What is the next step for a patient on sertraline (Selective Serotonin Reuptake Inhibitor) 100 mg for depression, recently started on risperidone (atypical antipsychotic) 2 mg with no improvement, who wants to try Wellbutrin (bupropion)?

Management of Inadequate Response to Risperidone in Depression

Discontinue risperidone immediately—it has only been 2 days, which is far too early to assess efficacy, and antipsychotics are not indicated as first-line augmentation for unipolar depression in this clinical scenario. 1

Rationale for Discontinuing Risperidone

• Risperidone was started only 2 days ago, making any assessment of efficacy premature and clinically meaningless 1
• Antipsychotics are not recommended as initial augmentation strategies for depression without psychotic features in evidence-based guidelines 1
• The patient is 69 years old, placing them at higher risk for antipsychotic-related adverse effects including metabolic syndrome, extrapyramidal symptoms, and cognitive impairment 1
• Continuing risperidone exposes the patient to unnecessary risks (weight gain, metabolic effects, movement disorders) without established benefit for non-psychotic depression 1

Appropriate Next Steps with Sertraline

Before adding bupropion, you must first determine if sertraline has been given an adequate trial:

• Sertraline requires 6-8 weeks at therapeutic dose to assess true efficacy 1
• If the patient has been on sertraline 100 mg for less than 6-8 weeks, continue current dose and reassess before making changes 1
• Monitor response every 1-2 weeks starting from treatment initiation to track improvement and assess for adverse effects including suicidality 1

Adding Bupropion as Augmentation Strategy

If sertraline has been trialed for 6-8 weeks without adequate response, augmenting with bupropion is a reasonable evidence-based strategy:

• Bupropion augmentation of SSRIs has demonstrated efficacy in treatment-refractory depression with similar outcomes to other augmentation strategies 1
• The combination of sertraline and bupropion has been reported as effective in treatment-refractory cases, with synergistic effects on serotonergic, dopaminergic, and noradrenergic systems 2
• Bupropion is specifically recommended for older adults (age 69) as a preferred agent due to favorable side effect profile 1
• Bupropion has significantly lower rates of sexual dysfunction compared to sertraline (15% vs 63% in men, 7% vs 41% in women), which may improve tolerability and adherence 3

Critical Safety Considerations for Bupropion + Sertraline

Monitor carefully for serotonin syndrome when combining these medications:

• Rare cases of serotonin syndrome have been reported with bupropion-SSRI combinations, likely due to bupropion's inhibition of CYP2D6 increasing SSRI blood levels 4
• Start bupropion at low dose (100-150 mg sustained-release daily) and titrate slowly while monitoring for symptoms of serotonin syndrome: confusion, agitation, tremors, hyperreflexia, autonomic instability 1, 4
• Bupropion lowers seizure threshold—use caution and avoid doses above 300 mg/day sustained-release formulation 1, 5
• The combination is generally well-tolerated when initiated cautiously, with no adverse effects reported in multiple case series 2

Drug Interaction Considerations

• Sertraline at doses up to 100 mg/day does not significantly affect risperidone levels if you were considering keeping it, but this is not clinically relevant since risperidone should be discontinued 6
• Sertraline has moderate CYP2D6 inhibition, which may slightly increase bupropion metabolite levels, but this is rarely clinically significant at standard doses 4, 6

Alternative Second-Step Strategies if Bupropion Fails

If augmentation with bupropion after 6-8 weeks proves inadequate:

• Switching to a different antidepressant (venlafaxine, duloxetine, escitalopram) shows similar efficacy to augmentation strategies 1
• All second-step strategies (switching vs. augmentation) demonstrate comparable response and remission rates in moderate-quality evidence 1
• Consider augmentation with cognitive behavioral therapy, which shows equivalent efficacy to medication augmentation strategies 1