]
• Consider augmentation with cognitive-behavioral therapy, which has shown comparable efficacy to medication adjustments [@3@]
• Assess whether emotional blunting represents undertreated depression versus medication side effect

For ADHD Optimization

• Ensure viloxazine dosing is optimized before adding additional agents [@2@]
• Consider whether guanfacine ER dose adjustment might improve overall symptom control [@