Regulating the Hyperdopaminergic Substrate in Restless Legs Syndrome With Augmentation: An Open-label Study on the Safety and Efficacy of Aripiprazole

Dopamine agonists (DA) were the first-line therapy for restless legs syndrome (RLS) for many years, but their long-term use is limited by augmentation: a paradoxical worsening of symptoms. Managing augmentation remains a clinical challenge, as DA withdrawal often exacerbates symptoms. Aripiprazole, a third-generation antipsychotic with dopaminergic stabilizing properties, may offer a novel therapeutic approach.

This open-label observational study recruited 18 adults with severe RLS and augmentation under dopaminergic therapy. Aripiprazole 5 mg daily was initiated, followed by gradual DA tapering. Efficacy was assessed with the International RLS Study Group Rating (IRLS) and Clinical Global Impression (CGI) scales. Safety, sleep outcomes, and changes in concomitant treatments were also evaluated.

All patients successfully discontinued DA (baseline levodopa equivalent dose: 64.66±55.71 mg). IRLS scores improved significantly (from 32.06±3.72 to 2.94±5.46; P<0.0001), as did CGI (6.89±1.75 to 1.78±1.31; P<0.0001). Subjective sleep time increased by 2.18±1.31 hours, and sleep quality improved from 3.4±1.35 to 7.03±1.23 (both P <0.0001). Mild and transient adverse events included akathisia (16.7%), fatigue (11.1%), somnolence (5.6%), and apathy (5.6%). Most side effects resolved after dose adjustments, without loss of efficacy.

Low-dose morning aripiprazole was effective and well tolerated in patients with severe RLS and augmentation, enabling complete DA withdrawal and substantial improvement in RLS symptoms and sleep. These findings suggest that dopaminergic stabilizers could be a promising therapeutic option for RLS with augmentation. Controlled trials are warranted to confirm these results.