What is the next best treatment option for a 67‑year‑old woman with a 20‑year history of chronic paroxetine use, recent sertraline 50 mg for one week, tremor from aripiprazole, worsening restless‑leg symptoms, multiple failed trials of SSRIs, SNRIs, atypical antipsychotics, ketamine, gabapentin, pregabalin, and mirtazapine, poor medication adherence, no psychotherapy, and a scheduled TMS consultation tomorrow?

Management of Treatment-Resistant Depression with Poor Medication Adherence

Immediate Priority: Address TMS Consultation and Medication Adherence

Your patient should proceed with the scheduled TMS consultation tomorrow, as this represents the most appropriate next-step intervention given her pattern of medication non-adherence and multiple failed pharmacologic trials. 1

TMS offers several critical advantages for this patient:

• Non-pharmacologic intervention eliminates concerns about medication side effects that have driven her repeated discontinuations 1
• Evidence-based efficacy for treatment-resistant depression after multiple SSRI failures, with approximately 25% achieving remission 2
• No systemic side effects that would exacerbate her restless leg syndrome concerns 1

The Wellbutrin Request: A Reasonable but Premature Option

While bupropion represents a rational pharmacologic choice, adding another medication at this juncture perpetuates the cycle of premature trials and discontinuations that has characterized her treatment course. 2, 1

Why Bupropion Makes Pharmacologic Sense:

• Different mechanism (norepinephrine-dopamine reuptake inhibition) after multiple serotonergic failures 1, 3
• May actually improve RLS symptoms rather than worsen them, unlike SSRIs 4, 5
• Lower sexual dysfunction rates compared to SSRIs, addressing a common discontinuation reason 2, 1
• Activating properties may address the low energy and motivation that often masquerade as anxiety 1, 3

Critical Problem with Adding Bupropion Now:

She has been on sertraline 50mg for only one week—this represents a grossly inadequate trial duration. 2, 1 The American College of Physicians explicitly states that treatment should not be modified before 6-8 weeks at therapeutic dose 2, 1. Her pattern of stopping medications after 2-3 weeks means she has never completed a single adequate antidepressant trial in the past year 2.

The Restless Leg Syndrome Concern: Valid but Manageable

Her concern about SSRIs worsening RLS has some evidence basis, but the risk is substantially lower than she likely believes from online sources. 5

Evidence on SSRIs and RLS:

• Sertraline appears to increase periodic limb movements that do not disrupt sleep and are unlikely to be clinically significant 5
• Mirtazapine and venlafaxine carry higher RLS risk than sertraline—she has already failed both 4, 5
• Bupropion may actually reduce RLS symptoms in the short term, making it a rational future choice if sertraline fails 5

Addressing Her RLS Symptoms:

If RLS symptoms genuinely worsen on sertraline 50mg over the next 2-4 weeks:

• Gabapentin or pregabalin are first-line RLS treatments, though she has already failed both 6
• This suggests her RLS may be secondary to anxiety/depression rather than primary RLS 4
• Successful depression treatment often improves RLS symptoms when they are secondary 4, 5

The Core Problem: Lack of Psychotherapy

The single most critical deficit in this patient's treatment plan is the complete absence of evidence-based psychotherapy. 2, 1

Why This Matters:

• Combination CBT plus medication demonstrates superior efficacy compared to medication alone for both depression and anxiety 2, 1
• Her medication non-adherence likely reflects untreated psychological factors including catastrophic thinking about side effects, poor distress tolerance, and lack of coping skills 1
• TMS combined with psychotherapy produces better outcomes than TMS alone 1

Recommended Treatment Algorithm

Step 1: Complete the Current Sertraline Trial (Weeks 1-8)

Continue sertraline 50mg daily for a minimum of 6-8 weeks before declaring treatment failure. 2, 1

• Increase to 100mg daily after week 2-3 if tolerated, as 50mg is subtherapeutic for most patients 1
• Target dose is 100-200mg daily for depression and anxiety 1
• Monitor weekly for the first month to address emerging concerns before she discontinues 1

Step 2: Initiate TMS Immediately

Proceed with TMS consultation tomorrow and begin treatment as soon as approved. 1

• TMS can be administered concurrently with sertraline without interaction concerns 1
• Typical course is 20-30 sessions over 4-6 weeks 1
• This provides non-pharmacologic intervention while completing an adequate sertraline trial 1

Step 3: Mandate Psychotherapy as Condition of Continued Prescribing

Make it explicit that continued medication management requires concurrent evidence-based psychotherapy. 2, 1

• CBT for depression and anxiety should begin within 2 weeks 2, 1
• Address medication adherence as a specific therapy target 1
• Cognitive restructuring around catastrophic side effect beliefs 1

Step 4: Reassess at Week 8

If inadequate response after 8 weeks of sertraline 100-200mg + TMS + CBT:

Option A: Augment sertraline with bupropion SR 150-300mg daily 1, 3

• This addresses her request for bupropion while maintaining any partial sertraline benefit 1
• Bupropion augmentation achieves ~50% remission rates vs 30% with SSRI monotherapy 1
• May improve RLS symptoms rather than worsen them 5

Option B: Switch to bupropion SR monotherapy 150-400mg daily 2, 1

• Appropriate after multiple SSRI failures 2, 1
• Different mechanism addresses treatment resistance 1, 3
• Lower discontinuation rate (12.5%) compared to other augmentation strategies 1

Option C: Consider aripiprazole 2-5mg daily augmentation 3

• She previously reported "great mood" on low-dose aripiprazole 2mg 3
• Tremors at 10mg suggest dose was excessive 3
• Restart at 2mg and maintain at lowest effective dose 3

Common Pitfalls to Avoid

Do not switch medications before completing an adequate 6-8 week trial at therapeutic dose. 2, 1 This perpetuates the cycle that has prevented any medication from working.

Do not add bupropion to sertraline 50mg after only one week. 2, 1 This represents premature polypharmacy before optimizing monotherapy.

Do not accept "I read online" as justification for discontinuation. 1 Address health anxiety and catastrophic thinking in therapy.

Do not continue prescribing without psychotherapy engagement. 2, 1 Medication alone has failed repeatedly; combination treatment is essential.

Do not restart aripiprazole at 10mg. 3 Her previous tremors indicate this dose was too high; 2-5mg is appropriate for augmentation.

Addressing the Anxiety vs Depression Question

Her presentation likely represents mixed anxiety-depression, but this distinction is less important than ensuring adequate treatment duration. 2, 1

• SSRIs treat both anxiety and depression with equal efficacy 2, 1
• Her "unrelenting anxiety" may reflect untreated depression with anxious distress 1
• Premature discontinuations prevent determining which symptoms respond to which medications 2, 1

The Conversation to Have Tomorrow

"I understand your concerns about restless legs and your interest in trying Wellbutrin. Here's what I recommend: First, keep your TMS consultation tomorrow—this is an excellent non-medication option that doesn't have the side effects you're worried about. Second, let's give the Zoloft a fair chance to work. You've been on 50mg for only one week, and we need at least 6-8 weeks at a therapeutic dose (100-200mg) to know if it will help. The research shows that Zoloft is actually less likely to worsen restless legs than some of the other medications you've tried. Third—and this is essential—we need to add therapy to your treatment plan. Medications alone haven't been enough, and the combination of medication plus therapy works much better than either alone. If after 8 weeks of Zoloft plus TMS plus therapy you're still struggling, then Wellbutrin becomes an excellent next option. But right now, we need to break the pattern of stopping medications before they have a chance to work." 2, 1, 5