Designing clinical trials for dystonia poses formidable methodological challenges because the disorder is both clinically and etiologically heterogeneous. A mechanism-based approach requires deeper understanding of underlying pathophysiology and identification of factors that may impact disease progression, while a phenotypic approach focuses on improving dystonic symptoms by discovering new drugs or building upon existing therapies. Primary outcome measures have been variable, relying mainly on patients’ subjective reports of therapeutic benefit, and objective quantification remains difficult due to the diversity of dystonia presentations. In 2013, the Movement Disorders Society commissioned a task force to review 36 potential rating scales, ultimately recommending seven for craniocervical, laryngeal, and generalized dystonia, including the Toronto Western Spasmodic Torticollis Rating Scale for cervical dystonia, the Jankovic Rating Scale for blepharospasm, the Voice Handicap Index for laryngeal dystonia, and the Fahn-Marsden Dystonia Rating Scale for generalized dystonia. The review’s authors emphasize that development of sensitive and objective clinical outcome measures will be a crucial prerequisite for successful future trials.

On the pharmacological front, the past five years have seen trials targeting the neurotransmitter pathways implicated in dystonia, including dopamine, acetylcholine, and GABA. Levodopa remains the cornerstone treatment for dopa-responsive dystonia, which accounts for about five percent of childhood dystonias, but there are currently no active clinical trials studying dopaminergic therapies. Trihexyphenidyl, an anticholinergic drug introduced in the 1950s, continues to be one of the most effective treatments for generalized dystonia, though side effects like confusion, dry mouth, and drowsiness often limit its use in adults. The Children’s Mercy Hospital in Kansas City is running the TRIKE2 trial, a Phase 1, 16-week, single-arm pilot study evaluating how CYP2D6 and CYP2C19 genotypes influence trihexyphenidyl metabolism in 40 pediatric patients with dystonic cerebral palsy, aiming to inform the feasibility of future pharmacogenomic trials. Meanwhile, the PREDICT-ITB trial at Baylor College of Medicine will enroll 65 children with dystonic cerebral palsy through 2029, following a standardized intrathecal baclofen titration protocol with the Barry-Albright Dystonia Scale as the primary outcome measure at baseline, three, six, and twelve months.

One of the most striking results came from the Massachusetts Eye and Ear Infirmary, which completed recruitment in 2024 for a randomized, placebo-controlled crossover trial of sodium oxybate in spasmodic dysphonia and voice tremor. The trial enrolled 117 participants with laryngeal dystonia, both alcohol-responsive and alcohol-nonresponsive, with and without voice tremor. Results published in 2025 showed that sodium oxybate significantly reduced symptom severity in the alcohol-responsive group, with a mean Visual Analog Scale severity score of 28.0 versus 14.2 for placebo, a difference that reached statistical significance at p = 0.008. No significant benefit was observed in the alcohol-nonresponsive group. Adverse events were mild to moderate, including dizziness in 48 percent, daytime sleepiness in 20 percent, and mild nausea in 14 percent, without serious adverse events. This is the first controlled clinical trial demonstrating sodium oxybate as a therapeutic option for laryngeal dystonia and voice tremor, particularly for alcohol-responsive patients.

VMAT-2 inhibitors, which received FDA approval as valbenazine and deutetrabenazine in 2017 for tardive dystonia and dyskinesia, have been repurposed in recent trials. From 2021 to 2023, the Orthopedic Foundation assessed valbenazine for cervical dystonia in a Phase 4 open-label study of 13 participants who completed 16 weeks of treatment titrated to 80 milligrams per day while maintaining botulinum toxin treatment. Preliminary abstract results reported significant improvements in the TWSTRS at p = 0.01 and in the Visual Analog Scale for pulling at p = 0.02. The University of Pennsylvania recently completed the AUDYT trial, an open-label study of deutetrabenazine in 15 adults with non-dopa-responsive isolated dystonia, titrating the drug from 12 to a maximum of 48 milligrams per day over 12 weeks. Only 40 percent of participants tolerated the maximum dose, and although the median change in the Global Dystonia Rating Scale was zero, the variability was notably wide, suggesting a need for a larger cohort in future trials. Glutamate-targeting drugs have also been explored: perampanel, an AMPA receptor antagonist, showed modest improvements in pain relief and sleep quality in cervical dystonia but was limited by tolerability, while dipraglurant, a negative allosteric modulator of the mGlu5 receptor, was well-tolerated in blepharospasm but provided no meaningful clinical benefit.

Botulinum toxin therapy continues to gain traction as a high-yield area for dystonia research, with five commercially available formulations FDA-approved for first-line treatment of cervical dystonia and only two approved for blepharospasm. The most significant recent advance is daxibotulinumtoxinA, whose molecular size and unique stabilizing excipient peptide enhance binding through electrostatic charge and reduce spread of the toxin, leading to a longer therapeutic duration. In the pivotal ASPEN-1 Phase 3 trial completed in 2020 across 60 international sites, 291 participants with cervical dystonia were randomized to daxibotulinumtoxinA 125 units, 250 units, or placebo. The placebo group had a mean TWSTRS reduction of 4.3 points compared to 12.7 points in the 125-unit group and 10.9 points in the 250-unit group, both highly significant. The duration from injection to loss of 80 percent of peak effect was significantly longer than other botulinum toxin type A formulations, lasting 24 weeks and 20 weeks respectively, with no dose-dependent increases in adverse events. The subsequent ASPEN-OLS open-label extension enrolled 357 patients over 52 weeks, confirming that successive treatments were well-tolerated with dysphagia rates remaining stable or decreasing after repeat dosing.

Other botulinum toxin formulations are being validated in clinical trials even without FDA approval for dystonia. PrabotulinumtoxinA, FDA-approved for glabellar lines, completed a Phase 2 randomized placebo-controlled trial in 57 patients with cervical dystonia, reporting no treatment-related serious adverse events up to 20 weeks, with peak efficacy occurring within two to eight weeks and wearing off starting at 16 weeks. NeubotulinumtoxinA, developed in South Korea as a cost-effective alternative, demonstrated comparable efficacy to abobotulinumtoxinA in a 48-week crossover study of 52 Thai patients with cervical dystonia. LetibotulinumtoxinA showed significant reduction in the Jankovic Rating Scale at four weeks in a 220-participant blepharospasm trial, confirming non-inferiority. Beyond new formulations, trials are optimizing injection parameters: a Phase 4 noninferiority study of 207 patients demonstrated that shorter incobotulinumtoxinA injection intervals of eight weeks were safe and effective for patients with early waning of benefit, while a Western University trial in Canada showed that kinematic-guided onabotulinumtoxinA injection achieved faster symptom reduction than visual assessment alone, with the kinematics group reducing TWSTRS from 39.1 to 27.9 points at six weeks.

Deep brain stimulation, FDA-approved for dystonia in 2003 under a Humanitarian Device Exemption, has seen exciting progress with new targets and innovative programming techniques. A 2024 French multicenter trial published by Cuartero and colleagues implanted dual DBS in 12 patients with medically refractory dystonia, comparing GPi, STN, and thalamic centromedian-parafascicular monotherapy against combined targets. The study confirmed the efficacy and safety of GPi-DBS with 44 percent improvement in dystonia severity at three months, but found no additional benefit from dual-target stimulation or alternative targets alone. In China, the MEIGES trial at Beijing Tiantan Hospital is enrolling 110 patients with idiopathic craniofacial dystonia to investigate whether STN-DBS is noninferior to GPi-DBS, while Qilu Hospital is comparing the two targets in Meige syndrome with 100 patients. Peking University People’s Hospital published results from 98 patients with primary Meige syndrome, showing BFMDRS improvements of 61 to 66 percent at one year and 65 to 71 percent at three years for DBS, compared to 58 percent at one year and 50 percent at three years for pallidotomy. Two active trials at Indiana University and Massachusetts Eye and Ear are exploring DBS for laryngeal dystonia using novel outcome measures including acoustic voice recordings, high-speed videoendoscopy, and intraoperative microelectrode recordings of brain signals during speech production.

Innovative DBS programming is advancing toward personalized therapy. The University of California, San Francisco has enrolled 25 patients, including five with dystonia, in a closed-loop DBS study formulating individualized adaptive algorithms based on specific cortical biomarkers, with each patient undergoing four weeks of open-loop versus four weeks of adaptive mode stimulation. Wuerzburg University Hospital is recruiting 80 participants for a prospective randomized double-blind crossover trial comparing computer-assisted image-based DBS programming against conventional clinician-based programming, aiming to optimize stimulation settings and reduce non-responder rates. Novel brain lesioning techniques are also being tested as alternatives to DBS. The University of Maryland launched a Phase 1 trial in 2024 for MR-guided focused ultrasound pallidotomy in task-specific focal hand dystonia, enrolling 10 patients who failed botulinum toxin and DBS, while the University of the Philippines Manila is investigating focused ultrasound pallidothalamic tractotomy for X-linked dystonia-parkinsonism, now available through expanded access until 2026. The All India Institute of Medical Sciences is planning a cohort study and registry of 250 patients undergoing lesioning procedures for movement disorders, with long-term functional outcomes assessed over a year.

Non-invasive brain stimulation, gene-targeted therapies, and rehabilitative approaches round out the therapeutic landscape. Transcranial magnetic stimulation has shown potential in small cohorts but variability in technique, administration, and response remains a barrier to FDA approval for dystonia. A randomized crossover trial at AIIMS New Delhi targeting the inferior parietal lobule in 16 patients with task-specific focal hand dystonia showed significant improvement in the Writer’s Cramp Rating Scale after real stimulation compared to sham, while Duke University is recruiting for accelerated TMS trials using functional MRI to guide individualized stimulation. Transcranial ultrasound stimulation is emerging as a novel modality, with the University Health Network in Toronto studying low-intensity ultrasound to non-invasively stimulate the basal ganglia. Gene therapy has made rapid advances: in November 2024, the FDA approved the first gene therapy for aromatic L-amino acid decarboxylase deficiency based on positive Phase 1/2 results, with the National Taiwan University Hospital trial showing mean Peabody Developmental Motor Scales-2 scores increasing from 10.4 to 80.5 and cerebrospinal fluid homovanillic acid rising from 6.6 to 30.2 nanomoles per liter in 26 patients. In vitro studies are exploring CRISPR-Cas9 disruption of mutant TorsinA in DYT1 dystonia fibroblasts, showing selective reduction of mutant protein with phenotypic recovery, though no active clinical trials yet test gene-targeted therapy in hereditary dystonia patients. Rehabilitative techniques including vibration therapy, transcutaneous electrical nerve stimulation, osteopathic manipulation, behavioral exercises, and neurofeedback brain-computer interface training are all being explored as adjunctive therapies, with a French TENS trial showing an eight-point TWSTRS reduction from baseline in painful cervical dystonia and the University of Minnesota demonstrating that laryngeal vibrotactile stimulation can improve voice quality within 15 to 20 minutes, though the benefit decays within 30 minutes. The review’s authors conclude that successful therapy development should be based on precise understanding of pathophysiology, validated by sensitive clinical outcome measures in well-designed trials, and supported by correlating changes in biomarkers, with a biology-tailored approach essential as understanding of dystonia subtypes advances.

Subject of Research: Neuroscience

Article Title: A narrative review: clinical trials in therapeutic interventions for dystonia (2020 – 2025)

Article References: Ly, A., Mushtaheed, A., Soliman, M. E., Karp, B., & Cho, H. J. (2025). A narrative review: clinical trials in therapeutic interventions for dystonia (2020 – 2025). Dystonia, 4, Article 14547. https://doi.org/10.3389/dyst.2025.14547

Image Credits: AI Generated

DOI: 10.3389/dyst.2025.14547

Keywords: dystonia, clinical trials, botulinum toxin, deep brain stimulation, gene therapy, movement disorders, neurology, transcranial magnetic stimulation, narrative, review, clinical, trials