What is the best course of action for a female adult patient with a history of depression, anxiety, and Restless Legs Syndrome (RLS), currently taking vortioxetine (Brintellix), pregabalin (Lyrica), and quetiapine (Seroquel), who continues to experience sadness and sleep disturbances, and had worsening RLS symptoms when vortioxetine was switched to sertraline (Zoloft)?

Management of Depression and RLS in a Patient with Worsening Symptoms on Sertraline

Return to vortioxetine immediately and optimize her pregabalin dose, as vortioxetine appears uniquely neutral or potentially beneficial for RLS compared to other antidepressants, while sertraline clearly worsened her symptoms. 1, 2, 3

Understanding Why Sertraline Failed

• SSRIs including sertraline are well-documented RLS exacerbators through serotonergic mechanisms, which explains why her RLS worsened when you switched from vortioxetine 1, 2
• The American Academy of Sleep Medicine explicitly recommends addressing and eliminating serotonergic medications as potential RLS exacerbating factors 1
• Vortioxetine has a multimodal mechanism of action on serotonin receptors that differs fundamentally from SSRIs, and emerging case series show it may actually improve RLS symptoms rather than worsen them 2, 3

Immediate Action Plan

Step 1: Reinstate vortioxetine at her previous effective dose for depression, as it does not worsen RLS and may provide some benefit 2, 3

Step 2: Optimize pregabalin dosing for both RLS and her persistent mood/sleep symptoms:

• She is already on pregabalin, which is first-line therapy for RLS per the American Academy of Sleep Medicine 1
• Pregabalin has demonstrated efficacy for treatment-resistant insomnia, anxiety, and depression in addition to RLS 4, 5
• If she is on a low dose (e.g., 150 mg/day or less), consider titrating up to 300-600 mg/day divided into twice-daily dosing for optimal 24-hour coverage of both RLS and mood symptoms 1, 4
• Pregabalin showed more rapid onset of anxiolytic action compared to sertraline in head-to-head trials, with equal efficacy and good tolerability 5

Step 3: Check iron status immediately if not done recently:

• Obtain morning fasting ferritin and transferrin saturation after avoiding iron supplements for 24 hours 1
• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% 1
• Consider IV ferric carboxymaltose if oral iron fails or is not tolerated after 3 months 1

Addressing Quetiapine's Role

• Quetiapine is a dopamine antagonist, and dopamine antagonism is a well-established mechanism for triggering or worsening RLS 1
• The American Academy of Sleep Medicine specifically recommends addressing antidopaminergic medications as potential RLS exacerbating factors 1
• Consider tapering quetiapine gradually while optimizing pregabalin, as higher pregabalin doses can address both sleep and anxiety without dopamine antagonism 1, 4, 5
• If quetiapine must be continued for mood stabilization, ensure it is the lowest effective dose and taken earlier in the evening rather than at bedtime 1

Why Vortioxetine is the Right Antidepressant Choice

• Case series of 7 patients showed that adding vortioxetine led to regression of RLS symptoms in 5 of 7 patients without needing additional RLS-specific treatment 2
• A case report documented partial improvement in 20-year RLS symptoms after vortioxetine treatment, whereas previous SSRIs had worsened the condition 3
• Vortioxetine's multimodal serotonin receptor activity appears to avoid the RLS exacerbation seen with traditional SSRIs 2, 3
• The FDA label for vortioxetine does not list RLS as an adverse effect, unlike SSRIs 6

Additional Considerations for Sleep

• Add melatonin 3-5 mg at bedtime, as it does not exacerbate RLS and can improve sleep quality 7
• The American Academy of Sleep Medicine confirms melatonin is safe in RLS patients and is not listed among medications that worsen RLS 7
• Eliminate caffeine, alcohol, and nicotine, particularly within 3 hours of bedtime, as these worsen RLS symptoms 1
• Ensure her sleep environment is optimized (dark, quiet, comfortable temperature) and encourage morning/afternoon exercise while avoiding vigorous exercise close to bedtime 1

Critical Pitfalls to Avoid

• Never use SSRIs or SNRIs in patients with comorbid RLS and depression—they consistently worsen RLS symptoms through serotonergic mechanisms 1, 2, 3
• Do not assume standard antidepressant doses of pregabalin (150 mg/day) are sufficient—RLS often requires 300-600 mg/day for optimal control 1, 4
• Do not add dopamine agonists (pramipexole, ropinirole) despite their historical use in RLS, as the American Academy of Sleep Medicine now recommends against them due to high augmentation risk 1, 8
• Do not overlook iron deficiency as a reversible contributor—brain iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal 1

If Symptoms Persist Despite Optimization

• Consider extended-release oxycodone or low-dose methadone/buprenorphine for refractory RLS, as these are conditionally recommended by the American Academy of Sleep Medicine for cases that fail first-line therapy 1
• Bilateral high-frequency peroneal nerve stimulation is a non-pharmacological option with conditional recommendation 1
• Reassess in 4-6 weeks after optimizing vortioxetine, pregabalin, and iron status before considering additional interventions 1