What is the appropriate next step in evaluating and managing a 52‑year‑old woman with treatment‑resistant major depressive disorder on bupropion (Wellbutrin) 300 mg daily and sertraline (Zoloft) 100 mg daily, now presenting with frequent crying spells, fragmented sleep, feeling “all over the place,” distractibility, and a history suggestive of adult ADHD?

Evaluation and Management of Treatment-Resistant Depression with Possible Undiagnosed Adult ADHD

Screen for Adult ADHD Before Adjusting Antidepressants

The clinical presentation—childhood restlessness, current distractibility, feeling "all over the place," family history of ADHD in all sons, and 10-year treatment resistance to standard antidepressants—strongly suggests undiagnosed adult ADHD masquerading as or complicating major depressive disorder. 1

Key Diagnostic Steps

• Obtain a structured ADHD assessment using validated tools (e.g., Adult ADHD Self-Report Scale) focusing on childhood symptoms of hyperactivity/impulsivity and current executive dysfunction, as the family history of ADHD in all sons significantly increases her pre-test probability. 1

• Distinguish ADHD symptoms from depression: The "all over the place" feeling and distractibility that persist despite 10 years of antidepressant treatment suggest primary ADHD rather than concentration difficulties secondary to depression, which typically improve with effective antidepressant therapy. 1

• Recognize that bupropion 300 mg daily may already be providing partial ADHD treatment through dopamine and norepinephrine reuptake inhibition, which could explain why she has tolerated this regimen for 10 years despite inadequate depression response. 2

Optimize Current Regimen While Evaluating for ADHD

Increase Sertraline Dose First

• Escalate sertraline from 100 mg to 150 mg daily immediately, with further titration to 200 mg daily if needed after 2 weeks, as approximately 38% of patients fail to respond at initial SSRI doses and require dose optimization before considering treatment resistance. 1

• Allow 6-8 weeks at the maximum tolerated sertraline dose (up to 200 mg daily) before declaring treatment failure, as full therapeutic effects may take up to 12 weeks and premature switching is a common pitfall. 1

Consider Augmentation Strategy

• If sertraline optimization fails after 8 weeks, augment with bupropion rather than switching, as the combination of bupropion and sertraline has demonstrated efficacy in treatment-refractory depression through synergistic effects on serotonergic, dopaminergic, and noradrenergic systems. 3

• The current bupropion 300 mg plus sertraline 100 mg combination is already in place but likely underdosed on the sertraline component, explaining the persistent symptoms despite 10 years of treatment. 3

Address Sleep Disturbance

• Take the second bupropion dose (if using divided dosing) no later than mid-afternoon to minimize insomnia risk, as late-day dosing of bupropion commonly disrupts sleep architecture. 4

• Assess whether "not good" sleep represents initial insomnia (difficulty falling asleep) versus middle-of-the-night awakening, as the former suggests bupropion timing issues while the latter may indicate inadequate depression treatment or unrecognized ADHD-related sleep disturbance. 1

Critical Safety Monitoring

• Monitor for serotonin syndrome when using bupropion plus sertraline, particularly after dose increases, as bupropion inhibits cytochrome P450 2D6 and can elevate SSRI blood levels, increasing risk of confusion, myoclonus, autonomic instability, and altered consciousness. 5

• Watch for early signs of serotonin syndrome that may be misinterpreted as worsening depression: myoclonic jerks, clumsiness, gait difficulties, fluctuating confusion, and alternating agitation/lethargy should prompt immediate medication review rather than dose escalation. 5

• Assess for treatment-emergent suicidality during the first 1-2 weeks after any sertraline dose increase, though the absolute risk is lower in patients over age 24 (pooled risk 0.7%, NNH = 143). 1

If ADHD Is Confirmed

• Continue the bupropion 300 mg daily as it provides dual benefit for both depression and ADHD through dopamine and norepinephrine reuptake inhibition, with evidence supporting efficacy in both conditions though ADHD data are mixed. 2

• Optimize sertraline to maximum tolerated dose (200 mg daily) before adding stimulant medication, as sertraline has minimal CYP450 interactions and lower risk of drug-drug complications when combined with methylphenidate or amphetamines compared to fluoxetine. 1

• If stimulant augmentation becomes necessary after optimizing both agents, initiate methylphenidate at low doses with close cardiovascular monitoring (blood pressure, heart rate) during the first 24-48 hours, as the combination carries theoretical serotonin syndrome risk though methylphenidate's serotonergic activity is weak. 1

Alternative Strategy If Current Regimen Fails

• Switch from sertraline to venlafaxine extended-release 75-225 mg daily while continuing bupropion 300 mg, as venlafaxine demonstrated statistically superior response rates compared to fluoxetine specifically for depression with prominent anxiety symptoms, and the venlafaxine-bupropion combination has documented efficacy in treatment-refractory cases. 1, 6

• Recognize that SNRIs like venlafaxine carry 40-67% higher discontinuation rates than SSRIs due to nausea and vomiting, requiring slower titration and more intensive side-effect management. 1

Common Pitfalls to Avoid

• Do not interpret the 10-year treatment duration as evidence of treatment failure—the issue is likely inadequate sertraline dosing (100 mg is mid-range) rather than true medication resistance. 1

• Do not add a third antidepressant before optimizing the current regimen and screening for ADHD, as polypharmacy without systematic dose optimization leads to unnecessary side effects and medication burden. 1

• Do not discontinue bupropion abruptly if switching strategies, as it may be providing unrecognized benefit for comorbid ADHD symptoms and its removal could unmask additional executive dysfunction. 2