What is the recommended management for periodic leg movement disorder in a patient taking Rexulti (brexpiprazole)?

Management of Periodic Leg Movement Disorder in Patients Taking Rexulti

First, determine if Rexulti is causing or worsening the periodic leg movements, as antipsychotics can induce or exacerbate restless legs syndrome (RLS) and periodic limb movement disorder (PLMD), though this is not specifically documented in the Rexulti FDA label.

Initial Assessment and Causality

The critical first step is distinguishing whether the PLMD is:

• Pre-existing and unrelated to Rexulti
• Drug-induced or drug-exacerbated by Rexulti
• Part of akathisia (which Rexulti can cause per FDA labeling 1)

Key clinical distinction: RLS/PLMD presents with dysesthesias primarily in the legs, an urge to move that worsens at rest and improves with movement, and is worse in the evening/night. Akathisia is a subjective sense of inner restlessness without the circadian pattern or relief with movement 2.

While there is no direct evidence linking brexpiprazole (Rexulti) to PLMD, other antipsychotics like risperidone have been documented to induce RLS/PLMD 2. If symptoms began or significantly worsened after starting Rexulti, consider this as a potential trigger.

Treatment Algorithm

Step 1: Optimize Iron Status (First-Line)

Check ferritin and transferrin saturation immediately. The 2025 AASM guidelines provide strong recommendations for iron therapy:

• If ferritin <75 ng/mL or transferrin saturation <20%: Use IV ferric carboxymaltose (strong recommendation, moderate certainty) 3
• Alternative IV iron options: low molecular weight iron dextran or ferumoxytol (conditional recommendations) 3
• Oral ferrous sulfate can be used but is less effective (conditional recommendation) 3

Important caveat: Ferric carboxymaltose can cause hypophosphatemia; monitor phosphate levels 4.

Step 2: First-Line Pharmacotherapy (If Iron Therapy Insufficient)

The 2025 AASM guidelines strongly recommend α2δ calcium channel ligands as first-line therapy 3:

1. Gabapentin enacarbil (strong recommendation, moderate certainty) 3
2. Gabapentin (strong recommendation, moderate certainty) 3
3. Pregabalin (strong recommendation, moderate certainty) 3

Critical shift in practice: Dopamine agonists (pramipexole, ropinirole, rotigotine) are now suggested against for standard use due to high risk of augmentation with long-term use 3, 4. They may only be considered for short-term use in patients who prioritize immediate symptom relief over long-term adverse effects.

Step 3: Consider Rexulti Modification

If PLMD symptoms are severe and temporally related to Rexulti initiation:

Option A: Continue Rexulti with aggressive PLMD treatment (gabapentinoids + iron)

• Justified if psychiatric indication is strong and symptoms are manageable

Option B: Switch to alternative antipsychotic

• Based on case report evidence, quetiapine may have lower risk of inducing RLS/PLMD compared to risperidone 2
• Coordinate with prescribing psychiatrist; never discontinue antipsychotic unilaterally

Step 4: Refractory Cases

For patients who fail gabapentinoids and iron therapy:

1. Extended-release oxycodone or other opioids (conditional recommendation, moderate certainty) 3

   • National RLS Opioid Registry data shows reassuring safety profile 4

2. Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 3

   • Can be used as adjunct therapy 4

3. Dipyridamole (conditional recommendation, low certainty) 3

What NOT to Do

The 2025 AASM guidelines recommend against 3:

• Valproic acid for PLMD (conditional recommendation)
• Triazolam for PLMD (conditional recommendation)
• Clonazepam (conditional recommendation)
• Carbamazepine (conditional recommendation)
• Cabergoline (strong recommendation against)

Monitoring Strategy

• Polysomnography is not required for diagnosis or routine management but can be helpful to confirm PLMD and quantify periodic limb movement index (PLMI) if diagnosis is uncertain 2
• Normal PLMI: <15 events/hour in adults 3
• Reassess symptoms every 4-6 weeks during treatment initiation
• Monitor for augmentation if dopamine agonists are used (worsening symptoms, earlier onset in day, spread to arms)

Special Considerations

Drug interactions with Rexulti: Gabapentin and pregabalin have no clinically significant interactions with Rexulti per FDA labeling 1. No dose adjustment of either medication is needed when used together.

If patient has end-stage renal disease: Gabapentin is still recommended (conditional recommendation), and IV iron sucrose should be used if ferritin <200 ng/mL and transferrin saturation <20% 3.